Cyclin-dependent kinase 7 inhibitors

Abstract

The present invention relates to novel compounds of formula I which have CDK7 inhibitor properties [Formula 1] TIFF2025532179000196.tif86111 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, as well as pharmaceutical compositions comprising the compounds, methods of treating diseases or disorders, and uses of the compounds as medicaments for treating diseases or disorders.

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, methods of treating diseases or disorders, and the use of the compounds as medicaments for treating diseases or disorders. [Background technology]

[0002] Cyclin-dependent kinase 7 (CDK7) is an enzyme widely expressed in various tissues throughout the body and a member of the cyclin-dependent protein kinase (CDK) family. Together with cyclin H and MAT1, CDK7 forms a CDK activation complex, which regulates cell cycle phase progression through phosphorylation of other CDKs. CDK7 is an essential component of the transcription factor TFIIH, which is involved in transcription initiation and DNA repair processes. Thus, CDK7 plays a crucial role in regulating 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 alterations in transcriptional processes are characteristic properties of malignant tumor cells. Excessive CDK7 activity has been observed in numerous cancer types, including gastric cancer, esophageal squamous cell carcinoma, ER+ and triple-negative breast cancer, and hepatocellular carcinoma, and correlates with an aggressive course of disease and poor patient prognosis (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 cells 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 2016;100(3):514-21). 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 antitumor effects by reducing the rate of cell proliferation and by affecting the transcription of genes involved in the malignant transformation of cells, such as ovarian cancer, T-cell acute lymphoblastic leukemia, neuroblastoma, glioma, small cell lung cancer, and other cells (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). Furthermore, protein inhibition enhances genomic instability, reduces PD-L1 expression, and induces antitumor immune responses (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 therapeutic efficacy via the p38α / MYC / PD-L1 signaling in non-small cell lung cancer. J Hematol Oncol. 2020;13(1):99). Summary of the Invention [Problem to be solved by the invention]

[0004] Therefore, there is a need to create new compounds that preferably target CDK7 and may offer a better risk-to-benefit ratio in the therapy of diseases associated with increased CDK7 activity. [Means for solving the problem]

[0005] The terms used in describing this invention are set out below. Optionally substituted at 1, 2, 3, 4 or several positions means that the specified group can be substituted at 1, 2, 3, 4 or 1-6 positions with a radical or any combination of radicals.

[0006] A "fused ring compound" or "fused compound" is a polycyclic compound that has two adjacent atoms in common. Examples of fused compounds include 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]azocine, 1H,4H,5H,8H,9H-pyrrolo[2,3-c]azocine, 1H,4H,7H,8H,9H-pyrrolo[2,3-c]azocine, 1H,6H,7H,8H,9H-pyrrolo[2,3-c]azocine, 1H,8H,9H-pyrrolo[2,3-c]azocine, 9H-Pyrrolo[2,3-c]azocine, 1H,4H,5H,6H-Pyrrolo[2,3-c]pyrrole, 1H-1,3-benzodiazole, 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 ... 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.

[0007] "Alkyl" refers to an aliphatic straight-chain or branched-chain hydrocarbon group having 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. Branched refers to an alkyl chain having one or more "lower alkyl" substituents. Examples of alkyl groups 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, and n-hexyl. Alkyl can have substituents, which can be the same or different in structure.

[0008] "Cycloalkyl" means a fully saturated carbocyclic ring containing 3 to 10 carbon ring atoms. Cycloalkyls can have substituents, which can be the same or different. Cycloalkyls can be fused with aryl, heteroaryl, or heterocyclyl. Examples of cycloalkyl groups include, but are not limited to, monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, and bicyclic groups such as bicycloheptyl or bicyclooctyl.

[0009] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon group having 2 to 12 carbon atoms, more preferably 2 to 6 carbon atoms, and containing one or more carbon-carbon double bonds. Alkenyl may have substituents, which may be the same or different in structure.

[0010] "Aryl" refers to an aromatic monocyclic or polycyclic ring system having 6 to 14 carbon atoms, more preferably 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, phenylene, benzenetriyl, indanyl, naphthyl, naphthylene, naphthalenetriyl, and anthrylene. The aryl may have a substituent, and the substituent may be the same or different in structure. The aryl may be fused with a heterocycle, cycloalkyl, or heteroaryl.

[0011] "Alkyloxy," "alkoxy," or "alkyloxy group" means an alkyl-O- group, where alkyl is defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, and isobutoxy.

[0012] "Amino group" refers to an R'R''N- group. "Aminocarbonyl" means the group --C(.dbd.O)NR'"R"". Examples of R', R'', R''', and R'''' include, but are not limited to, a substituent selected from the group including hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, heteroalkyl, or R' and R'' together with the carbon atom to which they are attached can form a 4- to 7-membered heterocyclyl or heteroaryl.

[0013] "Alkylsulfonyl" (-S(O)-(C-C)alkyl) refers to an "alkyl" or "cycloalkyl" as defined above linked to the corresponding molecular fragment via a sulfonyl group -SO-. Examples of alkylsulfonyl include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, and the like.

[0014] "Alkylsulfonamide" (-NH-S(O)-(C-C)alkyl) refers to an "alkyl" or "cycloalkyl" as defined above linked to the corresponding molecular fragment via the sulfonamide group -NH-SO-. Examples of alkylsulfonamides include, but are not limited to, methylsulfonamide, ethylsulfonamide, propylsulfonamide, cyclopropylsulfonamide, etc.

[0015] "Dialkylphosphine oxide" or "dialkylphosphoryl" (-P(O)((C1-C6)alkyl)2) means an "alkyl" or "cycloalkyl" as defined above linked to the corresponding molecular fragment 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.

[0016] The term "oxo" as used herein refers to the radical =O. "Lower alkyl" means a straight or branched chain alkyl having 1 to 4 carbon atoms.

[0017] "Halo" or "halogen" (Hal) means fluoro, chloro, bromo and iodo. The terms "heterocycle," "heterocyclyl," and "heterocycle" refer to a monocyclic or polycyclic ring system having 3 to 11 carbon atoms, one or more of which are replaced by heteroatoms, such as nitrogen, oxygen, or sulfur. A heterocycle may have one or more substituents, which may be the same or different. The nitrogen and sulfur atoms of a heterocycle may be oxidized to N-oxide, S-oxide, or S-dioxide. A heterocycle may be saturated, partially saturated, or unsaturated. A heterocyclyl may be represented by a bridged ring compound having one, two, or three -CH2- groups; or a heterocyclyl may be fused to a 4- or 5-membered heteroaryl, in which one, two, or three carbon atoms are replaced by a nitrogen atom. A heterocycle may be fused to a cycloalkyl, aryl, or heteroaryl. Examples of heterocycles are azetidine, pyrrolidine, piperidine, 2,8-diazaspiro[4.5]decane, piperazine, morpholine, diazepane, azepane, azabicycloheptane, oxane, 1H,4H,5H,6H,7H,8H,9H-pyrrolo[2,3-c]azocine, 1H,4H,5H,6H-pyrrolo[2,3-c]pyrrole, 1,2,3,4-tetrahydroquinoxaline, tetrahydroquinoline, 1,2-dihydroquinoxa ... azaspiro[3.5]nonane, azaspiro[2.5]octane, 5H,6H,7H,8H,9H-[1,2,4]triazolo[4,3-a]azepino, 5H,6H,7H-[1,2,4]triazolo[4,3-a]azepino, 1-azabicyclo[4.1.1]octano, 1-azabicyclo[4.1.1]oct-3-enylo, and others.

[0018] The terms "heteroaryl," "heteroarylyl," and "heteroaryl ring" refer to an aromatic monocyclic or polycyclic ring system having 5 to 11, preferably 5 to 10, carbon atoms, one or more of which are replaced by heteroatoms such as nitrogen, sulfur, or oxygen. The nitrogen atom of the heterocycle may be oxidized to an N-oxide. The heteroaryl may have one or more substituents, which may be the same or different in structure. The heteroaryl may be fused with a cycloalkyl, aryl, or heterocycle.Examples of heteroaryls 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-tetrazole, quinoxaline, imidazo[1,2-a]pyridine, indole, benzimidazole, quinoline, imidazole, thienopyridine, quinazoline, naphthyridine, thienopyrimidine, imidazopyridine, quinoline, isoquinoline, quinoxaline, indole, 1H-pyrrolo[2,3-b]pyridine, 1H,6H,7H-pyrrolo[2,3-c]pyridine, 1H,4H,5H,6H,7H-pyrrolo[2,3-c]pyridine, 1H,4H,5H,6H,7H- 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]azocine, 1H,4H,5H,8H,9H-Pyrrolo[2,3-c]azocine, 1H,4H, 7H,8H,9H-Pyrrolo[2,3-c]azocine, 1H,6H,7H,8H,9H-Pyrrolo[2,3-c]azocine, 1H,8H,9H-Pyrrolo[2,3-c]azocine, 9H-Pyrrolo[2,3-c]azocine, 1H,4H,5H,6H-Pyrrolo[2,3-c]pyrrole, 1H-1,3-benzodiazole, 1H,2H,3H,4H,5H,6H-Pyrrolo[2,3-f][1,4]oxazepine, 3,4,6,13-tetraazatricyclo[8.3.0.0]azocine. 2 , 6 ]trideca-1(10),2,4,11-tetraenyl, 1,4-diazatricyclo[7.1.1.0 3 , 7 ]undeca-3(7),5-dienyl, and others.

[0019] "Substituent" means a chemical radical attached to a scaffold (fragment). A "solvate" is a molecular aggregate of a compound of the present invention, including a pharmaceutically acceptable salt thereof, with one or two solvent molecules. The solvent molecules are common pharmaceutical solvent molecules known to be safe for the recipient, 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 a more desirable solvate.

[0020] The term "hydrate" refers to the complex where the solvent molecule is water. The solvates and / or hydrates preferably exist in crystalline form. The term "bond," "chemical bond," or "single bond" refers to the chemical joining of two atoms or two moieties (i.e., groups, fragments) where the atoms joined by the bond are considered to be part of a larger substructure.

[0021] "

[0022] [ka]

[0023] The chemical bond in the compounds of the present invention represented by "" means a double bond, where the stereostructure of the substituents corresponds to the formula: "

[0024] [ka]

[0025] The chemical bond in the compounds of the present invention designated by " " denotes a double bond, which may have both a cis- and a trans-configuration. The term "stereoisomers" refers to compounds that have identical chemical composition and structure, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers can include geometric isomers, enantiomers, and diastereomers.

[0026] The term "standard treatment" includes extraction, treatment with acid, alkali and / or salt solutions to neutralize or otherwise change the pH and / or remove interfering substances, filtration through celite, silica gel and other materials, addition of inert carriers (celite, silica gel), removal of volatile components and solvents in vacuo.

[0027] The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. "Pharmaceutical composition" refers to a composition comprising a compound of the present invention and at least one excipient. The excipient can be selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, adjuvants, dispersing and sensing agents, delivery agents, such as preservatives, stabilizers, bulking agents, disintegrants, humectants, emulsifiers, suspending agents, thickeners, sweeteners, flavorings, fragrances, antibacterial agents, fungicides, lubricants, and long-term delivery control agents, the selection and proportion of which depend on the nature and route of administration and the dose. Examples of suspending agents include ethoxylated isostearyl alcohol, polyoxyethene, sorbitol and sorbitol ethers, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, as well as combinations thereof. Protection against microbial attack can be achieved 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 prolonged activity of the composition can be achieved by agents that slow the absorption of the active ingredient, such as aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents, and delivery agents include water, ethanol, polyalcohols and their mixtures, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Examples of fillers include lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate, etc. Examples of disintegrants and dispersing agents include starch, alginic acid and its salts, silicates, etc. Examples of lubricants include magnesium stearate, sodium lauryl sulfate, talc, and high-molecular-weight polyethylene glycol. Pharmaceutical compositions for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, topical, or rectal administration of the active ingredient can be administered to animals and humans in standard dosage forms or in admixture with traditional pharmaceutical carriers, either alone or together with other active ingredients. Suitable standard dosage forms include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gum and oral solutions or suspensions; sublingual and buccal dosage forms; aerosols; implants; topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular dosage forms and rectal dosage forms.

[0028] "Pharmaceutically acceptable salts" refers to both relatively non-toxic organic and inorganic salts of the acids and bases disclosed herein. These salts can be prepared in situ during the synthesis, isolation, or purification process of the compounds, or can be specially prepared. In particular, base salts can be specially prepared from the disclosed compounds and a purified base of a suitable organic or inorganic acid. Examples of salts prepared in this manner include hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valeriate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, tosylate, citrate, maleate, fumarate, succinate, tartrate, mesylate, malonate, salicylate, propionate, ethane sulfonate, benzene sulfonate, sulfamate, and the like. (A detailed description of such salts is provided in Berge, S. M., et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66:1-19.) Salts of the disclosed acids can be prepared by reaction of the purified acid with a suitable base; in addition, metal and amine salts can also be synthesized. Metal salts are sodium, potassium, calcium, barium, zinc, magnesium, lithium, and aluminum salts, with sodium and potassium salts being most preferred. Suitable inorganic bases from which metal salts can be prepared include sodium hydroxide, sodium carbonate, sodium bicarbonate, and sodium hydride; potassium hydroxide and potassium bicarbonate, lithium hydroxide, calcium hydroxide, magnesium hydroxide, and zinc hydroxide. Organic bases from which salts of the disclosed acids can be prepared are amines and amino acids that are sufficiently basic to produce stable salts and are suitable for medical use (particularly those that must have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris(hydroxymethyl)aminomethane, and the like.Additionally, salts can be prepared using tetraalkylammonium hydroxides, such as holine, tetramethylammonium, tetraethylammonium, etc. Basic amino acids, ie, lysine, ornithine, and arginine, can be used as amino acids.

[0029] "Medicinal products (drugs, medicines)" are compounds (or mixtures of compounds as pharmaceutical compositions) in tablets, granules, capsules, injections, ointments and other prepared forms, intended for the restoration, improvement or correction of physiological functions in humans and animals, as well as for the treatment and prevention of diseases, diagnosis, anesthetics, contraception, cosmetics and others.

[0030] "Treating," "treatment," and "therapy" refer to a method of alleviating or eliminating a biological disorder and / or at least one of its associated symptoms. The term "alleviating" a disease, disorder, or condition means reducing the severity and / or frequency of occurrence of the symptoms of the disease, disorder, or condition. Furthermore, references herein to "treatment" include references to curative, symptomatic, and prophylactic treatment.

[0031] "Prevention" and "prophylactic treatment" refer to a set of measures aimed at preventing the occurrence of, eliminating risk factors for, or early detection of a disease or disorder, its progression, worsening course, exacerbation, recurrence, complications, or other consequences.

[0032] In one aspect, the subject, or patient, of the prophylaxis or treatment is a mammal, preferably a human subject. The subject may be male or female and of any age. The term "disorder" or "disease" refers to any condition whose symptoms or the prognosis of a subject suffering from the condition can benefit from treatment according to the present invention. This definition of the term includes chronic and acute disorders or diseases, including pathological conditions that predispose a mammal to the disorder in question. Non-limiting examples of diseases to be treated include breast cancer, metastatic breast cancer, HER2-positive breast cancer, estrogen receptor-expressing breast cancer, progesterone receptor-expressing breast cancer, triple-negative breast cancer (TNBC), estrogen and / or progesterone receptor-expressing HER2-negative breast cancer, 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, Neoplastic diseases selected from the group consisting of oral squamous cell carcinoma, hepatobiliary cancer, hepatocellular carcinoma, urothelial carcinoma, 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 cancer, fallopian tube cancer, sarcoma, Ewing's sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, and multiple myeloma; an autoimmune disease selected from the group including axial spondyloarthritis, antiphospholipid syndrome, vasculitis (Wegener's granulomatosis and related forms of vasculitis, temporal arteritis and polyarteritis nodosa, ANCA-associated vasculitis including necrotizing vasculitis), Goodpasture's syndrome, autoimmune thyroiditis, Graves' disease, bronchial asthma, cardiomyopathy, Crohn's disease, dermatomyositis, polymyositis, mixed connective tissue disease, glomerulonephritis, Guillain-Barré syndrome, Lyme arthritis, psoriasis, pemphigus, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis, and uveitis; Behçet's disease, Blau syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, acne, pustulosis, osteophytosis, and 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 neonatal neurocutaneous and articular (CINCA) syndrome, and Majeed syndrome , an autoinflammatory disease selected from the group including mevalonate kinase deficiency (hyperimmunoglobulin D syndrome), periodic fever, aphthous stomatitis, pharyngitis and cervical lymphadenitis (PFAPA) syndrome, septic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, Schnitzler syndrome, Sweet syndrome, systemic juvenile idiopathic arthritis, Still's disease, adult-onset Still's disease (AOSD), and tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS); Allergy (including, but not limited to, delayed hypersensitivity reactions, immediate hypersensitivity reactions, and anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, osteitis, adult respiratory distress syndrome, airway inflammation (bronchiolitis, bronchitis, bronchiectasis, cellular interstitial pneumonia, giant cell interstitial pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, (including but not limited to hypersensitivity pneumonitis, laryngitis, pneumonitis, pharyngitis, pleuritis, pneumonia, pneumoconiosis, asbestosis, beryllium disease, silicosis, tallithiasis, and common interstitial pneumonia), tonsillitis, bursitis, cellulitis, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes, encephalitis, endocarditis, epicondylitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, gingivitis, stomatitis, and phosphate Adenitis, hay fever, inflammatory bowel disease (including, but not limited to, appendicitis, enteritis, enterocolitis, ileitis, necrotizing enterocolitis, proctitis, and 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, and inflammatory bowel disease (inflammatory bowel disease). The present invention also includes infectious or non-infectious inflammatory diseases selected from the group consisting of horse fever, rhinitis, sinusitis, synovitis, tendonitis, necrotizing fasciitis, prostatitis, cystitis, epididymitis, omphalitis, oophoritis, orchitis, orchitis, transverse myelitis, urethritis, urocystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, and vulvovaginitis.

