Inhibitors of cyclin dependent kinase 7

Abstract

The present invention relates to novel compounds of formula I: # imgabs0 # or a pharmaceutically acceptable salt, salt or stereoisomer thereof, which have the properties of CDK7 inhibitors, to pharmaceutical compositions containing the compounds of the invention, to methods of treating diseases or conditions, and to the use of the compounds of the invention as pharmaceutical products for the treatment of diseases or conditions.

Description

Technical Field

[0001] The present invention relates to novel inhibitors of cyclin-dependent protein kinase 7 (CDK7), pharmaceutically acceptable salts, solvates or stereoisomers thereof, pharmaceutical compositions comprising the compounds of the present invention, methods for treating diseases or disorders, and the use of the compounds of the present invention as pharmaceutical products for treating diseases or disorders. Background Art

[0002] Cyclin-dependent kinase 7 (CDK7) is an enzyme ubiquitously expressed in different tissues of the body; it is a member of the cyclin-dependent protein kinase (CDK) family. CDK7 forms a CDK-activating complex together with cyclin H and MAT1, which regulates the progression of the cell cycle phases via phosphorylation of other CDKs. CDK7 is an essential component of the transcription factor TFIIH. The latter is involved in transcription initiation and DNA repair processes. Thus, CDK7 plays a key 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(11):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).

[0003] Uncontrolled proliferation and changes in transcriptional processes are characteristics unique to malignant tumor cells. Overactivation of CDK7 has been observed in many cancer types and is associated with the invasive course of the disease and poor prognosis of patients, 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 Triple-Negative 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 can have anti-tumor effects by reducing the cell proliferation rate and by affecting the transcription of genes involved in cell malignant transformation, such as cells of ovarian cancer, T-cell acute lymphoblastic leukemia, neuroblastoma, glioma, small cell lung cancer, etc. (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 et 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 enhances genomic instability and reduces PD-L1 expression; it triggers an anti-tumor immune response (Zhang et al. CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer. Cancer Cell 2020;37(1):37-54.e9; Wang et al. CDK7 inhibitor THZ1 enhances anti-PD-1 therapy efficacy via the p38α / MYC / PD-L1 signaling in non-small cell lung cancer. J Hematol Oncol. 2020;13(1):99).

[0004] Accordingly, there is a need to generate novel compounds that preferably target CDK7 and can provide a better risk-benefit ratio in the treatment of diseases associated with increased CDK7 activity. SUMMARY OF THE INVENTION

[0005] The terms used in the specification of the present invention are presented as follows.

[0006] Optionally substituted at one, two, three, four or several positions means that the specified group can be substituted at one, two, three, four or one to six positions by a group or any combination of groups.

[0007] "Fused-ring compound" or "fused compound" is a polycyclic compound having two common adjacent atoms. Examples of fused 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,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, 1H,8H-pyrrolo[2,3-c]azepine, 7H,8H-pyrrolo[2,3-c]azepine, 1H,4H,5H,6H,7H,8H,9H-pyrrolo[2,3-c]azacyclooctatetraene, 1H,4H,5H,8H,9H-pyrrolo[2,3-c]azacyclooctatetraene, 1H,4H,7H,8H,9H-pyrrolo[2,3-c]azacyclooctatetraene, 1H,6H,7H,8H,9H-pyrrolo[2,3-c]azacyclooctatetraene, 1H,8H,9H-pyrrolo[2,3-c]azacyclooctatetraene, 9H-pyrrolo[2,3-c]azacyclooctatetraene, 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-f][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.

[0008] "Alkyl" means an aliphatic straight-chain or branched hydrocarbon group having 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. Branched means an alkyl chain having one or more "lower alkyl" substituents. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl. The alkyl may have substituents that may be of the same or different structures.

[0009] "Cycloalkyl" means a fully saturated carbocyclic ring containing 3 to 10 carbon ring atoms. The cycloalkyl may have substituents that may be of the same or different structures. The cycloalkyl may be fused to an aryl, heteroaryl, or heterocyclic group. Examples of cycloalkyl include, but are not limited to, monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, and bicyclic groups such as bicycloheptyl or bicyclooctyl.

[0010] "Alkenyl" means a straight-chain or branched hydrocarbon group having 2 to 12 carbon atoms, more preferably 2 to 6 carbon atoms, containing one or more carbon-carbon double bonds. The alkenyl may have substituents that may be of the same or different structures.

[0011] "Aryl" means an aromatic monocyclic or polycyclic system having 6 to 14 carbon atoms, more preferably 6 to 10 carbon atoms. Examples of aryl include, but are not limited to, phenyl, phenylene, benzene triyl, indanyl, naphthyl, naphthylene, naphthalene triyl, and anthracene triyl. The aryl may have substituents that may be of the same or different structures. The aryl may be fused to a heterocycle, cycloalkyl, or heteroaryl.

[0012] "Alkyloxy", "alkoxy", or "alkoxy group" means an alkyl-O-group, where alkyl is defined in this section. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy.

[0013] "Amino" means an R'R”N-group.

[0014] "Aminocarbonyl" means a -C(=O)NR”'R”” group.

[0015] Examples of R', R”, R”', R”” include, but are not limited to, substituents selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group, heteroaryl, heteroalkyl, or R' and R” together with the carbon atom to which they are attached may form a 4-7 membered heterocyclic group or heteroaryl.

[0016] "Alkylsulfonyl" (-S(O)2-(C1-C6)alkyl) means the "alkyl" or "cycloalkyl" as defined above attached to the corresponding fragment of the molecule via the sulfonyl group -SO2-. Examples of alkylsulfonyl include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, etc.

[0017] “Alkylsulfonamide” (-NH-S(O)2-(C1-C6)alkyl) means that “alkyl” or “cycloalkyl” as defined above is attached to the corresponding fragment of the molecule via a sulfonamide group -NH-SO2-. Examples of alkylsulfonamides include, but are not limited to, methylsulfonamide, ethylsulfonamide, propylsulfonamide, cyclopropylsulfonamide, and the like.

[0018] “Dialkylphosphine oxide” or “dialkylphosphoryl” (-P(O)((C1-C6)alkyl)2) means that “alkyl” or “cycloalkyl” as defined above is attached to the corresponding fragment of the molecule via a phosphoryl group. Examples of dialkylphosphine oxides include, but are not limited to, dimethylphosphine oxide, diethylphosphine oxide, methylethylphosphine oxide, dipropylphosphine oxide, dicyclopropylphosphine oxide, and the like.

[0019] As used herein, the term “oxo” refers to the group ═O.

[0020] “Lower alkyl” means a straight-chain or branched-chain alkyl having 1 to 4 carbon atoms.

[0021] “Halo” or “halogen” (Hal) means fluorine, chlorine, bromine, and iodine.

[0022] “Heterocycle”, “heterocyclic group”, “heterocyclic ring” means a monocyclic or polycyclic system having 3 to 11 carbon atoms, wherein one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, sulfur. The heterocycle may have one or more substituents, which may be of the same or different structures. The nitrogen and sulfur atoms of the heterocycle may be oxidized to N-oxides, S-oxides or S-dioxides. The heterocycle may be saturated, partially saturated or unsaturated. The heterocyclic group may be represented by a bridged-ring compound having one, two or three -CH2- groups; or it may be fused with a 4-5 membered heteroaryl, wherein one, two or three carbon atoms are replaced by nitrogen atoms. The heterocycle may be fused with a 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, ethylene oxide, 1H,4H,5H,6H,7H,8H,9H-pyrrolo[2,3-c]azocine, 1H,4H,5H,6H-pyrrolo[2,3-c]pyrrole, 1,2,3,4-tetrahydroquinoxaline, tetrahydroquinoline, 1,2-dihydroquinoline, dihydroindole, azaspiro[3.5]nonane, azaspiro[2.5]octane, 5H,6H,7H,8H,9H-[1,2,4]triazolo[4,3-a]azepine, 5H,6H,7H-[1,2,4]triazolo[4,3-a]azepine, 1-azabicyclo[4.1.1]octane, 1-azabicyclo[4.1.1]oct-3-enyl, and the like.

[0023] "Heteroaryl", "heteroarylyl", "heteroaryl ring" means an aromatic monocyclic or polycyclic system having 5 to 11 carbon atoms, preferably 5 to 10 carbon atoms, wherein one or more carbon atoms are replaced by heteroatoms such as nitrogen, sulfur or oxygen. The nitrogen atom of the heterocycle can be oxidized to an N-oxide. The heteroaryl can have one or more substituents, which can be of the same or different structures. The heteroaryl can be fused with a cycloalkyl, aryl or heterocycle. Examples of heteroaryl include, but are not limited to, 1H-pyrrolo[2,3-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, pyrrole, furan, pyridine, pyrazine, pyrimidine, pyridazine, isoxazole, 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-tetrazoloquinoxaline, imidazo[1,2-a]pyridine, indole, benzimidazole, quinoline, imidazole, thiophenopyridine, quinazoline, naphthyridine, thiophenopyrimidine, 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, 1H,8H-pyrrolo[2,3-c]azepine, 7H,8H-pyrrolo[2,3-c]azepine, 1H,4H,5H,6H,7H,8H,9H-pyrrolo[2,3-c]azacyclooctatetraene, 1H,4H,5H,8H,9H-pyrrolo[2,3-c]azacyclooctatetraene, 1H,4H,7H,8H,9H-pyrrolo[2,3-c]azacyclooctatetraene, 1H,6H,7H,8H,9H-pyrrolo[2,3-c]azacyclooctatetraene, 1H,8H,9H-pyrrolo[2,3-c]azacyclooctatetraene, 9H-pyrrolo[2,3-c]azacyclooctatetraene, 1H,4H,5H,6H-pyrrolo[2,3-c]pyrrole, 1H-1,3-benzodiazole, 1H,2H,3H,4H,5H,6H-pyrrolo[2,3-f][1,4]oxazepine, 3,4,6,13-tetraazatricyclo[8.3.0.0 2 , 6 tridec-1(10),2,4,11-tetraenyl, 1,4-diazatricyclo[7.1.1.0 3 , 7 undec-3(7),5-dienyl, etc.

[0024] "Substituent" means a chemical group attached to a scaffold (fragment).

[0025] "Solvate" is a molecular aggregate composed of a compound of the present invention (including its pharmaceutically acceptable salts) and one or more solvent molecules. The solvent molecules are common pharmaceutical solvent molecules known to be safe for receptors, such as water, ethanol, ethylene glycol, etc. Other solvents (such as MeOH, methyl tert-butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, (R)-propylene glycol, 1,4-butanediol, etc.) can be used as intermediate solvates to obtain more desirable solvates.

[0026] The term "hydrate" refers to a complex in which the solvent molecule is water.

[0027] Solvates and / or hydrates preferably exist in crystalline form.

[0028] The terms "bond", "chemical bond" or "single bond" refer to the chemical bond between two atoms or two moieties (i.e., groups, fragments) when the atoms connected by the bond are considered as part of a larger substructure.

[0029] The chemical bond in the compounds of the present invention shown as "=" means a double bond, in which the configuration of the substituent corresponds to the formula.

[0030] Shown as The chemical bond in the compounds of the present invention means a double bond, which can have both cis and trans configurations.

[0031] The term "stereoisomer" refers to compounds having the same chemical composition and the same structure, but different spatial arrangements of atoms or groups. Stereoisomers can include geometric isomers, enantiomers, and diastereoisomers.

[0032] The term "standard processing" includes extraction, processing with solutions of acids, bases, and / or salts to neutralize or otherwise change the pH and / or remove interfering substances; filtration through diatomaceous earth, silica gel, and other materials; addition of inert carriers (diatomaceous earth, silica gel); and vacuum removal of volatile components and solvents.

[0033] The term "excipient" is used herein to describe any component other than one or more compounds of the present invention.

[0034] "Pharmaceutical composition" means a composition comprising a compound of the invention and at least one excipient. The excipients can be selected from pharmaceutically acceptable and pharmacologically compatible fillers; solvents; diluents; carriers; adjuvants; dispensing and sensing agents; delivery agents such as preservatives, stabilizers, fillers, disintegrants, wetting agents, emulsifying agents, suspending agents, thickening agents, sweetening agents, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and extended delivery control agents, the selection and proportion of which depend on the nature and route of administration and the dose. Examples of suspending agents are ethoxylated isostearyl alcohol, polyethylene oxide, sorbitol and sorbitol ethers, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum and mixtures thereof. Protection against the action of microorganisms can be provided by various antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid and similar compounds. The composition may also contain isotonic agents such as sugars, sodium chloride and similar compounds. The extended action of the composition can be achieved by agents that slow down the absorption of the active ingredient (e.g., aluminum monostearate and gelatin). Examples of suitable carriers, solvents, diluents and delivery agents are water for injection, ethanol, polyols and mixtures thereof, vegetable oils (such as olive oil) and organic esters (such as ethyl oleate). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate, etc. Examples of disintegrants and dispensing agents are starch, alginic acid and its salts, silicates, etc. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc and high molecular weight polyethylene glycol. The pharmaceutical composition for oral, sublingual, percutaneous, intramuscular, intravenous, subcutaneous, topical or rectal administration of the active ingredient can be administered alone or in combination with another active ingredient in a mixture with a conventional pharmaceutical carrier in standard dosage forms to animals and humans. Suitable standard dosage 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; topical, percutaneous, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms; and rectal administration forms.

[0035] "Pharmaceutically acceptable salts" mean both relatively non-toxic organic and inorganic salts of the acids and bases disclosed in the present invention. These salts can be prepared in situ during the synthesis, isolation or purification of the compound, or they can be prepared specifically. In particular, salts of bases can be prepared specifically from the purified bases of the disclosed compounds and suitable organic or inorganic acids. Examples of salts prepared in this manner are hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, p-toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, mesylate, malonate, salicylate, propionate, ethanesulfonate, benzenesulfonate, aminosulfonate, etc. (A detailed description of the properties of such salts is given in the following literature: Berge S.M. et al., "Pharmaceutical Salts" J.Pharm.Sci. 1977, 66:1-19). Salts of the disclosed acids can be prepared by reacting the purified acid with a suitable base; in addition, metal salts and amine salts can also be synthesized. Metal salts are salts of sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum; sodium salts and potassium salts are most preferred. Suitable inorganic bases for preparing metal salts are: sodium hydroxide, sodium carbonate, sodium bicarbonate and sodium hydride, potassium hydroxide and potassium bicarbonate, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. Organic bases for preparing salts of the disclosed acids are amines and amino acids, which are basic enough to produce stable salts and are suitable for medical purposes (in particular, they must have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris(hydroxymethyl)aminomethane, etc. In addition, tetraalkylammonium hydroxides such as choline, tetramethylammonium, tetraethylammonium, etc. can be used to prepare salts. Basic amino acids, namely lysine, ornithine and arginine, can be used as amino acids.

[0036] "Pharmaceutical product (drug product, medicine)" is a compound in such a form (or a mixture of compounds as a pharmaceutical composition): tablets, granules, capsules, injections, ointments and other ready-to-use forms intended for restoring, improving or altering the physiological functions of humans and animals and for treating and preventing diseases, for diagnosis, anesthesia, contraception, beauty, etc.

[0037] "Treat", "treatment" and "therapy" mean methods of alleviating or eliminating at least one of a biological disorder and / or its accompanying symptoms. The term "alleviate" a disease, disorder or condition means reducing the severity and / or frequency of the symptoms of the disease, disorder or condition. In addition, "treatment" as mentioned herein includes curative, palliative and prophylactic treatments.

[0038] "Prevention" and "preventive therapy" refer to a set of measures aimed at preventing the onset of a disease or disorder, eliminating risk factors, or early detection of a disease or disorder, its progression, deterioration of the course, exacerbation, recurrence, complications, or other consequences.

[0039] In one aspect, the subject or patient being prevented or treated is a mammal, preferably a human subject. The subject can be male or female of any age.

[0040] The term "disorder" or "disease" means any condition: the manifestation of which can benefit from treatment according to the present invention or the prognosis of a subject suffering from said condition can benefit from treatment according to the present invention. The definition of the term includes chronic and acute disorders or diseases, including those pathological conditions that render a mammal susceptible to said disorder. Non-limiting examples of diseases to be treated include neoplastic diseases, which are selected from breast cancer, metastatic breast cancer, HER2-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 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 carcinoma, oral 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 lymphoma, diffuse large B-cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, endometrial cancer, fallopian tube cancer, sarcoma, Ewing sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, multiple myeloma;

[0041] Autoimmune diseases, which are selected from axial spondyloarthritis, antiphospholipid syndrome, vasculitis (ANCA-associated vasculitis, including Wegener's granulomatosis and related forms of vasculitis, 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, Sjögren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis, and uveitis;

[0042] Autoinflammatory diseases, which are selected from Behçet's disease; Blau syndrome; chronic recurrent multifocal osteomyelitis (CRMO); synovitis; acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome, cryopyrin-associated periodic syndromes (CAPS); interleukin-1 receptor antagonist deficiency (DIRA); familial Mediterranean fever (FMF); NLRP12-related autoinflammatory disease; neonatal-onset multisystem inflammatory disease (NOMID); chronic infantile neurologic cutaneous and articular (CINCA) syndrome; Majeed syndrome; mevalonate kinase deficiency (hyperimmunoglobulin-D syndrome); periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome; pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome; Schnitzler syndrome; Sweet syndrome; systemic juvenile idiopathic arthritis; Still's disease; adult-onset Still's disease (AOSD); tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS);

[0043] An infectious or non-infectious inflammatory disease, selected from allergies (including but not limited to: delayed-type hypersensitivity, immediate hypersensitivity, anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, osteoarthritis (arthrostitis), adult respiratory distress syndrome, respiratory tract inflammation (including but not limited to: bronchiolitis, bronchitis, bronchiectasis, interstitial cell pneumonia, giant cell interstitial pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonia, laryngitis, pneumonia, pharyngitis, pleurisy, pneumonitis, pneumoconiosis, asbestosis, berylliosis, silicosis, talcosis, usual interstitial pneumonia), tonsillitis, bursitis, cellulitis, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes, 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 skin diseases), 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 (orchitis), orchitis (testitis), transverse myelitis, urethritis, cystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis.

[0044] "A therapeutically effective amount" means the amount of a therapeutic agent administered during treatment that will reduce the severity of the disease being treated or eliminate the symptoms of the disease being treated.

[0045] As used in this specification and the appended claims, unless the context otherwise requires, the words "have", "include", and "comprise" or variations thereof such as "has", "having", "includes", "including", "comprises", or "comprising" will be understood to imply the inclusion of the stated integer or group of integers but not the exclusion of any other integer or group of integers. Brief Description of the Drawings

[0046] Figure 1Shows the tumor growth kinetics of NCI-H69 xenografts in the control group and the group receiving compound CDK7_1187 (at a dose of 6 mg / kg QD for 21 days). Data are shown as the arithmetic mean of tumor volume ± standard error of the mean.

[0047] Note: * - p < 0.05; statistically significant difference from the control group (Mann-Whitney test). Detailed implementation mode

[0048] In one embodiment, the present invention relates to a compound of formula I:

[0049]

[0050] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,

[0051] R1 is -C(Hal)3, -CH(Hal)2, -CH2Hal, -Hal, -Η, -NO2, unsubstituted or substituted by one or more Hal atoms -(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;

[0052] R2 and R3 are each independently H, -(C1-C6)alkyl;

[0053] Or R2 and R3 together form an unsubstituted or substituted by one or more -(C1-C6)alkyl -(C3-C6)cycloalkyl;

[0054] L1 and L2 are each independently a chemical bond, -NR5-, -O-, -S-, -S(O)-, -S(O)2-, -С(Ο)-, -С(Ο)O-, -С(S)-, -С(=NH)-, -(СR 6a R 6b ) 1-3 -, -Ρ(Ο)(СΗ3)-, -Ο-(СΗ2) 1-3 -, -(СΗ2) 1-3 -Ο-, -NR 5a -(СΗ2) 1-3 -, -(СΗ2) 1-3 -NR 5a -, -C(O)-(СΗ2) 1-3 -, -(СΗ2) 1-3 -C(Ο)-, -C(O)-NH- or -NH-C(O)-;

[0055] A is an unsubstituted or R7-substituted 6-10 membered aryl group; an unsubstituted or R 7a -substituted 6-10 membered aryl group, which is fused with an unsubstituted or R 8a -substituted -(C3-C6) cycloalkyl group; an unsubstituted or R 7b -substituted 6-10 membered aryl group, which is fused with an unsubstituted or R 8b -substituted 4-10 membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; an unsubstituted or R 7c -substituted 6-10 membered aryl group, which is fused with an unsubstituted or R 8c -substituted 5-6 membered heteroaryl group having 1, 2, 3 or 4 heteroatoms selected from N, O or S; an unsubstituted or R 7d -substituted 5-6 membered heteroaryl group having 1, 2, 3 or 4 N atoms; an unsubstituted or R 7e -substituted 5-6 membered heteroaryl group having 1, 2, 3 or 4 heteroatoms selected from N, O or S, which is fused with an unsubstituted or R 8e -substituted (C3-C6) cycloalkyl group; an unsubstituted or R 7f -substituted 5-6 membered heteroaryl group having 1, 2, 3 or 4 heteroatoms selected from N, O or S, which is fused with an unsubstituted or R 8f -substituted 4-10 membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; an unsubstituted or R 7g -substituted 5-6 membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; an unsubstituted or R 7h -substituted 5-6 membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O, which is fused with an unsubstituted or R 8h -substituted 4-10 membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O;

[0056] R4 is -H; -Hal; (=O); -OH; -C(O)OH; -NR 4a R 4b ; -P(O)(C1-C6 alkyl)2; -S(O)2NH2; -S(O)2C1-C6 alkyl; an unsubstituted or R 4c -substituted -(C1-C6) alkyl group; an unsubstituted or R 4d -substituted -O-C1-C6 alkyl group; an unsubstituted or R 4eSubstituted phenyl; unsubstituted or substituted by one or several Rs 4f Substituted 4- to 7-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; unsubstituted or substituted by one or several Rs 4g Substituted -(C3-C6) cycloalkyl; unsubstituted or substituted by one or several Rs 4h Substituted C2-C6 alkenyl; unsubstituted or substituted by one or several Rs 4i Substituted 5- to 6-membered heteroaryl having 1, 2, 3 or 4 N atoms; unsubstituted or substituted by one or several Rs 4j Substituted 4- to 7-membered heterocyclic group having 1 or 2 heteroatoms selected from N, S or O, which is fused with unsubstituted or substituted phenyl; unsubstituted or substituted by one or several Rs 4k Substituted phenyl fused; unsubstituted or substituted by one or several Rs 4l Substituted 5- to 6-membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O or S, which is fused with unsubstituted or substituted phenyl; unsubstituted or substituted by one or several Rs 4m Substituted phenyl fused;

[0057] R 4a 、R 4b 、R 4c 、R 4d 、R 4е 、R 4f 、R 4g 、R 4h 、R 4i 、R 4j 、R 4k 、R 4l 、R 4m Each independently is -H; (=O); -OH; -NH2; -Hal; -CN; C1-C6 alkyl unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl; O-C1-C6 alkyl unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl; C3-C6 cycloalkyl unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl, C1-C6 alkyl; -S(O)2C1-C6 alkyl, -S(O)2NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, morpholinyl, thiazolyl, phenyl;

[0058] R5, R 5a Each independently is -H, C1-C6 alkyl;

[0059] R 6a 、R 6bEach is independently -Η, C1-C6 alkyl, -Hal;

[0060] Or R 6a And R 6b Together with the C atom to which they are attached form an unsubstituted or several -(C1-C6) alkyl-substituted C3-C6 cycloalkyl;

[0061] R7, R 7a 、R 7b 、R 7c 、R 7d 、R 7e 、R 7f 、R 7g 、R 7h Each is independently -Hal; -OH; -NH2; -CN; (=Ο); unsubstituted or one or several -Hal-substituted -(C1-C6) alkyl; unsubstituted or one or several -Hal-substituted -O(C1-C6) alkyl;

[0062] R 8a 、R 8b 、R 8c 、R 8d 、R 8e 、R 8f 、R 8h Each is independently -Hal, -OH, -NH2, -CN, (=Ο), unsubstituted or one or several -Hal-substituted -(C1-C6) alkyl;

[0063] Hal is an atom of F, Cl, Br, I.

[0064] In one embodiment, the present invention relates to a compound of formula I:

[0065]

[0066] Or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,

[0067] R1 is -C(Hal)3, -CH(Hal)2, -CH2Hal, -Hal, -Η, -NO2, unsubstituted or one or several Hal atom-substituted -(C1-C6) alkyl, unsubstituted or one or several Hal atom-substituted -O-(C1-C6) alkyl, unsubstituted or one or several Hal atom-substituted -S-(C1-C6) alkyl;

[0068] R2, R3 are each independently H, -(C1-C6) alkyl;

[0069] Alternatively, R2 and R3 together form an unsubstituted or (C1-C6) alkyl-substituted (C3-C6) cycloalkyl;

[0070] L1 and L2 are each independently a chemical bond, -NR5-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -C(S)-, -C(=NH)-, -(CR 6a R 6b ) 1-3 -, -P(O)(CH3)-, -O-(CH2) 1-3 -, -(CH2) 1-3 -O-, -NR 5a -(CH2) 1-3 -, -(CH2) 1-3 -NR 5a -, -C(O)-(CH2) 1-3 -, -(CH2) 1-3 -C(O)-, -C(O)-NH- or -NH-C(O)-;

[0071] A is an unsubstituted or R7-substituted 6-10 membered aryl; an unsubstituted or R 7a substituted 6-10 membered aryl which is fused to an unsubstituted or R 8a substituted (C3-C6) cycloalkyl; an unsubstituted or R 7b substituted 6-10 membered aryl which is fused to an unsubstituted or R 8b substituted 4-10 membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; an unsubstituted or R 7c substituted 6-10 membered aryl which is fused to an unsubstituted or R 8c substituted 5-6 membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O or S; an unsubstituted or R 7d substituted 5-6 membered heteroaryl having 1, 2, 3 or 4 N atoms; an unsubstituted or R 7e substituted 5-6 membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O or S which is fused to an unsubstituted or R 8e substituted (C3-C6) cycloalkyl; an unsubstituted or R 7f substituted 5-6 membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O or S which is fused to an unsubstituted or R 8ffused to a 4- to 10-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; unsubstituted or substituted by one or more R 7g a 5- to 6-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; unsubstituted or substituted by one or more R 7h a 5- to 6-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O, which is unsubstituted or substituted by one or more R 8h fused to a 4- to 10-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O;

[0072] R4 is -Η; -Hal; (=Ο); -OH; -C(O)OH; -NR 4a R 4b ; -P(O)(C1-C6 alkyl)2; -S(O)2NH2; -S(O)2C1-C6 alkyl; unsubstituted or substituted by one or more R 4c substituted -(C1-C6)alkyl; unsubstituted or substituted by one or more R 4d substituted -O-C1-C6 alkyl; unsubstituted or substituted by one or more R 4e substituted phenyl; unsubstituted or substituted by one or more R 4f a 4- to 7-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; unsubstituted or substituted by one or more R 4g substituted -(C3-C6)cycloalkyl; unsubstituted or substituted by one or more R 4h substituted -C2-C6 alkenyl; unsubstituted or substituted by one or more R 4i a 5- to 6-membered heteroaryl having 1, 2, 3 or 4 N atoms; unsubstituted or substituted by one or more R 4j a 4- to 7-membered heterocyclic group having 1 or 2 heteroatoms selected from N, S or O, which is fused to an unsubstituted or substituted phenyl; unsubstituted or substituted by one or more R 4k substituted phenyl; unsubstituted or substituted by one or more R 4l a 5- to 6-membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O or S, which is fused to an unsubstituted or substituted phenyl; 4m substituted phenyl;

[0073] R 4a 、R 4b 、R 4c 、R 4d 、R 4е 、R 4f 、R 4g 、R 4h 、R 4i 、R4j , R 4k , R 4l , R 4m Each independently is -H; (═O); -OH; -NH2; -Hal; -CN; unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl -C1-C6 alkyl; unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl -O-C1-C6 alkyl; unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl, -C1-C6 alkyl -C3-C6 cycloalkyl; -S(O)2C1-C6 alkyl, -S(O)2NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, morpholinyl, thiazolyl, phenyl;

[0074] R5, R 5a Each independently is -H, C1-C6 alkyl;

[0075] R 6a , R 6b Each independently is -Η, C1-C6 alkyl, -Hal;

[0076] Or R 6a and R 6b together with the C atom to which they are attached form an unsubstituted or substituted by several -(C1-C6) alkyl -C3-C6 cycloalkyl;

[0077] R7, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h Each independently is -Hal; -OH; -NH2; -CN; (═O); unsubstituted or substituted by one or several -Hal -(C1-C6) alkyl; unsubstituted or substituted by one or several -Hal -O(C1-C6) alkyl;

[0078] R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8h Each independently is -Hal, -OH, -NH2, -CN, (═O), unsubstituted or substituted by one or several -Hal -(C1-C6) alkyl;

[0079] Hal is an atom of F, Cl, Br, or I.

[0080] In one embodiment, the present invention relates to a compound of formula I.b:

[0081]

[0082] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,

[0083] R1 is -C(Hal)3, -CH(Hal)2, -CH2Hal, -Hal, -Η, -NO2, unsubstituted or substituted by one or more Hal atoms -(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;

[0084] R2 and R3 are each independently H, -(C1-C6)alkyl;

[0085] or R2 and R3 together form an unsubstituted or substituted by one or more -(C1-C6)alkyl -(C3-C6)cycloalkyl;

[0086] L1 and L2 are each independently a chemical bond, -NR5-, -O-, -S-, -S(O)-, -S(O)2-, -С(Ο)-, -С(Ο)O-, -С(S)-, -С(=NH)-, -(СR 6a R 6b ) 1-3 -, -Ρ(Ο)(СΗ3)-, -Ο-(СΗ2) 1-3 -, -(СΗ2) 1-3 -Ο-, -NR 5a -(СΗ2) 1-3 -, -(СΗ2) 1-3 -NR 5a -, -C(O)-(СΗ2) 1-3 -, -(СΗ2) 1-3 -C(Ο)-, -C(O)-NH-, or -NH-C(O)-;

[0087] A is an unsubstituted or substituted by one or more R7 6-10-membered aryl; unsubstituted or substituted by one or more R 7a substituted 6-10-membered aryl, which is fused to an unsubstituted or substituted by one or more R 8a substituted -(С3-C6)cycloalkyl; unsubstituted or substituted by one or more R 7b substituted 6-10-membered aryl, which is fused to an unsubstituted or substituted by one or more R8b fused to a 4- to 10-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; unsubstituted or substituted by one or more Rs 7c substituted 6- to 10-membered aryl, which is unsubstituted or substituted by one or more Rs 8c fused to a 5- to 6-membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O or S; unsubstituted or substituted by one or more Rs 7d substituted 5- to 6-membered heteroaryl having 1, 2, 3 or 4 N atoms; unsubstituted or substituted by one or more Rs 7e substituted 5- to 6-membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O or S, which is fused to an unsubstituted or substituted (C3-C6) cycloalkyl; unsubstituted or substituted by one or more Rs 8e substituted (C3-C6) cycloalkyl; unsubstituted or substituted by one or more Rs 7f substituted 5- to 6-membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O or S, which is fused to an unsubstituted or substituted 4- to 10-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; unsubstituted or substituted by one or more Rs 8f fused to a 4- to 10-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; unsubstituted or substituted by one or more Rs 7g substituted 5- to 6-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; unsubstituted or substituted by one or more Rs 7h substituted 5- to 6-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O, which is fused to an unsubstituted or substituted 4- to 10-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; unsubstituted or substituted by one or more Rs 8h fused to a 4- to 10-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O;

[0088] R4 is -H; -Hal; (=O); -OH; -C(O)OH; -NR 4a R 4b ; -P(O)(C1-C6 alkyl)2; -S(O)2NH2; -S(O)2C1-C6 alkyl; unsubstituted or substituted by one or more Rs 4c substituted -(C1-C6) alkyl; unsubstituted or substituted by one or more Rs 4d substituted -O-C1-C6 alkyl; unsubstituted or substituted by one or more Rs 4e substituted phenyl; unsubstituted or substituted by one or more Rs 4f substituted 4- to 7-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; unsubstituted or substituted by one or more Rs 4g substituted -(C3-C6) cycloalkyl; unsubstituted or substituted by one or more Rs 4h substituted -C2-C6 alkenyl; unsubstituted or substituted by one or more Rs4i A 5- or 6-membered heteroaryl group substituted with 1, 2, 3 or 4 N atoms; unsubstituted or substituted with one or more R 4j A 4- to 7-membered heterocyclic group substituted with 1 or 2 heteroatoms selected from N, S or O, which is fused to an unsubstituted or substituted phenyl group by an unsubstituted or substituted by one or more R 4k A substituted phenyl group; unsubstituted or substituted with one or more R 4l A 5- or 6-membered heteroaryl group substituted with 1, 2, 3 or 4 heteroatoms selected from N, O or S, which is fused to an unsubstituted or substituted phenyl group by an unsubstituted or substituted by one or more R 4m A substituted phenyl group;

[0089] R 4a R 4b R 4c R 4d R 4е R 4f R 4g R 4h R 4i R 4j R 4k R 4l R 4m Each independently is -H; (=O); -OH; -NH2; -Hal; -CN; a C1-C6 alkyl group unsubstituted or substituted with one or more groups selected from -Hal, -OH, -NH2, -CN, phenyl; an O-C1-C6 alkyl group unsubstituted or substituted with one or more groups selected from -Hal, -OH, -NH2, -CN, phenyl; a C3-C6 cycloalkyl group unsubstituted or substituted with one or more groups selected from -Hal, -OH, -NH2, -CN, phenyl, C1-C6 alkyl; -S(O)2C1-C6 alkyl, -S(O)2NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, morpholinyl, thiazolyl, phenyl;

[0090] R5, R 5a Each independently is -H, C1-C6 alkyl;

[0091] R 6a R 6b Each independently is -Η, C1-C6 alkyl, -Hal;

[0092] Or R 6a And R 6b Together with the C atom to which they are attached form a C3-C6 cycloalkyl group unsubstituted or substituted with several -(C1-C6) alkyl groups;

[0093] R7, R 7a R7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h Each independently is -Hal; -OH; -NH2; -CN; (=Ο); unsubstituted or substituted by one or several -Hal of -(С1-С6) alkyl; unsubstituted or substituted by one or several -Hal of -O(С1-С6) alkyl;

[0094] R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8h Each independently is -Hal, -OH, -NH2, -CN, (=Ο), unsubstituted or substituted by one or several -Hal of -(С1-С6) alkyl;

[0095] Hal is an atom of F, Cl, Br, I.

[0096] In one embodiment, the present invention relates to the S-isomer of the compound of formula I.

[0097] In one embodiment, the present invention relates to a compound, wherein -A-L2-R4 is:

[0098]

[0099]

[0100]

[0101] wherein k and m are each independently 0, 1, 2 or 3;

[0102] X1, X2, X3, X4, X5, X6 are each independently a C atom, an N atom, СΗ, CH2, NH, S or O;

[0103] Y1, Y2, Y3, Y4, Y5 are each independently a C atom, an N atom or СΗ;

[0104] L2 is a chemical bond, -NR5-, -O-, -S-, -S(O)-, -S(O)2-, -С(Ο)-, -С(Ο)O-, -С(S)-, -С(=NH)-, -(СR 6a R 6b ) 1-3 -, -Ρ(Ο)(СΗ3)-, -Ο-(СΗ2) 1-3-, -(CH2) 1-3 -O-, -NR 5a -(CH2) 1-3 -,-(CH2) 1-3 -NR 5a -,-C(O)-(CH2) 1-3 -,-(CH2) 1-3 -C(O)-, -C(O)-NH- or -NH-C(O)-;

[0105] R4 is -H; -Hal; (=O); -OH; -C(O)OH; -NR 4a R 4b ; -P(O)(C1-C6 alkyl)2; -S(O)2NH2; -S(O)2C1-C6 alkyl; unsubstituted or substituted by one or several R 4c substituted -(C1-C6)alkyl; unsubstituted or substituted by one or several R 4d substituted -O-C1-C6 alkyl; unsubstituted or substituted by one or several R 4e substituted phenyl; unsubstituted or substituted by one or several R 4f substituted 4-7 membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; unsubstituted or substituted by one or several R 4g substituted -(C3-C6)cycloalkyl; unsubstituted or substituted by one or several R 4h substituted -C2-C6 alkenyl; unsubstituted or substituted by one or several R 4i substituted 5-6 membered heteroaryl having 1, 2, 3 or 4 N atoms; unsubstituted or substituted by one or several R 4j substituted 4-7 membered heterocyclic group having 1 or 2 heteroatoms selected from N, S or O, fused with unsubstituted or substituted phenyl; unsubstituted or substituted by one or several R 4k substituted phenyl; unsubstituted or substituted by one or several R 4l substituted 5-6 membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O or S, fused with unsubstituted or substituted phenyl; 4m substituted phenyl;

[0106] R 4a 、R 4b 、R 4c 、R 4d 、R 4е 、R 4f 、R 4g 、R 4h 、R 4i 、R 4j 、R 4k 、R 4l 、R 4mEach is independently -H; (=O); -OH; -NH2; -Hal; -CN; C1-C6 alkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl; O-C1-C6 alkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl; C3-C6 cycloalkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl, C1-C6 alkyl; -S(O)2C1-C6 alkyl, -S(O)2NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, morpholinyl, thiazolyl, phenyl;

[0107] R5, R 5a Each is independently -H, C1-C6 alkyl;

[0108] R 6a , R 6b Each is independently -Η, C1-C6 alkyl, -Hal;

[0109] Or R 6a and R 6b together with the C atom to which they are attached form C3-C6 cycloalkyl which is unsubstituted or substituted by several -(C1-C6) alkyl groups;

[0110] R7, R 7b , R 7d , R 7f Each is independently -Hal; -OH; -NH2; -CN; (=O); (C1-C6) alkyl which is unsubstituted or substituted by one or several -Hal; O(C1-C6) alkyl which is unsubstituted or substituted by one or several -Hal;

[0111] R 8b , R 8d , R 8f Each is independently -Hal, -OH, -NH2, -CN, (=O), (C1-C6) alkyl which is unsubstituted or substituted by one or several -Hal;

[0112] Hal is an atom of F, Cl, Br, I.

[0113] In one embodiment, the present invention relates to a compound wherein -A-L2-R4 is:

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125] wherein each p is independently 0 or 1, and each q is independently 0, 1 or 2, and the total number of substituents in each ring does not exceed 3;

[0126] X1, X2, X3, X4, X5, X6 are each independently a C atom, an N atom, CH, CH2, NH, S or O;

[0127] Y1, Y2, Y3, Y4, Y5 are each independently a C atom, an N atom or CH;

[0128] L2 is a chemical bond, -NR5-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -C(S)-, -C(=NH)-, -(CR 6a R 6b ) 1-3 -, -P(O)(CH3)-, -O-(CH2) 1-3 -, -(CH2) 1-3 -O-, -NR 5a -(CH2) 1-3 -, -(CH2) 1-3 -NR 5a -, -C(O)-(CH2) 1-3 -, -(CH2) 1-3 -C(O)-, -C(O)-NH- or -NH-C(O)-;

[0129] R4 is -H; -Hal; (=O); -OH; -C(O)OH; -NR 4a R 4b; -P(O)(C1-C6 alkyl)2; -S(O)2NH2; -S(O)2C1-C6 alkyl; unsubstituted or substituted by one or more R 4c substituted -(C1-C6) alkyl; unsubstituted or substituted by one or more R 4d substituted -O-C1-C6 alkyl; unsubstituted or substituted by one or more R 4e substituted phenyl; unsubstituted or substituted by one or more R 4f substituted 4-7 membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; unsubstituted or substituted by one or more R 4g substituted -(C3-C6) cycloalkyl; unsubstituted or substituted by one or more R 4h substituted -C2-C6 alkenyl; unsubstituted or substituted by one or more R 4i substituted 5-6 membered heteroaryl having 1, 2, 3 or 4 N atoms; unsubstituted or substituted by one or more R 4j substituted 4-7 membered heterocyclic group having 1 or 2 heteroatoms selected from N, S or O, which is fused to an unsubstituted or substituted phenyl; unsubstituted or substituted by one or more R 4k substituted phenyl; unsubstituted or substituted by one or more R 4l substituted 5-6 membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O or S, which is fused to an unsubstituted or substituted phenyl; unsubstituted or substituted by one or more R 4m substituted phenyl;

[0130] R 4a , R 4b , R 4c , R 4d , R 4е , R 4f , R 4g , R 4h , R 4i , R 4j , R 4k , R 4l , R 4mEach is independently -H; (=O); -OH; -NH2; -Hal; -CN; C1-C6 alkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl; O-C1-C6 alkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl; C3-C6 cycloalkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl, C1-C6 alkyl; -S(O)2C1-C6 alkyl, -S(O)2NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, morpholinyl, thiazolyl, phenyl;

[0131] R5, R 5a Each is independently -H, C1-C6 alkyl;

[0132] R 6a , R 6b Each is independently -Η, C1-C6 alkyl, -Hal;

[0133] Or R 6a and R 6b together with the C atom to which they are attached form C3-C6 cycloalkyl which is unsubstituted or substituted by several -(C1-C6) alkyl groups;

[0134] R7, R 7b , R 7d , R 7f Each is independently -Hal; -OH; -NH2; -CN; (=O); (C1-C6) alkyl which is unsubstituted or substituted by one or several -Hal; O(C1-C6) alkyl which is unsubstituted or substituted by one or several -Hal;

[0135] R 8b , R 8d , R 8f Each is independently -Hal, -OH, -NH2, -CN, (=O), (C1-C6) alkyl which is unsubstituted or substituted by one or several -Hal;

[0136] Hal is an atom of F, Cl, Br, I.

[0137] In one embodiment, the present invention relates to a compound wherein -A-L2-R4 is

[0138]

[0139]

[0140] wherein k and m are each independently 0, 1, 2 or 3;

[0141] L2 is a chemical bond, -NR5-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -C(S)-, -C(=NH)-, -(CR 6a R 6b ) 1-3 -, -P(O)(CH3)-, -O-(CH2) 1-3 -, -(CH2) 1-3 -O-, -NR 5a -(CH2) 1-3 -, -(CH2) 1-3 -NR 5a -, -C(O)-(CH2) 1-3 -, -(CH2) 1-3 -C(O)-, -C(O)-NH- or -NH-C(O)-;

[0142] R4 is -H; -Hal; (=O); -OH; -C(O)OH; -NR 4a R 4b ; -P(O)(C1-C6 alkyl)2; -S(O)2NH2; -S(O)2C1-C6 alkyl; unsubstituted or substituted by one or more R 4c substituted -(C1-C6) alkyl; unsubstituted or substituted by one or more R 4d substituted -O-C1-C6 alkyl; unsubstituted or substituted by one or more R 4e substituted phenyl; unsubstituted or substituted by one or more R 4f substituted 4-7-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; unsubstituted or substituted by one or more R 4g substituted -(C3-C6) cycloalkyl; unsubstituted or substituted by one or more R 4h substituted -C2-C6 alkenyl; unsubstituted or substituted by one or more R 4i substituted 5-6-membered heteroaryl having 1, 2, 3 or 4 N atoms; unsubstituted or substituted by one or more R 4j substituted 4-7-membered heterocyclic group having 1 or 2 heteroatoms selected from N, S or O, which is fused to an unsubstituted or substituted phenyl; unsubstituted or substituted by one or more R 4k substituted; unsubstituted or substituted by one or more R 4l substituted 5-6-membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O or S, which is fused to an unsubstituted or substituted phenyl; 4m substituted;

[0143] R 4a 、R 4b 、R 4c 、R 4d 、R 4е 、R 4f 、R 4g 、R 4h 、R 4i 、R 4j 、R 4k 、R 4l 、R 4m Each independently is -H; (=O); -OH; -NH2; -Hal; -CN; unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl -C1-C6 alkyl; unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl -O-C1-C6 alkyl; unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl, -C1-C6 alkyl -C3-C6 cycloalkyl; -S(O)2C1-C6 alkyl, -S(O)2NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, morpholinyl, thiazolyl, phenyl;

[0144] R5, R 5a Each independently is -H, C1-C6 alkyl;

[0145] R 6a 、R 6b Each independently is -Η, C1-C6 alkyl, -Hal;

[0146] Or R 6a and R 6b Together with the C atom to which they are attached form an unsubstituted or several -(C1-C6) alkyl substituted C3-C6 cycloalkyl;

[0147] R7, R 7b 、R 7d 、R 7f Each independently is -Hal; -OH; -NH2; -CN; (=O); unsubstituted or substituted by one or several -Hal substituted -(C1-C6) alkyl; unsubstituted or substituted by one or several -Hal substituted -O(C1-C6) alkyl;

[0148] R 8b 、R 8d 、R 8feach independently is -Hal, -OH, -NH2, -CN, (=Ο), unsubstituted or substituted by one or several -Hal -(C1-C6) alkyl;

[0149] Hal is an atom of F, Cl, Br, I.

[0150] In one embodiment, the present invention relates to a compound, wherein -A-L2-R4 is

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160] wherein p is independently 0 or 1, and q is independently 0, 1 or 2, and the total number of substituents in each ring does not exceed 3;

[0161] L2 is a chemical bond, -NR5-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -C(S)-, -C(=NH)-, -(CR 6a R 6b ) 1-3 -, -P(O)(CH3)-, -O-(CH2) 1-3 -, -(CH2) 1-3 -O-, -NR 5a -(CH2) 1-3 -, -(CH2) 1-3 -NR 5a -, -C(O)-(CH2) 1-3 -, -(CH2) 1-3 -C(O)-, -C(O)-NH- or -NH-C(O)-;

[0162] R4 is -Η; -Hal; (=Ο); -OH; -C(O)OH; -NR 4a R 4b ; -P(O)(С1-С6 alkyl)2; -S(O)2NH2; -S(O)2С1-С6 alkyl; unsubstituted or substituted by one or several R 4c substituted -(С1-С6) alkyl; unsubstituted or substituted by one or several R 4d substituted -O-С1-С6 alkyl; unsubstituted or substituted by one or several R 4e substituted phenyl; unsubstituted or substituted by one or several R 4f substituted 4-7 membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; unsubstituted or substituted by one or several R 4g substituted -(С3-C6) cycloalkyl; unsubstituted or substituted by one or several R 4h substituted -С2-С6 alkenyl; unsubstituted or substituted by one or several R 4i substituted 5-6 membered heteroaryl having 1, 2, 3 or 4 N atoms; unsubstituted or substituted by one or several R 4j substituted 4-7 membered heterocyclic group having 1 or 2 heteroatoms selected from N, S or O, fused to an unsubstituted or substituted phenyl; unsubstituted or substituted by one or several R 4k substituted phenyl; unsubstituted or substituted by one or several R 4l substituted 5-6 membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O or S, fused to an unsubstituted or substituted phenyl; 4m substituted phenyl;

[0163] R 4a R 4b R 4c R 4d R 4е R 4f R 4g R 4h R 4i R 4j R 4k R 4l R 4mEach is independently -H; (═O); -OH; -NH2; -Hal; -CN; C1-C6 alkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl; O-C1-C6 alkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl; C3-C6 cycloalkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl, C1-C6 alkyl; -S(O)2C1-C6 alkyl, -S(O)2NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, morpholinyl, thiazolyl, phenyl;

[0164] R5, R 5a Each is independently -H, C1-C6 alkyl;

[0165] R 6a , R 6b Each is independently -H, C1-C6 alkyl, -Hal;

[0166] Or R 6a and R 6b together with the C atom to which they are attached form C3-C6 cycloalkyl which is unsubstituted or substituted by several -(C1-C6) alkyl groups;

[0167] R7, R 7b , R 7d , R 7f Each is independently -Hal; -OH; -NH2; -CN; (═O); (C1-C6) alkyl which is unsubstituted or substituted by one or several -Hal; O(C1-C6) alkyl which is unsubstituted or substituted by one or several -Hal;

[0168] R 8b , R 8d , R 8f Each is independently -Hal, -OH, -NH2, -CN, (═O), (C1-C6) alkyl which is unsubstituted or substituted by one or several -Hal;

[0169] Hal is an atom of F, Cl, Br, I.

[0170] In one embodiment, the present invention relates to a compound, wherein L1 and L2 are each independently 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)-.

[0171] In one embodiment, the present invention relates to a compound, wherein R1 is -H, -CF3, -CCl3, -CHF2, -CH2F, -CHCl2, -CH2Cl, -NO2.

[0172] In one embodiment, the present invention relates to a compound, wherein R2 and R3 are each independently -H, methyl, ethyl, propyl, or R2 and R3 together with the C atom to which they are attached form cyclopropyl, cyclobutyl or cyclopentyl.

[0173] In one embodiment, the present invention relates to a compound, wherein R4 is -H; (=O); -OH; -F; -Cl; -Br; -P(O)(C1-C6 alkyl)2; -S(O)2NH2; -S(O)2-(C1-C6) alkyl; unsubstituted or substituted by one or several (=O), -Hal, -CN, -S(O)2-(C1-C6) alkyl of -(C1-C6) alkyl; unsubstituted or substituted by one or several (=O), -CN, -Hal of -O-(C1-C6) alkyl; unsubstituted or substituted by one or several (=O), -OH, -Hal, -CN of -(C3-C6) cycloalkyl; unsubstituted or substituted by one or several -Hal, -CN, morpholine, -P(O)(CH3)2 of phenyl; unsubstituted or substituted by -(C1-C6) alkyl, (=O), -Hal, -CN of 5-6 membered heterocyclic group having 1, 2 or 3 heteroatoms selected from N or O; unsubstituted or substituted by (=O), -(C1-C6) alkyl, -(C3-C6) cycloalkyl, -Hal, -CN of 5-6 membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O or S; unsubstituted or substituted by one or several (=O), -(C1-C6) alkyl of 5-6 membered heteroaryl having 1 or 2 N atoms, which is fused with phenyl; -NR 4a R 4b ;

[0174] R 4a 、R 4bEach is independently -H, (=O), morpholinyl, -F, -S(O)2CH3, -СN, -keto, cyclopropyl, thiazolyl, -С1-С3 alkyl which is unsubstituted or substituted with phenyl, -P(O)(CH3)2.

[0175] In one embodiment, the invention relates to a compound wherein R4 is -H; -OH; (=O); -P(O)(CH3)2; -CH3; -CH2CH3; tert-butyl; -CH2CF3; -CH2CH2S(O)2CH3; -CF3; -Cl; -OCF3; -S(O)2NH2; -S(O)2CH3; phenyl which is unsubstituted or substituted by one or more -Hal, -СN; methylpiperazinyl; piperazinyl; imidazolyl; thiazolyl; methylpyrazolyl; pyrazolyl; pyridinyl; pyrimidinyl; morpholine; oxanyl; oxolanyl; cyclohexyl; cyclopentyl; cyclopropyl; oxazolyl; methyloxazolyl; dimethyloxazolyl; dihydropyridinyl; methyldihydropyridinyl; -NR 4a R 4b ;

[0176] R 4a , R 4b Each is independently -H, (=O), morpholinyl, -F, -S(O)2CH3, -СN, -keto, cyclopropyl, thiazolyl, -С1-С3 alkyl which is unsubstituted or substituted with phenyl, -P(O)(CH3)2.

[0177] In one embodiment, the invention relates to a compound wherein R 4a , R 4b , R 4c , R 4d , R 4е , R 4f , R 4g , R 4h , R 4i , R 4j , R 4k , R 4l , R 4m Each is independently -H, (=O)-CH3, morpholinyl, -F, -S(O)2CH3, -СN, -OH, cyclopropyl, thiazolyl, -С1-С3 alkyl which is unsubstituted or substituted with phenyl, -P(O)(CH3)2.

[0178] In one embodiment, the invention relates to a compound, wherein R5 is -H, -CH3.

[0179] In one embodiment, the invention relates to a compound wherein R 6a and R 6b Each independently is -H, -F, -СH3, or R6a and R 6b Together with the C atoms to which they are attached, form a cyclopropyl group.

[0180] In one embodiment, the present invention relates to a compound, wherein R7, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h are each independently (=Ο), -Hal, -СΗ3, -ΟСΗ3, -СHal3, -OСΗal3.

[0181] In one embodiment, the present invention relates to a compound, wherein R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8h are each independently (=Ο), -Hal, -СΗ3, -ΟСΗ3, -СHal3, -OСΗal3.

[0182] The compounds according to the present invention can be obtained and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: acid addition salts formed by reacting the free base form of the compound with the following acids: pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; or organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanedisulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-3-hydroxy-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxy naphthoic acid, salicylic acid, stearic acid, muconic acid, etc.

[0183] Various methods can be used to analyze and identify the corresponding counterions of pharmaceutically acceptable salts, including but not limited to ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectrometry, mass spectrometry, or any combination thereof.

[0184] The salt is recovered by using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or in the case of an aqueous solution, lyophilization. It should be understood that reference to a pharmaceutically acceptable salt includes its solvate addition form or crystalline form, particularly solvates or polymorphs. Solvates contain a stoichiometric or non-stoichiometric amount of solvent and can form during the crystallization process using pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is an alcohol. Solvates of the compounds described in this patent can be conveniently prepared or formed during the methods described in the present invention. Additionally, the compounds provided in the present invention can exist in non-solvated form as well as solvated form. Generally, for the purposes of the compounds and methods provided in the present invention, the solvated form is considered equivalent to the non-solvated form.

[0185] The compounds described in the present invention can be provided in various forms, including but not limited to amorphous form, milled form, and nanoparticle form. Additionally, the compounds described in the present invention include crystalline forms, also known as polymorphs. Polymorphs include different crystal packing arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, different densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, crystallization rate, and storage temperature can result in one crystal form being dominant.

[0186] The screening and characterization of pharmaceutically acceptable salts, polymorphs, and / or solvates can be accomplished using a variety of techniques, including but not limited to thermal analysis, X-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis methods are dedicated to analyzing thermochemical degradation or thermophysical processes, including but not limited to polymorphic transitions, and such methods are used to analyze the relationships between polymorphic forms, to determine weight loss, to find the glass transition temperature, or for excipient compatibility studies. Such methods include but are not limited to differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), thermogravimetric and infrared analysis (TG / IR). Crystallization methods include but are not limited to single crystal and powder diffractometers and synchrotron radiation sources. The various spectroscopic techniques used include but are not limited to Raman (combinational scattering), FTIR, UVIS, and NMR (liquid and solid state). The various microscopy techniques include but are not limited to polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive X-ray analysis (EDX), environmental scanning electron microscopy with EDX (in a gas or water vapor atmosphere), IR microscopy, and Raman microscopy.

[0187] In another embodiment, the present invention relates to compounds selected from the group consisting of:

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257] The present invention also relates to a method for inhibiting the biological activity of cyclin-dependent protein kinase CDK7 in a subject, which comprises contacting cyclin-dependent protein kinase CDK7 with a compound according to the present invention.

[0258] CDK7 inhibitory compounds can be used to manufacture pharmaceutical products intended for the treatment of any pathological condition described herein. For example, compounds of formula I, pharmaceutically acceptable salts, solvates or stereoisomers can be used for the prevention or treatment of diseases or medical conditions associated, alone or in part, with CDK7 activity, such as tumors, infectious inflammatory or non-infectious inflammatory, autoinflammatory, autoimmune diseases. Exemplary tumor diseases that can be treated with the above compounds are selected from breast cancer, metastatic breast cancer, HER2-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, 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 carcinoma, oral 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 lymphoma, diffuse large B-cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, endometrial cancer, fallopian tube cancer, sarcoma, Ewing sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, multiple myeloma, but are not limited thereto.

[0259] Exemplary autoimmune diseases are selected from axial spondyloarthritis, antiphospholipid syndrome, vasculitis (ANCA-associated vasculitis, including Wegener's granulomatosis and related forms of vasculitis, 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, Sjögren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis and uveitis, but are not limited thereto.

[0260] Exemplary autoinflammatory diseases are selected from Behçet's disease; Blau syndrome; chronic recurrent multifocal osteomyelitis (CRMO); synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome; cryopyrin-associated periodic syndromes (CAPS); interleukin-1 receptor antagonist deficiency (DIRA); familial Mediterranean fever (FMF); NLRP12-associated autoinflammatory disease; neonatal-onset multisystem inflammatory disease (NOMID); chronic infantile neurologic cutaneous and articular (CINCA) syndrome; Majeed syndrome; mevalonate kinase deficiency (hyperimmunoglobulin-D syndrome); periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome; pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome; Schnitzler syndrome; Sweet's syndrome; systemic juvenile idiopathic arthritis; Still's disease; adult-onset Still's disease (AOSD); tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), but are not limited thereto.

[0261] Exemplary infectious or non-infectious inflammatory diseases are selected from allergies (including but not limited to: delayed hypersensitivity, immediate hypersensitivity, anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, osteoarthritis, adult respiratory distress syndrome, respiratory tract inflammation (including but not limited to: bronchiolitis, bronchitis, bronchiectasis, interstitial cell pneumonia, giant cell interstitial pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonia, laryngitis, pneumonia, pharyngitis, pleurisy, pneumonitis, pneumoconiosis, asbestosis, berylliosis, silicosis, talcosis, usual interstitial pneumonia), tonsillitis, bursitis, cellulitis, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes, 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 skin diseases), 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 (orchitis), orchitis (testitis), transverse myelitis, urethritis, cystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis, but are not limited thereto.