[0033] A "therapeutically effective amount" refers to the amount of a therapeutic agent administered in the course of treatment that reduces the severity of or eliminates the symptoms of the disease being treated. As used in this specification and the claims that follow, unless the context dictates otherwise, the words "have," "include," and "comprise" or variations thereof, such as "has," "having," "includes," "including," "comprises," or "comprising," are understood to imply the inclusion of a specified integer or group of integers, but not the exclusion of any other integer or group of integers. [Brief explanation of the drawings]

[0034] [Figure 1] Figure 1 shows tumor growth kinetics of NCI-H69 xenografts in the control group and in the group receiving compound CDK7_1187 at a dose of 6 mg / kg QD for 21 days. Data are presented as the arithmetic mean of tumor volume ± standard error of the mean.

[0035] Note: * - p<0.05; statistically significant difference from the control group (Mann-Whitney test). DETAILED DESCRIPTION OF THE INVENTION

[0036] In one aspect, the present invention provides a compound of formula I

[0037] [ka]

[0038] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof wherein R1 is -C(Hal)3, -CH(Hal)2, -CH2Hal, -Hal, -H, -NO2, -(C1-C6)alkyl which is unsubstituted or substituted by one or several Hal atoms, -O-(C1-C6)alkyl which is unsubstituted or substituted by one or several Hal atoms, -S-(C1-C6)alkyl which is unsubstituted or substituted by one or several Hal atoms, R2 and R3 are each independently H or -(C1-C6) alkyl; or R2 and R3 together form a -(C3-C6)cycloalkyl which is unsubstituted or substituted by one or several -(C1-C6)alkyl groups; L1 and L2 each independently represent 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 -, -Р(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 a 6- to 10-membered aryl unsubstituted or substituted by one or several R7; 7a and is unsubstituted or substituted with one or several R 8a 6-10 membered aryl fused to -(C3-C6)cycloalkyl substituted by; unsubstituted or one or several R 7b and containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, and is unsubstituted or substituted with one or several R 8b a 6- to 10-membered aryl fused to a 4- to 10-membered heterocyclyl substituted by 7c and containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, and is unsubstituted or substituted with one or several R 8c a 6- to 10-membered aryl fused to a 5- to 6-membered heteroaryl substituted by 7d5-6 membered heteroaryl substituted by: 7e and is unsubstituted or substituted with one or several R 8e 5-6 membered heteroaryl fused to (C3-C6)cycloalkyl substituted by: 7f and containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, and is unsubstituted or substituted with one or several R 8f a 5- to 6-membered heteroaryl fused to a 4- to 10-membered heterocyclyl substituted by 7g 5-6 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted with one or several R 7h and containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, and is unsubstituted or substituted with one or several R 8h a 5- to 6-membered heterocyclyl fused to a 4- to 10-membered heterocyclyl substituted by 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 one or several R 4c -(C1-C6) alkyl substituted by; unsubstituted or one or several R 4d -O-C1-C6 alkyl substituted by; unsubstituted or one or several R 4e phenyl substituted by one, two, three or four heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R 4f 4- to 7-membered heterocyclyl substituted by; unsubstituted or substituted by one or several R 4g-(C3-C6)cycloalkyl substituted by; unsubstituted or one or several R 4h -C2-C6 alkenyl containing 1, 2, 3 or 4 N atoms and unsubstituted or substituted by one or several R 4i 5-6 membered heteroaryl containing one or two heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R 4j and is unsubstituted or substituted with one or several R 4k 4- to 7-membered heterocyclyl fused to phenyl substituted by 4l and is unsubstituted or substituted with one or several R 4m is a 5- to 6-membered heteroaryl fused to a phenyl substituted by 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 -H, (=O), -OH, -NH2, -Hal, -CN, -C1-C6 alkyl unsubstituted or substituted by one or several radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -O-C1-C6 alkyl unsubstituted or substituted by one or several radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -C3-C6 cycloalkyl unsubstituted or substituted by one or several radicals 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 5aare each independently —H or C1-C6 alkyl, R 6a , R 6b are each independently -H, C1-C6 alkyl, or -Hal; Or, R 6a and R 6b form together with the C atom to which they are attached a C3-C6 cycloalkyl which is unsubstituted or substituted by several -(C1-C6)alkyls, R7, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h are each independently -Hal, -OH, -NH, -CN, (=O), -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8h are each independently -Hal, -OH, -NH, -CN, (=O), or -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; Hal is an atom of F, Cl, Br, or I).

[0039] In one aspect, the present invention provides a compound of formula I

[0040] [ka]

[0041] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof wherein R1 is -C(Hal)3, -CH(Hal)2, -CH2Hal, -Hal, -H, -NO2, -(C1-C6)alkyl which is unsubstituted or substituted by one or several Hal atoms, -O-(C1-C6)alkyl which is unsubstituted or substituted by one or several Hal atoms, -S-(C1-C6)alkyl which is unsubstituted or substituted by one or several Hal atoms, R2 and R3 are each independently H or -(C1-C6) alkyl; or R2 and R3 together form a -(C3-C6)cycloalkyl which is unsubstituted or substituted by one or several -(C1-C6)alkyl groups; L1 and L2 each independently represent 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 -, -Р(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 a 6- to 10-membered aryl unsubstituted or substituted by one or several R7; 7a and is unsubstituted or substituted with one or several R 8a 6-10 membered aryl fused to -(C3-C6)cycloalkyl substituted by; unsubstituted or one or several R 7b and containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, and is unsubstituted or substituted with one or several R 8b a 6- to 10-membered aryl fused to a 4- to 10-membered heterocyclyl substituted by 7cand containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, and is unsubstituted or substituted with one or several R 8c a 6- to 10-membered aryl fused to a 5- to 6-membered heteroaryl substituted by 7d 5-6 membered heteroaryl substituted by: 7e and is unsubstituted or substituted with one or several R 8e 5-6 membered heteroaryl fused to (C3-C6)cycloalkyl substituted by: 7f and containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, and is unsubstituted or substituted with one or several R 8f a 5- to 6-membered heteroaryl fused to a 4- to 10-membered heterocyclyl substituted by 7g 5-6 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted with one or several R 7h and containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, and is unsubstituted or substituted with one or several R 8h a 5- to 6-membered heterocyclyl fused to a 4- to 10-membered heterocyclyl substituted by 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 one or several R 4c -(C1-C6) alkyl substituted by; unsubstituted or one or several R 4d -O-C1-C6 alkyl substituted by; unsubstituted or one or several R4e phenyl substituted by one, two, three or four heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R 4f 4- to 7-membered heterocyclyl substituted by; unsubstituted or substituted by one or several R 4g -(C3-C6)cycloalkyl substituted by; unsubstituted or one or several R 4h -C2-C6 alkenyl containing 1, 2, 3 or 4 N atoms and unsubstituted or substituted by one or several R 4i 5-6 membered heteroaryl containing one or two heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R 4j and is unsubstituted or substituted with one or several R 4k 4- to 7-membered heterocyclyl fused to phenyl substituted by 4l and is unsubstituted or substituted with one or several R 4m is a 5- to 6-membered heteroaryl fused to a phenyl substituted by 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 4mare each independently -H, (=O), -OH, -NH2, -Hal, -CN, -C1-C6 alkyl unsubstituted or substituted by one or several radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -O-C1-C6 alkyl unsubstituted or substituted by one or several radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -C3-C6 cycloalkyl unsubstituted or substituted by one or several radicals 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 are each independently —H or C1-C6 alkyl, R 6a , R 6b are each independently -H, C1-C6 alkyl, or -Hal; Or, R 6a and R 6b form together with the C atom to which they are attached a C3-C6 cycloalkyl which is unsubstituted or substituted by several -(C1-C6)alkyls, R7, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h are each independently -Hal, -OH, -NH, -CN, (=O), -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8hare each independently -Hal, -OH, -NH, -CN, (=O), or -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; Hal is an atom of F, Cl, Br, or I).

[0042] In one aspect, the present invention provides a compound of formula Ib

[0043] [ka]

[0044] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof wherein R1 is -C(Hal)3, -CH(Hal)2, -CH2Hal, -Hal, -H, -NO2, -(C1-C6)alkyl which is unsubstituted or substituted by one or several Hal atoms, -O-(C1-C6)alkyl which is unsubstituted or substituted by one or several Hal atoms, -S-(C1-C6)alkyl which is unsubstituted or substituted by one or several Hal atoms, R2 and R3 are each independently H or -(C1-C6) alkyl; or R2 and R3 together form a -(C3-C6)cycloalkyl which is unsubstituted or substituted by one or several -(C1-C6)alkyl groups; L1 and L2 each independently represent 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 -, -Р(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 a 6- to 10-membered aryl unsubstituted or substituted by one or several R7; 7a and is unsubstituted or substituted with one or several R 8a 6-10 membered aryl fused to -(C3-C6)cycloalkyl substituted by; unsubstituted or one or several R 7b and containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, and is unsubstituted or substituted with one or several R 8b a 6- to 10-membered aryl fused to a 4- to 10-membered heterocyclyl substituted by 7c and containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, and is unsubstituted or substituted with one or several R 8c a 6- to 10-membered aryl fused to a 5- to 6-membered heteroaryl substituted by 7d 5-6 membered heteroaryl substituted by: 7e and is unsubstituted or substituted with one or several R 8e 5-6 membered heteroaryl fused to (C3-C6)cycloalkyl substituted by: 7f and containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, and is unsubstituted or substituted with one or several R 8f a 5- to 6-membered heteroaryl fused to a 4- to 10-membered heterocyclyl substituted by 7g 5-6 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted with one or several R7h and containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, and is unsubstituted or substituted with one or several R 8h a 5- to 6-membered heterocyclyl fused to a 4- to 10-membered heterocyclyl substituted by 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 one or several R 4c -(C1-C6) alkyl substituted by; unsubstituted or one or several R 4d -O-C1-C6 alkyl substituted by; unsubstituted or one or several R 4e phenyl substituted by one, two, three or four heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R 4f 4- to 7-membered heterocyclyl substituted by; unsubstituted or substituted by one or several R 4g -(C3-C6)cycloalkyl substituted by; unsubstituted or one or several R 4h -C2-C6 alkenyl containing 1, 2, 3 or 4 N atoms and unsubstituted or substituted by one or several R 4i 5-6 membered heteroaryl containing one or two heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R 4j and is unsubstituted or substituted with one or several R 4k 4- to 7-membered heterocyclyl fused to phenyl substituted by 4l and is unsubstituted or substituted with one or several R 4m is a 5- to 6-membered heteroaryl fused to a phenyl substituted by R 4a , R 4b , R 4c , R 4d , R 4e , R4f , R 4g , R 4h , R 4i , R 4j , R 4k , R 4l , R 4m are each independently -H, (=O), -OH, -NH2, -Hal, -CN, -C1-C6 alkyl unsubstituted or substituted by one or several radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -O-C1-C6 alkyl unsubstituted or substituted by one or several radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -C3-C6 cycloalkyl unsubstituted or substituted by one or several radicals 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 are each independently —H or C1-C6 alkyl, R 6a , R 6b are each independently -H, C1-C6 alkyl, or -Hal; Or, R 6a and R 6b form together with the C atom to which they are attached a C3-C6 cycloalkyl which is unsubstituted or substituted by several -(C1-C6)alkyls, R7, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h are each independently -Hal, -OH, -NH, -CN, (=O), -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; R 8a , R8b , R 8c , R 8d , R 8e , R 8f , R 8h are each independently -Hal, -OH, -NH, -CN, (=O), or -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; Hal is an atom of F, Cl, Br, or I).

[0045] In one aspect, the present invention relates to the S isomer of the compound of formula I. In one aspect, the present invention provides a compound in which -A-L2-R4 is

[0046] [ka]

[0047] [ka]

[0048] [ka]

[0049] (In the formula, k and m each independently represent 0, 1, 2, or 3, X1, X2, X3, X4, X5, and X6 each independently represent a C atom, a N atom, CH, CH2, NH, S, or O; Y1, Y2, Y3, Y4, and Y5 each independently represent a C atom, a N atom, 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 -, -Р(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 -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 one or several R 4c -(C1-C6) alkyl substituted by; unsubstituted or one or several R 4d -O-C1-C6 alkyl substituted by; unsubstituted or one or several R 4e phenyl substituted by one, two, three or four heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R 4f 4- to 7-membered heterocyclyl substituted by; unsubstituted or substituted by one or several R 4g -(C3-C6)cycloalkyl substituted by; unsubstituted or one or several R 4h -C2-C6 alkenyl containing 1, 2, 3 or 4 N atoms and unsubstituted or substituted by one or several R 4i 5-6 membered heteroaryl containing one or two heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R 4j and is unsubstituted or substituted with one or several R 4k 4- to 7-membered heterocyclyl fused to phenyl substituted by 4l and is unsubstituted or substituted with one or several R 4m is a 5- to 6-membered heteroaryl fused to a phenyl substituted by R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R4g , R 4h , R 4i , R 4j , R 4k , R 4l , R 4m are each independently -H, (=O), -OH, -NH2, -Hal, -CN, -C1-C6 alkyl unsubstituted or substituted by one or several radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -O-C1-C6 alkyl unsubstituted or substituted by one or several radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -C3-C6 cycloalkyl unsubstituted or substituted by one or several radicals 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 are each independently —H or C1-C6 alkyl, R 6a , R 6b are each independently -H, C1-C6 alkyl, or -Hal; Or, R 6a and R 6b form together with the C atom to which they are attached a C3-C6 cycloalkyl which is unsubstituted or substituted by several -(C1-C6)alkyls, R7, R 7b , R 7d , R 7f are each independently -Hal, -OH, -NH, -CN, (=O), -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; R 8b , R 8d , R 8fare each independently -Hal, -OH, -NH, -CN, (=O), or -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; Hal is an atom of F, Cl, Br, I).

[0050] In one aspect, the present invention provides a compound in which -A-L2-R4 is

[0051] [ka]

[0052] [ka]

[0053] [ka]

[0054] [ka]

[0055] [ka]

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] [ka]

[0060] [ka]

[0061] [ka]

[0062] (wherein each p is independently 0 or 1, each q is independently 0, 1 or 2, and the total number of substituents on each ring is 3 or less; X1, X2, X3, X4, X5, and X6 each independently represent a C atom, a N atom, CH, CH2, NH, S, or O; Y1, Y2, Y3, Y4, and Y5 each independently represent a C atom, a N atom, 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 -, -Р(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 -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 one or several R 4c -(C1-C6) alkyl substituted by; unsubstituted or one or several R 4d-O-C1-C6 alkyl substituted by; unsubstituted or one or several R 4e phenyl substituted by one, two, three or four heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R 4f 4- to 7-membered heterocyclyl substituted by; unsubstituted or substituted by one or several R 4g -(C3-C6)cycloalkyl substituted by; unsubstituted or one or several R 4h -C2-C6 alkenyl containing 1, 2, 3 or 4 N atoms and unsubstituted or substituted by one or several R 4i 5-6 membered heteroaryl containing one or two heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R 4j and is unsubstituted or substituted with one or several R 4k 4- to 7-membered heterocyclyl fused to phenyl substituted by 4l and is unsubstituted or substituted with one or several R 4m is a 5- to 6-membered heteroaryl fused to a phenyl substituted by 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 4mare each independently -H, (=O), -OH, -NH2, -Hal, -CN, -C1-C6 alkyl unsubstituted or substituted by one or several radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -O-C1-C6 alkyl unsubstituted or substituted by one or several radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -C3-C6 cycloalkyl unsubstituted or substituted by one or several radicals 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 are each independently —H or C1-C6 alkyl, R 6a , R 6b are each independently -H, C1-C6 alkyl, or -Hal; Or, R 6a and R 6b form together with the C atom to which they are attached a C3-C6 cycloalkyl which is unsubstituted or substituted by several -(C1-C6)alkyls, R7, R 7b , R 7d , R 7f are each independently -Hal, -OH, -NH, -CN, (=O), -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; R 8b , R 8d , R 8f are each independently -Hal, -OH, -NH, -CN, (=O), or -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; Hal is an atom of F, Cl, Br, I).

[0063] In one aspect, the present invention provides a compound in which -A-L2-R4 is

[0064] [ka]

[0065] [ka]

[0066] [ka]

[0067] (In the formula, k and m each independently represent 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 -, -Р(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 -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 one or several R 4c -(C1-C6) alkyl substituted by; unsubstituted or one or several R 4d -O-C1-C6 alkyl substituted by; unsubstituted or one or several R 4ephenyl substituted by one, two, three or four heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R 4f 4- to 7-membered heterocyclyl substituted by; unsubstituted or substituted by one or several R 4g -(C3-C6)cycloalkyl substituted by; unsubstituted or one or several R 4h -C2-C6 alkenyl containing 1, 2, 3 or 4 N atoms and unsubstituted or substituted by one or several R 4i 5-6 membered heteroaryl containing one or two heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R 4j and is unsubstituted or substituted with one or several R 4k 4- to 7-membered heterocyclyl fused to phenyl substituted by 4l and is unsubstituted or substituted with one or several R 4m is a 5- to 6-membered heteroaryl fused to a phenyl substituted by 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 4mare each independently -H, (=O), -OH, -NH2, -Hal, -CN, -C1-C6 alkyl unsubstituted or substituted by one or several radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -O-C1-C6 alkyl unsubstituted or substituted by one or several radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -C3-C6 cycloalkyl unsubstituted or substituted by one or several radicals 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 are each independently —H or C1-C6 alkyl, R 6a , R 6b are each independently -H, C1-C6 alkyl, or -Hal; Or, R 6a and R 6b form together with the C atom to which they are attached a C3-C6 cycloalkyl which is unsubstituted or substituted by several -(C1-C6)alkyls, R7, R 7b , R 7d , R 7f are each independently -Hal, -OH, -NH, -CN, (=O), -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; R 8b , R 8d , R 8f are each independently -Hal, -OH, -NH, -CN, (=O), or -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; Hal is an atom of F, Cl, Br, I).