[0262] In one embodiment, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof as described herein and one or more pharmaceutically acceptable excipients.

[0263] In one embodiment, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt, solvate, stereoisomer thereof as described herein and one or more pharmaceutically acceptable excipients.

[0264] In another embodiment, the pharmaceutical composition of the present invention is intended for the treatment or prevention of diseases or disorders associated with an increased activity of cyclin-dependent protein kinase CDK7. In another embodiment of the present invention, the pharmaceutical composition according to the present invention is intended for the prevention and treatment of diseases or disorders associated with an increased activity of cyclin-dependent protein kinase CDK7, wherein the diseases or disorders associated with an increased activity of cyclin-dependent protein kinase CDK7 are tumors, infectious inflammatory or non-infectious inflammatory, autoinflammatory, autoimmune diseases.

[0265] In another embodiment of the present invention, a pharmaceutical composition comprising a compound of the present invention is intended for the prevention or treatment of

[0266] tumor diseases selected from breast cancer, metastatic breast cancer, HER2-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 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 carcinoma, oral 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 lymphoma, diffuse large B-cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, endometrial cancer, fallopian tube cancer, sarcoma, Ewing sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, multiple myeloma;

[0267] autoimmune diseases selected from axial spondyloarthritis, antiphospholipid syndrome, vasculitis (ANCA-associated vasculitis, including Wegener's granulomatosis and related forms of vasculitis, 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, Sjögren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis and uveitis;

[0268] Autoinflammatory diseases, which are selected from Behçet's disease; Blau syndrome; chronic recurrent multifocal osteomyelitis (CRMO); synovitis; synovitis; acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome, cryopyrin-associated periodic syndromes (CAPS); interleukin-1 receptor antagonist deficiency (DIRA); familial Mediterranean fever (FMF); NLRP12-related autoinflammatory diseases; neonatal-onset multisystem inflammatory disease (NOMID); chronic infantile neurologic cutaneous and articular (CINCA) syndrome; Majeed syndrome; mevalonate kinase deficiency (hyperimmunoglobulin D syndrome); periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome; pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome; Schnitzler syndrome; Sweet syndrome; systemic juvenile idiopathic arthritis; Still's disease; adult-onset Still's disease (AOSD); tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS);

[0269] Infectious inflammatory diseases or non-infectious inflammatory diseases, which are selected from allergies (including but not limited to: delayed hypersensitivity, immediate hypersensitivity, anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, osteoarthritis, adult respiratory distress syndrome, respiratory tract inflammation (including but not limited to: bronchiolitis, bronchitis, bronchiectasis, interstitial cell pneumonia, giant cell interstitial pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonia, laryngitis, pneumonia, pharyngitis, pleurisy, pneumonia, pneumoconiosis, asbestosis, berylliosis, silicosis, talcosis, usual interstitial pneumonia), tonsillitis, bursitis, cellulitis, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes, 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 skin diseases), 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, transverse myelitis, urethritis, cystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis.

[0270] In another embodiment of the present invention, a pharmaceutical composition comprising a compound according to the present invention is intended for the prevention or treatment of tumor diseases, which are breast cancer, metastatic breast cancer, HER2-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 receptor, HER2-negative breast cancer, small cell lung cancer, metastatic small cell lung cancer.

[0271] The pharmaceutical composition of the present invention may comprise, for example, about 5% to about 100% by weight of the active ingredient, about 10% to about 100% by weight of the active ingredient, about 10% to about 60% by weight of the active ingredient. It should be understood that each dosage unit may not contain an effective amount of one or more active ingredients, since a sufficient effective amount can be achieved by administering multiple dosage unit forms.

[0272] Typical compositions are prepared by mixing the compounds of the present invention with carriers, diluents or excipients. Suitable carriers, diluents and fillers are known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. The particular carrier, diluent or filler used will depend on the manner and purpose of applying the compounds of the present invention. Solvents are generally selected based on solvents that are considered safe for administration to mammals by those skilled in the art. Generally, safe solvents are aqueous solvents such as water and other solvents that are soluble in or miscible with water. Suitable aqueous solvents include water (as the main component), ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), etc. and mixtures thereof. The composition may also contain one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents and other known additives to provide an elegant appearance of the pharmaceutical product (i.e., the compound of the present invention or its pharmaceutical composition) or to facilitate the manufacture of the pharmaceutical product (i.e., the medicinal product). The pharmaceutical composition should preferably be manufactured in accordance with GMP (Good Manufacturing Practice for Pharmaceuticals) requirements.

[0273] The pharmaceutical composition may also contain salts, solvates and hydrates of the compounds of the present invention, or stable forms of the compounds (e.g., complexes with cyclodextrin derivatives or other known complexing agents).

[0274] The pharmaceutical composition of the present invention is typically suitable for oral administration. Oral administration may include swallowing such that the compound enters the gastrointestinal tract; and / or oral, sublingual or buccal administration, by which the compound enters the bloodstream directly from the mouth.

[0275] Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; granules; soft or hard capsules containing multi-microparticles or nanoparticles, liquid or powder; lozenges (including liquid-filled lozenges); chewables; gels; rapidly dispersing dosage forms; films; ovules; sprays; and buccal / mucosal adhesive patches. More preferred oral administration formulations are tablets, granules and capsules.

[0276] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules (e.g., made of gelatin or hydroxypropylmethylcellulose), and typically contain a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil and one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared by, for example, reconstitution of solids from sachets.

[0277] The pharmaceutical compositions of the present invention can also be administered parenterally. As used herein, "parenteral administration" of a pharmaceutical composition includes any route of administration characterized by physical breaching of the tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue, thus typically resulting in direct administration into the bloodstream, muscle or viscera. Thus, parenteral administration particularly includes administering the pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-permeable non-surgical wound, etc. In particular, parenteral administration is envisioned to particularly include subcutaneous, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intracardiac, intraurethral, intracranial, intraarticular injection or infusion; and renal dialysis infusion techniques. Intratumoral delivery (e.g., intratumoral injection) may also be advantageous. Regional perfusion is also provided.

[0278] Formulations 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 saline. Such formulations can be prepared and packaged in a form suitable for bolus administration or continuous administration. Injectable formulations can be prepared and packaged in unit dosage form, such as in an ampoule or in a multi-dose container containing a preservative. Formulations for parenteral administration particularly include suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, etc.

[0279] The compounds of the present invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (alone, as a mixture or as component particles mixed, e.g., with a suitable pharmaceutically acceptable excipient) administered from a dry powder inhaler, as an aerosol from a pressurized container, pump, spray, nebulizer (preferably a nebulizer using electrohydrodynamics to generate a fine mist) or atomizer, with or without a suitable propellant, or as a nasal drop.

[0280] Pressurized containers, pumps, sprayers, atomizers or nebulizers typically contain a solution or suspension of the compounds of the present invention, said solution or suspension comprising, for example, suitable agents for dispersing, dissolving or extending the release of the active ingredient, and a propellant as a solvent.

[0281] Before use as a dry powder or suspension, pharmaceutical products are typically micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any suitable comminution method such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.

[0282] Capsules, blisters and cartridges for use in inhalers or insufflators can be formulated to contain a powder mixture of the compounds of the present invention, a suitable powder matrix and a performance modifier.

[0283] Suitable solution formulations for use in nebulizers that generate fine mists using electrohydrodynamics can contain a suitable dose of the compounds of the present invention per actuation, and the actuation volume can vary, for example, from 1 μL to 100 μL.

[0284] Suitable flavorings such as menthol and levomenthol or sweeteners such as saccharin or sodium saccharin can be added to those formulations of the present invention intended for inhalation / intranasal administration.

[0285] Formulations can be formulated for immediate release and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

[0286] In one embodiment, the present invention relates to a method for preventing or treating a disease or disorder associated with an increase in the activity of cyclin-dependent protein kinase CDK7, which comprises administering to a subject in need of such treatment or prevention 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.

[0287] In another embodiment, the present invention relates to a method for preventing or treating a disease or disorder, wherein the disease or disorder associated with an increase in the activity of cyclin-dependent kinase CDK7 is a tumor, an infectious inflammatory or non-infectious inflammatory, an autoinflammatory, an autoimmune disease.

[0288] In another embodiment, the present invention relates to a method for preventing or treating a disease or disorder, wherein the disease or disorder associated with an increase in the activity of cyclin-dependent protein kinase CDK7 is

[0289] A tumor disease selected from breast cancer, metastatic breast cancer, HER2-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 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 carcinoma, oral 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 lymphoma, diffuse large B-cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, uterine body cancer, fallopian tube cancer, sarcoma, Ewing sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, multiple myeloma;

[0290] An autoimmune disease selected from axial spondyloarthritis, antiphospholipid syndrome, vasculitis (ANCA-associated vasculitis, including Wegener's granulomatosis and related forms of vasculitis, 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, Sjögren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis, and uveitis;

[0291] An autoinflammatory disease selected from Behçet's disease; Blau syndrome; chronic recurrent multifocal osteomyelitis (CRMO); synovitis; acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome, cryopyrin-associated periodic syndromes (CAPS); interleukin-1 receptor antagonist deficiency (DIRA); familial Mediterranean fever (FMF); NLRP12-associated autoinflammatory disease; neonatal-onset multisystem inflammatory disease (NOMID); chronic infantile neurologic cutaneous and articular (CINCA) syndrome; Majeed syndrome; mevalonate kinase deficiency (hyperimmunoglobulinemia D syndrome); periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome; pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome; Schnitzler syndrome; Sweet's syndrome; systemic juvenile idiopathic arthritis; Still's disease; adult-onset Still's disease (AOSD); tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS);

[0292] An infectious or non-infectious inflammatory disease, selected from allergies (including but not limited to: delayed hypersensitivity, immediate hypersensitivity, anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, osteoarthritis, adult respiratory distress syndrome, respiratory inflammation (including but not limited to: bronchiolitis, bronchitis, bronchiectasis, interstitial cell pneumonia, giant cell interstitial pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonia, laryngitis, pneumonia, pharyngitis, pleurisy, pneumonitis, pneumoconiosis, asbestosis, berylliosis, silicosis, talcosis, usual interstitial pneumonia), tonsillitis, bursitis, cellulitis, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes, 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 skin diseases), 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 (orchitis), orchitis (testitis), transverse myelitis, urethritis, cystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis.

[0293] In another embodiment, the present invention relates to a method for preventing or treating a disease or disorder, wherein the disease or disorder associated with an increased activity of cyclin-dependent protein kinase CDK7 is a tumor disease selected from breast cancer, HER2-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 receptor, HER2-negative breast cancer, small cell lung cancer, metastatic small cell lung cancer.

[0294] Means that the compounds of the present invention can be used in the prevention and treatment methods as described above, can be used in the treatment as described above, and / or can be used in the manufacture of the therapeutic product (drug) for treatment as described above.

[0295] In one embodiment, the present invention relates to the use of a compound according to the present invention or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the above-mentioned pharmaceutical composition for treating a disease or disorder associated with an increased activity of CDK7 in a subject in need of such treatment.

[0296] In one embodiment, the present invention relates to the use of a compound according to the present invention or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or the above-mentioned pharmaceutical composition for treating a disease or disorder associated with an increased activity of CDK7, wherein the disease or disorder associated with an increased activity of CDK7 is a tumor, an infectious inflammatory or non-infectious inflammatory, autoinflammatory, autoimmune disease.

[0297] In another embodiment, the present invention relates to the above-mentioned use, wherein the disease or disorder associated with an increased activity of CDK7 is

[0298] a tumor disease selected from breast cancer, metastatic breast cancer, HER2-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 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 carcinoma, oral 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 lymphoma, diffuse large B-cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, endometrial cancer, fallopian tube cancer, sarcoma, Ewing sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, multiple myeloma;

[0299] an autoimmune disease selected from axial spondyloarthritis, antiphospholipid syndrome, vasculitis (ANCA-associated vasculitis, including Wegener's granulomatosis and related forms of vasculitis, 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, Sjögren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis and uveitis;

[0300] Autoinflammatory diseases, which are selected from Behçet's disease; Blau syndrome; chronic recurrent multifocal osteomyelitis (CRMO); synovitis; acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome, cryopyrin-associated periodic syndromes (CAPS); interleukin-1 receptor antagonist deficiency (DIRA); familial Mediterranean fever (FMF); NLRP12-associated autoinflammatory disease; neonatal-onset multisystem inflammatory disease (NOMID); chronic infantile neurologic cutaneous and articular (CINCA) syndrome; Maggiore syndrome; mevalonate kinase deficiency (hyperimmunoglobulin-D syndrome); periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome; pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome; Schnitzler syndrome; Sweet syndrome; systemic juvenile idiopathic arthritis; Still's disease; adult-onset Still's disease (AOSD); tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS);

[0301] Infectious or non-infectious inflammatory diseases, which are selected from allergies (including but not limited to: delayed hypersensitivity, immediate hypersensitivity, anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, osteoarthritis, adult respiratory distress syndrome, respiratory inflammation (including but not limited to: bronchiolitis, bronchitis, bronchiectasis, interstitial cell pneumonia, giant cell interstitial pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonia, laryngitis, pneumonia, pharyngitis, pleurisy, pneumonitis, pneumoconiosis, asbestosis, berylliosis, silicosis, talcosis, usual interstitial pneumonia), tonsillitis, bursitis, cellulitis, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes, 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 skin disease), 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 (orchitis), orchitis (testitis), transverse myelitis, urethritis, cystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis.

[0302] In another embodiment, the present invention relates to the above use, wherein the tumor disease is selected from breast cancer, HER2-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 receptor, HER2-negative breast cancer, small cell lung cancer, metastatic small cell lung cancer.

[0303] The compounds of the present invention can be administered alone or in combination with one or more other pharmaceutical products or monoclonal antibody-based pharmaceutical products (or any combination thereof). Accordingly, the pharmaceutical compositions, methods and uses of the present invention also cover embodiments of combination (co-administration) with other active agents.

[0304] As used herein, the terms "co-administered", "co-administering" or "in combination" in reference to a compound with one or more other therapeutic agents are intended to mean, refer to or include the following:

[0305] · Co-administering to a patient in need of treatment a combination of a compound of the present invention and a therapeutic agent, wherein such components are formulated together into a single dosage form that releases said components substantially simultaneously,

[0306] · Co-administering to a patient in need of treatment a combination of a compound of the present invention and a therapeutic agent, wherein such components are formulated separately from each other into separate dosage forms that are administered to said patient substantially simultaneously, such that said components are released in said patient substantially simultaneously,

[0307] · Sequentially administering to a patient in need of treatment such components of a compound of the present invention and a therapeutic agent, wherein such components are formulated separately from each other into separate dosage forms to be taken by said patient at successive times, with a significant time interval between each administration, such that

[0308] said components are released in said patient at different times; and

[0309] · Sequentially administering to a patient in need of treatment such components of a compound of the present invention and a therapeutic agent, wherein such components are formulated together into a single dosage form that releases said components in a controlled manner, such that they are released into said patient in parallel, continuously and / or overlappingly at the same and / or different times, wherein the respective portions can be administered by the same or different routes.

[0310] As is well known to those skilled in the art, when pharmaceutical products are used in combination therapy, the therapeutically effective dose can vary. Methods for experimentally determining the therapeutically effective doses of pharmaceutical products and other agents for combination therapy regimens have been described in the literature. For example, the use of metronomic dosing, i.e., providing more frequent lower doses to minimize toxic side effects, has been described in the literature. Combination therapy also includes cyclical therapy that starts and stops at different times according to the patient's treatment plan. For the combination therapies described in this patent, the doses of the co-administered compounds can vary depending on the type of co-drug used, the specific drugs used, the condition or disorder being treated, etc.

[0311] The above anti-tumor therapy can be used as a monotherapy or in combination with surgery, or radiotherapy, or pharmacotherapy. Such therapy can be administered concurrently, simultaneously, sequentially, or separately with the treatment with the compounds according to the invention, and can comprise one or more agents selected from the following classes of anti-tumor agents: anti-proliferative / anti-tumor therapy products for medical oncology and their combinations, such as alkylating agents, alkyl sulfonates, nitrosoureas or triazenes; antimetabolites; hormonal agents or hormone antagonists; platinum compounds; anti-tumor antibiotics; topoisomerase inhibitors.

[0312] Examples of antimetabolites include, but are not limited to, folic acid antagonists (e.g., methotrexate, trimetrexate, pemetrexed, pralatrexate, raltitrexed, calcium levofolinate) or pyrimidine antagonists (e.g., cytarabine, tegafur, fluorouracil, capecitabine, floxuridine, azacitidine, enocitabine, carmofur, gemcitabine, sapacitabine, elacitarabine, doxifluridine) or purine antagonists (e.g., mercaptopurine, thioguanine, pentostatin, fludarabine, cladribine, nelarabine, azathioprine, clofarabine) or asparaginase.

[0313] Examples of alkylating agents include, but are not limited to, nitrogen mustard, cyclophosphamide, chlorambucil, melphalan, bendamustine, hexamethylmelamine, thiotepa, busulfan, carmustine, lomustine, ranimustine, semustine, streptozocin, dacarbazine, ifosfamide, improsulfan, mitobronitol, mitolactol, nimustine, remustine, temozolomide, treosulfan, carboquone, apaziquinone, fotemustine, hexamethylamine, gluphosphamide, pipobroman, trophosfamide, uramustine, evophosphamide, VAL-083.

[0314] 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, calusteron, chlorotrianizene, degarelix, dexamethasone, flocortolone, fulvestrant, goserelin, histrelin, leuprolide, mitotane, nafarelin, nandrolone, nilutamide, octreotide, raloxifene, thyrotropin alfa, toremifene, triptorelin, diethylstilbestrol, acolbifene, danazol, delorelin, cyproterone, orteronel, enzalutamide, aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone, formestane.

[0315] Examples of platinum compounds include, but are not limited to, cisplatin, carboplatin, oxaliplatin, etoplatin, nedaplatin hydrate, lobaplatin, nedaplatin, picoplatin, satraplatin.

[0316] Examples of antitumor antibiotics include, but are not limited to, doxorubicin, daunomycin, idarubicin, carubicin, valrubicin, zorubicin, aclarubicin, pirarubicin, nemorubicin, amrubicin, epirubicin, bleomycin, dactinomycin, plicamycin, peplomycin, mitomycin C, zinostatin, streptozocin.

[0317] Examples of topoisomerase inhibitors include, but are not limited to, irinotecan, topotecan, belotecan, teniposide, etoposide, voreloxin, amonafide.

[0318] Examples of anti-tumor agents include, but are not limited to, any one of the following agents: microtubule-targeting drugs such as taxanes (e.g., paclitaxel, nab-paclitaxel, docetaxel, cabazitaxel, tesetaxel), vinca alkaloids (e.g., vinorelbine, vincaleukoblastine, vincristine, vindesine, vinflunine); mitogen-activated protein kinase 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 (e.g., palivizumab, 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, ocrelizumab, okaratuzumab, oregovomab, ramucirumab, rituximab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, daratumumab, onartuzumab, rakortuomab, tabalumab, abagovomab); kinase inhibitors (fosmatanib, entospotenienib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, vemurafenib, gefitinib, crizotinib, dazatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, bozutinib, axitinib, afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, motesanib, neratinib, orantinib,Ponatinib, Radotinib, Tipifarnib, Tivantinib, Tivozanib, Trametinib, Apatinib, Ibrutinib, Acalabrutinib, Cobimetinib, Fedratinib, Brivanib Alaninate, Cediranib, Cabozantinib, Icotinib, Cipatinib, Rigosertib, Pimasertib, Buparlisib, Idelalisib, Midostaurin, Perifosine, Tesevatinib; Photosensitizers (e.g., Talaporfin, Temoporfin, Porfimer Sodium); Cytokines (e.g., Aldesleukin, Interferon Alfa, Interferon Alfa-2a, Interferon Alfa-2b, Simtuzumab, Tasonermin, Recombinant Interleukin-2, Oprelvekin, Recombinant Interferon Beta-1a); Vaccines (e.g., Picibanil, Sipuleucel-T, Vitespen, Emepepimut-S, OncoVAX, Rindopepimut, TroVAX, MGN-1601, MGN-1703); Bisantrene, Decitabine, Mitoxantrone, Procarbazine, Trabectedin, Amsacrine, Brostallicin, Miltefosin, Romidepsin, Plitidepsin, Eribulin, Ixabepilone, Fosbretabulin, Denileukin Diftitox, Ibritumomab Tiuxetan, Prednimustine, Trastuzumab Emtansine, Estramustin, Gemtuzumab Ozogamicin, Aflibercept,oportuzumab monatox, cintredekin besudotox, edotreotide, inotuzumab ozogamicin, naptumomab estafenatox, 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, sizofiran, vismodegib, vorinostat, entinostat, panobinostat, celecoxib, cilengitide, etanidazole, ganetespib, idronoxil, iniparib, lonidamine, nimorazole, procodazole, tasquinimod, telotristat, belinostat, thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar, gendicine, reolisin, retaspimicin, trebananib, virulisin.

[0319] Thus, in another embodiment of the present invention, a pharmaceutical product is described which comprises a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof as defined above in combination with an anti-tumor agent as defined above, which is intended for the combined treatment of cancer.

[0320] Dosage regimens may be adjusted to provide the optimum desired response. For example, a single dose may be administered, several divided doses may be administered over time, or the dose may be proportionally decreased or increased as indicated by the exigencies of the treatment situation. It is especially advantageous to formulate oral compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein, a unit dosage form refers to a physically discrete unit suitable as a unit dose for the patient / subject to be treated; each unit contains a predetermined quantity of the active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications of the unit dosage forms of the present invention are typically determined by, and directly depend 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 compounds for the sensitivity of the subject to be treated.

[0321] Accordingly, based on the disclosure provided herein, one of ordinary skill in the art will understand that the dosage and dosing regimen are adjusted according to methods well known in the art of treatment. That is, the maximum tolerable dose can be readily established, and the effective amount that provides a detectable therapeutic effect to the patient can also be determined, as can the time requirements for administering each agent to provide a detectable therapeutic effect to the patient. Thus, although certain dosages and dosing regimens are illustrated herein, these examples in no way limit the dosages and dosing regimens that can be provided to a patient in practicing the embodiments of the present invention.

[0322] It should be noted that the dosage values can vary depending on the type and severity of the condition to be alleviated and can include single or multiple doses. In addition, it should be understood that for any particular subject, the specific dosage regimen should be adjusted over time according to individual needs and the judgment of the medical professional administering or supervising the administration of the composition, and the dosage ranges set forth in this specification are merely exemplary and are not intended to limit the scope or practice of the claimed composition. In addition, the dosage regimen for using the compositions of the present invention can be based on a variety of factors, including the type of disease of the patient, age, weight, sex, medical condition, severity of the condition, route of administration, and the particular compound of the present invention employed. Accordingly, the dosage regimen can vary widely but can be routinely determined using standard methods. For example, the dosage can be adjusted based on pharmacokinetic and pharmacodynamic parameters, which can include clinical effects such as toxic effects or laboratory values. Accordingly, the present invention encompasses dose escalation within a patient as determined by those skilled in the art. Methods for determining appropriate dosages and regimens are well known in the art and will be understood by those skilled in the art once the ideas disclosed herein are provided.

[0323] Typically, the dosage for treating adults is usually in the range of 0.01 - 5000 mg per day, or 0.1 - 500 mg per day, or 0.1 - 100 mg per day.

[0324] Once the condition of the patient improves, a maintenance dose is administered if needed. Subsequently, the dosage or frequency or both of the administration can be decreased as the symptoms change to maintain the improved disease, disorder, or condition. However, after any recurrence of symptoms, the patient may require long-term regular treatment.

[0325] The above ranges are merely suggestive because the number of variables regarding individual treatment regimens is large and it is not uncommon for there to be substantial deviations from these recommended values. These dosages can be altered according to many variables, which are not limited to the activity of the compound used, the disorder or condition to be treated, the method of administration, the requirements of the individual subject, the severity of the disorder or condition to be treated, and the judgment of the physician.

[0326] The following examples are provided to better understand the present invention. These examples are for illustrative purposes only and are not to be construed as limiting the scope of the present invention in any way.

[0327] The compounds and methods of the present invention will be better understood in connection with the following synthetic schemes, which illustrate methods by which the compounds of the invention can be prepared. The starting materials can be obtained from commercial sources or prepared using conventional prior art methods known to those of ordinary skill in the art. Those of ordinary skill in the art will also readily understand that, in order to successfully complete the syntheses described below, the steps of selective protection and deprotection, and the order of these steps, can be carried out in a different order depending on the nature of the substituents.

[0328] The abbreviations used in this specification, including those given in the subsequent illustrative drawings and examples, are well known to those of ordinary skill in the art.

[0329] DIPEA – Diisopropylethylamine;

[0330] TBAF – Tetrabutylammonium fluoride;

[0331] DMF – N,N-Dimethylformamide;

[0332] THF – Tetrahydrofuran;

[0333] BINAP – (±)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene;

[0334] MTBE – Methyl tert-butyl ether;

[0335] TMEDA – N,N,N',N'-Tetramethylethane-1,2-diamine;

[0336] HATU – 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate;

[0337] NBS – N-Bromosuccinimide;

[0338] TEA – Triethylamine;

[0339] DMAP – 4-Dimethylaminopyridine;

[0340] TFA – Trifluoroacetic acid;

[0341] TIPS – Triisopropylsilyl;

[0342] dppf – 1,1'-Bis(diphenylphosphino)ferrocene;

[0343] ac – Acetyl;

[0344] boc – tert-Butoxycarbonyl;

[0345] pin – Pinacolato;

[0346] HOBt – 1-Hydroxybenzotriazole;

[0347] EDC – 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide;

[0348] PPA – Polyphosphoric acid;

[0349] HPLC – High Performance Liquid Chromatography;

[0350] Ph – Phenyl;

[0351] HMDS – Hexamethyldisilazane.

[0352] Example

[0353] Example 1. Synthesis of Compound 1.6.

[0354]

[0355] Synthesis of Compound 1.2

[0356] TEA (4.28 g, 42.2 mmol), DMAP (0.679 g, 5.50 mmol) and benzenesulfonyl chloride (3.64 g, 21.7 mmol) were added to a solution of 1.1 (4.00 g, 18.34 mmol) in 40 ml of dichloromethane. The reaction mixture was stirred at room temperature for 20 h. After standard work-up, the product was separated by silica gel column chromatography. 5.63 g (86%) of Compound 1.2 was obtained.

[0357] Synthesis of Compound 1.3

[0358] 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)Cl2 (0.417 g, 0.56 mmol) in 50 ml of 1,4-dioxane were stirred at 100 °C for 10 h under a nitrogen atmosphere. After standard work-up, the reaction product was separated by silica gel column chromatography. 2.16 g (76%) of Compound 1.3 was obtained.

[0359] Synthesis of Compound 1.5

[0360] 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), and 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 at 100 °C for 4 h under a nitrogen atmosphere. After standard workup, the product was separated by silica gel column chromatography. 0.95 g (84%) of compound 1.5 was obtained.

[0361] Synthesis of Compound 1.6

[0362] 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 it was completely dissolved (10 ml), and the pH of the mixture was adjusted to 3 with 10% citric acid solution. The precipitate was filtered off and the residual solvent was removed in vacuo. 0.6 g (92%) of product 1.6 was obtained.

[0363] Example 2. Synthesis of Compound 2.4.

[0364]

[0365] Synthesis of Compound 2.1

[0366] 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 it was completely dissolved, the pH of the mixture was adjusted to 3 with concentrated HCl, the precipitate was filtered off, washed with water, and the residual solvent was removed in vacuo. 7.1 g (90%) of compound 2.1 was obtained.

[0367] Synthesis of Compound 2.2

[0368] 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 volatile components were removed in vacuo, the residue was dissolved in 20 ml of dichloromethane, and added dropwise to a solution of tert-butanol (2.77 g, 37.1 mmol) and TEA (15.0 g, 148 mmol) in 10 ml of dichloromethane while cooling in an ice bath, and stirred at room temperature for 20 h. After standard workup, the product was separated by silica gel column chromatography. 3.7 g (81%) of compound 2.2 was obtained.

[0369] Synthesis of Compound 2.3

[0370] TEA (4.28 g, 42.2 mmol), DMAP (0.22 g, 1.79 mmol) and benzenesulfonyl chloride (3.24 g, 20.2 mmol) were added to a solution of 2.2 (4.5 g, 18.3 mmol) in 50 ml of dichloromethane. The reaction mixture was stirred at room temperature for 20 h. After standard workup, the product was separated by silica gel column chromatography. 6.73 g (80%) of product 2.3 was obtained.

[0371] Synthesis of Compound 2.4

[0372] 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. The reaction mixture was stirred at room temperature for 20 h. Volatile components were removed in vacuo. 0.43 g (95%) of product 2.4 was obtained.

[0373] 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

[0374]

[0375] Synthesis of Compound 3.1

[0376] 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 at room temperature for 20 h. After standard workup, the product was separated by silica gel column chromatography. 0.035 g (51%) of compound 3.1 was obtained.

[0377] Synthesis of Compound CDK7_951

[0378] 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 removed under reduced pressure and the product was separated by preparative HPLC. 0.015 g (54%) of compound CDK7_951 was obtained.

[0379] Similarly, the following compounds were produced from Compound 1.6 and the corresponding amines:

[0380]

[0381] Example 4. Synthesis of Compounds CDK7_538, CDK7_539, CDK7_834, CDK7_836, CDK7_837, CDK7_838

[0382]

[0383] Synthesis of Compound 4.2

[0384] 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 hours. The volatile components were removed under vacuum, and the residue was dissolved in 5 ml of dichloromethane and added dropwise 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 with stirring and cooling in an ice bath. The reaction mixture was stirred at room temperature for 20 hours. After standard workup, the product was separated by silica gel column chromatography. 0.3 g (80%) of Compound 4.2 was obtained.

[0385] Synthesis of Compound 4.3

[0386] 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)Cl2 (0.021 g, 0.03 mmol) were dissolved in 2 ml of 1,4-dioxane and heated at 100 °C for 6 hours with stirring in a nitrogen atmosphere in a sealed vessel. The reaction mixture was filtered through a layer of diatomaceous earth and the solvent was removed. Compound 1.4 (0.088 g, 0.33 mmol), Na2CO3 (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 at 100 °C for 3 hours with stirring in a nitrogen atmosphere in a sealed vessel. After standard workup, the product was separated by silica gel column chromatography. 0.075 g (44%) of Compound 4.3 was obtained.

[0387] Synthesis of Compound 4.4

[0388] An aqueous NaOH solution (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 reaction mixture was stirred at 50 °C for 3 h. After standard workup, the product was separated by silica gel column chromatography. 0.042 g (72%) of compound 4.4 was obtained.

[0389] Synthesis of compound CDK7_836

[0390] 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, and the reaction mixture was stirred at 20 °C for 20 h. The solvent was removed. The product was separated by HPLC. 0.012 g (34%) of compound CDK7_836 was obtained.

[0391] The following compounds shown in the table below were produced similarly.

[0392]

[0393] *Unseparated intermediate

[0394]

[0395] Synthesis of compound 4.5

[0396] Compound 2.1 (0.6 g, 3.16 mmol), N-methylpiperazine (0.425 ml, 3.79 mmol), HATU (1.58 g, 4.11 mmol), and 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 separated by silica gel column chromatography. 0.86 g (99%) of compound 4.5 was obtained.

[0397] Synthesis of compound 4.6

[0398] TEA (0.769 ml, 5.52 mmol), DMAP (0.023 g, 0.18 mmol), and benzenesulfonyl chloride (0.36 g, 2.02 mmol) were added to a solution of 4.5 (0.5 g, 1.84 mmol) in 15 ml of dichloromethane. The reaction mixture was stirred at room temperature for 20 h. After standard workup, the product was separated by silica gel column chromatography. 0.56 g (74%) of product 4.6 was obtained.

[0399] Synthesis of compound 4.7

[0400] Compound 4.6 (0.56 g, 1.36 mmol), (BPin)2 (0.698 g, 2.72 mmol), KOAc (0.413 g, 4.08 mmol), and Pd(dppf)Cl2 (0.112 g, 0.14 mmol) in 12 ml of 1,4-dioxane were stirred at 100 °C for 10 h under a nitrogen atmosphere. After standard workup, the reaction product was separated by silica gel column chromatography. 0.52 g (83%) of compound 4.7 was obtained.

[0401] Synthesis of Compound 4.8

[0402] Borated ether 4.7 (0.149 g, 0.32 mmol), pyrimidine 1.4 (0.1 g, 0.26 mmol), Na2CO3 (0.07 g, 0.65 mmol), and Pd(dppf)Cl2 (0.024 g, 0.03 mmol) in 2 ml of 1,4-dioxane and 0.7 ml of water were stirred at 100 °C for 4 h under a nitrogen atmosphere. After standard workup, the reaction product was separated by silica gel column chromatography. 0.05 g (23%) of compound 4.8 was obtained.

[0403] Synthesis of Compound 4.9

[0404] Compound 4.8 (0.05 g, 0.07 mmol) and NaOH (0.065 g, 1.61 mmol) in 0.5 ml of ethanol and 0.5 ml of H2O were stirred at 50 °C for 2 h. 2 ml of 10% citric acid solution was added, and the mixture was extracted with ethyl acetate. After removal of the solvent in vacuo, 0.016 g (42%) of compound 4.9 was obtained.

[0405] Synthesis of Compound CDK7_539

[0406] Compound 4.9 (0.016 g, 0.03 mmol) was dissolved in 1 ml of dichloromethane, 0.2 ml of a 1,4-dioxane solution of 4H HCl was added, and the reaction mixture was stirred at 20 °C for 18 h. Volatile components were removed in vacuo, and the product was separated by preparative HPLC. 0.010 g (77%) of compound CDK7_539 was obtained.

[0407] Example 5. Synthesis of Compound CDK7_535

[0408]

[0409] Synthesis of Compound 5.2

[0410] While stirring at -78 °C under a nitrogen atmosphere, a solution of 0.75 ml (1.84 mmol) of 2.5 M n-butyllithium in hexane was added to a solution of compound 5.1 (0.45 g, 1.23 mmol) in 50 ml of THF. The mixture was stirred for 30 minutes, then benzoyl chloride (0.262 g, 1.84 mmol) was added, and stirring was continued for another 30 minutes. After standard workup, the product was separated by silica gel column chromatography. 0.3 g (62%) of compound 5.2 was obtained.

[0411] Synthesis of compound 5.3

[0412] Pyrrole 5.2 (0.126 g, 0.35 mmol), (BPin)2 (0.124 g, 0.48 mmol), KOAc (0.063 g, 0.63 mmol), and Pd(dppf)Cl2 (0.012 g, 0.02 mmol) were dissolved in 5 ml of 1,4-dioxane and heated at 100 °C for 7 hours in a sealed vessel. After standard workup, the product was separated by silica gel column chromatography. 0.05 g (36%) of compound 5.3 was obtained.

[0413] Synthesis of compound 5.4

[0414] Boronic ether 5.3 (0.05 g, 0.1 mmol), pyrimidine 1.4 (0.027 g, 0.07 mmol), Na2CO3 (0.021 g, 0.2 mmol), and Pd(dppf)Cl2 (0.007 g, 0.01 mmol) in 1.5 ml of 1,4-dioxane and 0.5 ml of water were stirred at 90 °C for 3 hours under a nitrogen atmosphere. After standard workup, the reaction product was separated by silica gel column chromatography. 0.04 g (62%) of compound 5.4 was obtained.

[0415] Synthesis of compound 5.5

[0416] Similar to compound 4.9, compound 5.5 was produced in a yield of 87%.

[0417] Synthesis of compound CDK7_535

[0418] Similar to compound 539, compound CDK7_535 was produced in a yield of 38%.

[0419] Example 6. Synthesis of compounds CDK7_845, CDK7_924, CDK7_959, CDK7_961, CDK7_1052.

[0420]

[0421] Synthesis of compound 6.2

[0422] Similar to compound 4.2, the said compound was produced with a yield of 93%.

[0423] Synthesis of compound 6.3

[0424] Amide 6.2 (0.29 g, 1.00 mmol) and 0.97 g of methanesulfonic acid (10 mmol) were stirred at 20 °C for 72 h. 5 ml of water was added while cooling the reaction mixture, and the mixture was stirred for 1 h. The precipitate was filtered off, washed with water, and the residual solvent was removed in vacuo. 0.19 g (84%) of compound 6.3 was obtained.

[0425] Synthesis of compound 6.4

[0426] 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 pyrrolopyridinone 6.3 (0.19 g, 0.84 mmol) in 6 ml of dichloromethane. The reaction mixture was stirred at 20 °C for 18 h. After standard work-up, the product was separated by silica gel column chromatography. 0.26 g (73%) of compound 6.4 was obtained.

[0427] Synthesis of compound 6.5

[0428] 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)Cl2 (0.045 g, 0.06 mmol) in 5 ml of 1,4-dioxane were heated at 100 °C for 7 h under a nitrogen atmosphere with stirring. After standard work-up, the product was separated by silica gel column chromatography. 0.14 g (59%) of compound 6.5 was obtained.

[0429] Synthesis of compound 6.6

[0430] Compound 6.5 (0.54 g, 1.30 mmol), pyrimidine 1.4 (0.495 g, 1.30 mmol), Na2CO3 (0.348 g, 3.25 mmol), Pd(dppf)Cl2 (0.97 g, 0.13 mmol) in a mixture of 12 ml of 1,4-dioxane and 4 ml of water were stirred at 100 °C for 4 h under a nitrogen atmosphere. After standard work-up, the reaction product was separated by silica gel column chromatography. 0.26 g (32%) of compound 6.6 was obtained.

[0431] Synthesis of compound 6.7

[0432] Similar to compound 4.9, the said compound was produced with a yield of 95%.

[0433] Synthesis of compound CDK7_845

[0434] Similar to compound CDK7_539, the said compound was produced in a yield of 38%.

[0435] The following compounds were similarly produced:

[0436]

[0437] Example 7. Synthesis of compound CDK7_944

[0438]

[0439] Synthesis of compound 7.3

[0440] Compound 7.1 (2.30 g, 12.9 mmol), compound 7.2 (1.49 g, 12.9 mmol) and Ag2CO3 (1.87 g, 0.065 mmol) in 23 ml of 1,4 - dioxane were stirred at 100 °C for 5 hours. After standard work - up, the product was separated by silica gel column chromatography. 3.00 g (82%) of compound 7.3 was obtained.

[0441] Synthesis of compound 7.4

[0442] 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 at 55 °C for 8 hours. Methanol was removed under reduced pressure, the pH of the mixture was adjusted to 2, the precipitate was filtered off and the residual solvent was removed in vacuo. 2.10 g (97%) of compound 7.4 was obtained.

[0443] Synthesis of compound 7.5

[0444] Compound 7.4 (1.070 g, 4.0 mmol), SOCl2 (0.980 g, 8.0 mmol) and DMF (0.015 g, 0.2 mmol) in 10 ml of dichloromethane were stirred at 40 °C for 2 hours. A 5 - ml solution of 4N HCl in 1,4 - dioxane was added to the mixture and stirred at room temperature for 16 hours. After standard work - up, the product was separated by silica gel column chromatography. 0.540 g (99%) of compound 7.5 was obtained.

[0445] Synthesis of compound 7.6

[0446] Compound 7.5 (0.30 g, 2.09 mmol) was dissolved in 30 ml of THF. To the resulting solution was added NaH (0.125 g, 3.13 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. Then TIPSCl (0.540 g, 2.72 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. After standard workup, the product was separated by silica gel column chromatography. 0.611 g (99%) of compound 7.6 was obtained.

[0447] Synthesis of Compound 7.7

[0448] Compound 7.6 (0.611 g, 1.98 mmol) was dissolved in 20 ml of THF. To the solution was added a solution of NBS (0.356 g, 1.98 mmol) in 10 ml of THF at -78 °C, and the mixture was stirred at -78 °C for 30 minutes and at room temperature for 30 minutes. After standard workup, the product was separated by silica gel column chromatography. 0.735 g (100%) of compound 7.7 was obtained.

[0449] Synthesis of Compound 7.8

[0450] Compound 7.7 (0.625 g, 1.60 mmol) and 30% TBAF in tetrahydrofuran (1.59 g, 1.76 mmol) were mixed in 20 ml of THF. The mixture was stirred at 25 °C for 30 minutes. After standard workup, the product was separated by silica gel column chromatography. 0.240 g (70%) of compound 7.8 was obtained.

[0451] Synthesis of Compound 7.9

[0452] Compound 7.8 (0.240 g, 1.06 mmol) was dissolved in 30 ml of THF; to the resulting solution was added NaH (0.064 g, 1.59 mmol) at 0 °C, and the mixture was stirred for 30 minutes, then benzenesulfonyl chloride (0.227 g, 1.27 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After standard workup, the product was separated by silica gel column chromatography. 0.31 g (82%) of compound 7.9 was obtained.

[0453] Synthesis of Compound 7.10

[0454] Similar to compound 1.3, compound 7.10 was produced in 80% yield.

[0455] Synthesis of Compound 7.11

[0456] Similar to compound 1.5, compound 7.11 was produced in 65% yield.

[0457] Synthesis of Compound 7.12

[0458] Similar to compound 1.6, compound 7.12 was produced with a yield of 97%.

[0459] Synthesis of compound CDK7_944

[0460] Similar to compound CDK7_951, compound CDK7_944 was produced with a yield of 60%.

[0461] Example 8. Synthesis of compound CDK7_929.

[0462]

[0463] Synthesis of compound 8.2

[0464] 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 LiAlH4 in 100 ml of THF while stirring and cooling. The reaction mixture was stirred at 100 °C for 5 hours, cooled to 0 °C, and 50 ml of water was added. After standard workup, the product was separated by silica gel column chromatography. 0.5 g (12%) of compound 8.2 was obtained.

[0465] Synthesis of compound 8.3

[0466] Similar to compound 6.2, compound 8.3 was produced with a yield of 70%.

[0467] Synthesis of compound 8.4

[0468] Similar to compound 6.3, compound 8.4 was produced with a yield of 13%.

[0469] Synthesis of compound 8.5

[0470] Similar to compound 6.4, compound 8.5 was produced with a yield of 56%.

[0471] Synthesis of compound 8.6

[0472] Similar to compound 6.5, compound 8.6 was produced with a yield of 64%.

[0473] Synthesis of compound 8.7

[0474] Similar to compound 6.6, compound 8.7 was produced with a yield of 31%.

[0475] Synthesis of compound 8.8

[0476] Similar to compound 6.7, compound 8.8 was produced with a yield of 95%.

[0477] Synthesis of Compound CDK7_929

[0478] Similar to Compound CDK7_845, Compound CDK7_929 was produced with a yield of 90%.

[0479] Example 9. Synthesis of Compound CDK7_966

[0480]

[0481] Synthesis of Compound 9.2

[0482] 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 was added. The reaction mixture was stirred for 24 hours, the solvent was removed, and the product was separated by silica gel column chromatography. 0.5 g (21%) of Compound 9.2 was obtained.

[0483] Synthesis of Compound 9.3

[0484] Compound 9.2 (0.40 g, 1.48 mmol) was dissolved in 10 ml of dichloromethane, and a solution of NBS (0.38 g, 2.13 mol) in 10 ml of dichloromethane was added. The reaction mixture was stirred for 1 hour. After standard workup, the product was separated by silica gel column chromatography. 0.16 g (31%) of Compound 9.3 was obtained.

[0485] Synthesis of Compound 9.4

[0486] 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)Cl2 (0.01 g, 0.01 mmol) were dissolved in 1 ml of 1,4 - dioxane and heated at 100 °C for 1 hour in a sealed vessel. The reaction mixture was filtered through Celite and the solvent was removed in vacuo. 0.055 g (99%) of the product in the form of a brown oil was obtained.

[0487] Synthesis of Compound 9.5

[0488] Similar to Compound 1.5, Compound 9.5 was produced with a yield of 93%.

[0489] Synthesis of Compound CDK7_966

[0490] Similar to Compound CDK7_951, Compound CDK7_966 was produced with a yield of 69%.

[0491] Example 10. Synthesis of Compound CDK7_972

[0492]

[0493] Synthesis of Compound 10.2

[0494] Similar to Compound 1.3, Compound 10.2 was derived from Compound 10.1 with a yield of 98%.

[0495] Synthesis of Compound 10.3

[0496] Similar to Compound 1.5, Compound 10.3 was produced with a yield of 3%.

[0497] Synthesis of Compound CDK7_972

[0498] Similar to Compound CDK7_951, Compound CDK7_972 was produced with a yield of 33%.

[0499] Example 11. Synthesis of Compound CDK7_921

[0500]

[0501] Synthesis of Compound 11.2

[0502] Similar to Compound 1.3, Compound 11.2 was produced with a yield of 62%.

[0503] Synthesis of Compound 11.3

[0504] Similar to Compound 1.5, Compound 11.3 was produced with a yield of 34%.

[0505] Synthesis of Compound CDK7_921

[0506] Similar to Compound CDK7_951, Compound CDK7_921 was produced with a yield of 34%.

[0507] Example 12. Synthesis of Compound CDK7_901

[0508]

[0509] Synthesis of Compound 12.2

[0510] Similar to Compound 1.3, Compound 12.2 was produced with a yield of 87%.

[0511] Synthesis of Compound 12.3

[0512] Similar to Compound 1.5, Compound 12.3 was produced with a yield of 46%.

[0513] Synthesis of Compound CDK7_901

[0514] Similar to compound CDK7_951, compound CDK7_901 was produced with a yield of 89%.

[0515] Example 13. Synthesis of compound CDK7_766.

[0516]

[0517] Synthesis of compound 13.2

[0518] Boronic ether 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), PPh3 (0.008 g, 0.03 mmol), and Na2CO3 (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 a nitrogen atmosphere for 8 hours. After standard workup, the product was separated by silica gel column chromatography. 0.046 g (68%) of compound 13.2 was obtained.

[0519] Synthesis of compound CDK7_766

[0520] Compound 13.2 (0.025 g, 0.05 mmol) was dissolved in 3 ml of dichloromethane, 0.2 ml of TFA was added, and the mixture was stirred at 20 °C for 18 hours. The solvent was removed in vacuo, and the product was separated by preparative HPLC. 0.008 g (40%) of compound CDK7_766 was obtained.

[0521] Example 14. Synthesis of compounds CDK7_809, CDK7_810, CDK7_811, CDK7_829, CDK7_830, CDK7_897

[0522]

[0523] Synthesis of compound 14.1

[0524] Method a:

[0525] NaH (0.014 g, 0.302 mmol) was added to a solution of indole (0.031 g, 0.276 mmol) in 2 ml of DMF, and the mixture was stirred for 30 minutes. A solution of pyrimidine 1.4 (0.100 g, 0.263 mmol) in 1 ml of DMF was added, and the reaction mixture was stirred for 20 h. Saturated NaHCO3 solution was added, and the mixture was extracted with ethyl acetate. The product was separated by silica gel column chromatography using a mixture of hexane - ethyl acetate (92:8) as the eluent. 0.081 mg (67%) of compound 14.1 was obtained.

[0526] Method b: Similar to Method A, using K2CO3 instead of NaH and MeCN instead of DMF; instead of stirring at room temperature, the reaction mixture was heated while boiling until the initial reagents disappeared.

[0527] Synthesis of compound CDK7_809

[0528] Method a:

[0529] Compound 14.1 (0.063 g, 0.137 mmol) was dissolved in a 1,4 - dioxane solution of 7.65 M HCl (1.5 ml). The reaction mixture was stirred at 20 °C for 18 h. The solvent was removed in vacuo, the residue was treated with ether, the precipitate was filtered off, and the residual solvent was removed in vacuo. 0.014 g (24%) of compound CDK7_809 as the hydrochloride salt was obtained.

[0530] Method b was similar to Method A, using TFA instead of the 1,4 - dioxane solution of 7.65 M HCl and dichloromethane as the solvent.

[0531] The following compounds were produced similarly:

[0532]

[0533] Example 15. Synthesis of compounds CDK7_548, CDK7_550, CDK7_735, CDK7_754, CDK7_888, CDK7_891, CDK7_898, CDK7_900, CDK7_903, CDK7_904

[0534]

[0535] Synthesis of compound 15.2

[0536] DIPEA (0.214 g, 1.66 mmol) was added to a solution of N-(2-hydroxyphenyl)carbamic acid tert-butyl ester (0.289 g, 1.38 mmol) in 3 ml of anhydrous ethanol. A solution of compound 15.1 (0.300 g, 1.38 mmol) in 2 ml of anhydrous ethanol was added to the resulting mixture at 0 °C. The mixture was stirred at 0 °C for 30 minutes and then at room temperature for 16 hours. After standard workup, the product was separated by silica gel column chromatography. Product 15.2 (0.45 g, 84%) was obtained.

[0537] Synthesis of compound 15.3

[0538] Compound 15.2 (0.445 g, 1.14 mmol), tert-butyl 3(S)-3-aminopiperidinecarboxylate (0.229 g, 1.14 mmol), and DIPEA (0.221 mg, 1.71 mmol) in 2 ml of i-PrOH were stirred at room temperature for 16 hours. After standard workup, the product was separated by silica gel column chromatography and then by preparative TLC. 0.057 g (9%) of compound 15.3 was obtained.

[0539] Synthesis of compound CDK7_548

[0540] A 1,4-dioxane solution of 1 ml of 7.65 M HCl was added to a solution of compound 15.3 (0.057 g, 0.107 mmol) in 1 ml of ethanol. The mixture was stirred at room temperature for 12 hours, the volatile components were removed, and the residue was recrystallized from MTBE:acetone:i-PrOH (4:1:1). 0.015 g (yield 31%) of compound CDK7_548 as the hydrochloride salt was obtained.

[0541] The following compounds were similarly produced:

[0542]

[0543]

[0544] Reaction conditions: Stage 1a: DIPEA, EtOH, room temperature; b: DIPEA, MeCN, room temperature or 40 °C

[0545] Stage 2a: DIPEA, i-PrOH, room temperature; b: DIPEA, i-PrOH, boiling; c: DIPEA, MeCN, room temperature; d: DIPEA, MeCN, boiling.

[0546] Stage 3: a: HCl, 1,4-dioxane; b: TFA, dichloromethane.

[0547] Example 16. Preparation of Compound CDK7_991

[0548]

[0549] Synthesis of Compound 16.2

[0550] Similar to Compound 4.2, it is produced from Compound 16.1. Yield: 64%.

[0551] Synthesis of Compound 16.3

[0552] Similar to Compound 1.2, Compound 16.3 is produced with a yield of 92%.

[0553] Synthesis of Compound 16.4

[0554] Similar to Compound 1.3, Compound 16.4 is produced with a yield of 38%.

[0555] Synthesis of Compound 16.5

[0556] Similar to Compound 1.5, Compound 16.5 is produced with a yield of 32%.

[0557] Synthesis of Compound 16.6

[0558] Similar to Compound 4.5, Compound 16.6 is produced with a yield of 99%.

[0559] Synthesis of Compound CDK7_991

[0560] Similar to Compound CDK7_951, Compound CDK7_991 is produced with a yield of 26%.

[0561] Example 17. Preparation of Compound CDK7_1017

[0562]

[0563] Synthesis of Compound 17.1

[0564] NaH (60% paraffin oil suspension) (0.087 g, 2.17 mmol) was added to a solution of 4-bromo-N,N-dimethyl-1H-pyrrole-2-carboxamide (0.332 g, 1.45 mmol) in 15 ml of THF at 0 °C. The reaction mixture was stirred for 30 minutes, and CH3I (0.270 g, 1.88 mmol) was added. The reaction mixture was heated to room temperature and stirred for 24 hours. After standard workup, the product was separated by silica gel column chromatography. 0.33 g (99%) of Compound 17.1 was obtained.

[0565] Synthesis of Compound 17.2

[0566] Similar to compound 1.3, compound 17.2 was produced with a yield of 98%.

[0567] Synthesis of compound 17.3

[0568] Similar to compound 1.5, compound 17.3 was produced with a yield of 40%.

[0569] Synthesis of compound CDK7_1017

[0570] Similar to compound CDK7_951, compound CDK7_1017 was produced with a yield of 10%.

[0571] Example 18. Synthesis of compound CDK7_953.

[0572]

[0573] Synthesis of compound 18.2

[0574] Similar to compound 8.3, compound 18.2 was produced from acid 2.1 and amine 18.1 with a yield of 71%.

[0575] Synthesis of compound 18.3

[0576] 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 at 20 °C for 18 hours, and the volatile components were removed under vacuum. Polyphosphoric acid (PPA) (9.34 g, 36.2 mmol) and phosphoric anhydride (1.05 g, 3.62 mmol) were added to the residue, and the mixture was heated at 110 °C for 3 hours with stirring. 10 g of ice was added, and the mixture was stirred for 2 hours. The precipitate was filtered out, washed with water, and the residual solvent was removed under vacuum. 0.32 g (69%) of compound 18.3 was obtained.

[0577] Synthesis of compound 18.4

[0578] While cooling in an ice bath, 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. The reaction mixture was stirred at the same temperature for 1 hour and then at 20 °C for 72 hours. After standard workup, the product was separated by silica gel column chromatography. 0.076 g (88%) of compound 18.4 was obtained.

[0579] Synthesis of compound 18.5

[0580] A 1,4-dioxane solution of 4N HCl (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 separated by silica gel column chromatography. 0.14 g (77%) of product 18.5 was obtained.

[0581] Synthesis of compound 18.6

[0582] TEA (0.52 g, 5.00 mmol), DMAP (0.024 g, 0.2 mmol) and benzenesulfonyl chloride (0.21 g, 1.18 mmol) were added to a solution of compound 18.5 (0.14 g, 0.49 mmol) in 6 ml of dichloromethane, and the reaction mixture was stirred at 20 °C for 40 h. After standard workup, the product was separated by silica gel column chromatography. 0.15 g (78%) of product 18.6 was obtained.

[0583] Synthesis of compound 18.7

[0584] Compound 18.7 was synthesized from 0.15 g of compound 18.6 similar to 6.5. After boration, the reaction mixture was filtered through a silica gel layer, the solvent was removed, and 0.54 g of product in the form of a dark red oil was obtained, which contained 30% of the target compound 18.7. The product was used in the next stage without further purification.

[0585] Synthesis of compound 18.8

[0586] Compound 18.7 (0.54 g, 0.38 mmol), pyrimidine 1.4 (0.111 g, 0.29 mmol), Na2CO3 (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 mixed in a nitrogen atmosphere at 100 °C for 3 h. After standard workup, the product was separated by silica gel column chromatography. 0.081 g (43%) of compound 18.8 was obtained.

[0587] Synthesis of compound 18.9

[0588] Compound 18.9 was produced from 0.081 g of compound 18.8 similar to compound 6.7 with a yield of 91%.

[0589] Synthesis of compound 18.10

[0590] 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. Hydrogenation was carried out at atmospheric pressure for 3 h, the reaction material was filtered through a layer of diatomaceous earth, and the solvent was removed in vacuo. 0.033 g (54%) of compound 18.10 was obtained.

[0591] Synthesis of compound CDK7_953

[0592] 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 material was stirred at 20 °C for 18 h, the volatile components were removed in vacuo, and the product was separated by preparative HPLC. 0.009 g (36%) of compound CDK7_953 was obtained.

[0593] Example 19. Synthesis of compound 19.6.

[0594]

[0595] Synthesis of compound 19.2

[0596] Aldehyde 19.1 (5.00 g, 34.9 mmol), 2,2-dimethoxyethan-1-amine (3.87 ml, 34.9 mmol), and 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 separated by silica gel column chromatography. 6.31 g (80%) of compound 19.2 was obtained.

[0597] Synthesis of compound 19.3

[0598] Oxalyl chloride (0.451 ml, 5.26 mmol) and a drop of DMF were added to a suspension of 4-bromo-1H-pyrrole-2-carboxylic acid (0.5 g, 2.63 mmol) in 5 ml of dichloromethane, and the mixture was stirred at room temperature for 2 h. The volatile components were removed in vacuo, and at 0 °C, it was added to a solution of compound 19.2 (0.592 g, 2.63 mmol) and TEA in 5 ml of dichloromethane, and the mixture was stirred for 1 h. After standard workup, the product was separated by silica gel column chromatography. 1.00 g (95%) of compound 19.3 was obtained.

[0599] Synthesis of compound 19.4

[0600] Compound 19.3 (2.68 g, 6.41 mmol) was dissolved in 15 ml of TFA and stirred for 6 days. The volatile components were removed in vacuo, and the product was separated by column chromatography. 1.78 g (83%) of compound 19.4 was obtained.

[0601] Synthesis of Compound 19.5

[0602] Similar to Compound 6.4, Compound 19.5 was produced in a yield of 83%.

[0603] Synthesis of Compound 19.6

[0604] Compound 19.5 (0.440 g, 0.880 mmol) was dissolved in 2 ml of TFA in a sealed vessel and heated at 100 °C for 30 hours while stirring. The volatile components were removed and the product was separated by column chromatography. 0.22 g (71%) of Compound 19.6 was obtained.