[0068] In one aspect, the present invention provides a compound in which -A-L2-R4 is

[0069] [ka]

[0070] [ka]

[0071] [ka]

[0072] [ka]

[0073] [ka]

[0074] [ka]

[0075] [ka]

[0076] [ka]

[0077] [ka]

[0078] [ka]

[0079] (wherein each p is independently 0 or 1, each q is independently 0, 1 or 2, and the total number of substituents on each ring is 3 or less; 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 -, -Р(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 -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 one or several R 4c -(C1-C6) alkyl substituted by; unsubstituted or one or several R 4d -O-C1-C6 alkyl substituted by; unsubstituted or one or several R 4e phenyl substituted by one, two, three or four heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R 4f 4- to 7-membered heterocyclyl substituted by; unsubstituted or substituted by one or several R 4g -(C3-C6)cycloalkyl substituted by; unsubstituted or one or several R 4h -C2-C6 alkenyl containing 1, 2, 3 or 4 N atoms and unsubstituted or substituted by one or several R 4i 5-6 membered heteroaryl containing one or two heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R 4jand is unsubstituted or substituted with one or several R 4k 4- to 7-membered heterocyclyl fused to phenyl substituted by 4l and is unsubstituted or substituted with one or several R 4m is a 5- to 6-membered heteroaryl fused to a phenyl substituted by 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 are each independently -H, (=O), -OH, -NH2, -Hal, -CN, -C1-C6 alkyl unsubstituted or substituted by one or several radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -O-C1-C6 alkyl unsubstituted or substituted by one or several radicals selected from -Hal, -OH, -NH2, -CN, phenyl; -C3-C6 cycloalkyl unsubstituted or substituted by one or several radicals 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 are each independently —H or C1-C6 alkyl, R 6a , R 6b are each independently -H, C1-C6 alkyl, or -Hal; Or, R 6a and R 6bform together with the C atom to which they are attached a C3-C6 cycloalkyl which is unsubstituted or substituted by several -(C1-C6)alkyls, R7, R 7b , R 7d , R 7f are each independently -Hal, -OH, -NH, -CN, (=O), -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; R 8b , R 8d , R 8f are each independently -Hal, -OH, -NH, -CN, (=O), or -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal; Hal is an atom of F, Cl, Br, I).

[0080] In one aspect, the present invention relates to compounds 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-, -Π(O)(CH3)-, -C(O)O-, -C(O)-NH-, or -NH-C(O)-.

[0081] In one aspect, the present invention relates to compounds wherein R1 is -H, -CF3, -CCl3, -CHF2, -CH2F, -CHCl2, -CH2Cl, -NO2. In one aspect, the present invention relates to compounds in which R2, 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.

[0082] In one aspect, the present invention provides a method for the preparation of a compound in which R4 is -H, (=O), -OH, -F, -Cl, -Br, -P(O)(C1-C6 alkyl)2; -S(O)2NH2; -S(O)2-(C1-C6)alkyl; -(C1-C6)alkyl unsubstituted or substituted with one or several (=O), -Hal, -CN, -S(O)2-(C1-C6)alkyl; -O-(C1-C6)alkyl unsubstituted or substituted with one or several (=O), -CN, -Hal; -(C3-C6)cycloalkyl unsubstituted or substituted with one or several (=O), -OH, -Hal, -CN; -(C3-C6)cycloalkyl unsubstituted or substituted with one or several (=O), -OH, -Hal, -CN; phenyl substituted with phosphorus or -P(O)(CH3)2; 5- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N or O and unsubstituted or substituted with -(C1-C6)alkyl, (=O), -Hal, or -CN; 5- to 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S and unsubstituted or substituted with (=O), -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -Hal, or -CN; 5- to 6-membered heteroaryl containing 1 or 2 N atoms and unsubstituted or substituted with one or several (=O), -(C1-C6)alkyl, and fused to a phenyl; -NR 4a R 4b and R 4a , R 4b are each independently -H, (=O), morpholinyl, -F, -S(O)2CH3, -CN, -one, cyclopropyl, thiazolyl, -C1-C3 alkyl unsubstituted or substituted with phenyl, -P(O)(CH3)2.

[0083] In one aspect, the present invention provides a compound in which R4 is -H, -OH, (=O), -P(O)(CH3)2, -CH3, -CH2CN3, tert-butyl, -CH2CF3, -CH2CH2S(O)2CH3, -CF3, -Cl, -OCF3, -S(O)2NH2, -S(O)2CH3, unsubstituted or substituted by one or several -Hal, -CN, phenyl, methylpiperazinyl, piperazinyl, imidazolyl, thiazolyl, methylpyrazolyl, pyrazolyl, pyridinyl, pyrimidinyl, morpholine, oxanyl, oxolanyl, cyclohexyl, cyclopentyl, cyclopropyl, oxazolyl, methyloxazolyl, dimethyloxazolyl, dihydropyridinyl, methyldihydropyridinyl, -NR 4a R 4b and R 4a , R 4b are each independently -H, (=O), morpholinyl, -F, -S(O)2CH3, -CN, -one, cyclopropyl, thiazolyl, -C1-C3 alkyl unsubstituted or substituted with phenyl, -P(O)(CH3)2.

[0084] In one aspect, the present invention provides a compound comprising 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 are each independently -H, (=O)-CH3, morpholinyl, -F, -S(O)2CH3, -CN, -OH, cyclopropyl, thiazolyl, -C1-C3 alkyl unsubstituted or substituted with phenyl, -P(O)(CH3)2.

[0085] In one aspect, the present invention relates to compounds wherein R5 is -H, -CH3. In one aspect, the present invention provides a compound comprising R 6a and R 6bare each independently -H, -F, or -CH3, or R 6a and R 6b together with the C atom to which they are attached is cyclopropyl.

[0086] In one aspect, the present invention provides a compound comprising R7, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h are each independently (=O), -Hal, -CH3; -OCH3; -CHal3; -OCHal3.

[0087] In one aspect, the present invention provides a compound comprising R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8h are each independently (=O), -Hal, -CH3; -OCH3; -CHal3; -OCHal3.

[0088] The compounds described in the present invention can be obtained and / or used as pharmaceutically acceptable salts.The types of pharmaceutically acceptable salts include salts obtained by dissolving the free base compounds with pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; or salts obtained by dissolving the free base compounds with pharmaceutically acceptable inorganic 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-hydroxybenzoylbenzoic acid, ... and the like. Examples of suitable acid salts include, but are not limited to, acid salts formed by reacting with organic acids such as ethanedisulfonic 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, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.

[0089] The corresponding counter ions of pharmaceutically acceptable salts can be analyzed and identified using a variety of methods, including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectrometry, mass spectrometry, or any combination thereof.

[0090] The salts are recovered by at least one of the following methods: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, lyophilization. Reference to a pharmaceutically acceptable salt should be understood to include its solvent addition forms or crystalline forms, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and can be formed during the crystallization process using a pharmaceutically acceptable solvent, such as water, ethanol, etc. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Solvates of the compounds described in this patent can be conveniently prepared or formed during the processes described in the present invention. In addition, the compounds provided in the present invention can exist in both unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided in the present invention.

[0091] The compounds described in the present invention can be provided in various forms, including but not limited to amorphous form, pulverized form and nanoparticle form.In addition, the compounds described in the present invention also include crystalline forms, also known as polymorphs.Polymorphs include different crystalline structures of the same elemental composition of a 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.Depending on various factors, such as recrystallization solvent, crystallization speed and storage temperature, one crystalline form may be dominant.

[0092] Screening and characterization of pharmaceutically acceptable salts, polymorphs, and / or solvates can be achieved using a variety of techniques, including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis techniques rely on the analysis of thermochemical decomposition or thermophysical processes, including, but not limited to, polymorphic transitions, and are used to analyze relationships between polymorphic forms, determine weight loss, find glass transition temperatures, or for excipient compatibility studies. Such techniques include, but are not limited to, differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), thermogravimetry, and infrared analysis (TG / IR). Crystallographic techniques include, but are not limited to, single crystal and powder diffractometers and synchrotron radiation sources. Various spectroscopic techniques used include, but are not limited to, Raman (combined scattering), FTIR, UVIS, and NMR (liquid and solid state). 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.

[0093] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising:

[0094] [Table 1-1]

[0095] [Table 1-2]

[0096] [Table 1-3]

[0097] [Table 1-4]

[0098]

Table 1-5

[0099]

Table 1-6

[0100]

Table 1-7

[0101]

Table 1-8

[0102]

Table 1-9

[0103]

Table 1-10

[0104]

Table 1-11

[0105]

Table 1-12

[0106]

Table 1-13

[0107]

Table 1-14

[0108]

Table 1-15

[0109]

Table 1-16

[0110]

Table 1-17

[0111]

Table 1-18

[0112]

Table 1-19

[0113]

Table 1-20

[0114]

Table 1-21

[0115]

Table 1-22

[0116]

Table 1-23

[0117]

Table 1-24

[0118]

Table 1-25

[0119]

Table 1-26

[0120]

Table 1-27

[0121]

Table 1-28

[0122]

Table 1-29

[0123]

Table 1-30

[0124]

Table 1-31

[0125]

Table 1-32

[0126]

Table 1-33

[0127]

Table 1-34

[0128]

Table 1-35

[0129]

Table 1-36

[0130]

Table 1-37

[0131]

Table 1-38

[0132]

Table 1-39

[0133]

Table 1-40

[0134]

Table 1-41

[0135]

Table 1-42

[0136]

Table 1-43

[0137]

Table 1-44

[0138]

Table 1-45

[0139]

Table 1-46

[0140]

Table 1-47

[0141]

Table 1-48

[0142]

Table 1-49

[0143]

Table 1-50

[0144]

Table 1-51

[0145]

Table 1-52

[0146]

Table 1-53

[0147]

Table 1-54

[0148]

Table 1-55

[0149]

Table 1-56

[0150]

Table 1-57

[0151]

Table 1-58

[0152]

Table 1-59

[0153]

Table 1-60

[0154]

Table 1-61

[0155]

Table 1-62

[0156]

Table 1-63

[0157]

Table 1-64

[0158]

Table 1-65

[0159] [Table 1-66]

[0160] The present invention relates to a compound selected from the group comprising: The present invention also relates to a method of inhibiting the biological activity of cyclin-dependent protein kinase CDK7 in a subject, comprising the step of contacting the cyclin-dependent protein kinase CDK7 with a compound of the present invention.

[0161] CDK7 inhibitor compounds can be used to manufacture medicaments intended to treat any disease state described herein, for example, the compounds of formula I, pharmaceutically acceptable salts, solvates or stereoisomers are useful in the prevention or treatment of diseases or medical conditions associated solely or partially with CDK7 activity, such as neoplastic, infectious inflammatory or non-infectious inflammatory, autoinflammatory, autoimmune diseases.Exemplary neoplastic diseases that may be suitable for treatment using the compounds include breast cancer, metastatic breast cancer, HER2-positive breast cancer, estrogen receptor-expressing breast cancer, progesterone receptor-expressing breast cancer, triple-negative breast cancer (TNBC), estrogen and / or progesterone receptor-expressing HER2-negative breast cancer, 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, The cancer is selected from the group including, but not limited to, oral cancer, oral squamous cell carcinoma, hepatobiliary cancer, hepatocellular carcinoma, urothelial carcinoma, 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 cancer, fallopian tube cancer, sarcoma, Ewing's sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, and multiple myeloma.

[0162] Exemplary autoimmune diseases are selected from the group including, but not limited to, axial spondyloarthritis, antiphospholipid syndrome, vasculitis (Wegener's granulomatosis and related forms of vasculitis, temporal arteritis and polyarteritis nodosa, ANCA-associated vasculitis including necrotizing vasculitis), Goodpasture's syndrome, autoimmune thyroiditis, Graves' disease, bronchial asthma, cardiomyopathy, Crohn's disease, dermatomyositis, polymyositis, mixed connective tissue disease, glomerulonephritis, Guillain-Barré syndrome, Lyme arthritis, psoriasis, pemphigus, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis, and uveitis.

[0163] Exemplary autoinflammatory diseases include Behçet's disease, Blau syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, cryopyrin-associated periodic syndromes (CAPS), interleukin-1 receptor antagonist molecule deficiency (DIRA), familial Mediterranean fever (FMF), NLRP12-associated autoinflammatory disease, neonatal-onset multisystem inflammatory disease (NOMID), chronic neonatal neurocutaneous and articular (CINCA) syndrome, and Majeed syndrome. syndrome, mevalonate kinase deficiency (hyperimmunoglobulin D syndrome), periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome, septic 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).

[0164] Exemplary infectious or non-infectious inflammatory diseases include allergies (including, but not limited to, delayed hypersensitivity reactions, immediate hypersensitivity reactions, and anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, osteitis, adult respiratory distress syndrome, inflammation of the airways (bronchiolitis, bronchitis, bronchiectasis, interstitial pneumonia, giant cell interstitial pneumonia), and the like. (including but not limited to) lymphoid interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonitis, laryngitis, pneumonitis, pharyngitis, pleuritis, pneumonia, pneumoconiosis, asbestosis, beryllium disease, silicosis, tallithiasis, and usual interstitial pneumonia), tonsillitis, bursitis, cellulitis, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes, encephalitis, endocarditis, epicondylitis, fasciitis, and 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 sclerosis The inflammatory bowel disease may be selected from the group including, but not limited to, cholangitis, reperfusion injury, acute rheumatic fever, rhinitis, sinusitis, synovitis, tendonitis, necrotizing fasciitis, prostatitis, cystitis, epididymitis, omphalitis, oophoritis, orchitis, orchitis, transverse myelitis, urethritis, urocystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, and vulvovaginitis.

[0165] In one aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

[0166] In one aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

[0167] In another aspect, the pharmaceutical composition of the present invention is intended for treating or preventing a disease or disorder associated with increased activity of the cyclin-dependent protein kinase CDK7. In another aspect of the present invention, the pharmaceutical composition according to the present invention is intended for preventing or treating a disease or disorder associated with increased activity of the cyclin-dependent protein kinase CDK7, wherein the disease or disorder associated with increased activity of the cyclin-dependent protein kinase CDK7 is a neoplastic, infectious or non-infectious inflammatory, autoinflammatory, or autoimmune disease.

[0168] In another aspect of the invention, pharmaceutical compositions comprising the compounds of the invention are intended to prevent or treat: Breast cancer, metastatic breast cancer, HER2-positive breast cancer, estrogen receptor-expressing breast cancer, progesterone receptor-expressing breast cancer, triple-negative breast cancer (TNBC), estrogen and / or progesterone receptor-expressing HER2-negative breast cancer, 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 Neoplastic diseases selected from the group consisting of hepatobiliary cancer, hepatocellular carcinoma, urothelial carcinoma, 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 cancer, fallopian tube cancer, sarcoma, Ewing's sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, and multiple myeloma; an autoimmune disease selected from the group including axial spondyloarthritis, antiphospholipid syndrome, vasculitis (Wegener's granulomatosis and related forms of vasculitis, temporal arteritis and polyarteritis nodosa, ANCA-associated vasculitis including necrotizing vasculitis), Goodpasture's syndrome, autoimmune thyroiditis, Graves' disease, bronchial asthma, cardiomyopathy, Crohn's disease, dermatomyositis, polymyositis, mixed connective tissue disease, glomerulonephritis, Guillain-Barré syndrome, Lyme arthritis, psoriasis, pemphigus, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis, and uveitis; Behçet's disease, Blau syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, acne, pustulosis, osteophytosis, and 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 neonatal neurocutaneous and articular (CINCA) syndrome, and Majeed syndrome , an autoinflammatory disease selected from the group including mevalonate kinase deficiency (hyperimmunoglobulin D syndrome), periodic fever, aphthous stomatitis, pharyngitis and cervical lymphadenitis (PFAPA) syndrome, septic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, Schnitzler syndrome, Sweet syndrome, systemic juvenile idiopathic arthritis, Still's disease, adult-onset Still's disease (AOSD), and tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS); Allergy (including, but not limited to, delayed hypersensitivity reactions, immediate hypersensitivity reactions, and anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, osteitis, adult respiratory distress syndrome, airway inflammation (bronchiolitis, bronchitis, bronchiectasis, cellular interstitial pneumonia, giant cell interstitial pneumonia, lymphocytic interstitial pneumonia, and desquamative interstitial pneumonia) , hypersensitivity pneumonitis, laryngitis, pneumonitis, pharyngitis, pleuritis, pneumonia, pneumoconiosis, asbestosis, beryllium disease, silicosis, talculosis, and common interstitial pneumonia), tonsillitis, bursitis, cellulitis, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes, encephalitis, endocarditis, epicondylitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, gingivitis, and stomatitis. Lymphadenitis, hay fever, inflammatory bowel disease (including, but not limited to, appendicitis, enteritis, enterocolitis, ileitis, necrotizing enterocolitis, proctitis, and 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, and reperfusion injury , acute rheumatic fever, rhinitis, sinusitis, synovitis, tendonitis, necrotizing fasciitis, prostatitis, cystitis, epididymitis, omphalitis, oophoritis, orchitis, orchitis, transverse myelitis, urethritis, urocystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, and vulvovaginitis.