[0605] Example 20. Synthesis of Compound CDK7_1105

[0606]

[0607] Synthesis of Compound 20.1

[0608] Compound 19.6 (0.040 g, 0.110 mmol) in 4 ml of tetrahydrofuran, cyclopropylboronic acid (0.029 g, 0.330 mmol), pyridine (0.018 ml, 0.220 mmol), and triethylamine (0.081 ml, 0.550 mmol) were heated in a microwave reactor at 150 °C for 1 hour. After standard workup, the product was separated by silica gel column chromatography. 0.042 g (98%) of Compound 20.1 was obtained.

[0609] Synthesis of Compound 20.2

[0610] Compound 20.1 (0.042 g, 0.100 mmol), (BPin)2 (0.039 g, 0.150 mmol), KOAc (0.051 g, 0.500 mmol), and Pd(dppf)Cl2 (0.015 g, 0.020 mmol) were dissolved in 2 ml of 1,4-dioxane and heated in a sealed vessel at 100 °C for 1 hour. The reaction mixture was filtered through celite and the solvent was removed in vacuo. 0.04 g (91%) of the product in the form of a brown oil was obtained.

[0611] Synthesis of Compound 20.3

[0612] Compound 20.2 (0.04 g, 0.090 mmol), pyrimidine 1.4 (0.034 g, 0.090 mmol), Na2CO3 (0.019 g, 0.180 mmol), and Pd(dppf)Cl2 (0.010 g, 0.010 mmol) in a mixture of 2 ml of 1,4-dioxane and 0.5 ml of water were stirred at 100 °C for 1 hour under a nitrogen atmosphere. After standard workup, the product was separated by silica gel column chromatography. 0.026 g (44%) of compound 20.3 was obtained.

[0613] Synthesis of compound 20.4

[0614] Compound 20.3 (0.026 g, 0.04 mmol) and NaOH (0.105 g, 2.60 mmol) in a mixture of 5 ml of methanol and 0.5 ml of water were stirred at room temperature for 3 hours, filtered through diatomaceous earth, and the solvent was removed in vacuo. 0.02 g (95%) of compound 20.4 was obtained.

[0615] Synthesis of compound CDK7_1105

[0616] Compound 20.4 (0.020 g, 0.04 mmol) was dissolved in 2 ml of TFA, and the reaction mixture was stirred at 20 °C for 18 hours. The volatile components were removed in vacuo, evaporated again with dichloromethane, and the volatile components were removed in vacuo. The product was separated by preparative HPLC. 0.017 g (47%) of compound CDK7_1105 was obtained.

[0617] Example 21. Synthesis of compound CDK7_1062.

[0618]

[0619] Synthesis of compound 21.1

[0620] While stirring at -78 °C under a nitrogen atmosphere, a solution of 2.23 ml (5.56 mmol) of 2.5 M n-butyllithium in hexane was added to a solution of 2-chloropyrimidine (0.5 g, 4.28 mmol) in 10 ml of THF. The mixture was stirred for 30 minutes, then tributyltin hydride (1.42 ml, 5.14 mmol) was added and stirring was continued for 30 minutes. The temperature was adjusted to room temperature and the mixture was stirred at room temperature for 12 hours. After standard workup, the product was separated by silica gel column chromatography. 0.55 g (35%) of compound 21.1 was obtained.

[0621] Synthesis of compound 21.2

[0622] Compound 21.1 (0.089 g, 0.240 mmol) in 20.1 ml of DMF, 1-phenylsulfonyl-4-bromo-2-iodo-1H-pyrrole (0.1 g, 0.240 mmol), copper(I) iodide (0.014 g, 0.070 mmol), Pd(PPh3)4 (0.028 g, 0.020 mmol) were heated in a sealed vessel under an inert atmosphere at 120 °C for 4 hours. After standard workup, the product was separated by silica gel column chromatography. 0.035 g (40%) of compound 21.2 was obtained.

[0623] Synthesis of compound 21.3

[0624] Compound 21.2 (0.051 g, 0.140 mmol), (BPin)2 (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 and heated in a sealed vessel at 110 °C for 10 hours. The reaction mixture was filtered through Celite and the solvent was removed in vacuo. 0.058 g (99%) of compound 21.3 was obtained as a brown oil.

[0625] Synthesis of compound 21.4

[0626] Compound 21.3 (0.058 g, 0.140 mmol), pyrimidine 1.4 (0.053 g, 0.140 mmol), Na2CO3 (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 a nitrogen atmosphere at 110 °C for 2 hours. After standard workup, the product was separated by silica gel column chromatography. 0.044 g (50%) of compound 21.4 was obtained.

[0627] Synthesis of compound 21.5

[0628] Similar to compound 6.7, compound 21.5 was produced in 99% yield.

[0629] Synthesis of compound CDK7_1062

[0630] Similar to compound 6.7, compound CDK7_1062 was produced in 37% yield.

[0631] Example 22. Synthesis of compound CDK7_1058

[0632]

[0633] Synthesis of Compound 22.2

[0634] Compound 19.6 (0.12 g, 0.34 mmol) in 2 ml of DMF, 2-bromothiazole (0.1 g, 0.6 mmol), CuI (0.06 g, 0.3 mmol), and K2CO3 (0.09 g, 0.65 mmol) were heated in a sealed vessel with stirring 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 separated by column chromatography. 0.1 g of a mixture in the form of an oil was obtained. According to HPLC, the content of Compound 22.1 was 60% (0.06 g, 60%). 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 were added to this mixture. The reaction mixture was stirred at room temperature for 18 h. After standard workup, the product was separated by silica gel column chromatography. 0.015 g (16%) of Compound 22.2 was obtained.

[0635] Synthesis of Compound CDK7_1058

[0636] 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)Cl2 (0.01 g, 0.01 mmol), and 1 ml of 1,4-dioxane were mixed, and the mixture was heated in a sealed vessel at 100 °C for 1 h. After cooling, the reaction mixture was filtered through diatomaceous earth, and the solvent was removed in vacuo. Pyrimidine 1.4 (0.011 g, 0.03 mmol), Na2CO3 (0.006 g, 0.06 mmol), and 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 were added to the residue containing 22.3. The resulting mixture was stirred in a nitrogen atmosphere at 110 °C for 2 h, the reaction mixture was filtered through diatomaceous earth, 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 mass was stirred at 60 °C for 6 h, the solvent was removed in vacuo, water was added to the residue until completely dissolved (1 ml), acidified to pH 4 with 10% citric acid solution, extracted with ethyl acetate, and the volatile components were removed in vacuo. The residue was dissolved in 1 ml of TFA, the reaction mass was stirred at 20 °C for 18 h, the volatile components were removed in vacuo, and the product was separated by preparative HPLC. 1.3 mg (total yield: 7%) of Compound CDK7_1058 was obtained.

[0637] Example 23. Synthesis of Compounds CDK7_1060 and CDK7_1103.

[0638]

[0639] Synthesis of Compound 23.2

[0640] A mixture of 4-bromo-1H-pyrrole-2-carbonitrile (0.40 g, 2.29 mmol) (23.1), NH2OH·HCl (0.804 g, 11.45 mmol) and TEA (1.6 ml, 11.45 mmol) in 20 ml of ethanol was boiled for 1 hour while stirring. After standard work-up and without further purification, 0.465 g (99%) was produced and used in the next step.

[0641] Synthesis of Compound 23.3

[0642] EDC (0.137 g, 0.71 mmol) and 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 for 1 hour at room temperature under a nitrogen atmosphere. Then Compound 23.2 (0.100 g, 0.47 mmol) was added to 3 ml of 1,4-dioxane and stirred for 12 hours at room temperature. Volatile components were removed in vacuo. The intermediate was produced by column chromatography, dissolved in 2 ml of 1,4-dioxane, heated in a microwave reactor at 130 °C for 2 hours, and volatile components were removed in vacuo. The product was separated using silica gel column chromatography. 0.025 g (23%) of Compound 23.3 was obtained.

[0643] Synthesis of Compound 23.4

[0644] Compound 23.4 was produced in a yield of 71% similar to Compound 1.2.

[0645] Synthesis of Compound 23.5

[0646] 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)Cl2 (0.009 g, 0.01 mmol) in 1 ml of 1,4-dioxane were heated at 100 °C for 4 hours under a nitrogen atmosphere while stirring. After standard work-up, the product was separated using silica gel column chromatography. 0.034 g (68%) of Compound 23.5 was obtained.

[0647] Synthesis of Compound 23.6

[0648] Similar to compound 20.3, compound 23.6 was produced with a yield of 41%.

[0649] Synthesis of compound CDK7_1060

[0650] 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 hours. After standard workup, the residue containing compound 23.7 was dissolved in 1 ml of dichloromethane, 0.058 ml of TFA was added, and the reaction mixture was stirred at 20 °C for 18 hours. Volatile components were removed in vacuo, and the product was separated by preparative HPLC. 0.008 g (66%) of compound CDK7_1060 was obtained.

[0651] Compound CDK7_1103 was similarly produced using cyclopropylformic acid with an overall yield of 1%.

[0652] Example 24. Synthesis of compounds CDK7_1061 and CDK7_533.

[0653]

[0654] Synthesis of compound 24.2

[0655] A mixture of pyridine 24.1 (0.304 g, 0.82 mmol), 1-(phenylsulfonyl)-4-bromo-2-iodo-1H-pyrrole (0.228 g, 0.55 mmol), CuI (0.032 g, 0.16 mmol), Pd(PPh3)4 (0.064 g, 0.06 mmol) in 5 ml of 1,4-dioxane was heated at 100 °C for 4 hours with stirring under a nitrogen atmosphere. After standard workup, the product was separated by silica gel column chromatography. 0.054 g (32%) of compound 24.2 was obtained.

[0656] Synthesis of compound 24.3

[0657] 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)Cl2 (0.04 g, 0.05 mmol) in 2 ml of 1,4-dioxane were heated at 100 °C for 4 hours with stirring under a nitrogen atmosphere. After standard workup, the product was separated by silica gel column chromatography. 0.074 g (99%) of compound 24.3 was obtained.

[0658] Synthesis of compound 24.4

[0659] Compound 3.3 (0.074 g, 0.18 mmol), pyrimidine 1.4 (0.069 g, 0.18 mmol), Na2CO3 (0.058 g, 0.54 mmol), and Pd(dppf)Cl2 (0.04 g, 0.05 mmol) in a mixture of 2 ml of 1,4-dioxane and 1 ml of water were stirred at 100 °C for 2 h under a nitrogen atmosphere. After standard workup, the reaction product was separated by silica gel column chromatography. 0.04 g (35%) of compound 24.4 was obtained.

[0660] Synthesis of compound 24.5

[0661] Compound 24.4 (0.04 g, 0.06 mmol) and 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 workup, 0.029 g (99%) of compound 24.5 was obtained.

[0662] Synthesis of compound CDK7_1061

[0663] Similar to compound CDK7_1060, compound CDK7_1061 was produced in 44% yield.

[0664] Compound CDK7_533 was similarly produced using the corresponding boronic acid (conditions similar to the synthesis of compound 21.4) in an overall yield of 22%.

[0665] Example 25. Synthesis of compound CDK7_1000

[0666]

[0667] Synthesis of compound 25.2

[0668] At 0 °C, NaH (0.045 g, 1.13 mmol) was added to a solution of 4-bromo-1H-pyrrole-2-carbonitrile 25.1 (0.130 g, 0.750 mmol) in 3 ml of tetrahydrofuran. The mixture was stirred for 30 minutes, then 0.217 ml (1.2 mmol) of SEMCl was added, and the mixture was stirred at room temperature for 1 hour. After standard workup, the volatile components were removed under vacuum. The residue was dissolved in 2.5 ml of DMF, then NaN3 (0.058 g, 0.88 mmol) and NH4Cl (0.047 g, 0.88 mmol) were added, and the mixture was heated at 160 °C for 2 hours with stirring in a microwave synthesis vial. 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 hours. The volatile components were removed, and the product was separated by column chromatography. (BPin)2 (0.168 g, 0.66 mmol), KOAc (0.134 g, 1.32 mmol), and Pd(dppf)Cl2 (0.025 g, 0.03 mmol) in 2 ml of 1,4-dioxane were added to the residue containing compound 25.2, and the mixture was heated at 100 °C for 4 hours with stirring under a nitrogen atmosphere. After standard workup, the reaction mixture was filtered through a silica gel layer, and the volatile components 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, then pyrimidine 1.4 (0.118 g, 0.310 mmol), Na2CO3 (0.100 g, 0.930 mmol), and Pd(dppf)Cl2 (0.069 g, 0.090 mmol) were added, and the mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere. After standard workup, the reaction mixture was filtered through a silica gel layer, and the volatile components were removed. 1 ml of dichloromethane and 0.07 ml of TFA were added to the residue containing compound 25.4, and the reaction mixture was stirred at 20 °C for 18 hours. The volatile components were removed under vacuum. 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 hours. After standard workup, the reaction product was separated by preparative HPLC. Compound CDK7_1000 was obtained.

[0669] Example 26. Synthesis of Compound CDK7_1124

[0670]

[0671] Synthesis of Compound 26.2

[0672] At 0 °C, 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, and the mixture was stirred at 0 °C for 15 minutes. The solvent was removed in vacuo, and the product was isolated by recrystallization. 0.446 g (50%) of compound 26.2 was obtained.

[0673] Synthesis of compound 26.3

[0674] At 0 °C, NaH (0.069 g, 1.72 mmol) was added to a solution of compound 26.2 (0.200 g, 1.06 mmol) in 10 ml of THF and stirred for 30 minutes. Benzenesulfonyl chloride (0.222 ml, 1.72 mmol) was added and the mixture was stirred at room temperature for 1 hour. After standard workup, the product was isolated by silica gel column chromatography. 0.270 g (75%) of compound 26.3 was obtained.

[0675] Synthesis of compound 26.4

[0676] Compound 26.3 (0.246 g, 0.78 mmol), 1,2-diaminobenzene (0.089 g, 0.78 mmol), and Na2S2O5 (0.148 g, 0.78 mmol) in 6 ml of DMF were stirred in a microwave reactor at 80 °C for 25 minutes. After standard workup, the reaction product was isolated by recrystallization. 0.100 g (32%) of compound 26.4 was obtained.

[0677] Synthesis of compound 26.5

[0678] At 0 °C, NaH (0.015 g, 0.38 mmol) was added to a solution of compound 26.4 (0.100 g, 0.25 mmol) in 5 ml of THF (or DMF) and stirred for 20 minutes. Iodomethane (0.045 g, 0.30 mmol) was added and the mixture was stirred at room temperature for 18 hours. After standard workup, the product was isolated by silica gel column chromatography. 0.103 g (99%) of compound 26.5 was obtained.

[0679] Synthesis of compound 26.6

[0680] Compound 26.5 (0.110 g, 0.250 mmol), (BPin)2 (0.130 g, 0.500 mmol), KOAc (0.076 g, 0.75 mmol), and Pd(dppf)Cl2 (0.056 g, 0.07 mmol) were mixed in 3 ml of 1,4-dioxane and heated at 100 °C for 4 h in a sealed vessel. After cooling, the reaction mixture was filtered through celite and the solvent was removed in vacuo. Pyrimidine 1.4 (0.095 g, 0.250 mmol), Na2CO3 (0.08 g, 0.750 mmol), and Pd(dppf)Cl2 (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 at 110 °C for 4 h in a nitrogen atmosphere, the reaction mixture was filtered through celite, and the solvent was removed in vacuo. The product was separated by silica gel column chromatography. 0.042 g (25%) of compound 26.6 was obtained.

[0681] Synthesis of compound 26.7

[0682] Compound 26.6 (0.042 g, 0.060 mmol) and 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 give 0.028 g (88%) of compound 26.7.

[0683] Synthesis of compound CDK7_1124

[0684] 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 mass was stirred at room temperature for 16 h. The volatile components were removed in vacuo. The product was separated by preparative HPLC. 0.008 g (36%) of compound CDK7_1124 was obtained.

[0685] Example 27. Synthesis of compound CDK7_1021

[0686]

[0687] Synthesis of compound 27.1

[0688] Compound 18.3 (0.250 g, 0.830 mmol) was dissolved in 15 ml of THF. To the resulting solution was added NaH (0.037 g, 0.910 mmol) at 0 °C, and the mixture was stirred for 10 minutes. Benzenesulfonyl chloride (0.139 ml, 1.08 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After standard workup, the product was separated by silica gel column chromatography. 0.131 g (40%) of compound 27.1 was obtained.

[0689] Synthesis of compound 27.2

[0690] 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)Cl2 (0.023 g, 0.030 mmol) in 5 ml of 1,4-dioxane were stirred in a nitrogen atmosphere at 100 °C for 8 hours. After standard workup, the reaction product was separated by silica gel column chromatography. 0.06 g (43%) of compound 27.2 was obtained.

[0691] Synthesis of compound 27.3

[0692] Compound 27.3 was produced similar to compound 4.3 in a yield of 23%.

[0693] Synthesis of compound CDK7_1021

[0694] Compound 27.3 (0.021 g, 0.03 mmol), NaOH (0.012 g, 0.03 mmol) in 0.5 ml of ethanol and 0.5 ml of H2O were stirred at room temperature for 2 hours. After standard workup, the residue containing compound 27.4 was dissolved in 1 ml of dichloromethane, 0.093 ml of TFA was added, and the mixture was stirred at room temperature for 20 hours. After standard workup, the product was separated by preparative HPLC. 0.006 g (35%) of compound CDK7_1021 was obtained.

[0695] Example 28. Synthesis of compound CDK7_1121

[0696]

[0697] Synthesis of compound 28.1

[0698] Compound 19.6 (0.071 g, 0.190 mmol), oxolan-4-yl methanesulfonate (0.070 g, 0.380 mmol), and Cs2CO3 (0.125 g, 0.380 mmol) in a mixture of 1 mL of DMF and 1 mL of dimethoxyethane were heated at 90 °C for 40 h with stirring. After standard workup, the product was separated by silica gel column chromatography. 0.058 g (70%) of compound 28.1 was obtained.

[0699] Synthesis of compound 28.2

[0700] Compound 28.1 (0.058 g, 0.120 mmol), (BPin)2 (0.050 g, 0.190 mmol), KOAc (0.039 g, 0.380 mmol), and Pd(dppf)Cl2 (0.009 g, 0.010 mmol) were dissolved in 1 mL of 1,4-dioxane and heated at 110 °C for 4 h in a sealed vessel. After standard workup, the product was separated by column chromatography. 0.049 g (85%) of compound 28.2 was obtained.

[0701] Synthesis of compound 28.3

[0702] Compound 28.2 (0.049 g, 0.100 mmol), pyrimidine 1.4 (0.046 g, 0.120 mmol), Na2CO3 (0.040 g, 0.370 mmol), and 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 at 110 °C for 1 h in a nitrogen atmosphere. After standard workup, the product was separated by silica gel column chromatography. 0.040 g (57%) of compound 28.3 was obtained.

[0703] Synthesis of compound CDK7_1121

[0704] Compound 28.3 (0.040 g, 0.060 mmol) and NaOH (0.121 g, 3.00 mmol) in a mixture of 1 mL of ethanol and 1 mL of H2O were stirred at room temperature for 2 h. After standard workup, the residue containing compound 28.4 was dissolved in 3 mL of dichloromethane, 0.696 mL of TFA was added, and the mixture was stirred at room temperature for 18 h. After standard workup, the product was separated by preparative HPLC. 0.003 g (11%) of compound CDK7_1121 was obtained.

[0705] Example 29. Synthesis of compound 29.5.

[0706]

[0707] Synthesis of Compound 29.1

[0708] 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 hour. Then the volatile components were removed, the residue was dissolved in 30 ml of dichloromethane, and the solution was added dropwise to a solution of methyl 3-aminopropionate hydrochloride (4.11 g, 29.4 mmol) and TEA (16.6 ml, 113 mmol) in 30 ml of dichloromethane at 0 °C. The mixture was stirred at room temperature for 1 hour. After standard workup, the product was separated by silica gel column chromatography. 5.70 g (92%) of Compound 29.1 was obtained.

[0709] Synthesis of Compound 29.2

[0710] Compound 29.1 (3.90 g, 12.8 mmol) was dissolved in 40 ml of ethanol, and NaOH (1.08 g, 26.8 mmol) and 20 ml of water were added. The reaction mixture was stirred at room temperature for 18 hours. After standard workup, 2.8 g (84%) of Product 29.2 was obtained.

[0711] Synthesis of Compound 29.3

[0712] A mixture of Compound 29.2 (4.07 g, 14.8 mmol), PPA (38.2 g, 148 mmol), and P2O5 (4.29 g, 14.8 mmol) was stirred at 110 °C for 2 hours. After standard workup, 3.51 g (97%) of Compound 29.3 was obtained.

[0713] Synthesis of Compound 29.4

[0714] Compound 29.3 (2.04 g, 6.72 mmol) and triethylsilane (3.16 g, 26.9 mmol) in 31 ml of TFA were stirred at room temperature for 20 hours. After standard workup, 1.22 g (79%) of Compound 29.4 was obtained.

[0715] Synthesis of Compound 29.5

[0716] Similar to Compound 2.3, Compound 29.5 was produced with a yield of 50%.

[0717] Example 30. Synthesis of Compound CDK7_955.

[0718]

[0719] Synthesis of Compound 30.1

[0720] Compound 29.5 (0.346 g, 0.920 mmol) in 14 ml of 1,4-dioxane, 4-iodo-1-methyl-1H-pyrazole (1.17 g, 5.52 mmol), CuI (0.088 g, 0.460 mmol), (1R,2R)-cyclohexane-1,2-diamine (0.107 g, 0.920 mmol) were heated at 120 °C for 7 hours while stirring. After standard workup, the product was separated by column chromatography. 0.247 g (60%) of compound 30.1 was obtained.

[0721] Synthesis of compound 30.2

[0722] Compound 30.1 (0.130 g, 0.290 mmol), (BPin)2 (0.221 g, 0.870 mmol), KOAc (0.132 g, 1.30 mmol), Pd(dppf)Cl2 (0.065 g, 0.09 mmol) were dissolved in 9 ml of 1,4-dioxane and heated at 110 °C for 12 hours in a sealed vessel. After standard workup, the product was separated by column chromatography. 0.141 g (98%) of compound 34.2 was obtained.

[0723] Synthesis of compound 30.3

[0724] Compound 30.2 (0.225 g, 0.12 mmol), pyrimidine 1.4 (0.059 g, 0.160 mmol), Na2CO3 (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 at 100 °C for 10 hours in a nitrogen atmosphere. After standard workup, the product was separated by silica gel column chromatography. 0.060 g (70%) of compound 30.3 was obtained.

[0725] Synthesis of compound 30.4

[0726] Compound 30.3 (0.026 g, 0.04 mmol) and NaOH (0.112 g, 2.80 mmol) in a mixture of 5 ml of ethanol and 5 ml of water were stirred at room temperature for 1 hour, filtered through diatomaceous earth, and the solvent was removed in vacuo. 0.08 g (99%) of compound 30.4 was obtained.

[0727] Synthesis of compound CDK7_955

[0728] 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 hours. After standard workup, the product was separated by preparative HPLC. 0.043 g (65%) of compound CDK7_955 was obtained.

[0729] Synthesis of Compound 30.5

[0730] Compound 29.5 (0.201 g, 0.53 mmol) in 5 ml of toluene, 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) were stirred at 100 °C for 12 hours. After standard workup, the product was separated by silica gel column chromatography. 0.098 g (44%) of product 30.5 was obtained.

[0731] Synthesis of Compound 30.6

[0732] 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)Cl2 (0.139 g, 0.190 mmol) were dissolved in 30 ml of 1,4-dioxane and heated in a sealed vessel at 100 °C for 24 hours. After standard workup, the product was separated by column chromatography. 0.700 g (66%) of compound 30.6 was obtained.

[0733] Example 31. Synthesis of Compounds CDK7_1122 and CDK7_1225.

[0734]

[0735] Synthesis of Compound 31.2

[0736] Compound 30.2 (0.216 g, 0.440 mmol), pyrimidine 31.1 (0.125 g, 0.390 mmol), Na2CO3 (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 at 120 °C for 4 hours under a nitrogen atmosphere. After standard workup, the product was separated by silica gel column chromatography. 0.114 g (46%) of compound 31.2 was obtained.

[0737] Synthesis of Compound CDK7_1122

[0738] Compound 31.2 (0.171 g, 0.270 mmol) in 2 ml of ethanol and 1 ml of water, and NaOH (0.109 g, 2.70 mmol) were stirred at room temperature for 4 hours. After standard workup, the product was separated by preparative HPLC. 0.028 g (21%) of compound CDK7_1122 was obtained.

[0739] Compound CDK7_1225 was produced similarly with an overall yield of 69%.

[0740] Example 32. Synthesis of compound CDK7_1123.

[0741]

[0742] Synthesis of compound 32.2

[0743] Compound 32.2 was produced similarly to compound 4.2 with a yield of 79%.

[0744] Synthesis of compound 32.3

[0745] Amide 32.2 (7.34 g, 20.5 mmol) and 27 ml of methanesulfonic acid (410 mmol) were stirred at 20 °C for 16 hours. After standard workup, 4.98 g (83%) of compound 32.3 was obtained.

[0746] Synthesis of compound 32.4

[0747] DIPEA (6.68 g, 51.2 mmol), DMAP (1.05 g, 8.53 mmol), and benzenesulfonyl chloride (4.87 g, 27.3 mmol) were added to a solution of pyrrolopyridinone 32.3 (5.00 g, 17.1 mmol) in 100 ml of dichloromethane, and the reaction mixture was stirred at room temperature for 18 hours. After standard workup, the product was separated by silica gel column chromatography. 3.00 g (41%) of compound 32.4 was obtained.

[0748] Synthesis of compound 32.5

[0749] Compound 32.4 (1.50 g, 3.46 mmol), (BPin)2 (1.76 g, 6.92 mmol), KOAc (1.05 g, 10.4 mmol), and Pd(dppf)Cl2 (0.258 g, 0.350 mmol) in 20 ml of 1,4-dioxane were heated at 100 °C for 3 hours with stirring under a nitrogen atmosphere. After standard workup, the product was separated by silica gel column chromatography. 1.60 g (96%) of compound 32.5 was obtained.

[0750] Synthesis of compound 32.6

[0751] Compound 32.5 (0.117 g, 0.230 mmol), pyrimidine 31.1 (0.110 g, 0.210 mmol), Na2CO3 (0.067 g, 0.630 mmol), and 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 at 100 °C for 18 h under a nitrogen atmosphere. After standard workup, 0.130 g (98%) of compound 32.6 was obtained.

[0752] Synthesis of compound CDK7_1123

[0753] Compound 32.6 (0.600 g, 0.960 mmol) and NaOH (0.384 g, 9.60 mmol) in a mixture of 18 ml of ethanol and 3 ml of water were stirred at 45 °C for 3 h. After standard workup, the product was separated by preparative HPLC. 0.106 g (23%) of compound CDK7_1123 was obtained.

[0754] Example 33. Synthesis of compounds CDK7_1176, CDK7_1172, CDK7_1177, CDK7_1188.

[0755]

[0756] Synthesis of compound 33.1

[0757] Compound 33.1 was produced in a yield of 83% similar to compound 30.1.

[0758] Synthesis of compound 33.2

[0759] Compound 33.2 was produced in a yield of 99% similar to compound 30.2.

[0760] Synthesis of compound 33.3

[0761] Compound 33.3 was produced in a yield of 53% similar to compound 30.3.

[0762] Synthesis of compound 33.4

[0763] Compound 33.4 was produced in a yield of 99% similar to compound 30.4.

[0764] Synthesis of compound CDK7_1176

[0765] Compound CDK7_1176 was produced in a yield of 70% similar to compound CDK7_955. The following compounds were produced in a similar manner:

[0766]

[0767] *The conditions and methods of said stage are described in the synthesis of compound 30.5

[0768] Example 34. Synthesis of compound CDK7_1187

[0769]

[0770] Synthesis of compound 34.1

[0771] Method A:

[0772] Similar to compound 26.5, compound 34.1 was produced with a yield of 79%.

[0773] Method B:

[0774] Similar to 44.3, compound 34.1 was produced from compound 43.1 and MeI with an overall yield of 70.0%

[0775] Synthesis of compound 34.2

[0776] Similar to compound 30.2, compound 34.2 was produced with a yield of 99%.

[0777] Synthesis of compound CDK7_1187

[0778] Compound 34.2 (0.069 g, 0.120 mmol), pyrimidine 31.1 (0.062 g, 0.120 mmol), Na2CO3 (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 at 100 °C for 6 hours under a nitrogen atmosphere. After standard workup, the product was separated by preparative HPLC. 0.05 g (10%) of compound CDK7_1187 was obtained.