[0169] In another aspect of the invention, the pharmaceutical composition comprising the compound according to the invention is intended for the prevention or treatment of the following neoplastic diseases: breast cancer, metastatic breast cancer, HER2-positive breast cancer, estrogen receptor-expressing breast cancer, progesterone receptor-expressing breast cancer, triple-negative breast cancer (TNBC), estrogen and / or progesterone receptor-expressing HER2-negative breast cancer, HER2-negative breast cancer, small cell lung cancer, metastatic small cell lung cancer.

[0170] The pharmaceutical composition of the present invention may contain, for example, about 5% to about 100% by weight of the active ingredient, about 10% to about 100% of the active ingredient, or about 10% to about 60% of the active ingredient. Since a sufficiently effective amount can be achieved by administering multiple dosage unit forms, it is understood that each dosage unit may not contain an effective amount of the active ingredient or raw material components.

[0171] A typical composition is prepared by mixing a compound of the present invention with a carrier, diluent, or excipient. Suitable carriers, diluents, and fillers are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and other materials. The particular carrier, diluent, or filler used will depend on the means and purpose for which the compound of the present invention is to be administered. Solvents are generally selected based on solvents recognized by those skilled in the art as safe for mammalian administration. Generally, safe solvents are aqueous solvents, such as water, and other solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and the like, as the major raw material component, and mixtures thereof. The composition may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents, and other additives to enhance the appearance of the medicament (i.e., the compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of the pharmaceutical product (i.e., a drug product). Pharmaceutical compositions should preferably be manufactured in accordance with the requirements of Good Manufacturing Practice (GMP).

[0172] Pharmaceutical compositions may also include salts, solvates and hydrates of the compounds of the invention, or stabilized forms of the compounds (eg, complexes with cyclodextrin derivatives or other known complexing agents).

[0173] Pharmaceutical compositions of the invention are typically suitable for oral administration, which may involve swallowing, so that the compound enters the gastrointestinal tract, and / or buccal, lingual, or sublingual administration, so that the compound enters the blood stream directly from the mouth.

[0174] Suitable formulations for oral administration include solid, semi-solid and liquid systems, such as tablets, granules, soft or hard capsules containing multiparticulates or nanoparticles, liquids, or powders, lozenges (including those filled with liquids), chewable tablets, gels, fast-dispersing dosage forms, films, vaginal ovals, sprays, and buccal / mucoadhesive patches. More preferred formulations for oral administration are tablets, granules, and capsules.

[0175] Liquid preparations include suspensions, solutions, syrups and elixirs.Such preparations can be used as fillers for soft or hard capsules (for example, made of gelatin or hydroxypropylmethylcellulose), and typically contain carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils, and one or more emulsifiers and / or suspending agents.Liquid preparations can also be prepared by reconstitution from solids, for example, sachets.

[0176] The pharmaceutical composition of the present invention can also be administered parenterally.As used herein, "parenteral administration" of pharmaceutical compositions includes any route of administration characterized by physically opening a hole in the target tissue and administering the pharmaceutical composition through the hole in the tissue, thus generally resulting in direct administration to the bloodstream, muscle or internal organs.Therefore, parenteral administration includes, among others, the administration of pharmaceutical compositions by injection of the composition, by applying the composition through a surgical incision, by applying the composition through a tissue-penetrating non-surgical wound, etc.In particular, parenteral administration is intended to include, in particular, subcutaneous, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, ​​intracranial, intrasynovial injection or infusion; and kidney dialysis infusion techniques.Intratumoral delivery, for example, intratumoral injection, can also be advantageous.Local perfusion is also provided.

[0177] The pharmaceutical composition preparation suitable for parenteral administration typically comprises the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline.Such preparations can be prepared and packaged in a form suitable for bolus administration or continuous administration.Injection preparations can be prepared and packaged in unit dosage forms, such as ampoules or multi-dose containers containing preservatives.Preparations for parenteral administration include suspensions, solutions, emulsions, pastes, etc. in oily or aqueous media.

[0178] The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, in a mixture, or as mixed component particles, e.g., mixed with suitable pharmaceutically acceptable excipients) from a dry powder inhaler, as an aerosol pressurized container, pump, spray, atomizer (preferably one that uses electrohydrodynamic power to produce a fine mist), or nebulizer with or without the use of a suitable propellant, or as nasal drops.

[0179] The pressurized container, pump, spray, atomizer, or nebulizer typically contains a solution or suspension of a compound of the invention, including suitable agents to disperse, solubilize, or prolong the release of the active ingredient, such as a propellant, as a solvent.

[0180] Prior to use as a dry powder or suspension, pharmaceutical agents are typically micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any suitable comminuting method, such as spiral jet milling to form nanoparticles, fluid bed jet milling, supercritical fluid processing, high pressure homogenization, or spray drying.

[0181] Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention, a suitable powder base and a performance modifier.

[0182] Suitable solution formulations for use in nebulizers that use electrohydrodynamics to generate a fine mist can contain a suitable dose of a compound of the invention per actuation, and actuation volumes can vary, for example, from 1 μL to 100 μL.

[0183] Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled / intranasal administration.

[0184] The formulations may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release. In one aspect, the present invention relates to a method for the prevention or treatment of a disease or disorder associated with increased cyclin-dependent protein kinase CDK7 activity, comprising the step of administering a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition of the invention to a subject in need of such treatment or prevention.

[0185] In another aspect, the present invention relates to a method for the prevention or treatment of a disease or disorder, wherein the disease or disorder associated with increased cyclin-dependent protein kinase CDK7 activity is a neoplastic, infectious or non-infectious inflammatory, autoinflammatory, or autoimmune disease.

[0186] In another aspect, the present invention relates to a method for preventing or treating a disease or disorder, wherein the disease or disorder associated with increased cyclin-dependent protein kinase CDK7 activity comprises: Breast cancer, metastatic breast cancer, HER2-positive breast cancer, estrogen receptor-expressing breast cancer, progesterone receptor-expressing breast cancer, triple-negative breast cancer (TNBC), estrogen and / or progesterone receptor-expressing HER2-negative breast cancer, 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 Neoplastic diseases selected from the group consisting of hepatobiliary cancer, hepatocellular carcinoma, urothelial carcinoma, 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 cancer, fallopian tube cancer, sarcoma, Ewing's sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, and multiple myeloma; an autoimmune disease selected from the group including axial spondyloarthritis, antiphospholipid syndrome, vasculitis (Wegener's granulomatosis and related forms of vasculitis, temporal arteritis and polyarteritis nodosa, ANCA-associated vasculitis including necrotizing vasculitis), Goodpasture's syndrome, autoimmune thyroiditis, Graves' disease, bronchial asthma, cardiomyopathy, Crohn's disease, dermatomyositis, polymyositis, mixed connective tissue disease, glomerulonephritis, Guillain-Barré syndrome, Lyme arthritis, psoriasis, pemphigus, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis, and uveitis; Behçet's disease, Blau syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, acne, pustulosis, osteophytosis, and 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 neonatal neurocutaneous and articular (CINCA) syndrome, and Majeed syndrome , an autoinflammatory disease selected from the group including mevalonate kinase deficiency (hyperimmunoglobulin D syndrome), periodic fever, aphthous stomatitis, pharyngitis and cervical lymphadenitis (PFAPA) syndrome, septic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, Schnitzler syndrome, Sweet syndrome, systemic juvenile idiopathic arthritis, Still's disease, adult-onset Still's disease (AOSD), and tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS); Allergy (including, but not limited to, delayed hypersensitivity reactions, immediate hypersensitivity reactions, and anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, osteitis, adult respiratory distress syndrome, airway inflammation (bronchiolitis, bronchitis, bronchiectasis, cellular interstitial pneumonia, giant cell interstitial pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, (including but not limited to hypersensitivity pneumonitis, laryngitis, pneumonitis, pharyngitis, pleuritis, pneumonia, pneumoconiosis, asbestosis, beryllium disease, silicosis, tallithiasis, and common interstitial pneumonia), tonsillitis, bursitis, cellulitis, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes, encephalitis, endocarditis, epicondylitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, gingivitis, stomatitis, rheumatoid arthr ... Myelitis, myocarditis, 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 ...elitis, myocarditis, myelitis, nephritis, pyelonephritis, osteitis, osteomyelitis, optic neuritis, otitis, pancreatitis, mumps, pemphigoid, pericarditis, pernicious anemia, phlebitis, acute myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myel The infectious or non-infectious inflammatory disease is selected from the group consisting of rheumatic fever, rhinitis, sinusitis, synovitis, tendonitis, necrotizing fasciitis, prostatitis, cystitis, epididymitis, omphalitis, oophoritis, orchitis, orchitis, transverse myelitis, urethritis, urocystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, and vulvovaginitis.

[0187] In another aspect, the present invention relates to a method for preventing or treating a disease or disorder, wherein the disease or disorder associated with increased cyclin-dependent protein kinase CDK7 activity is a neoplastic disease selected from the group comprising breast cancer, HER2-positive breast cancer, estrogen receptor-expressing breast cancer, progesterone receptor-expressing breast cancer, triple-negative breast cancer (TNBC), estrogen and / or progesterone receptor-expressing HER2-negative breast cancer, HER2-negative breast cancer, small cell lung cancer, metastatic small cell lung cancer.

[0188] It is meant that the compounds of the invention can be used in the prophylactic, therapeutic methods described above, can be used in the treatments described above, and / or can be used in the manufacture of therapeutic products (medicines) for the treatments described above.

[0189] In one aspect, the present invention relates to the use of a compound according to the invention or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition as described above, for the treatment of a disease or disorder associated with increased CDK7 activity in a subject in need of such treatment.

[0190] In one aspect, the present invention relates to the use of a compound according to the invention or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition as described above, for the treatment of a disease or disorder associated with increased CDK7 activity, wherein the disease or disorder associated with increased CDK7 activity is a neoplastic, infectious or non-infectious inflammatory, autoinflammatory, autoimmune disease.

[0191] In another aspect, the present invention relates to the use as described above, wherein the disease or disorder associated with increased CDK7 activity is Breast cancer, metastatic breast cancer, HER2-positive breast cancer, estrogen receptor-expressing breast cancer, progesterone receptor-expressing breast cancer, triple-negative breast cancer (TNBC), estrogen and / or progesterone receptor-expressing HER2-negative breast cancer, 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 Neoplastic diseases selected from the group consisting of hepatobiliary cancer, hepatocellular carcinoma, urothelial carcinoma, 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 cancer, fallopian tube cancer, sarcoma, Ewing's sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, and multiple myeloma; an autoimmune disease selected from the group including axial spondyloarthritis, antiphospholipid syndrome, vasculitis (Wegener's granulomatosis and related forms of vasculitis, temporal arteritis and polyarteritis nodosa, ANCA-associated vasculitis including necrotizing vasculitis), Goodpasture's syndrome, autoimmune thyroiditis, Graves' disease, bronchial asthma, cardiomyopathy, Crohn's disease, dermatomyositis, polymyositis, mixed connective tissue disease, glomerulonephritis, Guillain-Barré syndrome, Lyme arthritis, psoriasis, pemphigus, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis, and uveitis; Behçet's disease, Blau syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, acne, pustulosis, osteophytosis, and 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 neonatal neurocutaneous and articular (CINCA) syndrome, and Majeed syndrome , an autoinflammatory disease selected from the group including mevalonate kinase deficiency (hyperimmunoglobulin D syndrome), periodic fever, aphthous stomatitis, pharyngitis and cervical lymphadenitis (PFAPA) syndrome, septic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, Schnitzler syndrome, Sweet syndrome, systemic juvenile idiopathic arthritis, Still's disease, adult-onset Still's disease (AOSD), and tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS); Allergy (including, but not limited to, delayed hypersensitivity reactions, immediate hypersensitivity reactions, and anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, osteitis, adult respiratory distress syndrome, airway inflammation (bronchiolitis, bronchitis, bronchiectasis, cellular interstitial pneumonia, giant cell interstitial pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, (including but not limited to hypersensitivity pneumonitis, laryngitis, pneumonitis, pharyngitis, pleuritis, pneumonia, pneumoconiosis, asbestosis, beryllium disease, silicosis, tallithiasis, and common interstitial pneumonia), tonsillitis, bursitis, cellulitis, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes, encephalitis, endocarditis, epicondylitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, gingivitis, stomatitis, rheumatoid arthr ... Myelitis, myocarditis, 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 ...elitis, myocarditis, myelitis, nephritis, pyelonephritis, osteitis, osteomyelitis, optic neuritis, otitis, pancreatitis, mumps, pemphigoid, pericarditis, pernicious anemia, phlebitis, acute myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myelitis, myel The infectious or non-infectious inflammatory disease is selected from the group consisting of rheumatic fever, rhinitis, sinusitis, synovitis, tendonitis, necrotizing fasciitis, prostatitis, cystitis, epididymitis, omphalitis, oophoritis, orchitis, orchitis, transverse myelitis, urethritis, urocystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, and vulvovaginitis.

[0192] In another aspect, the present invention relates to the use as described above, wherein the neoplastic disease is selected from the group comprising breast cancer, HER2-positive breast cancer, estrogen receptor-expressing breast cancer, progesterone receptor-expressing breast cancer, triple-negative breast cancer (TNBC), estrogen and / or progesterone receptor-expressing HER2-negative breast cancer, HER2-negative breast cancer, small cell lung cancer, metastatic small cell lung cancer.

[0193] The compounds of the present invention can be administered alone or in combination with one or more other drugs or monoclonal antibody-based drugs (or any combination thereof). Thus, the pharmaceutical compositions, methods and uses of the present invention also encompass embodiments of combination (co-administration) with other active drugs.

[0194] As used herein, the terms "co-administration," "co-administered," or "in combination with," referring to a compound with one or more other therapeutic agents, are intended to mean, refer to, or include: - simultaneous administration to a patient in need of treatment of such a combination of a compound of the invention and a therapeutic agent, wherein such components are formulated together in a single dosage form that releases said components substantially simultaneously; - simultaneous administration of such a combination of a compound of the invention and a therapeutic agent to a patient in need of treatment, wherein such components are formulated separately from one another in separate dosage forms which are administered to said patient at substantially the same time, resulting in substantially simultaneous release of said components in said patient; - sequential administration of such a combination of a compound of the invention and a therapeutic agent to a subject in need of treatment, wherein such components are formulated apart from one another in separate dosage forms that are taken by the patient multiple times with a reasonable time interval between each administration, such that the components are released at different times in the patient; and - Sequential administration of such combinations of a compound of the invention and a therapeutic agent to a subject in need of treatment, wherein such components are formulated together into a single dosage form that releases said components in a controlled manner and is released to said patient simultaneously and / or at different times in parallel, sequential and / or overlapping fashion, and each portion may be administered by either the same or different routes.

[0195] As is well known to those skilled in the art, when drugs are used in combination therapy, therapeutically effective doses can vary.Methods for experimentally determining the therapeutically effective doses of drugs and other drugs for use in combination therapy regimens have been described in the literature.For example, the use of regular administration, i.e., giving reduced doses more frequently in order to minimize toxic side effects, has been described in the literature.Combination therapy also includes intermittent treatment, which starts and stops at various times according to the patient's treatment plan.For the combination therapy described in this patent, the dose of co-administered compounds can vary depending on the type of conjugated agent used, the specific drug used, the condition or disorder being treated, etc.

[0196] The antitumor treatments described above can be used as a monotherapy or in combination with surgery, radiation therapy, or drug therapy.Such treatments can be administered in parallel with the treatment with the compound according to the present invention, simultaneously, sequentially, or separately, and can include one or more agents from the following categories of antitumor agents: antiproliferative / antitumor therapeutic products and their combinations used in medical oncology, such as alkylating agents, alkylating sulfonates, nitrosoureas, or triazenes; antimetabolites; hormonal agents or hormone antagonists; platinum compounds; antitumor antibiotics; topoisomerase inhibitors.

[0197] Examples of antimetabolites include, without limitation, folate antagonists (e.g., methotrexate, trimetrexate, pemetrexed, pralatrexate, raltitrexed, levofolinate calcium), or pyrimidine antagonists (e.g., cytarabine, tegafur, fluorouracil, capecitabine, floxuridine, azacitidine, enocitabine, karmofur, gemcitabine, sapacitabine, elacitarabine, doxifluridine), or purine antagonists (e.g., mercaptopurine, thioguanine, pentostatin, fludarabine, cladribine, nelarabine, azathioprine, clofarabine), or asparaginase.

[0198] Examples of alkylating agents include, without limitation, mechlorethamine, cyclophosphamide, chlorambucil, melphalan, bendamustine, hexamethylmelamine, thiotepa, busulfan, carmustine, lomustine, laromustine, semustine, streptozocin, dacarbazine, ifosfamide, improsulfan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, treosulfan, carboquinone, apaziquinone, fotemustine, altretamine, glufosfamide, pipobroman, trofosfamide, uramustine, evofosfamide, and VAL-083.

[0199] Examples of hormone agents and hormone antagonists include, without limitation, hydrocortisone, dexamethasone, prednisone, hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate, diethylstilbestrol, estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, leuprolide, abarelix, abiraterone, bicalutamide, buserelin, calsterone, chlorotrianizene, degarelix , dexamethasone, fluocortolone, fulvestrant, goserelin, histrelin, leuprorelin, mitotane, nafarelin, nandrolone, nilutamide, octreotide, raloxifene, thyrotropin alfa, toremifene, triptorelin, diethylstilbestrol, acolbifene, danazol, deslorelin, epitiostanol, orteronel, enzalutamide, aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone, and formestane.

[0200] Examples of platinum compounds include, without limitation, cisplatin, carboplatin, oxaliplatin, eptaplatin, miriplatin hydrate, lobaplatin, nedaplatin, picoplatin, satraplatin.

[0201] Examples of antitumor antibiotics include, without limitation, doxorubicin, daunorubicin, idarubicin, carubicin, valrubicin, zorubicin, aclarubicin, pirarubicin, nemorubicin, amrubicin, epirubicin, bleomycin, dactinomycin, plicamycin, peplomycin, mitomycin-C, zinostatin, and streptozotocin.

[0202] Examples of topoisomerase inhibitors include, without limitation, irinotecan, topotecan, belotecan, teniposide, etoposide, voreloxin, and amonafide. Examples of anti-tumor agents include, without limitation, 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, vinblastine, vincristine, vindesine, vinflunine); mitogen-activated protein kinase inhibitors (e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY43-9006, wortmannin, or LY294002); mTOR inhibitors (e.g., sirolimus, temsirolimus, everolimus, ridaforolimus); antibodies (e.g., prorugolimab, rituximab, trastuzumab, alemtuzumab, Ipilimumab, besilesomab, cetuximab, denosumab, ipilimumab, bevacizumab, pertuzumab, pembrolizumab, nivolumab, cemiplimab, durvalumab, atezolizumab, avelumab, ofatumumab, panitumumab, tositumomab, catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab nimotuzumab, obinutuzumab, okaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutuzumab, zanolimumab, matuzumab, dalotuzumab, onartuzumab, rakotumomab, tabalumab, abituzumab);Kinase inhibitors (fosmatanib, entospletenib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, vemurafenib, gefitinib, crizotinib, dazatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, bosutinib, axitimib) Nib, afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, nintedanib, lenvatinib, linifanib, lincitinib, masitinib, motesanib, neratinib, orantinib, ponatinib, radotinib, tipifanib, tivantinib, tivozanib, trametinib, apatinib, ibrutinib, acalabrutinib, cobimetinib, fedratinib, brivanib boualaninate, cediranib, cabozantinib, icotinib, cipatinib, rigosertib, pimasertib, bupalisib, idelalisib, midostaurin, perifosine, tesevatinib; photosensitizers (e.g., talaporfin, temoporfin, porfimer sodium); cytokines (e.g., aldesleukin, interferon alpha, interferon alpha-2a, interferon alpha-2b, cermoleukin, 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, miltefosine, romidepsin, plitidepsin, eribulin, ixabepilone, fosbretabine, denileukin diftitox, ibiritumomab tiuxetan, prednimustine, trastuzumab emtansine, estramustine, 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, bis Modegib, vorinostat, entinostat, panobinostat, celecoxib, cilengitide, etanidazole, ganetespib, idronoxyl, iniparib, lonidamine, nimorazole, procodazole, tasquinimod, telotristat, belinstat, simalfasin, tirapazamine, tosedostat, travedelsen, ubenimex, valspodar, gendicin, reolisin, retaspimicin, trebananib, virulisin;

[0203] Thus, in another aspect of the present invention, a pharmaceutical product comprising a compound of formula (I) as defined hereinbefore or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is described in combination with an antitumor agent as defined hereinbefore, intended for the combination therapy of cancer.

[0204] Dosage regimens can be adjusted to provide the optimum desired response. For example, a single dose can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral compositions in a single dosage form. As used herein, a unit dosage form refers to a physically discrete unit suitable as a unitary dose for the patient / subject to be treated, each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect together with the desired pharmaceutical carrier. The specifications for the unit dosage forms of the present invention are typically governed by and directly dependent on (a) the inherent characteristics of the therapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the technology for compounding such active compounds to treat susceptibility in a subject.

[0205] Therefore, based on the disclosure provided herein, those skilled in the art will understand that dosage and administration regimen can be prepared according to well-known methods in the therapeutic field.That is, the maximum tolerated dosage can be easily established, and the effective amount that produces detectable therapeutic effect in patients can also be determined, as well as the time requirement for administering each drug that produces detectable therapeutic effect in patients.Therefore, although specific dosage and administration regimen are exemplified herein, these examples do not in any way limit the dosage and administration regimen that can be provided to patients when implementing the aspects of the present invention.

[0206] It is recognized that dosage values ​​may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. Furthermore, for any particular subject, specific dosage regimens should be adjusted over time according to the individual needs and the judgment of the medical professional administering or supervising the administration of the composition, and it is understood that the dosage ranges set forth in this disclosure are merely exemplary and are not intended to limit the scope or practice of the claimed compositions. Furthermore, dosage regimens using the compositions of the present invention may be based on a variety of factors, including the type of disease, the patient's age, weight, sex, medical condition, severity of the condition, route of administration, and the particular compound of the present invention being utilized. Thus, dosage regimens may vary widely but can be routinely determined using standard techniques. For example, dosages may be adjusted based on pharmacokinetic and pharmacodynamic parameters, which may include clinical effects such as toxic effects or laboratory values. Thus, the present invention encompasses intrapatient dose escalation, 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 given the concepts disclosed herein.

[0207] Typically, the dose used to treat an adult is usually in the range of 0.01 to 5000 mg per day, or 0.1 to 500 mg per day, or 0.1 to 100 mg per day. If the patient's condition improves, a maintenance dose is administered if necessary.Subsequently, depending on the symptoms, the dosage or frequency, or both, of administration can be reduced to a level at which the improved disease, disorder or condition is maintained.However, if any symptoms recur, the patient may require regular treatment on a long-term basis.

[0208] Due to the number of variables involved in any particular treatment regime, the following ranges are only suggestive, and significant deviations from these recommended values ​​are not uncommon. These dosages may vary depending upon many variables, including but not limited to, the activity of the compound being used, the disorder or condition being treated, the manner of administration, the requirements of the individual subject, the severity of the disorder or condition being treated, and the judgment of the physician.

[0209] The following examples are provided for a better understanding of the present invention. These examples are for illustrative purposes only and are not to be construed as limiting the scope of the invention in any way.

[0210] The compounds and processes of the present invention will be better understood in conjunction with the following synthetic schemes, which illustrate how the compounds of the present invention can be prepared. The starting products can be obtained from commercial sources or prepared using conventional methods known to those skilled in the art. Those skilled in the art will also readily appreciate that the optional protection and deprotection steps, as well as the order of these steps, can be performed in different orders depending on the nature of the substitutions in order to successfully complete the synthesis described below.

[0211] Abbreviations used in this description, including those given in the illustrative diagrams and examples that follow, are well known to those skilled in the art. DIPEA - diisopropylethylamine; TBAF - tetrabutylammonium fluoride; DMF - N,N-dimethylformamide; THF - tetrahydrofuran; BINAP - (±)-2,2'-bis(diphenylphosphino)-1,1'-dinaphthalene; MTBE - methyl tert-butyl ether; TMEDA - N,N,N',N'-tetramethylethane-1,2-diamine; HATU - 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; NBS - N-bromosuccinimide; TEA - triethylamine; DMAP - 4-dimethylaminopyridine; TFA - Trifluoroacetic acid TIPS - Triisopropylsilane; dppf - 1,1'-bis(diphenylphosphino)ferrocene; ac - acetyl; boc - tert-butoxycarbonyl; pin - pinacolato; HOBt - 1-hydroxybenzotriazole; EDC - 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; PPA - polyphosphoric acid; HPLC - High Performance Liquid Chromatography; Ph - phenyl; HMDS - hexamethyldisilazane. [Example]

[0212] Example 1 Synthesis of compound 1.6.

[0213] [ka]

[0214] Synthesis of compound 1.2 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 was stirred at room temperature for 20 h. After standard workup, the product was isolated using silica gel column chromatography. 5.63 g (86%) of compound 1.2 was obtained. Synthesis of compound 1.3 Compound 1.2 (2.5 g, 6.98 mmol), (BPin) (3.62 g, 13.96 mmol), KOAc (1.77 g, 17.45 mmol), and Pd(dppf)Cl (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 workup, the reaction product was isolated using silica gel column chromatography. 2.16 g (76%) of compound 1.3 was obtained. Synthesis of compound 1.5 Compound 1.3 (0.90 g, 2.0 mmol), pyrimidine 1.4 (0.692 g, 1.82 mmol), NaCO (0.448 g, 4.18 mmol), and Pd(dppf)Cl (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 under a nitrogen atmosphere for 4 h. After standard workup, the product was isolated using silica gel column chromatography. 0.95 g (84%) of compound 1.5 was obtained. Synthesis of compound 1.6 Compound 1.5 (0.90 g, 1.44 mmol) was dissolved in 9 mL of ethanol, and NaOH (0.35 g, 8.64 mmol) and 9 mL of water were added. The reaction was stirred at 60 °C for 6 h, the solvent was removed, and water (10 mL) was added to the residue until it was completely dissolved. The pH of the mixture was adjusted to 3 with 10% citric acid solution. The precipitate was filtered, and the residual solvent was removed in vacuo. 0.6 g (92%) of product 1.6 was obtained.

[0215] Example 2 Synthesis of compound 2.4.

[0216] [ka]

[0217] Synthesis of compound 2.1 Compound 1.1 (9.08 g, 41.6 mmol) was dissolved in 90 mL of ethanol, and NaOH (6.73 g, 167 mmol) and 45 mL of water were added. The reaction was stirred at 70 °C for 6 h, the ethanol was removed in vacuo, and water was added to the residue until it was completely dissolved. The pH of the mixture was adjusted to HCl. conc. The precipitate was filtered off, washed with water and the residual solvent was removed in vacuo to yield 7.1 g (90%) of compound 2.1. Synthesis of compound 2.2 Compound 2.1 (3.52 g, 18.5 mmol) was dissolved in 40 mL of dichloromethane, and oxalyl chloride (9.41 g, 74.1 mmol) and 0.3 mL of DMF were added. The reaction was stirred for 2 h, the volatile components were removed in vacuo, and the residue was dissolved in 20 mL of dichloromethane. The mixture was added 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 isolated using silica gel column chromatography. 3.7 g (81%) of compound 2.2 was obtained. Synthesis of compound 2.3 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 was stirred at room temperature for 20 h. After standard workup, the product was isolated using silica gel column chromatography. 6.73 g (80%) of compound 2.3 was obtained. Synthesis of compound 2.4 TFA (1.37 g, 12.0 mmol) was added to a solution of 2.3 (0.579 g, 1.50 mmol) in 12 mL of dichloromethane, and the reaction was stirred at room temperature for 20 h. The volatile components were removed in vacuo, yielding 0.43 g (95%) of product 2.4.

[0218] 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.

[0219] [ka]

[0220] Synthesis of compound 3.1 Compound 1.6 (0.065 g, 0.14 mmol), HATU (0.108 g, 0.28 mmol), cyclopropylamine (0.012 g, 0.21 mmol), and 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 isolated using silica gel column chromatography. 0.035 g (51%) of compound 3.1 was obtained. Synthesis of compound CDK7_951 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 isolated using preparative HPLC. 0.015 g (54%) of compound CDK7_951 was obtained. Similarly, the following compounds were prepared from compound 1.6 and the corresponding amines:

[0221] [Table 2]

[0222] Example 4 Synthesis of compounds CDK7_538, CDK7_539, CDK7_834, CDK7_836, CDK7_837, and CDK7_838

[0223] [ka]

[0224] Synthesis of compound 4.2 Compound 2.4 (0.3 g, 0.91 mmol) was dissolved in 5 mL of dichloromethane, and oxalyl chloride (0.289 g, 2.28 mmol) and 0.1 mL of DMF were added. The reaction was stirred for 3 h. The volatile components were removed in vacuo, 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 was stirred at room temperature for 20 h. After standard workup, the product was isolated using silica gel column chromatography. 0.3 g (80%) of compound 4.2 was obtained. Synthesis of compound 4.3 Compound 4.2 (0.10 g, 0.25 mmol), (BPin) (0.13 g, 0.50 mmol), KOAc (0.063 g, 0.63 mmol), and Pd(dppf)Cl (0.021 g, 0.03 mmol) were dissolved in 2 mL of 1,4-dioxane and heated at 100 °C in a sealed vessel under a nitrogen atmosphere with stirring for 6 h. The reaction mixture was filtered through a pad of Celite, 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 was heated at 100 °C in a sealed vessel under a nitrogen atmosphere for 3 h. After standard workup, the product was isolated using silica gel column chromatography. Yield: 0.075 g (44%) of compound 4.3. Synthesis of compound 4.4 An aqueous solution of NaOH (0.089 g, 2.2 mmol) was added to a solution of 4.3 (0.075 g, 0.11 mmol) in ethanol (1.5 ml) and stirred at 50 °C for 3 h. After standard workup, the product was isolated using silica gel column chromatography. 0.042 g (72%) of compound 4.4 was obtained. Synthesis of compound CDK7_836 Compound 4.4 (0.042 g, 0.08 mmol) was dissolved in 2 ml of dichloromethane, TFA (0.092 g, 0.8 mmol) was added, the reaction was stirred at 20 °C for 20 h, and the solvent was removed. The product was isolated by HPLC. 0.012 g (34%) of compound CDK7_836 was obtained. In a similar manner, the following compounds shown in the table below were prepared:

[0225] [Table 3]

[0226] [ka]

[0227] Synthesis of compound 4.5 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 isolated using silica gel column chromatography. 0.86 g (99%) of compound 4.5 was obtained. Synthesis of compound 4.6 TEA (0.769 g, 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 was stirred for 20 h at room temperature. After standard workup, the product was isolated using silica gel column chromatography. 0.56 g (74%) of product 4.6 was obtained. Synthesis of compound 4.7 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 isolated using silica gel column chromatography. 0.52 g (83%) of compound 4.7 was obtained. Synthesis of compound 4.8 A mixture of boronic acid ether 4.7 (0.149 g, 0.32 mmol), pyrimidine 1.4 (0.1 g, 0.26 mmol), NaCO (0.07 g, 0.65 mmol), and Pd(dppf)Cl (0.024 g, 0.03 mmol) in 2 mL of 1,4-dioxane and 0.7 mL of water was stirred at 100 °C under a nitrogen atmosphere for 4 h. After standard workup, the reaction product was isolated using silica gel column chromatography. 0.05 g (23%) of compound 4.8 was obtained. Synthesis of compound 4.9 Compound 4.8 (0.05 g, 0.07 mmol), NaOH (0.065 g, 1.61 mmol) in 0.5 mL of ethanol and 0.5 mL of HO were stirred for 2 h at 50 °C. 2 mL of 10% citric acid solution was added, and extraction with ethyl acetate was carried out, yielding 0.016 g (42%) of compound 4.9 after removal of the solvent in vacuo. Synthesis of compound CDK7_539 Compound 4.9 (0.016 g, 0.03 mmol) was dissolved in 1 ml of dichloromethane, 0.2 ml of a solution of 4H HCl in 1,4-dioxane was added, the reaction was stirred at 20 °C for 18 h, the volatile components were removed in vacuo, and the product was isolated by preparative HPLC to yield 0.010 g (77%) of compound CDK7_539.

[0228] Example 5 Synthesis of compound CDK7_535

[0229] [ka]

[0230] Synthesis of compound 5.2 0.75 ml (1.84 mmol) of a 2.5 M n-butyllithium solution in hexane was added to a stirred solution of compound 5.1 (0.45 g, 1.23 mmol) in 50 ml of THF at −78° C. under a nitrogen atmosphere, and the mixture was stirred for 30 min. Benzoyl chloride (0.262 g, 1.84 mmol) was then added and stirred for an additional 30 min. After standard workup, the product was isolated using silica gel column chromatography. 0.3 g (62%) of compound 5.2 was obtained. Synthesis of compound 5.3 Pyrrole 5.2 (0.126 g, 0.35 mmol), (BPin) (0.124 g, 0.48 mmol), KOAc (0.063 g, 0.63 mmol), and Pd(dppf)Cl (0.012 g, 0.02 mmol) were dissolved in 5 mL of 1,4-dioxane and heated in a sealed vessel at 100 °C for 7 h. After standard workup, the product was isolated using silica gel column chromatography. 0.05 g (36%) of compound 5.3 was obtained. Synthesis of compound 5.4 A mixture of boronic acid ether 5.3 (0.05 g, 0.1 mmol), pyrimidine 1.4 (0.0.027 g, 0.07 mmol), NaCO (0.021 g, 0.2 mmol), and Pd(dppf)Cl (0.007 g, 0.01 mmol) in 1.5 mL of 1,4-dioxane and 0.5 mL of water was stirred at 90 °C under a nitrogen atmosphere for 3 h. After standard workup, the reaction product was isolated using silica gel column chromatography. 0.04 g (62%) of compound 5.4 was obtained. Synthesis of compound 5.5 Compound 5.5 was produced in 87% yield in a similar manner to compound 4.9. Synthesis of compound CDK7_535 Compound CDK7_535 was produced in a 38% yield in a similar manner to compound 539.

[0231] Example 6 Synthesis of compounds CDK7_845, CDK7_924, CDK7_959, CDK7_961, and CDK7_1052.