[0779] Example 35. Synthesis of compounds CDK7_999, CDK7_1102

[0780]

[0781] Synthesis of compound 35.1

[0782] Similar to compound 4.2, compound 35.1 was produced with a yield of 96%.

[0783] Synthesis of compound 35.2

[0784] Dissolve compound 35.1 in 10 ml of acetonitrile; add NaN3 (0.136 g, 2.07 mmol). Then add a solution of trifluoromethanesulfonic anhydride (0.570 g, 1.88 mmol) in 5 ml of acetonitrile, and stir at room temperature for 18 hours. After standard workup, the product was separated by column chromatography. 0.162 g (76%) of compound 35.2 was obtained.

[0785] Synthesis of compound 35.3

[0786] Similar to compound 26.3, compound 35.3 was produced in 49% yield.

[0787] Synthesis of compound 35.4

[0788] Similar to compound 20.2, compound 35.4 was produced in 50% yield.

[0789] Synthesis of compound 35.5

[0790] Similar to compound 20.3, compound 35.5 was produced in 84% yield.

[0791] Synthesis of compound 35.6

[0792] Similar to compound 24.5, compound 35.6 was produced in 74% yield.

[0793] Synthesis of compound CDK7_999

[0794] Similar to compound CDK7_951, compound CDK7_999 was produced in 58% yield.

[0795] Similarly using cyclopropylamine, compound CDK7_1102 was produced in an overall yield of 1%.

[0796] Example 36. Synthesis of compound CDK7_814.

[0797]

[0798] Synthesis of compound CDK7_814

[0799] Compound 36.1 (0.152 g, 0.210 mmol), pyrimidine 1.4 (0.080 g, 0.210 mmol), Na2CO3 (0.067 g, 0.630 mmol), Pd(dppf)Cl2 (0.047 g, 0.060 mmol) in a mixture of 3 ml of 1,4 - dioxane and 1.5 ml of water were stirred at 100 °C for 1 hour under a nitrogen atmosphere. The volatile components were removed and the product was separated by column chromatography. 3 ml of TFA was added to the residue containing compound 36.2 and stirred at room temperature for 12 hours. After standard workup, the product was separated by preparative chromatography. 0.023 g (30%) of compound CDK7_814 was obtained.

[0800] Example 37. Synthesis of compound CDK7_843.

[0801]

[0802] Synthesis of compound 37.2

[0803] A solution of 1 M LiHMDS in THF (0.405 ml, 0.410 mmol) was added dropwise to a solution of compound 37.1 (0.082 g, 0.340 mmol) in 4 ml of THF at - 10 °C and stirred for 1 hour; methyl iodide (0.161 g, 1.12 mmol) was added and stirred at 0 °C for 10 minutes and then at room temperature for 2 hours. After standard workup, the product was separated by silica gel column chromatography. 0.067 g (79%) of compound 37.2 was obtained.

[0804] Synthesis of compound CDK7_843

[0805] 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), and 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 minutes. Then, a solution of compound 37.2 (0.085 g, 0.330 mmol) in 1 ml of THF was added, and the mixture was heated at 70 °C for 2 hours in a sealed vessel, and then at room temperature for 12 hours. After cooling, the mixture was filtered through a silica gel layer, and the solvent was removed in vacuo. Pyrimidine 1.4 (0.122 g, 0.320 mmol), Na2CO3 (0.103 g, 0.960 mmol), and 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 were added to the residue containing compound 37.3. The resulting mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere, the reaction mixture was filtered through a silica gel layer, and the solvent was removed in vacuo. The product was separated by silica gel column chromatography. Then, the residue containing compound 37.4 was dissolved in 3 ml of TFA and stirred at room temperature for 12 hours. After standard workup, the product was separated by preparative HPLC. 0.006 g (5%) of compound CDK7_843 was obtained.

[0806] Example 38. Synthesis of compound CDK7_1019.

[0807]

[0808] Synthesis of compound 38.1

[0809] Compound 16.5 (0.220 g, 0.350 mmol) was dissolved in 1 ml of TFA and stirred at room temperature for 32 hours, and the solvent was removed in vacuo. Then, the dried residue was 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 hours. After standard workup, the product was separated by column chromatography. 0.160 g (85%) of compound 38.1 was obtained.

[0810] Synthesis of compound CDK7_1019

[0811] Compound 38.1 (0.160 g, 0.280 mmol) in 6 ml of ethanol and 6 ml of water and NaOH (0.226 g, 5.60 mmol) were stirred at room temperature for 1 hour. The solvent was removed in vacuo and the product was separated by preparative HPLC. 0.035 g (32%) of compound CDK7_1019 was obtained.

[0812] Example 39. Synthesis of compound CDK7_1020.

[0813]

[0814] Synthesis of compound CDK7_1020

[0815] Compound 1.5 (0.050 g, 0.080 mmol) in 2 ml of ethanol and 2 ml of water and NaOH (0.065 g, 1.60 mmol) were stirred at room temperature for 1 hour. After standard workup, the residue was dissolved in 1.5 ml of TFA and stirred at room temperature for 16 hours. After standard workup, the product was separated by preparative HPLC. 0.015 g (48%) of compound CDK7_1020 was obtained.

[0816] Example 40. Synthesis of compound 40.2.

[0817]

[0818] Synthesis of compound 40.2

[0819] Compound 40.2 was produced in a yield of 48% similar to compound 15.3.

[0820] Example 41. Synthesis of compound CDK7_1199.

[0821]

[0822] Synthesis of compound CDK7_1199

[0823] Compound 32.5 (0.053 g, 0.100 mmol), pyrimidine 40.2 (0.028 g, 0.090 mmol), Na2CO3 (0.106 g, 0.270 mmol), Pd(dppf)Cl2 (0.020 g, 0.027 mmol) in a mixture of 1 ml of 1,4-dioxane and 0.5 ml of water were stirred at 100 °C for 2 h under a nitrogen atmosphere. After standard workup, intermediate 41.1 was used for the next stage without further purification. NaOH (0.032 g, 0.800 mmol), 4 ml of ethanol and 4 ml of water were added to the residue containing compound 41.1, and the reaction mass was stirred at room temperature for 1 h. After standard workup, the product was separated by preparative HPLC. 0.001 g (3%) of compound CDK7_1199 was obtained.

[0824] Example 42. Synthesis of compound CDK7 1254.

[0825]

[0826] Synthesis of compound 42.2

[0827] Compound 42.2 was produced analogously to compound 29.1 in 97% yield.

[0828] Synthesis of compound 42.3

[0829] Compound 42.3 was produced analogously to compound 29.2 in 62% yield.

[0830] Synthesis of compound 42.4

[0831] Compound 42.4 was produced analogously to compound 29.3 in 72% yield.

[0832] Synthesis of compound 42.6

[0833] While cooling in an ice bath, NaBH4 (0.062 g, 1.64 mmol) was added to a solution of compound 42.4 (0.220 g, 0.410 mmol) in 7 ml of ethanol, and the reaction mass was stirred at 20 °C for 24 h. After standard workup, the product was separated by silica gel column chromatography. The residue containing compound 42.5 was dissolved in 4 ml of dichloromethane, and a 1,4-dioxane solution of 0.57 ml of 4 N HCl was added, and the reaction mass was stirred at 20 °C for 20 h. After standard workup, the product was separated by column chromatography. 0.077 g (79%) of compound 42.6 was obtained.

[0834] Synthesis of compound 42.7

[0835] Similar to compound 2.3, compound 42.7 was produced with a yield of 87%.

[0836] Synthesis of compound 42.8

[0837] Similar to compound 27.2, compound 42.8 was produced with a yield of 83%.

[0838] Synthesis of compound 42.9

[0839] Similar to compound 1.5, compound 42.9 was produced with a yield of 41%.

[0840] Synthesis of compound 42.10

[0841] 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. Hydrogenation was carried out at atmospheric pressure for 20 h, the reaction material was filtered through a layer of diatomaceous earth, and the solvent was removed in vacuo. 0.023 g (55%) of compound 42.10 was obtained.

[0842] Synthesis of compound CDK7_1254

[0843] Similar to compound CDK7_836, compound CDK7_1254 was produced with a yield of 29%.

[0844] Example 43. Synthesis of compound 43.1.

[0845]

[0846] Synthesis of compound 43.1

[0847] NaH (0.227 g, 5.68 mmol) was added to a solution of compound 29.4 (1.00 g, 4.37 mmol) in 50 ml of tetrahydrofuran at 0 °C, stirred for 30 minutes, 0.789 ml (4.37 mmol) of SEMCl was added, and stirred at room temperature for 3 h. After standard workup, the reaction product was separated by column chromatography. 0.927 g (59%) of compound 43.1 was obtained.

[0848] Example 44. Synthesis of compounds CDK7_1154, CDK7_1155, CDK7_1226, CDK7_1227, CDK7_1229, CDK7_1259, CDK7_1268.

[0849]

[0850] Synthesis of compound 44.1

[0851] At 0 °C, NaH (0.948 g, 23.7 mmol) was added to a solution of compound 43.1 (0.300 g, 0.790 mmol) in 15 ml of DMF. The mixture was stirred for 10 minutes, bromocyclopentane (3.72 g, 23.7 mmol) was added, and the mixture was stirred at room temperature for 28 hours. After standard workup, the reaction product was separated by column chromatography. 0.154 g (46%) of compound 44.1 was obtained.

[0852] Synthesis of compound 44.3

[0853] Compound 44.1 was dissolved in 5 ml of TFA and stirred at room temperature for 1 hour. Then the volatile components were removed in vacuo, and the dry residue was dissolved in 5 ml of ethanol. 3 ml of 3M NaOH solution was added, and the mixture was stirred at room temperature for 1 hour. The volatile components were removed. After standard workup, the product was purified by column chromatography. Then the residue containing compound 44.2 was dissolved in 5 ml of DMF; at 0 °C, NaH (0.029 g, 0.720 mmol) was added and stirred for 30 minutes; then benzenesulfonyl chloride (0.134 g, 0.720 mmol) was added and stirred at room temperature for 16 hours. After standard workup, the product was separated by column chromatography. 0.054 g (34%) of compound 44.3 was obtained.

[0854] Synthesis of compound 44.4

[0855] Compound 44.4 was produced in a similar manner to compound 30.2.

[0856] Synthesis of compound 44.5

[0857] Compound 44.5 was produced using pyrimidine 31.1 in a similar manner to compound 32.6 in a 54% yield.

[0858] Synthesis of compound CDK7_1154

[0859] Compound CDK7_1154 was produced in a similar manner to compound CDK7_1122 in a 12% yield.

[0860] The following compounds were produced in a similar manner:

[0861]

[0862]

[0863] Example 45. Synthesis of compounds CDK7_1201 and CDK7_1277.

[0864]

[0865] Synthesis of compound 45.1

[0866] Similar to compound 44.1, compound 45.1 was produced using 2-iodopropane with a yield of 74%.

[0867] Synthesis of compound 45.2

[0868] Similar to compound 44.2, compound 45.2 was produced with a yield of 92%.

[0869] Synthesis of compound 45.3

[0870] Similar to compound 44.3, compound 45.3 was produced with a yield of 96%.

[0871] Synthesis of compound 45.4

[0872] Similar to compound 44.4, compound 45.4 was produced with a yield of 60%.

[0873] Synthesis of compound 45.6

[0874] Similar to compound 18.8, compound 45.6 was produced with a yield of 85%.

[0875] Synthesis of compound 45.7

[0876] Compound 45.6 (1.55 g, 2.65 mmol) was dissolved in 15 ml of a 4N HCl solution in 1,4-dioxane, and the reaction mixture was stirred at 60 °C for 30 minutes. After standard workup, the product was filtered and the volatile components were removed in vacuo. 1.15 g (88%) of compound 45.7 was obtained.

[0877] Synthesis of compound 45.8

[0878] Compound 45.7 (0.470 g, 0.900 mmol) was dissolved in 6 ml of POCl3 and stirred at 90 °C for 30 minutes. After standard workup, the product was separated by column chromatography. 0.367 g (79%) of compound 45.8 was obtained.

[0879] Synthesis of compound CDK7_1277

[0880] 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 hours. 2 ml of 3M NaOH solution was added to the resulting mixture and mixed at room temperature for 2 hours. After standard workup, the product was separated by preparative HPLC. 0.170 g (35%) of product CDK7_1277 was obtained.

[0881] Similarly, compound CDK7_1201 was produced with an overall yield of 3%.

[0882] Example 46. Synthesis of compound CDK7_1276.

[0883]

[0884] Synthesis of compound 46.1

[0885] Similar to compound 18.8, compound 46.1 was produced using pyrimidine 45.5 with a yield of 75%.

[0886] Synthesis of compound 46.2

[0887] Similar to compound 45.7, compound 46.2 was produced using pyrimidine 45.5 with a yield of 75%.

[0888] Synthesis of compound CDK7_1276

[0889] Compound 46.2 (0.075 g, 0.140 mmol) was dissolved in 0.5 ml of POCl3 and stirred at 90 °C for 30 minutes. After standard workup, the product was separated 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) were mixed in 8 ml of anhydrous ethanol at room temperature for 72 hours. 2 ml of 3M NaOH solution was added to the resulting mixture and stirred at room temperature for 4 hours. After standard workup, the product was separated by preparative HPLC. 0.012 g of product CDK7_1276 (15%) was obtained.

[0890] Example 47. Analysis of the resulting compounds.

[0891] The purity and structure of the resulting compounds were confirmed by chromatography / mass spectrometry LC / MS-ESI and 1 1H NMR spectroscopy (Tables 3 and 4).

[0892] Equipment data:

[0893] Table 1. Chromatography / mass spectrometry

[0894]

[0895] Table 2. NMR spectrometer

[0896]

[0897] Table 3. Analytical data of exemplary compounds

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916] Table 4. Analytical data of exemplary compounds

[0917]

[0918]

[0919] Example 48. Inhibiting the enzymatic activities of CDK7-CycH, CDK2-CycA, CDK9-CycK, and CDK13-CycK.

[0920] Measurements were carried out in a 384-well plate (Corning Inc., catalog number 4513) in a 5 μl reaction volume. The substance to be titrated was analyzed at 11 concentration points in 4-fold increments from 50 μM in normal-strength kinase buffer A (Thermo Fisher Scientific Inc, registration number PV3189) supplemented with DTT (Sigma, catalog number 646563 - 10X.5ML) and prepared with water (Panreac, catalog number 701074). The kinase was diluted in a similar buffer, mixed with the test compound in the wells of the plate, and pre-incubated at 25 °C for 10 minutes. After incubation, a mixture of the reaction substrate (CDKtide (SignalChem, catalog number C06-58) or Histone H1 (SignalChem, catalog number H10-54N) or PDKtide (SignalChem, catalog number P10-58)) and ATP (SignalChem, catalog number V915B) prepared in normal-strength kinase buffer A was added. A 1% dimethyl sulfoxide (DMSO) (Sigma-Aldrich, catalog number D2438) solution in the reaction volume was used as a negative control. The final concentrations of all reaction components are shown in Table 5. The plate was centrifuged at 400 rcf (Eppendorf, 5804R) for 1 minute and incubated at 25 °C for 40 - 60 minutes. Then the ADP-Glo TM detection system was used to measure the amount of ATP consumed in the kinase reaction. The luminescence signal was measured using a Spark 20M plate multimode microplate reader (Tecan Group Ltd, Switzerland). The IC 50 value was calculated using Magellan 7.2 (Tecan Group Ltd, Switzerland) by approximating the experimental points with a four-parameter model under Levenberg-Marquardt optimization:

[0921]

[0922] where A is the upper asymptote; D is the lower asymptote; C is the IC 50 , the half-maximal inhibitory concentration of the kinase, nM; and B is the curvature (slope).

[0923] Table 5. Final concentrations of kinase reaction components.

[0924]

[0925] Table 6. Biochemical test results of the inhibition of CDK7 / cyclin H / MNAT1, CDK2 / cyclin A, CDK9 / cyclin K kinase activities. IC 50Shown as the average from multiple measurements, "A" represents IC 50 <5 nM, "B" represents 5 nM <IC 50 <50 nM, "C" represents 50 nM <IC 50 <200 nM, and "D" represents IC 50 > 200 nM, "N / A" means the given compound was not analyzed in this test.

[0926]

[0927]

[0928]

[0929]

[0930] Table 7. Biochemical test results of the inhibition of CDK7 / cyclin H / MNAT1, CDK2 / cyclin A, CDK9 / cyclin K, CDK13 / cyclin K kinase activities. IC 50 Shown as the average of data from multiple measurement series:

[0931]

[0932] The results of these experiments confirmed the generation of highly affinity CDK7 inhibitors selective for CDK9, CDK13, and CDK2.

[0933] Example 49. Anti-proliferative activity against sensitive cell lines in vitro.

[0934] Continuous cell cultures were used in the cell tests: MDA-MB-468 (triple-negative breast cancer, HTB-132 TM ) and NCl-H82 (small cell lung cancer, HTB-175 TM) The anti-proliferative activity of the CDK7 inhibitors according to the present invention was evaluated using the live AlamarBlue dye (ThermoFisher Scientific Inc, catalog number DAL1100). Cells were grown in DMEM (PanEco, catalog number C330π) and RPMI-1640 (PanEco, catalog number C330π), respectively. The basal growth medium was enriched with L-glutamine (PanEco, catalog number Φ032) at a concentration of 2 mM and 10% fetal bovine serum (Gibco, catalog number 16140-071). The night before measurement, MDA-MB-468 adherent cells were detached from the plastic with trypsin-EDTA solution (PanEco, catalog number Π039π), then inactivated with DMEM complete medium solution, centrifuged at 1000 RPM (Eppendorf, 5804R), and a cell suspension was prepared in DMEM complete medium. It was introduced into a 96-well culture plate (Corning Inc, catalog number 3599) at 8×10 3 cells per well in 100 μl of medium. The next day, the test compound was dissolved in DMSO and diluted with DMEM complete medium to a final concentration ranging from 50 μM to 10 pM. A volume of 50 μl of the diluted compound was introduced in triplicate into the wells of the plate containing the cells (the final concentration of DMSO did not exceed 1%), and incubated in an incubator with 5% CO2 at 37 °C for 96 hours. The NCl-H82 suspension cell line was prepared on the day of analysis. 10×10 3 cells in 100 μl of RPMI-1640 complete medium were added to each well of the 96-well plate. The procedure for sample dilution was as described above. The cells with the test compound were incubated in an incubator with 5% CO2 at 37 °C for 120 hours. After incubation, 15 μl of AlamarBlue reagent (ThermoFisher Scientific Inc., catalog number DAL1100) was added to the wells, the contents of the plate were stirred on an orbital shaker (Biosan, Latvia), and then further incubated in an incubator with 5% CO2 at 37 °C for 5.5 - 6 hours. The number of live cells was detected using an Infinite M200Pro microplate spectrophotometer (Tecan Group Ltd, Switzerland) by measuring the fluorescence signal at an excitation wavelength (λEx) of 540 nm and an emission wavelength (λEm) of 590 nm.

[0935] The IC 50 value was calculated using Magellan software (Tecan Group Ltd, Switzerland) by approximating the experimental points with a four-parameter model under Levenberg-Marquardt optimization:

[0936] Table 8. Results of the antiproliferation assays on the MDA-MB-468 and NCl-H82 cell lines. IC 50 Shown as the mean from multiple measurements, "A" indicates IC 50 < 10 nM, "B" indicates 10 nM < IC 50 < 100 nM, "C" indicates 100 nM < IC 50 < 1000 nM, and "D" indicates IC 50 > 1000 nM, "N / A" means the given compound was not analyzed in this test.

[0937]

[0938]

[0939]

[0940] The results of these experiments confirmed the generation of inhibitors capable of arresting the growth of triple-negative breast cancer cells and small cell lung cancer cells at nM concentrations.

[0941] Example 50. General cytotoxicity against primary HepaRG hepatocytes in vitro.

[0942] The general cytotoxicity of the CDK7 inhibitors according to the invention was studied using primary differentiated HepaRG cells (Biopredic Int, lot number HPR101). One week before measurement, the cells were thawed and maintained in basal hepatocyte medium (Biopredic Int, lot number MIL700079), supplemented with HepaRG maintenance / metabolism medium supplement with antibiotics (Biopredic Int, lot number ADD620C). The medium in the vials containing the cells was changed every 2 - 3 days. One night before the test, the cells were plated at 25×10 3 cells per well in 100 μl of medium per well in the wells of a 96-well plate (Corning Inc., lot number 3599). The next day, the test compounds were introduced into the wells of the plate containing the cells at concentrations ranging from 200 μM to 0.2 nM and incubated for 72 hours. Cell viability was evaluated as described above.

[0943] Table 9. Results of the general toxicity study on primary HepaRG cells. CC 50 Shown as the mean from multiple measurements, "A" indicates CC 50 > 2000 nM, "B" indicates 2000 nM > CC 50 > 500 nM, "C" indicates 500 nM > CC 50> 100 nM, and "D" represents CC 50 < 100 nM, "N / A" means that the given compound was not analyzed in this test.

[0944]

[0945]

[0946] The results of these experiments confirmed the generation of non-toxic CDK7 inhibitors in a human hepatocyte model.

[0947] Example 51. Determination of Bromodeoxyuridine Incorporation into DNA

[0948] After adding bromodeoxyuridine (BrdU) to dividing cells, thymidine is replaced by its analogue BrdU, and BrdU is incorporated into DNA. Thus, the BrdU incorporated into DNA characterizes the intensity of DNA replication and the S phase during the cell cycle progression. Under the action of a compound, the reduction in the incorporation of bromodeoxyuridine into DNA characterizes the slowdown of the cell cycle and DNA replication.

[0949] In cell tests, a BrdU detection kit (Roche, serial number 11 669 915 001) was used for continuous cell cultures: MDA-MB-468 (triple-negative breast cancer, HTB-132 TM ) to evaluate the ability of the CDK7 inhibitor according to the present invention to inhibit BrdU incorporation into DNA. The cells were grown in DMEM medium (PanEco, serial number C330п). The basal growth medium was enriched with L-glutamine (PanEco, serial number Ф032) at a concentration of 2 mM and 10% fetal bovine serum (Gibco, serial number 16140-071). The adherent MDA-MB-468 cells were detached from the plastic with trypsin-EDTA solution (PanEco, serial number П039п), then inactivated with DMEM complete medium solution, centrifuged at 1000 RPM (Eppendorf, 5804R), and a cell suspension was prepared in DMEM complete medium, which was placed at 4 × 10 cells per well in 75 μl of medium 3Cells were seeded into a 96-well culture plate (Corning Inc, catalog number 3599). The test compounds were dissolved in DMSO and diluted to a final concentration ranging from 0.5 μM to 2 pM in complete DMEM medium. Serum-free growth medium was removed from the wells, and a 100 μl volume of the solution containing the diluted compound was added in the basal growth medium. The candidates were introduced in triplicate into the wells containing cells (the final concentration of DMSO not exceeding 1%), and incubated for 24 hours in an incubator with 5% CO2 at 37 °C. After incubation, 10 μl of a 10 μM BrdU solution was added to the wells, the contents of the plate were stirred on an orbital shaker (Biosan, Latvia), and incubated for an additional 72 hours in an incubator with 5% CO2 at 37 °C. Then the incorporated BrdU was detected according to the kit manufacturer's guidelines. The medium containing BrdU was removed from the wells, and the plate containing the cells was dried at 60 °C for 1 hour. To fix the cells, 200 ml of FixDenat solution was introduced into each well and incubated for 90 minutes at room temperature (+15 - 25 °C). The fixing solution was removed, and 100 ml of anti-BrdU-POD working solution was introduced, followed by incubation for 90 minutes at room temperature (+15 - 25 °C). The anti-BrdU-POD antibody solution was removed from the wells, and the wells were washed 3 times with 200 ml of wash solution (10 minutes at room temperature (+15 - 25 °C)). 100 μl of substrate solution was introduced into each assay well, and incubated for 3 minutes on an orbital shaker (Biosan, Latvia) at room temperature (+15 - 25 °C), and incubated for an additional 5 - 7 minutes without stirring.

[0950] The incorporation of BrdU was detected by measuring the luminescence signal on an Infinite M200Pro microplate spectrophotometer (Tecan Group Ltd, Switzerland). The IC 50 value was calculated using Magellan software (Tecan Group Ltd, Switzerland) by approximating the experimental points with a four-parameter model under Levenberg-Marquardt optimization:

[0951] Table 10. Results of BrdU incorporation into the DNA of the MDA-MB-468 cell line. The IC 50 is shown as the mean of data from multiple measurements, IC 50 , nM.

[0952]

[0953] The results of these experiments confirmed the production of CDK7 inhibitors, whose anti-proliferative activity against the MDA-MB-468 model (Example 49) was caused by arrested cell cycle and slowed DNA replication.

[0954] Example 52. Determination of passive membrane permeability through a PAMPA artificial membrane.

[0955] The passive membrane permeability of the compounds described in the present invention was determined at pH 7.4 using a PAMPA (Parallel Artificial Membrane Permeability Assay) model. We used a 96-well plate ( pre-coated PAMPA plate system, serial number 353015), which consists of a receptor part and a donor part, with a cell membrane-modeling PVDF filter pre-impregnated with a lecithin-phospholipid bilayer. A substance (at a concentration of 10 μmol) in 0.01 M phosphate buffer at pH 7.4 was introduced into the donor wells of the plate, and pure buffer was introduced into the receptor wells; then, the two parts were combined and incubated at room temperature for 20 hours to allow the compound to redistribute between the two wells and the membrane. Verapamil (USP, USA, serial number 1711202) and propranolol (MCE LLC, USA, registration number HY-B0573 / CS-2680) were used as control compounds with high and medium permeability. The samples were analyzed by reverse-phase HPLC with UV detection (Agilent 1260 chromatograph with UV detector) by determining the peak areas of the samples in the donor and receptor wells. The permeability rate (Pe, cm / s) and retention factor (R, %) in the lipid bilayer were calculated using the following formulas:

[0956] P e = (-ln[1 - C A (t) / C 平衡 ) / (A × (1 / V D + 1 / V A ) × t)

[0957] R = 1 - [C D (t) × V D + C A (t) × V A / (C o + V D ), where

[0958] C o is the donor-well concentration (μM) of the substance at the initial moment of time t;

[0959] C A (t) is the receptor-well concentration (μM) of the substance at time t;

[0960] V dis the donor - pore volume (0.3 ml);

[0961] V a is the acceptor - pore volume (0.15 ml).

[0962] C 平衡 =[C D (t)×V D +C A (t)×V A / (V D +V A )

[0963] A is the filtration area (0.3 cm 2 );

[0964] t is the incubation time (72000 seconds);

[0965] Table 11. Results of the study on the passive permeability through the PAMPA lipid membrane model. P e is shown as the mean from multiple measurements, "A" indicates P e > 1·10 -5 cm / s, "B" indicates 10 -5 cm / s > P e > 5·10 -6 cm / s, "C" indicates 5·10 -6 cm / s > P e > 1·10 -6 cm / s, and "D" indicates P e < 1·10 -6 cm / s, and "N / A" means that the given compound was not analyzed in this test.

[0966]

[0967]

[0968] The results of these experiments confirmed the generation of CDK7 inhibitors capable of passive permeation through the lipid membrane.

[0969] Example 53. In vitro microsomal stability study of compounds in human, rat, and mouse microsomes.

[0970] In the presence of the Phase I metabolic cofactor (NADPH), a procedure for studying the metabolism of selected compounds was carried out in the microsomal fraction of the liver (of rats, mice, humans).

[0971] The enzymatic degradation rate of the compound in liver microsomes was determined in an in vitro assay by maintaining a reaction mixture containing 0.5 mg / ml pooled human, rat, or mouse liver microsomes, 1 μM test compound, 1.5 mM β-nicotinamide adenine dinucleotide (Carbosynth, UK, registration number NN108711101), and 1.5 mM magnesium chloride in 0.1 M sodium phosphate buffer (pH 7.4) in a solid-state thermostat (XenoTech, USA, serial number H2610, registration number R1000, registration number M1000) at 37 °C. Incubations were performed in triplicate.

[0972] To determine the stability of the compound under the sample preparation conditions, duplicate aliquots of the microsomal fraction with the test compound were incubated at 37 °C for 40 minutes in the absence of the NADPH cofactor.

[0973] The reaction was stopped at 0, 10, 20, 30, and 40 minute time points by adding an ice-cold mixture of acetonitrile:methanol (3:1) containing an internal standard.