[0232] [ka]

[0233] Synthesis of compound 6.2 The compound was produced in 93% yield in a similar manner to compound 4.2. Synthesis of compound 6.3 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 to the reaction mixture with cooling and stirred for 1 h. The precipitate was filtered off, washed with water, and the residual solvent was removed in vacuo to yield 0.19 g (84%) of compound 6.3. Synthesis of compound 6.4 TEA (0.26 g, 2.60 mmol), DMAP (0.01 g, 0.08 mmol), and benzenesulfonyl chloride (0.165 g, 0.92 mmol) were added to a solution of pyrrolopyridone 6.3 (0.19 g, 0.84 mmol) in 6 mL of dichloromethane, and the reaction was stirred at 20 °C for 18 h. After standard workup, the product was isolated using silica gel column chromatography. 0.26 g (73%) of compound 6.4 was obtained. Synthesis of compound 6.5 Compound 6.4 (0.22 g, 0.60 mmol), (BPin) (0.31 g, 1.2 mmol), KOAc (0.153 g, 1.50 mmol), and Pd(dppf)Cl (0.045 g, 0.06 mmol) in 5 mL of 1,4-dioxane were heated at 100 °C with stirring under a nitrogen atmosphere for 7 h. After standard workup, the product was isolated using silica gel column chromatography. 0.14 g (59%) of compound 6.5 was obtained. Synthesis of compound 6.6 Compound 6.5 (0.54 g, 1.30 mmol), pyrimidine 1.4 (0.495 g, 1.30 mmol), NaCO (0.348 g, 3.25 mmol), and Pd(dppf)Cl (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 under a nitrogen atmosphere for 4 h. After standard workup, the reaction product was isolated using silica gel column chromatography. 0.26 g (32%) of compound 6.6 was obtained. Synthesis of compound 6.7 The compound was produced in 95% yield in a similar manner to compound 4.9. Synthesis of compound CDK7_845 The compound was produced in a 38% yield in a similar manner to compound CDK7_539. Similarly, the following compounds were prepared:

[0234] [Table 4]

[0235] Example 7 Synthesis of compound CDK7_944

[0236] [ka]

[0237] Synthesis of compound 7.3 Compound 7.1 (2.30 g, 12.9 mmol), compound 7.2 (1.49 g, 12.9 mmol), and AgCO (1.87 g, 0.065 mmol) in 23 mL of 1,4-dioxane were stirred at 100 °C for 5 h. After standard workup, the product was isolated using silica gel column chromatography. 3.00 g (82%) of compound 7.3 was obtained. Synthesis of compound 7.4 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 h. 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 to yield 2.10 g (97%) of compound 7.4. Synthesis of compound 7.5 Compound 7.4 (1.070 g, 4.0 mmol), SOCl (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 h. 5 mL of 4 N HCl solution in 1,4-dioxane was added to the mixture, which was then stirred at room temperature for 16 h. After standard workup, the product was isolated using silica gel column chromatography. 0.540 g (99%) of compound 7.5 was obtained. Synthesis of compound 7.6 Compound 7.5 (0.30 g, 2.09 mmol) was dissolved in 30 ml of THF and added to the resulting solution of NaH (0.125 g, 3.13 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. TIPSCI (0.540 g, 2.72 mmol) was then added dropwise and stirred at room temperature for 30 min. After standard workup, the product was isolated using silica gel column chromatography. 0.611 g (99%) of compound 7.6 was obtained. Synthesis of compound 7.7 Compound 7.6 (0.611 g, 1.98 mmol) was dissolved in 20 ml of THF, and a solution of NBS (0.356 g, 1.98 mmol) in 10 ml of THF was added at -78 °C. The mixture was stirred at -78 °C for 30 min and at room temperature for 30 min. After standard workup, the product was isolated using silica gel column chromatography. 0.735 g (100%) of compound 7.7 was obtained. Synthesis of compound 7.8 Compound 7.7 (0.625 g, 1.60 mmol) and a 30% TBAF solution 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 isolated using silica gel column chromatography. 0.240 g (70%) of compound 7.8 was obtained. Synthesis of compound 7.9 Compound 7.8 (0.240 g, 1.06 mmol) was dissolved in 30 mL of THF, and NaH (0.064 g, 1.59 mmol) was added to the resulting solution at 0 °C. The mixture was stirred for 30 min, and then benzenesulfonyl chloride (0.227 g, 1.27 mmol) was added and stirred at room temperature for 30 min. After standard workup, the product was isolated using silica gel column chromatography. 0.31 g (82%) of compound 7.9 was obtained. Synthesis of Compound 7.10 Compound 7.10 was produced in 80% yield in a similar manner to compound 1.3. Synthesis of Compound 7.11 Compound 7.11 was produced in 65% yield in a similar manner to compound 1.5. Synthesis of Compound 7.12 Compound 7.12 was produced in 97% yield in a similar manner to compound 1.6. Synthesis of compound CDK7_944 Compound CDK7_944 was produced in a 60% yield in a similar manner to compound CDK7_951.

[0238] Example 8 Synthesis of compound CDK7_929.

[0239] [ka]

[0240] Synthesis of Compound 8.2 Compound in 50 ml of THF 8.1 A solution of 4.6 g (0.026 mol) of HCl was slowly added to a suspension of 2.00 g (0.053 mol) of LiAlH in 100 mL of THF with stirring and cooling. The reaction was stirred at 100 °C for 5 h, cooled to 0 °C, and 50 mL of water was added. After standard workup, the product was isolated using silica gel column chromatography. 0.5 g (12%) of compound 8.2 was obtained. Synthesis of compound 8.3 Compound 8.3 was produced in 70% yield in a similar manner to compound 6.2. Synthesis of Compound 8.4 Compound 8.4 was produced in 13% yield in a similar manner to compound 6.3. Synthesis of Compound 8.5 Compound 8.5 was produced in 56% yield in a similar manner to compound 6.4. Synthesis of Compound 8.6 Compound 8.6 was produced in 64% yield in a similar manner to compound 6.5. Synthesis of compound 8.7 Compound 8.7 was produced in 31% yield in a similar manner to compound 6.6. Synthesis of compound 8.8 Compound 8.8 was produced in 95% yield in a similar manner to compound 6.7. Synthesis of compound CDK7_929 Compound CDK7_929 was produced in a 90% yield in a similar manner to compound CDK7_845.

[0241] Example 9 Synthesis of compound CDK7_966

[0242] [ka]

[0243] Synthesis of Compound 9.2 Compound 9.1 (2.4 g, 8.87 mmol) was dissolved in 30 mL of methanol. 50 mL of a 40% aqueous solution of dimethylamine (44.5 g, 0.395 mmol) was added. The reaction was stirred for 24 h, the solvent was removed, and the product was isolated using silica gel column chromatography. 0.5 g (21%) of Compound 9.2 was obtained. Synthesis of compound 9.3 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 was stirred for 1 h. After standard workup, the product was isolated using silica gel column chromatography. 0.16 g (31%) of compound 9.3 was obtained. Synthesis of Compound 9.4 Compound 9.3 (0.05 g, 0.14 mmol), (BPin) (0.047 g, 0.18 mmol), KOAc (0.042 g, 0.42 mmol), and Pd(dppf)Cl (0.01 g, 0.01 mmol) were dissolved in 1 ml of 1,4-dioxane and heated in a sealed vessel at 100 °C for 1 h. The reaction mixture was filtered through Celite and the solvent was removed in vacuo. 0.055 g (99%) of the product was obtained in the form of a brown oil. Synthesis of Compound 9.5 Compound 9.5 was produced in 93% yield in a similar manner to compound 1.5. Synthesis of compound CDK7_966 Compound CDK7_966 was produced in a 69% yield in a similar manner to compound CDK7_951.

[0244] Example 10 Synthesis of compound CDK7_972

[0245] [ka]

[0246] Synthesis of Compound 10.2 Compound 10.2 was derived from compound 10.1 in 98% yield in a similar manner to compound 1.3. Synthesis of Compound 10.3 Compound 10.3 was produced in 3% yield in a similar manner to compound 1.5. Synthesis of compound CDK7_972 Compound CDK7_972 was produced in a 33% yield in a similar manner to compound CDK7_951.

[0247] Example 11 Synthesis of compound CDK7_921

[0248] [ka]

[0249] Synthesis of Compound 11.2 Compound 11.2 was produced in 62% yield in a similar manner to compound 1.3. Synthesis of Compound 11.3 Compound 11.3 was produced in 34% yield in a similar manner to compound 1.5. Synthesis of compound CDK7_921 Compound CDK7_921 was produced in a 34% yield in a similar manner to compound CDK7_951.

[0250] Example 12 Synthesis of compound CDK7_901

[0251] [ka]

[0252] Synthesis of Compound 12.2 Compound 12.2 was produced in 87% yield in a similar manner to compound 1.3. Synthesis of Compound 12.3 Compound 12.3 was produced in 46% yield in a similar manner to compound 1.5. Synthesis of compound CDK7_901 Compound CDK7_901 was produced in a similar manner to compound CDK7_951 in 89% yield.

[0253] Example 13 Synthesis of compound CDK7_766.

[0254] [ka]

[0255] Synthesis of Compound 13.2 A mixture of boronic acid ether 13.1 (0.04 g, 0.17 mmol), pyrimidine 1.4 (0.059 g, 0.15 mmol), Pd(OAc) (0.003 g, 0.015 mmol), PPh (0.008 g, 0.03 mmol), and NaCO (0.05 g, 0.46 mmol) in 0.37 mL of 1,4-dioxane and 0.04 mL of water was stirred at 100 °C under a nitrogen atmosphere for 8 h. After standard workup, the product was isolated using silica gel column chromatography. 0.046 g (68%) of compound 13.2 was obtained. Synthesis of compound CDK7_766 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 h. The solvent was removed in vacuo, and the product was isolated by preparative HPLC to yield 0.008 g (40%) of compound CDK7_766.

[0256] Example 14 Synthesis of compounds CDK7_809, CDK7_810, CDK7_811, CDK7_829, CDK7_830, and CDK7_897

[0257] [ka]

[0258] Synthesis of Compound 14.1 Method a: 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 stirred for 30 min. A solution of pyrimidine 1.4 (0.100 g, 0.263 mmol) in 1 mL of DMF was added and the reaction was stirred for 20 h. Saturated NaHCO3 solution was added and extracted with ethyl acetate. The product was isolated using silica gel column chromatography using a hexane-ethyl acetate (92:8) mixture as the eluent. 0.081 g (67%) of compound 14.1 was obtained. Method b was similar to Method A, except that K2CO3 was used instead of NaH, MeCN was used instead of DMF, and instead of stirring at room temperature, the reaction mixture was heated to boiling until the original reagents were consumed. Synthesis of compound CDK7_809 Method a: Compound 14.1 (0.063 g, 0.137 mmol) was dissolved in 1.5 ml of 7.65 M HCl solution in 1,4-dioxane. The reaction 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 was obtained in the form of a hydrochloride salt. Method b was similar to method A, except that TFA was used instead of 7.65 M HCl solution in 1,4-dioxane, and dichloromethane was used as the solvent. Similarly, the following compounds were prepared:

[0259] [Table 5]

[0260] Example 15 Synthesis of compounds CDK7_548, CDK7_550, CDK7_735, CDK7_754, CDK7_888, CDK7_891, CDK7_898, CDK7_900, CDK7_903, and CDK7_904

[0261] [ka]

[0262] Synthesis of Compound 15.2 DIPEA (0.214 g, 1.66 mmol) was added to a solution of compound 15.1 (0.289 g, 1.38 mmol) of tert-butyl N-(2-hydroxyphenyl)carbamate in 3 mL of absolute ethanol. A solution of compound 15.1 (0.300 g, 1.38 mmol) in 2 mL of absolute 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 isolated using silica gel column chromatography. Product 15.2 (0.45 g, 84%) was obtained. Synthesis of Compound 15.3 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 h. After standard workup, the product was isolated using silica gel column chromatography followed by preparative TLC. 0.057 g (9%) of compound 15.3 was obtained. Synthesis of compound CDK7_548 1 ml of a 7.65 M HCl solution in 1,4-dioxane 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 h, the volatile components were removed, and the residue was recrystallized from a 4:1:1 mixture of MTBE:acetone:i-PrOH. 0.015 g (31% yield) of compound CDK7_548 was obtained in the form of a hydrochloride salt.

[0263] Similarly, the following compounds were prepared:

[0264] [Table 6]

[0265] Example 16 Preparation of compound CDK7_991

[0266] [ka]

[0267] Synthesis of Compound 16.2 This was prepared from compound 16.1 in a similar manner to compound 4.2. Yield: 64%. Synthesis of Compound 16.3 Compound 16.3 was produced in 92% yield in a similar manner to compound 1.2. Synthesis of Compound 16.4 Compound 16.4 was produced in 38% yield in a similar manner to compound 1.3. Synthesis of Compound 16.5 Compound 16.5 was produced in a 32% yield in a similar manner to compound 1.5. Synthesis of Compound 16.6 Compound 16.6 was produced in 99% yield in a similar manner to compound 4.5. Synthesis of compound CDK7_991 Compound CDK7_991 was produced in a 26% yield in a similar manner to compound CDK7_951.

[0268] Example 17 Preparation of compound CDK7_1017

[0269] [ka]

[0270] Synthesis of Compound 17.1 NaH (60% suspension in paraffin oil) (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 was stirred for 30 min, and CHCl (0.270 g, 1.88 mmol) was added. The reaction mixture was heated to room temperature and stirred for 24 h. After standard workup, the product was isolated using silica gel column chromatography. 0.33 g (99%) of compound 17.1 was obtained. Synthesis of Compound 17.2 Compound 17.2 was produced in 98% yield in a similar manner to compound 1.3. Synthesis of Compound 17.3 Compound 17.3 was produced in 40% yield in a similar manner to compound 1.5. Synthesis of compound CDK7_1017 Compound CDK7_1017 was produced in a 10% yield in a similar manner to compound CDK7_951.

[0271] Example 18 Synthesis of compound CDK7_953.

[0272] [ka]

[0273] Synthesis of Compound 18.2 In a manner similar to compound 8.3, compound 18.2 was produced from acid 2.1 and amine 18.1 in 71% yield. Synthesis of compound 18.3 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, and the reaction was stirred at 20 °C for 18 h. The volatile components were removed in vacuo. 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 with stirring at 110 °C for 3 h. 10 g of ice was added and the mixture was stirred for 2 h. The precipitate was filtered off, washed with water, and the residual solvent was removed in vacuo to yield 0.32 g (69%) of compound 18.3. Synthesis of Compound 18.4 NaBH4 (0.053 g, 1.32 mmol) was added to a solution of compound 18.3 (0.100 g, 0.33 mmol) in 3 mL of ethanol while cooling in an ice bath, and the reaction was stirred at the same temperature for 1 h and then at 20 °C for 72 h. After standard workup, the product was isolated using silica gel column chromatography. 0.076 g (88%) of compound 18.4 was obtained. Synthesis of Compound 18.5 A solution of 4N HCl in 1,4-dioxane (0.19 ml, 0.76 mmol) was added to a solution of compound 18.4 (0.22 g, 0.76 mmol) in 11 ml of chloroform, and the reaction was stirred for 3 h. After standard workup, the product was isolated using silica gel column chromatography. 0.14 g (77%) of product 18.5 was obtained. Synthesis of Compound 18.6 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 was stirred at 20 °C for 40 h. After standard workup, the product was isolated using silica gel column chromatography. 0.15 g (78%) of product 18.6 was obtained. Synthesis of Compound 18.7 Compound 18.7 was synthesized from 0.15 g of compound 18.6 in a manner similar to 6.5. Following the boronation reaction, the reaction was filtered through a layer of silica gel and the solvent was removed to yield 0.54 g of the product in the form of a dark red oil containing 30% of the target compound 18.7, which was used in the next step without further purification. Synthesis of Compound 18.8 Compound 18.7 (0.54 g, 0.38 mmol), pyrimidine 1.4 (0.111 g, 0.29 mmol), NaCO (0.094 g, 0.88 mmol), and Pd(dppf)Cl (0.022 g, 0.03 mmol) in a mixture of 6 mL of 1,4-dioxane and 2 mL of water were mixed at 100 °C under a nitrogen atmosphere for 3 h. After standard workup, the product was isolated using silica gel column chromatography. 0.081 g (43%) of compound 18.8 was obtained. Synthesis of Compound 18.9 In a manner similar to that for compound 6.7, compound 18.9 was produced from 0.081 g of compound 18.8 in 91% yield. Synthesis of Compound 18.10 5% Pd / C (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 mixture was filtered through a pad of Celite, and the solvent was removed in vacuo to yield 0.033 g (54%) of compound 18.10. Synthesis of compound CDK7_953 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 dichloromethyl methylcellulose, and the reaction was stirred at 20 °C for 18 h. The volatile components were removed in vacuo, and the product was isolated using preparative HPLC to yield 0.009 g (36%) of compound CDK7_953.

[0274] Example 19 Synthesis of compound 19.6.

[0275] [ka]

[0276] Synthesis of Compound 19.2 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 isolated using silica gel column chromatography. 6.31 g (80%) of compound 19.2 was obtained. Synthesis of compound 19.3 Oxalyl chloride (0.451 ml, 5.26 mmol) and one 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 stirred at room temperature for 2 h. The volatile components were removed in vacuo, and the mixture was added to a solution of compound 19.2 (0.592 g, 2.63 mmol) and TEA in 5 ml of dichloromethane at 0 °C and stirred for 1 h. After standard workup, the product was isolated using silica gel column chromatography. 1.00 g (95%) of compound 19.3 was obtained. Synthesis of Compound 19.4 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 isolated using column chromatography. 1.78 g (83%) of compound 19.4 was obtained. Synthesis of Compound 19.5 Compound 19.5 was produced in 83% yield in a similar manner to compound 6.4. Synthesis of Compound 19.6 Compound 19.5 (0.440 g, 0.880 mmol) was dissolved in 2 mL of TFA in a sealed vessel and heated with stirring at 100 °C for 30 h. Volatile components were removed and the product was isolated using column chromatography, yielding 0.22 g (71%) of compound 19.6.