[0974] The samples were then centrifuged to remove precipitated proteins, and the supernatants were analyzed by HPLC-MS / MS to determine the in vitro clearance (CL int ). An Agilent 6410 mass spectrometer (Agilent, USA) combined with an Agilent 1260 Infinity II HPLC liquid chromatograph (Agilent, USA) and a cooled autosampler (Agilent, USA) controlled by MassHunter software was used as the HPLC-MS / MS system. Chromatographic analysis was performed in a mobile phase system in a gradient elution mode on a C18 reversed-phase HPLC column (Agilent, Waters, or equivalent): water containing 0.1% formic acid / acetonitrile containing 0.1% formic acid, flow rate: 0.5 ml / min, column T = 35 °C. Mass spectrometric detection was performed by electrospray ionization in the multiple reaction monitoring mode. The precursor ion, fragment ion, and collision energy for each substance were selected experimentally.

[0975] A plot of the dependence of the logarithm of the ratio of the peak area of the substance to the peak area of the internal standard relative to time was established. The dependence coefficient of this line corresponds to the elimination rate constant k, based on which the in vitro clearance CLint was calculated:

[0976] Elimination rate constant (k) = (-gradient)

[0977]

[0978] Based on the obtained in vitro clearance CLint values, the microsomal stability of the selected compounds in humans, rats, and mice was inferred.

[0979] The results are shown in Tables 12 and 13.

[0980] Table 12. Results of in vitro microsomal stability in humans (HLM) for selected compounds. Clint is shown as the mean of multiple measurements, "A" indicates Clint < 20 μl / (min·mg protein), "B" indicates 50 μl / (min·mg protein) > Clint > 20 μl / (min·mg protein), "C" indicates 100 μl / (min·mg protein) > Clint > 50 μl / (min·mg protein), and "D" indicates Clint > 100 μl / (min·mg protein).

[0981]

[0982]

[0983] Table 13. Results of in vitro stability in rat (RLM) and mouse (MLM) microsomes for selected compounds. Clint is shown as the mean of multiple measurements, "A" indicates Clint < 20 μl / (min·mg protein), "B" indicates 50 μl / (min·mg protein) > Clint > 20 μl / (min·mg protein), "C" indicates 100 μl / (min·mg protein) > Clint > 50 μl / (min·mg protein), and "D" indicates Clint > 100 μl / (min·mg protein), and "N / A" means the given compound was not analyzed in this test.

[0984] Compound Number RLM MLM CDK7_953 A A CDK7_1187 A A CDK7_1188 A N / A CDK7_1225 A A CDK7_1227 A N / A CDK7_1229 A A CDK7_1259 A N / A CDK7_1276 B B CDK7_1277 B B

[0985] The results of these experiments confirmed the generation of CDK7 inhibitors that are resistant (B) and highly resistant (A) to the activities of human, mouse, and rat liver microsomal enzymes.

[0986] Example 54. Pharmacokinetic (PK) study.

[0987] Dose and Administration

[0988] Pharmacokinetic studies of the compound were performed on male CD-1 mice, approximately 8 weeks old, weighing 16 - 29 g. The animals were dosed as follows: administered orally (PO) (intragastrically) as a single dose at a dose of 10 mg / kg in a formulation in the form of a 0.2% solution of hydroxypropyl methylcellulose (HPMC) in 5% aqueous glucose solution, and for 1277 at a dose of 1.0 mg / kg and for substances CDK7_1187, CDK7_1225, CDK7_1229, and CDK7_1276 at a dose of 2.0 mg / kg as a single IV-bolus administration (intravenously) in a formulation containing 0.2% DMSO in 5% aqueous glucose solution.

[0989] For each substance, 21 - 30 animals were used for each PO and IV administration dose. All mice were weighed and randomized before dosing.

[0990] For each time point, 3 - 5 animals were used. Each animal was sampled at one time point. The animals were fasted for at least 12 hours before the start of the experiment while maintaining free access to water.

[0991] Blood was collected from the animals in the PO and IV groups before and 0.5, 2, 4, 8, 12, and 24 hours after administration of the substance.

[0992] Blood samples

[0993] Blood was collected by cardiac puncture using a closed method. Blood with a volume of 0.2 ml was collected into a polypropylene tube containing 20 μl of 5% EDTA. Plasma was separated by centrifugation at 10,000 rpm for 10 minutes at 4 ± 2 °C and transferred to a clean labeled tube.

[0994] Plasma analysis

[0995] A test mouse plasma sample with a volume of 50 μl was obtained from mice in the experimental group. Then, 200 ml of an internal standard (tolbutamide (Sigma, T0891)) solution with a concentration of 50 ng / ml prepared in acetonitrile and pre-cooled in a refrigerator at 2 - 8°C was added to the sample, stirred for 10 seconds in a vortex mixer (G560E, Scientific Industries), and incubated at 4°C for 15 minutes to precipitate proteins. Then the sample was centrifuged at 1500 g (5417R centrifuge, Eppendorf) for 10 minutes while cooled to 4°C. 150 μl of the supernatant was transferred to a 96-well plate for HPLC-MS / MS analysis. Quantitative determination of the test compound in plasma was performed by the absolute calibration method. A calibration curve was generated by analyzing plasma samples supplemented with standards of known amounts of the compound to be tested. The lower limit of quantification of the test compound in plasma was 1 ng / ml, and the analytical range of the technique was 1 ng / ml to 2000 ng / ml. The technique was partially validated in terms of selectivity, accuracy, precision, linearity, matrix effect, and stability.

[0996] The Qtrap 5500 mass spectrometer (AB Sciex) was combined with an Agilent 1290 Infinity II HPLC liquid chromatograph (Agilent) and a cooled multiple injector (Agilent 1290 Infinity II multiple injector G7167B) and used as an HPLC-MS / MS system. Chromatographic analysis was performed on a C18 reversed-phase HPLC column (YMC-Triart C18, 50 * 2 mm, 1.9 μm, YMC CO.Ltd). The mobile phase used was a mixture of deionized water and acetonitrile supplemented with 0.1% formic acid in gradient mode, flow rate: 0.5 ml / min, column T = 40°C, autosampler T = 8°C, analysis time: 2.8 minutes. Mass spectrometry detection was performed in the multiple reaction monitoring (MRM) mode. The precursor ion, fragment ion, and collision energy of each substance were selected through experiments. Two Q1 / Q3 transitions were used to record the MRM chromatograms of the analyte and the internal standard; one transition was used for quantitative calculation, and the other transition was used to confirm that the extraction time corresponded to the given substance. Based on the results of HPLC-MS / MS analysis of calibration samples using Analyst 1.6.3 software, a calibration dependence of the chromatographic analyte peak area normalized to the signal of the internal standard on the analyte concentration was established.

[0997] Pharmacokinetic analysis

[0998] Pharmacokinetic analysis was performed using the Phoenix WinNonlin 6.3 software package by non-compartmental methods. The main mean PK parameters were determined: time to maximum concentration (Tmax), elimination half-life (T1 / 2), maximum concentration (Cmax), area under the pharmacokinetic curve from the time of administration to the last measured concentration (AUClast), clearance (CL), steady-state volume of distribution (Vss), and absolute oral bioavailability value (F). The pharmacokinetic parameters of the compounds according to the invention are shown in Tables 14 - 15.

[0999] Table 14. Pharmacokinetic parameters of the compounds in mouse plasma after intravenous administration.

[1000]

[1001] Table 15. Pharmacokinetic parameters of the compounds in mouse plasma after oral administration.

[1002]

[1003] The compounds according to the invention correspond to the target pharmacokinetic characteristics: these compounds are well-absorbed and have sufficient oral absorption. Based on the mean area under the curve (AUClast), the absolute bioavailability of the compounds was calculated to be greater than 72.7%. This in turn demonstrates the possibility of achieving a pharmacodynamic effect upon oral administration of these compounds.

[1004] Example 55. Permeability of the blood-brain barrier (BBB)

[1005] The ability of a substance to penetrate the blood-brain barrier and enter the central nervous system (mouse brain) was evaluated by the ratio of the area under the pharmacokinetic curve of the substance in rat brain and plasma after oral administration, which characterized the tissue bioavailability in rat brain and was expressed as the AUCbrain / AUCplasma coefficient.

[1006] Dose and administration

[1007] A pharmacokinetic study of the compounds was conducted on male CD-1 mice, approximately 8 weeks old, weighing 16 - 29 g. The animals were administered a single oral (PO) dose of 10 mg / kg of the formulation in the form of a 0.2% solution of hydroxypropyl methylcellulose (HPMC) in 5% aqueous glucose solution (intragastrically).

[1008] Twenty-one animals were used for each substance. All mice were weighed and randomized before dosing.

[1009] Three animals were used for each time point. Biological materials were collected from each animal at one time point. The animals were fasted for at least 12 hours before the start of the experiment while allowing free access to water. Blood and brain samples were collected at 0.5, 2, 4, 6, 8, 12, and 16 hours after administration of the substance.

[1010] Blood samples

[1011] All procedures were carried out analogously to Example 54.

[1012] Brain samples

[1013] Perfusion of the mouse brain was carried out via the vascular system with a saline solution. For this purpose, the chest cavity was opened, the right atrium was incised with microsurgical scissors, and saline cooled to 4 °C was applied to the left ventricle using a 10-ml syringe until the liver turned white. After washing, the skull was opened and the brain was removed, weighed, and transferred to a labeled 5-ml tube.

[1014] Analysis of brain samples

[1015] Four volumes of water were added to the brain suspension and homogenized 2 times for 45 seconds using a homogenizer (Omni Bead Ruptor 24). Similarly, a whole mouse brain homogenate was prepared and then used to prepare calibration samples and QC samples. A calibration curve was generated by analyzing the brain homogenate samples in the presence of standards supplemented with known amounts of the compound to be tested.

[1016] The samples were precipitated with cooled acetonitrile at a 1:4 ratio containing the internal standard tolbutamide (Sigma, T0891) at a concentration of 50 ng / ml. The samples were vortexed (G560E, Scientific Industries) for 10 seconds and kept at 4 °C for 15 minutes to precipitate the proteins, and then centrifuged at 1500 g (5417R centrifuge, Eppendorf) for 10 minutes. 150 μl of the supernatant was collected and transferred to the corresponding wells of a 96-well plate for HPLC-MS / MS analysis. The quantitative determination of the test compound in the brain homogenate was carried out analogously to the procedure described in Example 54. The lower limit of quantification of the test compound in the brain homogenate was 0.3 ng / ml.

[1017] Pharmacokinetic analysis of the data was carried out analogously to the procedure described in Example 54.

[1018] In addition to the main PK parameters, the concentration ratio in the brain and plasma (AUC brain / AUC plasma) was calculated at the time points studied to evaluate the bioavailability in the brain (permeability across the blood-brain barrier).

[1019] Table 16. Pharmacokinetic parameters of the compound in mouse brain homogenate after oral administration.

[1020]

[1021]

[1022] The obtained data demonstrated the ability of the compounds according to the invention to penetrate the BBB.

[1023] Example 56. Study of anti-tumor activity in vivo.

[1024] For the subcutaneous xenograft model of the NCl-H69 line (small cell lung cancer, HTB-119 TM ) transplanted into BALB / c nude mice, the in vivo anti-tumor activity of CDK7_1187 was evaluated.

[1025] The NCl-H69 cell line was cultured in RPMI-1640 medium (PanEco, Russia), where the basal growth medium was enriched with L-glutamine (PanEco, Russia) at a concentration of 2 mM and 10% fetal bovine serum (Gibco, ThermoFisher Scientific, USA).

[1026] The study used 20 BALB / c nude mice (female) obtained from the Federal State Budgetary Scientific Institution “Federal Research Center Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences” (ICG SB RAS).

[1027] On the right outer side of the body of BALB / c nude mice, a suspension containing 5×10 6 NCI-H69 tumor cells and Matrigel ( Basement Membrane Matrix) was subcutaneously administered at a ratio of 1:1 at a volume of 200 μl.

[1028] An electronic caliper was used to measure the linear dimensions of the tumors. The volume of the tumor nodules was determined by the formula (1):

[1029] V = L×W 2 / 2, (1)

[1030] where L and W are the major diameter and minor diameter of the tumor nodules, respectively.

[1031] According to the calculation formula (2), the efficacy of the test product was measured by the tumor growth inhibition index (TGI, %).

[1032]

[1033] Where Vc and Vp are the average volumes of tumor nodules in the control group and the group of animals receiving the test substance, respectively.

[1034] After reaching an average tumor volume of 130 mm 3 the animals were divided into 2 groups of 10 animals each, and the volume of the tumor nodules was used as the randomization criterion. The day of the first administration of the product was designated as day 0.

[1035] The test substance CDK7_1187 was administered intragastrically at a dose of 6 mg / kg per day 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 a similar volume of 5% glucose solution and 0.1% DMSO solution.

[1036] Statistical analysis was performed using the GraphPad Prism 9 software package. When comparing the volumes of tumor nodules, the Mann-Whitney U test was used to evaluate the significance of the differences. If p < 0.05, the differences were identified as significant.

[1037] The kinetics of tumor growth is shown in Figure 1 The TGI index (%) is shown in Table 17.

[1038] Table 17. TGI index, %

[1039] Group Day 9 Day 13 Day 17 Day 21 CDK7_1187 10 36 40 48

[1040] The research results showed that after administering CDK7_1187 to BALB / c nude mice, on the 17th and 21st days of the experiment, the tumor volume was significantly smaller statistically than that of the control group animals. The index of tumor growth inhibition at the end of the observation period was 48%.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: R1 is -C(Hal)3, -CH(Hal)2, -CH2Hal, -Hal, -Η, -NO2, unsubstituted or substituted by one or several Hal atoms -(C1-C6)alkyl, unsubstituted or substituted by one or several Hal atoms -O-(C1-C6)alkyl, unsubstituted or substituted by one or several Hal atoms -S-(C1-C6)alkyl; R2 and R3 are each independently H, -(C1-C6)alkyl; or R2 and R3 together form an unsubstituted or substituted by one or several -(C1-C6)alkyl -(C3-C6)cycloalkyl; L1 and L2 are each independently a chemical bond, -NR5-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -C(S)-, -C(=NH)-, -(CR 6a R 6b ) 1-3 -, -P(O)(CH3)-, -O-(CH2) 1-3 -, -(CH2) 1-3 -O-, -NR 5a -(CH2) 1-3 -, -(CH2) 1-3 -NR 5a -, -C(O)-(CH2) 1-3 -, -(CH2) 1-3 -C(O)-, -C(O)-NH- or -NH-C(O)-; A is an unsubstituted or R7-substituted 6- to 10-membered aryl group; an unsubstituted or R 7a -substituted 6- to 10-membered aryl group, which is fused with an unsubstituted or R 8a -substituted (C3-C6) cycloalkyl group; an unsubstituted or R 7b -substituted 6- to 10-membered aryl group, which is fused with an unsubstituted or R 8b -substituted 4- to 10-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; an unsubstituted or R 7c -substituted 6- to 10-membered aryl group, which is fused with an unsubstituted or R 8c -substituted 5- to 6-membered heteroaryl group having 1, 2, 3 or 4 heteroatoms selected from N, O or S; an unsubstituted or R 7d -substituted 5- to 6-membered heteroaryl group having 1, 2, 3 or 4 N atoms; an unsubstituted or R 7e -substituted 5- to 6-membered heteroaryl group having 1, 2, 3 or 4 heteroatoms selected from N, O or S, which is fused with an unsubstituted or R 8e -substituted (C3-C6) cycloalkyl group; an unsubstituted or R 7f -substituted 5- to 6-membered heteroaryl group having 1, 2, 3 or 4 heteroatoms selected from N, O or S, which is fused with an unsubstituted or R 8f -substituted 4- to 10-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; an unsubstituted or R 7g -substituted 5- to 6-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; an unsubstituted or R 7h -substituted 5- to 6-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O, which is fused with an unsubstituted or R 8h -substituted 4- to 10-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; R4 is -Η; -Hal; (=Ο); -OH; -C(O)OH; -NR 4a R 4b ; -P(O)(С1-С6 (alkyl)2; -S(O)2NH2; -S(O)2C1-C6 alkyl; unsubstituted or substituted by one or more R 4c substituted -(C1-C6) alkyl; unsubstituted or substituted by one or more R 4d substituted -O-C1-C6 alkyl; unsubstituted or substituted by one or more R 4e substituted phenyl; unsubstituted or substituted by one or more R 4f substituted 4-7-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; unsubstituted or substituted by one or more R 4g substituted -(C3-C6) cycloalkyl; unsubstituted or substituted by one or more R 4h substituted -C2-C6 alkenyl; unsubstituted or substituted by one or more R 4i substituted 5-6-membered heteroaryl having 1, 2, 3 or 4 N atoms; unsubstituted or substituted by one or more R 4j substituted 4-7-membered heterocyclic group having 1 or 2 heteroatoms selected from N, S or O, fused to an unsubstituted or substituted phenyl; unsubstituted or substituted by one or more R 4k substituted phenyl; unsubstituted or substituted by one or more R 4l substituted 5-6-membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O or S, fused to an unsubstituted or substituted phenyl; 4m substituted phenyl; R 4a 、R 4b 、R 4c 、R 4d 、R 4е 、R 4f 、R 4g 、R 4h 、R 4i 、R 4j 、R 4k 、R 4l 、R 4m each independently is -H; (=O); -OH; -NH2; -Hal; -CN; C1-C6 alkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl; O-C1-C6 alkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl; C3-C6 cycloalkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl, C1-C6 alkyl; -S(O)2C1-C6 alkyl, -S(O)2NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, morpholinyl, thiazolyl, phenyl; R5, R 5a each independently is -H, C1-C6 alkyl; R 6a 、R 6b Each independently is -H, C1-C6 alkyl, -Hal; or R 6a and R 6b together with the C atom to which they are attached form an unsubstituted or (C1-C6)alkyl-substituted C3-C6 cycloalkyl; R7, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h each independently is -Hal; -OH; -NH2; -CN; (=O); unsubstituted or substituted by one or several -Hal -(C1-C6) alkyl; unsubstituted or substituted by one or several -Hal -O(C1-C6) alkyl; R 8a 、R 8b 、R 8c 、R 8d 、R 8e 、R 8f 、R 8h each independently is -Hal, -OH, -NH2, -CN, (=O), unsubstituted or substituted by one or several -Hal of -(C1-C6) alkyl; Hal is an atom of F, Cl, Br, I.

2. The compound according to claim 1, wherein -A-L2-R4 is: wherein k and m are each independently 0, 1, 2 or 3; X1, X2, X3, X4, X5, X6 are each independently C, N, CH, CH2, NH, S or O; Y1, Y2, Y3, Y4, Y5 are each independently C, N or CH; L2 is a chemical bond, -NR5-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -C(S)-, -C(=NH)-, -(CR 6a R 6b ) 1-3 -, -P(O)(CH3)-, -O-(CH2) 1-3 (-), -(CH2) 1-3 -O-, -NR 5a (-), -(CH2) 1-3 (-), -(CH2) 1-3 -NR 5a (-), -C(O)-(CH2) 1-3 (-), -(CH2) 1-3 -C(O)-, -C(O)-NH- or -NH-C(O)-; R4 is -Η; -Hal; (=Ο); -OH; -C(O)OH; -NR 4a R 4b ; -P(O)(С1-С6 (alkyl)2; -S(O)2NH2; -S(O)2C1-C6 alkyl; unsubstituted or substituted by one or several Rs 4c substituted -(C1-C6) alkyl; unsubstituted or substituted by one or several Rs 4d substituted -O-C1-C6 alkyl; unsubstituted or substituted by one or several Rs 4e substituted phenyl; unsubstituted or substituted by one or several Rs 4f substituted 4-7-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; unsubstituted or substituted by one or several Rs 4g substituted -(C3-C6) cycloalkyl; unsubstituted or substituted by one or several Rs 4h substituted -C2-C6 alkenyl; unsubstituted or substituted by one or several Rs 4i substituted 5-6-membered heteroaryl having 1, 2, 3 or 4 N atoms; unsubstituted or substituted by one or several Rs 4j substituted 4-7-membered heterocyclic group having 1 or 2 heteroatoms selected from N, S or O, fused with unsubstituted or substituted phenyl; unsubstituted or substituted by one or several Rs 4k substituted phenyl; unsubstituted or substituted by one or several Rs 4l substituted 5-6-membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O or S, fused with unsubstituted or substituted phenyl; unsubstituted or substituted by one or several Rs 4m substituted phenyl; R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f 、R 4g 、R 4h 、R 4i 、R 4j 、R 4k 、R 4l 、R 4m Each independently is -H; (=O); -OH; -NH2; -Hal; -CN; C1-C6 alkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl; O-C1-C6 alkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl; C3-C6 cycloalkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl, C1-C6 alkyl; -S(O)2C1-C6 alkyl, -S(O)2NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, morpholinyl, thiazolyl, phenyl; R5, R 5a each independently is -H, C1-C6 alkyl; R 6a 、R 6b Each independently is -H, C1-C6 alkyl, -Hal; or R 6a and R 6b together with the C atom(s) to which they are attached form an unsubstituted or (C1-C6)alkyl-substituted C3-C6 cycloalkyl group; R7, R 7b , R 7d , R 7f each independently is -Hal; -OH; -NH2; -CN; (=O); unsubstituted or substituted by one or several -Hal -(C1-C6)alkyl; unsubstituted or substituted by one or several -Hal -O(C1-C6)alkyl; R 8b 、R 8d 、R 8f Each independently is -Hal, -OH, -NH2, -CN, (=O), unsubstituted or -(C1-C6)alkyl substituted by one or several -Hal; Hal is an atom of F, Cl, Br, I.

3. The compound according to claims 1-2, wherein -A-L2-R4 is wherein k and m are each independently 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)-, -(CR 6a R 6b ) 1-3 -, -P(O)(CH3)-, -O-(CH2) 1-3 -, -(CH2) 1-3 -O-, -NR 5a -(CH2) 1-3 -, -(CH2) 1-3 -NR 5a -, -C(O)-(CH2) 1-3 -, -(CH2) 1-3 -C(O)-, -C(O)-NH- or -NH-C(O)-; R4 is -Η; -Hal; (=Ο); -OH; -C(O)OH; -NR 4a R 4b ; -P(O)(С1-С6 (alkyl)2; -S(O)2NH2; -S(O)2C1-C6 alkyl; unsubstituted or substituted by one or more R 4c substituted -(C1-C6) alkyl; unsubstituted or substituted by one or more R 4d substituted -O-C1-C6 alkyl; unsubstituted or substituted by one or more R 4e substituted phenyl; unsubstituted or substituted by one or more R 4f substituted 4-7-membered heterocyclic group having 1, 2, 3 or 4 heteroatoms selected from N, S or O; unsubstituted or substituted by one or more R 4g substituted -(C3-C6) cycloalkyl; unsubstituted or substituted by one or more R 4h substituted -C2-C6 alkenyl; unsubstituted or substituted by one or more R 4i substituted 5-6-membered heteroaryl having 1, 2, 3 or 4 N atoms; unsubstituted or substituted by one or more R 4j substituted 4-7-membered heterocyclic group having 1 or 2 heteroatoms selected from N, S or O, fused to an unsubstituted or substituted phenyl; unsubstituted or substituted by one or more R 4k substituted phenyl; unsubstituted or substituted by one or more R 4l substituted 5-6-membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O or S, fused to an unsubstituted or substituted phenyl; unsubstituted or substituted by one or more R 4m substituted phenyl; R 4a 、R 4b 、R 4c 、R 4d 、R 4е 、R 4f 、R 4g 、R 4h 、R 4i 、R 4j 、R 4k 、R 4l 、R 4m Each independently is -H; (=O); -OH; -NH2; -Hal; -CN; C1-C6 alkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl, -C1-C6 alkyl; O-C1-C6 alkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl; C3-C6 cycloalkyl which is unsubstituted or substituted by one or several groups selected from -Hal, -OH, -NH2, -CN, phenyl; -S(O)2C1-C6 alkyl, -S(O)2NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, morpholinyl, thiazolyl, phenyl; R5, R 5a each independently is -H, C1-C6 alkyl; R 6a 、R 6b Each independently is -H, C1-C6 alkyl, -Hal; or R 6a and R 6b together with the C atom to which they are attached form an unsubstituted or (C1-C6)alkyl-substituted C3-C6 cycloalkyl; R7, R 7b , R 7d , R 7f each independently is -Hal; -OH; -NH2; -CN; (=O); unsubstituted or substituted by one or several -Hal -(C1-C6)alkyl; unsubstituted or substituted by one or several -Hal -O(C1-C6)alkyl; R 8b 、R 8d 、R 8f Each independently is -Hal; -OH; -NH2; -CN; (=O); unsubstituted or substituted by one or several -Hal -(C1-C6) alkyl; unsubstituted or substituted by one or several -Hal -O(C1-C6) alkyl; Hal is an atom of F, Cl, Br, I.

4. The compound according to claims 1-3, wherein L1 and L2 are each independently 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. The compound according to claims 1-3, wherein R1 is -Η, -CF3, -CCl3, -CHF2, -CH2F, -CHCl2, -CH2Cl, -NO2.

6. The compound according to claims 1-3, wherein R2 and R3 are each independently -H, methyl, ethyl, propyl, or R2 and R3 together with the C atom to which they are attached form cyclopropyl, cyclobutyl or cyclopentyl.

7. A compound according to claims 1 - 3, wherein R4 is -Η; (=Ο); -ΟΗ; -F; -Cl; -Br; -P(O)(С1-С6 alkyl)2; -S(O)2NH2; -S(O)2-(С1-С6) alkyl; -(С1-С6) alkyl unsubstituted or substituted by one or several (=Ο), -Hal, -CN, -S(O)2-(С1-С6) alkyl; -O-(С1-С6) alkyl unsubstituted or substituted by one or several (=Ο), -CN, -Hal; -(С3-C6) cycloalkyl unsubstituted or substituted by one or several (=Ο), -OH, -Hal, -СN; phenyl unsubstituted or substituted by one or several -Hal, -СN, morpholine, -P(O)(CH3)2; a 5 - 6 membered heterocyclic group having 1, 2 or 3 heteroatoms selected from N or O, unsubstituted or substituted by -(С1-С6) alkyl, (=Ο), -Hal, -CN; a 5 - 6 membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, Ο or S, unsubstituted or substituted by (=Ο), -(С1-С6) alkyl, -(С3-С6) cycloalkyl, -Hal, -CN; a 5 - 6 membered heteroaryl having 1 or 2 N atoms, unsubstituted or substituted by one or several (=Ο), -(С1-С6) alkyl, fused to phenyl; -NR 4a R 4b ; R 4a 、R 4b Each independently is -Η, (=Ο), morpholinyl, -F, -S(O)2CH3, -СN, -ketone, cyclopropyl, thiazolyl, unsubstituted or phenyl-substituted -С1-С3 alkyl, -P(O)(CH3)2.

8. The compound according to claim 7, wherein R4 is -Η; -ketone; (=Ο); -P(O)(CH3)2; -CH3; -CH2CΗ3; tert-butyl; -CH2CF3; -CH2CH2S(O)2CH3; -CF3; -Cl; -OCF3; -S(O)2NH2; -S(O)2CH3; phenyl unsubstituted or substituted by one or several -Hal, -СN; methylpiperazinyl; piperazinyl; imidazolyl; thiazolyl; methylpyrazolyl; pyrazolyl; pyridyl; pyrimidinyl; morpholine; oxalkyl; oxolanyl; cyclohexyl; cyclopentyl; cyclopropyl; oxazolyl; methyloxazolyl; dimethyloxazolyl; dihydropyridyl; methyldihydropyridyl; -NR 4a R 4b ; R 4a 、R 4b Each independently is -Η, (=Ο), morpholinyl, -F, -S(O)2CH3, -СN, -ketone, cyclopropyl, thiazolyl, unsubstituted or phenyl-substituted -С1-С3 alkyl, -P(O)(CH3)2.

9. The compound according to claims 1 - 3, 7, wherein R 4a , R 4b , R 4c , R 4d , R 4е , R 4f , R 4g , R 4h , R 4i , R 4j , R 4k , R 4l , R 4m are each independently -Η, (=Ο)-CH3, morpholinyl, -F, -S(O)2CH3, -СN, -ketone, cyclopropyl, thiazolyl, unsubstituted or phenyl-substituted -С1-С3 alkyl, -P(O)(CH3)2.

10. The compound according to claims 1-3, wherein R5 is -H, -CH3.

11. The compound according to claims 1-3, wherein R 6a and R 6b are each independently -Η, -F, -СΗ3, or R 6a and R 6b together with the C atom to which they are attached form cyclopropyl.

12. The compound according to claims 1-3, wherein R7, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h are each independently (=Ο), -Hal, -СΗ3, -ΟСΗ3, -СHal3, -OСΗal3.

13. The compound according to claims 1-3, wherein R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8h are each independently (=O), -Hal, -CH3, -OCH3, -CHal3, -OCHal3.