[0277] Example 20 Synthesis of compound CDK7_1105

[0278] [ka]

[0279] Synthesis of Compound 20.1 Compound 19.6 (0.040 g, 0.110 mmol), cyclopropylboronic acid (0.029 g, 0.330 mmol), pyridine (0.018 mL, 0.220 mmol), and triethylamine (0.081 mL, 0.550 mmol) in 4 mL of tetrahydrofuran were heated in a microwave reactor at 150 °C for 1 h. After standard workup, the product was isolated using silica gel column chromatography. 0.042 g (98%) of compound 20.1 was obtained. Synthesis of Compound 20.2 Compound 20.1 (0.042 g, 0.100 mmol), (BPin) (0.039 g, 0.150 mmol), KOAc (0.051 g, 0.500 mmol), and Pd(dppf)Cl (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 h. The reaction mixture was filtered through Celite and the solvent was removed in vacuo. 0.04 g (91%) of the product was obtained in the form of a brown oil. Synthesis of Compound 20.3 Compound 20.2 (0.04 g, 0.090 mmol), pyrimidine 1.4 (0.034 g, 0.090 mmol), NaCO (0.019 g, 0.180 mmol), and Pd(dppf)Cl (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 under a nitrogen atmosphere for 1 h. After standard workup, the product was isolated using silica gel column chromatography. 0.026 g (44%) of compound 20.3 was obtained. Synthesis of Compound 20.4 Compound 20.3 (0.026 g, 0.04 mmol), NaOH (0.105 g, 2.60 mmol) in 5 mL of methanol and 0.5 mL of water was stirred at room temperature for 3 h, filtered through Celite, and the solvent was removed in vacuo to yield 0.02 g (95%) of Compound 20.4. Synthesis of compound CDK7_1105 Compound 20.4 (0.020 g, 0.04 mmol) was dissolved in 2 mL of TFA and the reaction was stirred at 20 °C for 18 h. The volatiles were removed in vacuo and re-evaporated with dichloromethane. The volatiles were removed in vacuo and the product was isolated using preparative HPLC to yield 0.017 g (47%) of compound CDK7_1105.

[0280] Example 21 Synthesis of compound CDK7_1062.

[0281] [ka]

[0282] Synthesis of Compound 21.1 2.23 mL (5.56 mmol) of a 2.5 M n-butyllithium solution in hexane was added to a solution of 2-chloropyrimidine (0.5 g, 4.28 mmol) in 10 mL of THF at −78° C. under a nitrogen atmosphere with stirring for 30 min. Tributyltin hydride (1.42 mL, 5.14 mmol) was then added and stirred for another 30 min. The temperature was then adjusted to room temperature and stirred for 12 h. After standard workup, the product was isolated using silica gel column chromatography. 0.55 g (35%) of compound 21.1 was obtained. Synthesis of Compound 21.2 Compound 21.1 (0.089 g, 0.240 mmol), 1-benzenesulfonyl-4-bromo-2-iodo-1H-pyrrole (0.1 g, 0.240 mmol), copper(I) iodide (0.014 g, 0.070 mmol), and Pd(PPh) (0.028 g, 0.020 mmol) in 20.1 mL of DMF were heated at 120 °C in a sealed vessel under an inert atmosphere for 4 h. After standard workup, the product was isolated using silica gel column chromatography. 0.035 g (40%) of compound 21.2 was obtained. Synthesis of Compound 21.3 Compound 21.2 (0.051 g, 0.140 mmol), (BPin) (0.073 g, 0.280 mmol), KOAc (0.035 g, 0.350 mmol), and Pd(dppf)Cl (0.010 g, 0.010 mmol) were dissolved in 2 mL of 1,4-dioxane and heated at 110 °C in a sealed vessel for 10 h. The reaction mixture was filtered through Celite and the solvent was removed in vacuo to yield 0.058 g (99%) of compound 21.3 in the form of a brown oil. Synthesis of Compound 21.4 Compound 21.3 (0.058 g, 0.140 mmol), pyrimidine 1.4 (0.053 g, 0.140 mmol), NaCO (0.019 g, 0.018 mmol), and Pd(dppf)Cl (0.031 g, 0.04 mmol) in a mixture of 2 mL of 1,4-dioxane and 1 mL of water were stirred at 110 °C under a nitrogen atmosphere for 2 h. After standard workup, the product was isolated using silica gel column chromatography. 0.044 g (50%) of compound 21.4 was obtained. Synthesis of Compound 21.5 Compound 21.5 was produced in 99% yield in a similar manner to compound 6.7. Synthesis of compound CDK7_1062 Compound CDK7_1062 was produced in 37% yield in a similar manner to compound 6.7.

[0283] Example 22 Synthesis of compound CDK7_1058

[0284] [ka]

[0285] Synthesis of Compound 22.2 Compound 19.6 (0.12 g, 0.34 mmol), 2-bromothiazole (0.1 g, 0.6 mmol), CuI (0.06 g, 0.3 mmol), and K2CO3 (0.09 g, 0.65 mmol) in 2 mL of DMF were heated in a sealed vessel at 130 °C with stirring for 2 h, cooled to room temperature, and 3 M NaOH solution was added until the pH reached 8. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo, and the product was isolated using column chromatography. HPLC yielded 0.1 g of a mixture in the form of an oil with a 60% compound 22.1 content (0.06 g, 60%). Benzene sulfonyl chloride (0.056 g, 0.32 mmol), DMAP (0.008 g, 0.06 mmol), triethylamine (0.064 g, 0.64 mmol), and dichloromethane (5 mL) were added to the mixture. The reaction mixture was stirred at room temperature for 18 hours. After standard workup, the product was isolated using silica gel column chromatography. The yield was 0.015 g (16%) of compound 22.2. Synthesis of compound CDK7_1058 0.015 g (0.21 mmol) of compound 22.2, (BPin) (0.012 g, 0.05 mmol), KOAc (0.01 g, 0.1 mmol), Pd(dppf)Cl (0.01 g, 0.01 mmol), and 1 mL of 1,4-dioxane were combined, and the mixture was heated at 100 °C in a sealed vessel for 1 h. After cooling, the reaction mixture was filtered through Celite, and the solvent was removed in vacuo. Pyrimidine 1.4 (0.011 g, 0.03 mmol), NaCO (0.006 g, 0.06 mmol), and Pd(dppf)Cl (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 at 110°C under a nitrogen atmosphere for 2 h. The reaction mixture was filtered through Celite and the solvent was removed in vacuo. The residue containing compound 22.4 was dissolved in 1.5 mL of ethanol and NaOH (0.12 g, 3.00 mmol) and 1 mL of water were added. The reaction was stirred at 60°C for 6 h, the solvent was removed in vacuo, and the residue was added with water (1 mL) until completely dissolved. The solution was 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, and the reaction was stirred at 20°C for 18 h. The volatile components were removed in vacuo, and the product was isolated using preparative HPLC. 1.3 mg (7% overall yield) of compound CDK7_1058 was produced.

[0286] Example 23 Synthesis of compounds CDK7_1060 and CDK7_1103.

[0287] [ka]

[0288] Synthesis of Compound 23.2 A mixture of 4-bromo-1H-pyrrole-2-carbonitrile (0.40 g, 2.29 mmol) (23.1), NHOH HCl (0.804 g, 11.45 mmol), and TEA (1.6 mL, 11.45 mmol) in 20 mL of ethanol was boiled with stirring for 1 h. After standard workup, 0.465 g (99%) was obtained, which was used in the next step without further purification. Synthesis of Compound 23.3 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 at room temperature for 1 h under a nitrogen atmosphere. Compound 23.2 (0.100 g, 0.47 mmol) was then added to 3 mL of 1,4-dioxane and stirred at room temperature for 12 h. The volatile components were removed in vacuo. The intermediate was purified by column chromatography, dissolved in 2 mL of 1,4-dioxane, and heated in a microwave reactor at 130 °C for 2 h. The volatile components were removed in vacuo. The product was isolated using silica gel chromatography. 0.025 g (23%) of Compound 23.3 was obtained. Synthesis of Compound 23.4 Compound 23.4 was produced in 71% yield in a similar manner to compound 1.2. Synthesis of Compound 23.5 Compound 23.4 (0.044 g, 0.120 mmol), (BPin) (0.04 g, 0.16 mmol), KOAc (0.036 g, 0.36 mmol), and Pd(dppf)Cl (0.009 g, 0.01 mmol) in 1 mL of 1,4-dioxane were heated at 100 °C with stirring under a nitrogen atmosphere for 4 h. After standard workup, the product was isolated using silica gel column chromatography. 0.034 g (68%) of compound 23.5 was obtained. Synthesis of Compound 23.6 Compound 23.6 was produced in 41% yield in a similar manner to compound 20.3. Synthesis of compound CDK7_1060 Compound 23.6 (0.016 g, 0.02 mmol), NaOH (0.016 g, 0.40 mmol) in 0.5 mL of ethanol and 0.4 mL of water were stirred at room temperature for 4 h. After standard workup, the residue containing compound 23.7 was dissolved in 1 mL of dichloromethane, 0.058 mL of TFA was added, and the reaction was stirred at 20 °C for 18 h. The volatile components were removed in vacuo, and the product was isolated by preparative HPLC. 0.008 g (66%) of compound CDK7_1060 was obtained.

[0289] Similarly, compound CDK7_1103 was produced using cyclopropylcarboxylic acid in 1% overall yield. Example 24 Synthesis of compounds CDK7_1061 and CDK7_533.

[0290] [ka]

[0291] Synthesis of Compound 24.2 A mixture of pyridine 24.1 (0.304 g, 0.82 mmol), 1-(benzenesulfonyl)-4-bromo-2-iodo-1H-pyrrole (0.228 g, 0.55 mmol), CuI (0.032 g, 0.16 mmol), and Pd(PPh) (0.064 g, 0.06 mmol) in 5 mL of 1,4-dioxane was heated at 100 °C with stirring under a nitrogen atmosphere for 4 h. After standard workup, the product was isolated using silica gel column chromatography. 0.054 g (32%) of compound 24.2 was obtained. Synthesis of Compound 24.3 Compound 24.2 (0.064 g, 0.18 mmol), (BPin) (0.093 g, 0.36 mmol), KOAc (0.055 g, 0.54 mmol), and Pd(dppf)Cl (0.04 g, 0.05 mmol) in 2 mL of 1,4-dioxane were heated at 100 °C with stirring under a nitrogen atmosphere for 4 h. After standard workup, the product was isolated using silica gel column chromatography. 0.074 g (99%) of compound 24.3 was obtained. Synthesis of Compound 24.4 Compound 3.3 (0.074 g, 0.18 mmol), pyrimidine 1.4 (0.069 g, 0.18 mmol), NaCO (0.058 g, 0.54 mmol), and Pd(dppf)Cl (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 under a nitrogen atmosphere for 2 h. After standard workup, the reaction product was isolated using silica gel column chromatography. 0.04 g (35%) of compound 24.4 was obtained. Synthesis of Compound 24.5 Compound 24.4 (0.04 g, 0.06 mmol), NaOH (0.024 g, 0.6 mmol) in a mixture of 3 mL of ethanol and 3 mL of water was stirred at room temperature for 1 h. After standard workup, 0.029 g (99%) of compound 24.5 was obtained. Synthesis of compound CDK7_1061 Compound CDK7_1061 was produced in a 44% yield in a similar manner to compound CDK7_1060.

[0292] Similarly, the corresponding boronic acid was used to produce compound CDK7_533 in 22% overall yield (conditions were similar to the synthesis of compound 21.4). Example 25 Synthesis of compound CDK7_1000

[0293] [ka]

[0294] Synthesis of Compound 25.2 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 at 0 °C and stirred for 30 min. 0.217 mL (1.2 mmol) of SEMCl was added and stirred at room temperature for 1 h. After standard workup, the volatile components were removed in vacuo. The residue was dissolved in 2.5 mL of DMF, and NaN (0.058 g, 0.88 mmol) and NH Cl (0.047 g, 0.88 mmol) were added. The mixture was heated with stirring at 160 °C for 2 h in a microwave synthesis vial. 0.069 mL (1.10 mmol) of methyl iodide was added to the reaction mixture and stirred at room temperature for 12 h. The volatile components were removed, and the product was isolated using 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 heated at 100 °C for 4 h with stirring under a nitrogen atmosphere. After standard workup, the reaction mixture was filtered through a silica gel pad and the volatile components were removed in vacuo. The residue containing compound 25.3 was dissolved in a mixture of 3 mL of 1,4-dioxane and 1.5 mL of water. Pyrimidine 1.4 (0.118 g, 0.310 mmol), 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 h under a nitrogen atmosphere. After standard workup, the reaction mixture was filtered through a silica gel layer to remove volatile components. 1 mL of dichloromethane and 0.07 mL of TFA were added to the residue containing compound 25.4, and the reaction was stirred at 20 °C for 18 h. The volatile components were then removed in vacuo. The residue was dissolved in 1 mL of ethanol, and NaOH (0.036 g, 0.90 mmol) and 1 mL of water were added and stirred at 20 °C for 18 h. After standard workup, the reaction product was isolated using preparative HPLC to yield CDK7_1000.

[0295] Example 26 Synthesis of compound CDK7_1124

[0296] [ka]

[0297] Synthesis of Compound 26.2 NBS (0.926 g, 122.87 mmol) was added to a solution of pyrrole-2-carbaldehyde 26.1 (0.5 g, 5.15 mmol) in 10 ml of THF at 0 °C and stirred for 15 min at 0 °C. The solvent was removed in vacuo and the product was isolated using recrystallization, yielding 0.446 g (50%) of compound 26.2. Synthesis of compound 26.3 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 at 0 °C and stirred for 30 min. Then, benzenesulfonyl chloride (0.222 mL, 1.72 mmol) was added and stirred at room temperature for 1 h. After standard workup, the product was isolated using silica gel column chromatography. 0.270 g (75%) of compound 26.3 was obtained. Synthesis of Compound 26.4 Compound 26.3 (0.246 g, 0.78 mmol), 1,2-diaminobenzene (0.089 g, 0.78 mmol), and NaSO (0.148 g, 0.78 mmol) in 6 mL of DMF were stirred at 80 °C for 25 min in a microwave reactor. After standard workup, the reaction product was isolated using recrystallization. 0.100 g (32%) of compound 26.4 was obtained. Synthesis of Compound 26.5 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) at 0 °C and stirred for 20 min. Methyl iodide (0.045 g, 0.30 mmol) was added and stirred at room temperature for 18 h. After standard workup, the product was isolated using silica gel column chromatography. 0.103 g (99%) of compound 26.5 was obtained. Synthesis of Compound 26.6 Compound 26.5 (0.110 g, 0.250 mmol), (BPin) (0.130 g, 0.500 mmol), KOAc (0.076 g, 0.75 mmol), and Pd(dppf)Cl (0.056 g, 0.07 mmol) were mixed in 3 mL of 1,4-dioxane and heated in a sealed vessel at 100 °C for 4 h. 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), NaCO (0.08 g, 0.750 mmol), and Pd(dppf)Cl (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 under a nitrogen atmosphere for 4 h. The reaction mixture was filtered through Celite and the solvent was removed in vacuo. The product was isolated using silica gel column chromatography, yielding 0.042 g (25%) of compound 26.6. Synthesis of Compound 26.7 Compound 26.6 (0.042 g, 0.060 mmol), NaOH (0.048 g, 1.20 mmol) in 3 mL of ethanol and 3 mL of water were stirred at room temperature for 1 h. The solvent was removed in vacuo to yield 0.028 g (88%) of compound 26.7. Synthesis of compound CDK7_1124 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 was stirred at room temperature for 16 h. Volatile components were removed in vacuo. The product was isolated using preparative HPLC. 0.008 g (36%) of compound CDK7_1124 was obtained.

[0298] Example 27 Synthesis of compound CDK7_1021

[0299] [ka]

[0300] Synthesis of Compound 27.1 Compound 18.3 (0.250 g, 0.830 mmol) was dissolved in 15 mL of THF, and NaH (0.037 g, 0.910 mmol) was added to the resulting solution at 0 °C. The mixture was stirred for 10 min, and then benzenesulfonyl chloride (0.139 mL, 1.08 mmol) was added and stirred at room temperature for 1 h. After standard workup, the product was isolated using silica gel column chromatography. 0.131 g (40%) of Compound 27.1 was obtained. Synthesis of Compound 27.2 Compound 27.1 (0.131 g, 0.310 mmol), (BPin) (0.157 g, 0.620 mmol), KOAc (0.0940 0.930 mmol), and Pd(dppf)Cl (0.023 g, 0.030 mmol) in 5 mL of 1,4-dioxane were stirred at 100 °C under a nitrogen atmosphere for 8 h. After standard workup, the reaction product was isolated using silica gel column chromatography. 0.06 g (43%) of compound 27.2 was obtained. Synthesis of compound 27.3 Compound 27.3 was produced in a 23% yield in a similar manner to compound 4.3. Synthesis of compound CDK7_1021 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 HO were stirred at room temperature for 2 h. After standard workup, the residue containing compound 27.4 was dissolved in 1 ml of dichloromethane, and 0.093 ml of TFA was added and stirred at room temperature for 20 h. After standard workup, the product was isolated using preparative HPLC. 0.006 g (35%) of compound CDK7_1021 was obtained.

[0301] Example 28 Synthesis of compound CDK7_1121

[0302] [ka]

[0303] Synthesis of Compound 28.1 Compound 19.6 (0.071 g, 0.190 mmol), oxan-4-yl methanesulfonate (0.070 g, 0.380 mmol), and CsCO (0.125 g, 0.380 mmol) in a mixture of 1 mL of DMF and 1 mL of dimethoxyethane were heated with stirring at 90 °C for 40 h. After standard workup, the product was isolated using silica gel column chromatography. 0.058 g (70%) of compound 28.1 was obtained. Synthesis of Compound 28.2 Compound 28.1 (0.058 g, 0.120 mmol), (BPin) (0.050 g, 0.190 mmol), KOAc (0.039 g, 0.380 mmol), and Pd(dppf)Cl (0.009 g, 0.010 mmol) were dissolved in 1 mL of 1,4-dioxane and heated in a sealed vessel at 110 °C for 4 h. After standard workup, the product was isolated using column chromatography. 0.049 g (85%) of compound 28.2 was obtained. Synthesis of compound 28.3 Compound 28.2 (0.049 g, 0.100 mmol), pyrimidine 1.4 (0.046 g, 0.120 mmol), NaCO (0.040 g, 0.370 mmol), and Pd(dppf)Cl (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 under a nitrogen atmosphere for 1 h. After standard workup, the product was isolated using silica gel column chromatography. 0.040 g (57%) of compound 28.3 was obtained. Synthesis of compound CDK7_1121 Compound 28.3 (0.040 g, 0.060 mmol), NaOH (0.121 g, 3.00 mmol) in a mixture of 1 mL of ethanol and 1 mL of HO were stirred at room temperature for 2 h. After standard workup, the residue containing compound 28.4 was dissolved in 3 mL of dichloromethane, and 0.696 mL of TFA was added and stirred at room temperature for 18 h. After standard workup, the product was isolated using preparative HPLC. 0.003 g (11%) of compound CDK7_1121 was obtained.