14. The compound according to claim 1, which is: 4-(2-Aminobenzoyl)-N-[(3S)-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-[(3S)-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-[(1S)-1-(2-Aminophenyl)ethyl]-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_541_b); 4-[(1R)-1-(2-Aminophenyl)ethyl]-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_541_c); 4-[2-(2-Aminophenyl)propan-2-yl]-N-[(3S)-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-[(3S)-piperidin-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]-N-[(3S)-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)thio]-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_545); 4-[(2-Aminophenyl)thio]-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_545_a); 4-(2-Aminobenzenesulfinyl)-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_546); 4-(2-Aminobenzenesulfinyl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_546_a); 4-[(R)-2-Aminobenzenesulfinyl]-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_546_b); 4-[(S)-2-Aminobenzenesulfinyl]-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_546_c); 4-(2-Aminobenzenesulfonyl)-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_547); 4-(2-Aminobenzenesulfonyl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_547_a); 4-(2-Aminophenoxy)-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_548); 4-(2-Aminophenoxy)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_548_a); N4-(2-Aminophenyl)-N2-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_550); N4-(2-Aminophenyl)-N2-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_550_a); N4-(2-Aminophenyl)-N4-methyl-N2-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_551); N4-(2-Aminophenyl)-N4-methyl-N2-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_551_a); N4-Phenyl-N2-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_812); N4-Phenyl-N2-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_812_a); 4-Phenoxy-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_754); 4-Phenoxy-N-(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-[(3S)-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-[(R)-(2-Aminophenyl)(methyl)phosphoryl]-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_552_b); 4-[(S)-(2-Aminophenyl)(methyl)phosphoryl]-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_552_c); N4-[2-(Dimethylphosphoryl)phenyl]-N2-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_735); N4-[2-(Dimethylphosphoryl)phenyl]-N2-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_735_a); 4-[2-(Dimethylphosphoryl)phenoxy]-N-[(3S)-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-[(3S)-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); N4-[3-(Dimethylphosphoryl)phenyl]-N2-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_888); N4-[3-(Dimethylphosphoryl)phenyl]-N2-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_888_a); N4-[2-(Dimethylphosphoryl)-5-methylphenyl]-N2-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_903); N4-[2-(Dimethylphosphoryl)-5-methylphenyl]-N2-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_903_a); N4-[2-(Dimethylphosphoryl)-4-methylphenyl]-N2-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_904); N4-[2-(Dimethylphosphoryl)-4-methylphenyl]-N2-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_904_a); N4-[2-(Dimethylphosphoryl)-5-(trifluoromethyl)phenyl]-N2-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_905); N4-[2-(Dimethylphosphoryl)-5-(trifluoromethyl)phenyl]-N2-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_905_a); N4-[2-(Dimethylphosphoryl)-4-(trifluoromethyl)phenyl]-N2-[(3S)-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); N4-[5-Chloro-2-(dimethylphosphoryl)phenyl]-N2-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_907); N4-[5-Chloro-2-(dimethylphosphoryl)phenyl]-N2-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_907_a); N4-[4-Chloro-2-(dimethylphosphoryl)phenyl]-N2-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_908); N4-[4-Chloro-2-(dimethylphosphoryl)phenyl]-N2-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_908_a); N4-[2-(Dimethylphosphoryl)-4-(trifluoromethoxy)phenyl]-N2-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_915); N4-[2-(Dimethylphosphoryl)-4-(trifluoromethoxy)phenyl]-N2-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_915_a); 2-[(2-{[(3S)-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-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_890); N4-(3-Methylsulfonylphenyl)-N2-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (CDK7_890_a); 3-[(2-{[(3S)-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-{[(3S)-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-Methylsulfonyloxyphenyl)-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_894); 4-(3-Methylsulfonyloxyphenyl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_894_a); 3-[(2-{[(3S)-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)-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_827); 4-(2,3-Dihydro-1H-indol-7-yloxy)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_827_a); 4-(1H-Indol-7-yloxy)-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_828); 4-(1H-Indol-7-yloxy)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_828_a); 4-(1,2,3,4-Tetrahydroquinolin-8-yloxy)-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_829); 4-(1,2,3,4-Tetrahydroquinolin-8-yloxy)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_829_a); N-[(3S)-Piperidin-3-yl]-5-(trifluoromethyl)-4-(quinolin-8-yloxy)pyrimidin-2-amine (CDK7_830); N-(Piperidin-3-yl)-5-(trifluoromethyl)-4-(quinolin-8-yloxy)pyrimidin-2-amine (CDK7_830_a); N-{2-[(2-{[(3S)-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-{[(3S)-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); N-[(3S)-6,6-dimethylpiperidin-3-yl]-4-(5-phenyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_460); N-(6,6-dimethylpiperidin-3-yl)-4-(5-phenyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_460_a); N-[(3S)-piperidin-3-yl]-4-(5-phenyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_533); N-(piperidin-3-yl)-4-(5-phenyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_533_a); 4-(4-phenyl-1H-pyrrol-3-yl)-N-[(3S)-piperidin-3-yl]-4-(4-phenyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_534); 4-(4-phenyl-1H-pyrrol-3-yl)-N-[piperidin-3-yl]-4-(4-phenyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_534_a); 4-(5-benzoyl-1H-pyrrol-3-yl)-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_535); 4-(5-benzoyl-1H-pyrrol-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_535_a); N,N-dimethyl-4-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_536); N,N-dimethyl-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxamide (CDK7_536_a); 4-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_537); 4-{2-[(Piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxamide (CDK7_537_a); N-Phenyl-4-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_538); N-Phenyl-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxamide (CDK7_538_a); 4-[5-(4-Methylpiperazine-1-carbonyl)-1H-pyrrol-3-yl]-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_539); 4-[5-(4-Methylpiperazine-1-carbonyl)-1H-pyrrol-3-yl]-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_539_a); 4-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid (CDK7_922); 4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxylic acid (CDK7_922_a); 4-[4-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrol-2-yl]benzonitrile (CDK7_695); 4-(4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrol-2-yl)benzonitrile (CDK7_695_a); 3-[4-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrol-2-yl]benzonitrile (CDK7_696); 3-(4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrol-2-yl)benzonitrile (CDK7_696_a); 3-(2-{[(3S)-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}- 1H,4H,5H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_814_a); 3-(2-{[(3S)-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}- 1H,4H,5H,6H,7H-Pyrrolo[3,2-c]pyridin-4-one (CDK7_815_a); 6-Methyl-3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_843); 6-Methyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_843_a); 3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H-pyrrolo[2,3-c]pyridin-4-one (CDK7_844); 3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}- 1H,4H,5H,6H,7H-pyrrolo[2,3-c]pyridin-4-one (CDK7_844_a); 6-Methyl-3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_845); 6-Methyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_845_a); N-(1H-Imidazol-2-yl)-4-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_833); N-(1H-Imidazol-2-yl)-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-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-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_835); 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)pyrimidin-4-yl}-N-(pyridin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_836_a); N-(4-Cyanophenyl)-4-(2-{[(3S)-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}-1H-pyrrole-2-carboxamide (CDK7_837_a); N-[4-(Morpholin-4-yl)phenyl]-4-(2-{[(3S)-Piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_838); N-[4-(Morpholin-4-yl)phenyl]-4-{2-[(Piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxamide (CDK7_838_a); N-Methyl-4-(2-{[(3S)-Piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_846); N-Methyl-4-{2-[(Piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxamide (CDK7_846_a); 4-(2-{[(3S)-Piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-N-(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-Methylsulfonylethyl)-4-(2-{[(3S)-Piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_848); N-(2-Methylsulfonylethyl)-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-[(3S)-Piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_849); 4-[5-(Morpholine-4-carbonyl)-1H-pyrrol-3-yl]-N-(Piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_849_a); N-(Oxan-4-yl)-4-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_850); N-(Oxan-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-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_851); N-(4-Hydroxycyclohexyl)-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxamide (CDK7_851_a); N-(4-Cyanocyclohexyl)-4-(2-{[(3S)-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-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_951); N-Cyclopropyl-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxamide (CDK7_951_a); 6-(3,5-Dimethyl-1,2-oxazol-4-yl)-3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_923); 6-(3,5-Dimethyl-1,2-oxazol-4-yl)-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_923_a); 6-(3,5-Dimethyl-1,2-oxazol-4-yl)-3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_924); 6-(3,5-Dimethyl-1,2-oxazol-4-yl)-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_924_a); 3-(2-{[(3S)-Piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_925); 3-{2-[(Piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_925_a); 3-(2-{[(3S)-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}-1H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_926_a); 3-(2-{[(3S)-Piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_927); 3-{2-[(Piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_927_a); 7-Methyl-3-(2-{[(3S)-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}-1H,4H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_928_a); 7-Methyl-3-(2-{[(3S)-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}-1H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_929_a); 7-Methyl-3-(2-{[(3S)-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-{[(3S)-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-{[(3S)-Piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H,9H-pyrrolo[2,3-c]azocan-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]azocan-9-one (CDK7_932_a); 8-Methyl-3-(2-{[(3S)-Piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H,9H-pyrrolo[2,3-c]azocan-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]azocan-9-one (CDK7_933_a); 3-(2-{[(3S)-Piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,8H,9H-pyrrolo[2,3-c]azocan-9-one (CDK7_934); 3-{2-[(Piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}- 1H,4H,5H,8H,9H-pyrrolo[2,3-c]azocan-9-one (CDK7_934_a); 8-Methyl-3-(2-{[(3S)-Piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,8H,9H-pyrrolo[2,3-c]azocan-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]azocan-9-one (CDK7_935_a); 3-(2-{[(3S)-Piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,7H,8H,9H-pyrrolo[2,3-c]azocan-9-one (CDK7_936); 3-{2-[(Piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}- 1H,4H,7H,8H,9H-pyrrolo[2,3-c]azocan-9-one (CDK7_936_a); 8-methyl-3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,7H,8H,9H-pyrrolo[2,3-c]azocan-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]azocan-9-one (CDK7_937_a); 3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H,8H,9H-pyrrolo[2,3-c]azocan-9-one (CDK7_938); 3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}- 1H,6H,7H,8H,9H-pyrrolo[2,3-c]azocan-9-one (CDK7_938_a); 8-methyl-3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H,8H,9H-pyrrolo[2,3-c]azocan-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]azocan-9-one (CDK7_939_a); 3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,8H,9H-pyrrolo[2,3-c]azocan-9-one (CDK7_940); 3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,8H,9H-pyrrolo[2,3-c]azocan-9-one (CDK7_940_a); 8-methyl-3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,8H,9H-pyrrolo[2,3-c]azocan-9-one (CDK7_941); 8-methyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,8H,9H-pyrrolo[2,3-c]azocan-9-one (CDK7_941_a); 3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-9H-pyrrolo[2,3-c]azocan-9-one (CDK7_942); 3-{2-[(Piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-9H-pyrrolo[2,3-c]azocan-9-one (CDK7_942_a); 3-(2-{[(3S)-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}-1H,4H,5H,6H-pyrrolo[2,3-c]pyrrol-6-one (CDK7_943_a); 5-Methyl-3-(2-{[(3S)-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); N-[(3S)-Piperidin-3-yl]-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_945); N-(Piperidin-3-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_945_a); 4-(1H-Imidazol-4-yl)-N-[(3S)-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); N-[(3S)-Piperidin-3-yl]-4-(1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_947); N-(Piperidin-3-yl)-4-(1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_947_a); N-[(3S)-Piperidin-3-yl]-4-(1H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_948); N-(Piperidin-3-yl)-4-(1H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_948_a); N-[(3S)-Piperidin-3-yl]-4-(1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_949); N-(Piperidin-3-yl)-4-(1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_949_a); N-[(3S)-Piperidin-3-yl]-4-(2H-1,2,3,4-tetrazol-5-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_950); N-(Piperidin-3-yl)-4-(2H-1,2,3,4-tetrazol-5-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_950_a); 4-(2-{[(3S)-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-{[(3S)-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-{[(3S)-Piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1,2-dihydroisoquinolin-1-one (CDK7_921); 4-{2-[(Piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1,2-dihydroisoquinolin-1-one (CDK7_921_a); N-Cyclopropyl-N-methyl-4-(2-{[(3S)-Piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_1001); N-Cyclopropyl-N-methyl-4-{2-[(Piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxamide (CDK7_1001_a); N-Methyl-4-(2-{[(3S)-Piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-N-(1,3-thiazol-2-yl)-1H-pyrrole-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_а); N-Benzyl-4-(2-{[(3S)-Piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_997); N-Benzyl-4-{2-[(Piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxamide (CDK7_997_а); N-Benzyl-N-methyl-4-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_998); N-Benzyl-N-methyl-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxamide (CDK7_998_a); 4-[5-(1-Methyl-1H-1,2,3,4-tetrazol-5-yl)-1H-pyrrol-3-yl]-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_999); 4-[5-(1-Methyl-1H-1,2,3,4-tetrazol-5-yl)-1H-pyrrol-3-yl]-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_999_a); 4-[5-(2-Methyl-2H-1,2,3,4-tetrazol-5-yl)-1H-pyrrol-3-yl]-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_1000); 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-[(3S)-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)pyrimidin-2-amine (CDK7_1060_a); 4-[5-(1-Cyclopropyl-1H-1,2,3,4-tetrazol-5-yl)-1H-pyrrol-3-yl]-N-[(3S)-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]-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_1103); 4-[5-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-1H-pyrrol-3-yl]-N-(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]-N-[(3S)piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_1124); 4-[5-(1-Methyl-1H-1,3-benzodiazol-2-yl)-1H-pyrrol-3-yl]-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_1124_a); Ethyl 4-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-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-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_1017); N,N,1-Trimethyl-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxamide (CDK7_1017_a); N-[(3S)-piperidin-3-yl]-4-[5-(pyridin-2-yl)-1H-pyrrol-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_1061); N-(piperidin-3-yl)-4-[5-(pyridin-2-yl)-1H-pyrrol-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_1061_a); N-[(3S)-piperidin-3-yl]-4-[5-(pyrimidin-2-yl)-1H-pyrrol-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_1062); N-(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}-N-[(3S)piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_1057); 4-{5-[2-(Dimethylphosphoryl)phenyl]-1H-pyrrol-3-yl}-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_1057_a); 7-(1-Methyl-1H-pyrazol-4-yl)-3-(2-{[(3S)-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-{[(3S)-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); 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-{[(3S)-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); 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-{[(6S)-4-Azaspiro[2.5]oct-6-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_1136); 3-[2-({4-Azaspiro[2.5]oct-6-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_1136_a); 3-(2-{[(7S)-5-Azaspiro[3.5]non-7-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_1137); 3-[2-({5-Azaspiro[3.5]non-7-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_1137_a); 3-(2-{[(3S)-6,6-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1,3-thiazol-2-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1138); 3-{2-[(6,6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-7-(1,3-thiazol-2-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1138_a); 7-(3,5-dimethyl-1,2-oxazol-4-yl)-3-(2-{[(3S)-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_1139); 7-(3,5-dimethyl-1,2-oxazol-4-yl)-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_1139_a); 5-[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]-1-methyl-1,2-dihydropyridin-2-one (CDK7_1140); 5-(3-{2-[(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)-1-methyl-1,2-dihydropyridin-2-one (CDK7_1140_a); 3-(2-{[(3S)-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); 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-{[(3S)-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); 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-{[(3S)-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-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_a); 3-(2-{[(3S)-6,6-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1144); 3-{2-[(6,6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-7-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1144_a); 3-(2-{[(3S)-6,6-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-[(1,3-thiazol-2-yl)methyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1145); 3-{2-[(6,6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-7-[(1,3-thiazol-2-yl)methyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1145_a); 7-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-3-(2-{[(3S)-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_1146); 7-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-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_1146_a); 3-(2-{[(3S)-6,6-Dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-[1-(1-methyl-1H-pyrazol-4-yl)ethyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1147); 3-{2-[(6,6-Dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-7-[1-(1-methyl-1H-pyrazol-4-yl)ethyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1147_a); 3-(2-{[(3S)-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); 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-{[(3S)-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-{[(3S)-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-{[(3S)-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); 3-(2-{[(3S)-6,6-dimethylpiperidin-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-(oxolan-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-{[(3S)-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-dimethylpiperidin-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-{[(3S)-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_1155); 7-(Cyclopentylmethyl)-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_1155_a); 3-(2-{[(3S)-6,6-Dimethylpiperidin-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-(oxan-4-yl)ethyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1156_a); 3-(2-{[(3S)-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); 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-{[(3S)-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-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1158_a); 7-tert-Butyl-3-(2-{[(3S)-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_1159); 7-tert-Butyl-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_1159_a); 3-(2-{[(3S)-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); 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-Dimethylbutan-2-yl)-3-(2-{[(3S)-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-Dimethylbutan-2-yl)-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_1161_a); 8-(2-{[(3S)-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-f][1,4]oxazepin-5-one (CDK7_1162); 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-f][1,4]oxazepin-5-one (CDK7_1162_a); (6S)-3-(2-{[(3S)-6,6-Dimethylpiperidin-3-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_1163); 3-{2-[(6,6-Dimethylpiperidin-3-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_1163_a); (6R)-3-(2-{[(3S)-6,6-dimethylpiperidin-3-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-3-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_a); 3-(2-{[(3S)-6,6-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-6,6-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1165); 3-{2-[(6,6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-6,6-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1165_a); 6-cyclopropyl-3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1105); 6-cyclopropyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1105_a); 3-(2-{[(3S)-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)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1058_a); 1-methyl-5-[7-oxo-3-(2-{[(3S)-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); N-[(3S)-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-{[(3S)-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-{[(3S)-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}-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1121_a); 4-(1H-Indol-1-yl)-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_809); 4-(1H-Indol-1-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_809_a); 4-(1H-1,3-Benzodiazol-1-yl)-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_810); 4-(1H-1,3-Benzodiazol-1-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_810_a); 4-(1H-1,2,3-Benzotriazol-1-yl)-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_811); 4-(1H-1,2,3-Benzotriazol-1-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_811_a); 7-Methyl-3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]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-c]azepin-8-one (CDK7_953_a); 6-(1-Methyl-1H-pyrazol-4-yl)-3-(2-{[(3S)-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-c]pyridin-7-one (CDK7_961); 6-Benzyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_961_a); N,N-Dimethyl-4-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-2-carboxamide (CDK7_966); N,N-Dimethyl-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-imidazole-2-carboxamide (CDK7_966_a); N,N-Dimethyl-4-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide (CDK7_991); N,N-Dimethyl-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-3-carboxamide (CDK7_991_a); 3-(2-{[(3S)-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-[(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_a); 3-(2-{[(3S)-6,6-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-methyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1187); 3-{2-[(6,6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-7-methyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1187_a); 3-(2-{[(6S)-4-azaspiro[2.5]oct-6-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_1199); 3-[2-({4-azaspiro[2.5]oct-6-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_1199_a); 3-(2-{[(6S)-4-azaspiro[2.5]oct-6-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-6-methyl-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1200); 3-[2-({4-azaspiro[2.5]oct-6-yl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]-6-methyl-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1200_a); 3-(2-{[(6S)-4-azaspiro[2.5]oct-6-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-methyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1201); 3-[2-({4-azaspiro[2.5]oct-6-yl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]-7-methyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1201_a); 3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-6-(1,3-thiazol-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1202); 3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-6-(1,3-thiazol-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1202_a); 3-(2-{[(3S)-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); 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-{[(3S)-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}-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1204_a); 6-(2-Methyl-1,3-thiazol-5-yl)-3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1205); 6-(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-{[(3S)-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}-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1206_a); 6-(5-Methyl-1,3-thiazol-2-yl)-3-(2-{[(3S)-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}-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1207_a); 6-(Cyclopropylmethyl)-3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-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-{[(3S)-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-{[(3S)-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-{[(3S)-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-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (CDK7_1212); 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-{[(3S)-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-{[(3S)-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-{[(3S)-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-{[(3S)-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-{[(3S)-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-{[(3S)-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-{[(3S)-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-{[(3S)-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-dimethylpiperidin-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-{[(3S)-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); 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-dimethylpiperidin-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-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1228); 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-{[(3S)-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); 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-{[(3S)-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); 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-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_1236); 4-{5-Methyl-3,4,6,13-tetraazatricyclo[8.3.0.0 2 , 6 tridec-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-[(3S)-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-{[(3S)-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); 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); (6S)-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_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-c]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-c]azepin-8-one (CDK7_1240_a); 7-Cyclopropyl-3-(2-{[(3S)-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-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_a); (6S)-7-Cyclopropyl-3-(2-{[(3S)-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_1242); 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_1242_a); (6R)-7-Cyclopropyl-3-(2-{[(3S)-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); 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-{[(3S)-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); 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-{[(3S)-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-{[(3S)-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-{[(3S)-6,6-Dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1,4-diazatricyclo[7.1.1.0 3 , 7 undec-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 undec-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-{[(3S)-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-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-7-yl)acetonitrile (CDK7_1269_a); 3-(2-{[(3S)-6,6-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-(oxetan-3-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1270); 3-{2-[(6,6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-7-(oxetan-3-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1270_a); 3-(2-{[(3S)-6,6-dimethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-[(oxetan-3-yl)methyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1271); 3-{2-[(6,6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-7-[(oxetan-3-yl)methyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1271_a); 3-(2-{[(6S)-4-azaspiro[2.5]oct-6-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-(2-methoxyethyl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1272); 3-[2-({4-azaspiro[2.5]oct-6-yl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]-7-(2-methoxyethyl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1272_a); 2-[3-(2-{[(6S)-4-azaspiro[2.5]oct-6-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-8-oxo-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-7-yl]acetonitrile (CDK7_1273); 2-{3-[2-({4-azaspiro[2.5]oct-6-yl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]-8-oxo-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-7-yl}acetonitrile (CDK7_1273_a); 3-(2-{[(6S)-4-Azaspiro[2.5]oct-6-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-(oxetan-3-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1274); 3-[2-({4-Azaspiro[2.5]oct-6-yl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]-7-(oxetan-3-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1274_a); 3-(2-{[(6S)-4-Azaspiro[2.5]oct-6-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-[(oxetan-3-yl)methyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1275); 3-[2-({4-Azaspiro[2.5]oct-6-yl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]-7-[(oxetan-3-yl)methyl]-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1275_a); 3-(2-{[(6S)-4-Azaspiro[2.5]oct-6-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-cyclopropyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1276); 3-[2-({4-Azaspiro[2.5]oct-6-yl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]-7-cyclopropyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1276_a); 3-(2-{[(6S)-4-Azaspiro[2.5]oct-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); 3-[2-({4-Azaspiro[2.5]oct-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 kinase CDK7 in a subject, comprising contacting cyclin-dependent protein kinase CDK7 with a compound according to any one of claims 1-14.

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

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

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

19. The pharmaceutical composition according to claim 18, wherein the tumor diseases are selected from breast cancer, metastatic breast cancer, HER2-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 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 carcinoma, oral 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 lymphoma, diffuse large B cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, endometrial cancer, fallopian tube cancer, sarcoma, Ewing sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, multiple myeloma; The autoimmune diseases are selected from axial spondyloarthritis, antiphospholipid syndrome, vasculitis (ANCA-associated vasculitis, including Wegener's granulomatosis and related forms of vasculitis, 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, Sjögren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis and uveitis; Autoinflammatory diseases are selected from Behcet's disease; Blau syndrome; chronic recurrent multifocal osteomyelitis (CRMO); synovitis; acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome, cryopyrin-associated periodic syndromes (CAPS); interleukin-1 receptor antagonist deficiency (DIRA); familial Mediterranean fever (FMF); NLRP12-related autoinflammatory diseases; neonatal-onset multisystem inflammatory disease (NOMID); chronic infantile neurocutaneous and articular (CINCA) syndrome; Majeed syndrome; mevalonate kinase deficiency (hyperimmunoglobulin-D syndrome); periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome; pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome; Schnitzler syndrome; Sweet syndrome; systemic juvenile idiopathic arthritis; Still's disease; adult-onset Still's disease (AOSD); tumor necrosis factor (TNF) receptor-associated periodic syndromes (TRAPS); Infectious or non-infectious inflammatory diseases are selected from allergies (including but not limited to: delayed hypersensitivity, immediate hypersensitivity, anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, osteoarthritis, adult respiratory distress syndrome, respiratory tract inflammation (including but not limited to: bronchiolitis, bronchitis, bronchiectasis, interstitial cell pneumonia, giant cell interstitial pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonia, laryngitis, pneumonia, pharyngitis, pleurisy, pneumonitis, pneumoconiosis, asbestosis, berylliosis, silicosis, talcosis, usual interstitial pneumonia), tonsillitis, bursitis, cellulitis, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes, 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 skin diseases), 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, transverse myelitis, urethritis, cystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis.

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

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

22. The method of treating a disease or disorder according to claim 21, wherein the tumor disease is selected from breast cancer, metastatic breast cancer, HER2-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 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 carcinoma, oral 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 lymphoma, diffuse large B cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, uterine body cancer, fallopian tube cancer, sarcoma, Ewing sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, multiple myeloma; The autoimmune diseases are selected from axial spondyloarthritis, antiphospholipid syndrome, vasculitis (ANCA-associated vasculitis, including Wegener's granulomatosis and related forms of vasculitis, 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, Sjögren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis and uveitis; The autoinflammatory diseases are selected from Behçet's disease; Blau syndrome; chronic recurrent multifocal osteomyelitis (CRMO); synovitis; acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome, cryopyrin-associated periodic syndromes (CAPS); interleukin-1 receptor antagonist deficiency (DIRA); familial Mediterranean fever (FMF); NLRP12-related autoinflammatory diseases; neonatal-onset multisystem inflammatory disease (NOMID); chronic infantile neurologic cutaneous and articular (CINCA) syndrome; Maggiore syndrome; mevalonate kinase deficiency (hyperimmunoglobulin D syndrome); periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome; pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome; Schnitzler syndrome; Sweet syndrome; systemic juvenile idiopathic arthritis; Still's disease; adult-onset Still's disease (AOSD); tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS); The infectious or non-infectious inflammatory diseases are selected from allergies (including but not limited to: delayed hypersensitivity, immediate hypersensitivity, anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, osteoarthritis, adult respiratory distress syndrome, respiratory inflammation (including but not limited to: bronchiolitis, bronchitis, bronchiectasis, interstitial cell pneumonia, giant cell interstitial pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonia, laryngitis, pneumonia, pharyngitis, pleurisy, pneumonitis, pneumoconiosis, asbestosis, berylliosis, silicosis, talcosis, usual interstitial pneumonia), tonsillitis, bursitis, cellulitis, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes, 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 skin disease), 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, transverse myelitis, urethritis, cystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis.

23. Use of a compound according to any one of claims 1-14 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or a pharmaceutical composition according to claim 16 for the treatment of a disease or disorder associated with increased activity of 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 increased activity of cyclin-dependent protein kinase CDK7 is a tumor, an infectious inflammatory or non-infectious inflammatory, autoinflammatory, autoimmune disease.

25. Use according to claim 24, wherein the tumor disease is selected from breast cancer, metastatic breast cancer, HER2-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 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 carcinoma, oral 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 lymphoma, diffuse large B cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, corpus cancer, fallopian tube cancer, sarcoma, Ewing sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, multiple myeloma; The autoimmune diseases are selected from axial spondyloarthritis, antiphospholipid syndrome, vasculitis (ANCA-associated vasculitis, including Wegener's granulomatosis and related forms of vasculitis, 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, Sjögren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis and uveitis; Autoinflammatory diseases are selected from Behçet's disease; Blau syndrome; chronic recurrent multifocal osteomyelitis (CRMO); synovitis; acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome, cryopyrin-associated periodic syndromes (CAPS); interleukin-1 receptor antagonist deficiency (DIRA); familial Mediterranean fever (FMF); NLRP12-associated autoinflammatory disease; neonatal-onset multisystem inflammatory disease (NOMID); chronic infantile neurologic cutaneous and articular (CINCA) syndrome; Maggiore syndrome; mevalonate kinase deficiency (hyperimmunoglobulin-D syndrome); periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome; pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome; Schnitzler syndrome; Sweet syndrome; systemic juvenile idiopathic arthritis; Still's disease; adult-onset Still's disease (AOSD); tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS); Infectious or non-infectious inflammatory diseases are selected from allergies (including but not limited to: delayed hypersensitivity, immediate hypersensitivity, anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, osteoarthritis, adult respiratory distress syndrome, respiratory tract inflammation (including but not limited to: bronchiolitis, bronchitis, bronchiectasis, interstitial cell pneumonia, giant cell interstitial pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonia, laryngitis, pneumonia, pharyngitis, pleurisy, pneumonitis, pneumoconiosis, asbestosis, berylliosis, silicosis, talcosis, usual interstitial pneumonia), tonsillitis, bursitis, cellulitis, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes, 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 skin disease), 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, transverse myelitis, urethritis, cystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis.

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