[0304] Example 29 Synthesis of compound 29.5.

[0305] [ka]

[0306] Synthesis of Compound 29.1 Oxalyl chloride (5.94 ml, 67.9 mmol) and one drop of DMF were added to acid 2.1 (4.30 g, 22.6 mmol) in 60 ml of dichloromethane and stirred at room temperature for 1 h. The volatile components were then removed, and the residue was dissolved in 30 ml of dichloromethane and added dropwise to a solution of methyl 3-aminopropanoate hydrochloride (4.11 g, 29.4 mmol) and TEA (16.6 ml, 113 mmol) in 30 ml of dichloromethane at 0 °C. The mixture was stirred at room temperature for 1 h. After standard workup, the product was isolated using silica gel column chromatography. 5.70 g (92%) of compound 29.1 was obtained. Synthesis of Compound 29.2 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 was stirred at room temperature for 18 h. After standard workup, 2.8 g (84%) of product 29.2 was obtained. Synthesis of Compound 29.3 A mixture of compound 29.2 (4.07 g, 14.8 mmol), PPA (38.2 g, 148 mmol), and PO (4.29 g, 14.8 mmol) was stirred at 110 °C for 2 h. After standard workup, 3.51 g (97%) of compound 29.3 was obtained. Synthesis of Compound 29.4 Compound 29.3 (2.04 g, 6.72 mmol), triethylsilane (3.16 g, 26.9 mmol) in 31 ml of TFA were stirred at room temperature for 20 h. After standard workup, 1.22 g (79%) of compound 29.4 was obtained. Synthesis of Compound 29.5 Compound 29.5 was produced in 50% yield in a similar manner to compound 2.3.

[0307] Example 30 Synthesis of compound CDK7_955.

[0308] [ka]

[0309] Synthesis of Compound 30.1 Compound 29.5 (0.346 g, 0.920 mmol), 4-iodo-1-methyl-1H-pyrazole (1.17 g, 5.52 mmol), CuI (0.088 g, 0.460 mmol), and (1R,2R)-cyclohexane-1,2-diamine (0.107 g, 0.920 mmol) in 14 mL of 1,4-dioxane were heated with stirring at 120 °C for 7 h. After standard workup, the product was isolated using column chromatography. 0.247 g (60%) of compound 30.1 was obtained. Synthesis of Compound 30.2 Compound 30.1 (0.130 g, 0.290 mmol), (BPin) (0.221 g, 0.870 mmol), KOAc (0.132 g, 1.30 mmol), and Pd(dppf)Cl (0.065 g, 0.09 mmol) were dissolved in 9 mL of 1,4-dioxane and heated in a sealed vessel at 110 °C for 12 h. After standard workup, the product was isolated using column chromatography. 0.141 g (98%) of compound 34.2 was obtained. Synthesis of Compound 30.3 Compound 30.2 (0.225 g, 0.12 mmol), pyrimidine 1.4 (0.059 g, 0.160 mmol), NaCO (0.039 g, 0.360 mmol), and Pd(dppf)Cl (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 under a nitrogen atmosphere for 10 h. After standard workup, the product was isolated using silica gel column chromatography. 0.060 g (70%) of compound 30.3 was obtained. Synthesis of Compound 30.4 Compound 30.3 (0.026 g, 0.04 mmol), NaOH (0.112 g, 2.80 mmol) in 5 ml of ethanol and 5 ml of water was stirred at room temperature for 1 hour, filtered through Celite, and the solvent was removed in vacuo to yield 0.08 g (99%) of Compound 30.4. Synthesis of compound CDK7_955 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 was stirred at 20 °C for 20 h. After standard workup, the product was isolated using preparative HPLC. 0.043 g (65%) of compound CDK7_955 was obtained. Synthesis of Compound 30.5 Compound 29.5 (0.201 g, 0.53 mmol), cyclopropylboronic acid (0.141 g, 1.59 mmol), copper(II) acetate (0.147 g, 0.079 mmol), triethanolamine (0.339 g, 3.18 mmol), and DMAP (0.196 g, 1.59 mmol) in 5 mL of toluene were stirred at 100 °C for 12 h. After standard workup, the product was isolated using silica gel column chromatography. 0.098 g (44%) of product 30.5 was obtained. Synthesis of Compound 30.6 Compound 30.5 (1.00 g, 2.32 mmol), (BPin) (1.80 g, 6.96 mmol), KOAc (0.704 g, 6.96 mmol), and Pd(dppf)Cl (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 h. After standard workup, the product was isolated using column chromatography. 0.700 g (66%) of compound 30.6 was obtained.

[0310] Example 31 Synthesis of compounds CDK7_1122 and CDK7_1225.

[0311] [ka]

[0312] Synthesis of Compound 31.2 Compound 30.2 (0.216 g, 0.440 mmol), pyrimidine 31.1 (0.125 g, 0.390 mmol), NaCO (0.124 g, 1.16 mmol), and Pd(dppf)Cl (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 under a nitrogen atmosphere for 4 h. After standard workup, the product was isolated using silica gel column chromatography. 0.114 g (46%) of compound 31.2 was obtained. Synthesis of compound CDK7_1122 Compound 31.2 (0.171 g, 0.270 mmol), NaOH (0.109 g, 2.70 mmol) in 2 ml of ethanol and 1 ml of water were stirred at room temperature for 4 h. After standard workup, the product was isolated using preparative HPLC. 0.028 g (21%) of compound CDK7_1122 was obtained.

[0313] Similarly, compound CDK7_1225 was produced in an overall yield of 69%. Example 32 Synthesis of compound CDK7_1123.

[0314] [ka]

[0315] Synthesis of Compound 32.2 Compound 32.2 was produced in a 79% yield in a similar manner to compound 4.2. Synthesis of Compound 32.3 The amide 32.2 (7.34 g, 20.5 mmol) and 27 mL (410 mmol) of methanesulfonic acid were stirred for 16 h at 20° C. After standard workup, 4.98 g (83%) of compound 32.3 was obtained. Synthesis of Compound 32.4 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 pyrrolopyridone 32.3 (5.00 g, 17.1 mmol) in 100 mL of dichloromethane, and the reaction was stirred at room temperature for 18 h. After standard workup, the product was isolated using silica gel column chromatography. 3.00 g (41%) of compound 32.4 was obtained. Synthesis of Compound 32.5 Compound 32.4 (1.50 g, 3.46 mmol), (BPin) (1.76 g, 6.92 mmol), KOAc (1.05 g, 10.4 mmol), and Pd(dppf)Cl (0.258 g, 0.350 mmol) in 20 mL of 1,4-dioxane were heated at 100 °C with stirring under a nitrogen atmosphere for 3 h. After standard workup, the product was isolated using silica gel column chromatography. 1.60 g (96%) of compound 32.5 was obtained. Synthesis of Compound 32.6 Compound 32.5 (0.117 g, 0.230 mmol), pyrimidine 31.1 (0.110 g, 0.210 mmol), NaCO (0.067 g, 0.630 mmol), and Pd(dppf)Cl (0.031 g, 0.040 mmol) in a mixture of 3 mL of 1,4-dioxane and 1 mL of water were stirred under a nitrogen atmosphere at 100 °C for 18 h. After standard workup, 0.130 g (98%) of compound 32.6 was obtained. Synthesis of compound CDK7_1123 Compound 32.6 (0.600 g, 0.960 mmol), NaOH (0.384 g, 9.60 mmol) in 18 ml of ethanol and 3 ml of water was stirred at 45 °C for 3 h. After standard workup, the product was isolated using preparative HPLC. 0.106 g (23%) of compound CDK7_1123 was obtained.

[0316] Example 33 Synthesis of compounds CDK7_1176, CDK7_1172, CDK7_1177, and CDK7_1188.

[0317] [ka]

[0318] Synthesis of Compound 33.1 Compound 33.1 was produced in 83% yield in a similar manner to compound 30.1. Synthesis of Compound 33.2 Compound 33.2 was produced in a similar manner to compound 30.2 in 99% yield. Synthesis of Compound 33.3 Compound 33.3 was produced in a similar manner to compound 30.3 in 53% yield. Synthesis of Compound 33.4 Compound 33.4 was produced in a similar manner to compound 30.4 in 99% yield. Synthesis of compound CDK7_1176 Compound CDK7_1176 was produced in a 70% yield in a similar manner to compound CDK7_955.

[0319] Similarly, the following compounds were prepared:

[0320] [Table 7]

[0321] Example 34 Synthesis of compound CDK7_1187.

[0322] [ka]

[0323] Synthesis of Compound 34.1 Method A: Compound 34.1 was produced in a 79% yield in a similar manner to compound 2630.51. Method B: In a manner similar to compound 44.3, compound 34.1 was produced from compound 43.1 and MeI in 70.0% overall yield. Synthesis of Compound 34.2 Compound 34.2 was produced in a similar manner to compound 30.2 in 99% yield. Synthesis of compound CDK7_1187 Compound 34.2 (0.069 g, 0.120 mmol), pyrimidine 31.1 (0.062 g, 0.120 mmol), NaCO (0.039 g, 0.360 mmol), and Pd(dppf)Cl (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 under a nitrogen atmosphere for 6 h. After standard workup, the product was isolated using preparative HPLC. 0.05 g (10%) of compound CDK7_1187 was obtained.

[0324] Example 35 Synthesis of compounds CDK7_999 and CDK7_1102.

[0325] [ka]

[0326] Synthesis of Compound 35.1 Compound 35.1 was produced in 96% yield in a similar manner to compound 4.2. Synthesis of Compound 35.2 Compound 35.1 was dissolved in 10 mL of acetonitrile and NaN3 (0.136 g, 2.07 mmol) was added. Then, a solution of trifluoromethanesulfonic anhydride (0.570 g, 1.88 mmol) in 5 mL of acetonitrile was added and stirred at room temperature for 18 h. After standard workup, the product was isolated using column chromatography. 0.162 g (76%) of Compound 35.2 was obtained. Synthesis of Compound 35.3 Compound 35.3 was produced in 49% yield in a similar manner to compound 26.3. Synthesis of Compound 35.4 Compound 35.4 was produced in 50% yield in a similar manner to compound 20.2. Synthesis of Compound 35.5 Compound 35.5 was produced in 84% yield in a similar manner to compound 20.3. Synthesis of Compound 35.6 Compound 35.6 was produced in a 74% yield in a similar manner to compound 24.5. Synthesis of compound CDK7_999 Compound CDK7_999 was produced in a 58% yield in a similar manner to compound CDK7_951.

[0327] Similarly, compound CDK7_1102 was produced using cyclopropylamine in 1% overall yield. Example 36 Synthesis of compound CDK7_814.

[0328] [ka]

[0329] Synthesis of compound CDK7_814 Compound 36.1 (0.152 g, 0.210 mmol), pyrimidine 1.4 (0.080 g, 0.210 mmol), NaCO (0.067 g, 0.630 mmol), and Pd(dppf)Cl (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 h under a nitrogen atmosphere. The volatile components were removed and the product was isolated using column chromatography. 3 mL of TFA was added to the residue containing compound 36.2 and stirred at room temperature for 12 h. After standard workup, the product was isolated using preparative chromatography. 0.023 g (30%) of compound CDK7_814 was obtained.

[0330] Example 37 Synthesis of compound CDK7_843.

[0331] [ka]

[0332] Synthesis of Compound 37.2 A 1M solution of LiHMDS in tetrahydrofuran (0.405 ml, 0.410 mmol) was added 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 h. Methyl iodide (0.161 g, 1.12 mmol) was added and stirred at 0 °C for 10 min, then at room temperature for 2 h. After standard workup, the product was isolated using silica gel column chromatography. 0.067 g (79%) of compound 37.2 was obtained. Synthesis of compound CDK7_843 A mixture of compound 37.2 (0.085 g, 0.330 mmol), (BPin) (0.128 g, 0.490 mmol), [Ir(OMe)cod] (0.016 g, 0.020 mmol), and 4,4'-di-tert-butyl-2,2'-bipyridine (0.013 g, 0.050 mmol) in 2 mL of THF was stirred at room temperature for 10 min, followed by addition of a solution of compound 37.2 (0.085 g, 0.330 mmol) in 1 mL of THF. The mixture was heated in a sealed vessel at 70 °C for 2 h and then at room temperature for 12 h. After cooling, the mixture was filtered through a pad of silica gel, 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 h under a nitrogen atmosphere. The reaction mixture was filtered through a silica gel pad, and the solvent was removed in vacuo. The product was isolated using silica gel column chromatography. The residue containing compound 37.4 was then dissolved in 3 mL of TFA and stirred at room temperature for 12 h. After standard workup, the product was isolated using preparative HPLC. 0.006 g (5%) of compound CDK7_843 was obtained.

[0333] Example 38 Synthesis of compound CDK7_1019.

[0334] [ka]

[0335] Synthesis of Compound 38.1 Compound 16.5 (0.220 g, 0.350 mmol) was dissolved in 1 mL of TFA and stirred at room temperature for 32 h, and the solvent was removed in vacuo. The dry residue was then dissolved in 15 mL of dichloromethane, and methyl iodide (0.024 mL, 0.390 mmol) and DIPEA (0.311 mL, 1.75 mmol) were added and stirred at room temperature for 12 h. After standard workup, the product was isolated using column chromatography. 0.160 g (85%) of compound 38.1 was obtained. Synthesis of compound CDK7_1019 Compound 38.1 (0.160 g, 0.280 mmol), NaOH (0.226 g, 5.60 mmol) in 6 mL of ethanol and 6 mL of water was stirred at room temperature for 1 h. The solvent was removed in vacuo and the product was isolated using preparative HPLC. 0.035 g (32%) of compound CDK7_1019 was obtained.

[0336] Example 39 Synthesis of compound CDK7_1020.

[0337] [ka]

[0338] Synthesis of compound CDK7_1020 Compound 1.5 (0.050 g, 0.80 mmol), NaOH (0.065 g, 1.60 mmol) in 2 mL of ethanol and 2 mL of water was stirred at room temperature for 1 h. After standard workup, the residue was dissolved in 1.5 mL of TFA and stirred at room temperature for 16 h. After standard workup, the product was isolated using preparative HPLC. 0.015 g (48%) of compound CDK7_1020 was obtained.

[0339] Example 40 Synthesis of compound 40.2.

[0340] [ka]

[0341] Synthesis of Compound 40.2 Compound 40.2 was produced in 48% yield in a similar manner to compound 15.3. Example 41 Synthesis of compound CDK7_1199.

[0342] [ka]

[0343] Synthesis of compound CDK7_1199 Compound 32.5 (0.053 g, 0.100 mmol), pyrimidine 40.2 (0.028 g, 0.090 mmol), NaCO (0.106 g, 0.270 mmol), and Pd(dppf)Cl (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 under a nitrogen atmosphere for 2 h. After standard workup, intermediate 41.1 was used in the next step 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 stirred at room temperature for 1 h. After standard workup, the product was isolated using preparative HPLC. 0.001 g (3%) of compound CDK7_1199 was obtained.

[0344] Example 42 Synthesis of compound CDK7 1254.

[0345] [ka]

[0346] Synthesis of Compound 42.2 Compound 42.2 was produced in 97% yield in a similar manner to compound 29.1. Synthesis of Compound 42.3 Compound 42.3 was produced in a 62% yield in a similar manner to compound 29.2. Synthesis of Compound 42.4 Compound 42.4 was produced in 72% yield in a similar manner to compound 29.3. Synthesis of Compound 42.6 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 while cooling in an ice bath, and the reaction was stirred at 20 °C for 24 h. After standard workup, the product was isolated using silica gel column chromatography. The residue containing compound 42.5 was dissolved in 4 mL of dichloromethane, and 0.57 mL of a 4 N HCl solution in 1,4-dioxane was added and stirred at 20 °C for 20 h. After standard workup, the product was isolated using column chromatography. Yield: 0.077 g (79%) of compound 42.6. Synthesis of Compound 42.7 Compound 42.7 was produced in 87% yield in a similar manner to compound 2.3. Synthesis of Compound 42.8 Compound 42.8 was produced in 83% yield in a similar manner to compound 27.2. Synthesis of Compound 42.9 Compound 42.9 was produced in 41% yield in a similar manner to compound 1.5. Synthesis of Compound 42.10 5% Pd / C (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 mixture was filtered through a pad of Celite, and the solvent was removed in vacuo to yield 0.023 g (55%) of compound 42.10. Synthesis of compound CDK7_1254 Compound CDK7_1254 was produced in a 29% yield in a similar manner to compound CDK7_836.

[0347] Example 43 Synthesis of compound 43.1.

[0348] [ka]

[0349] Synthesis of Compound 43.1 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 and stirred for 30 min. 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 isolated using column chromatography. 0.927 g (59%) of compound 43.1 was obtained.

[0350] Example 44 Synthesis of compounds CDK7_1154, CDK7_1155, CDK7_1226, CDK7_1227, CDK7_1229, CDK7_1259, and CDK7_1268.

[0351] [ka]

[0352] Synthesis of Compound 44.1 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 at 0 °C and stirred for 10 min. Bromocyclopentane (3.72 g, 23.7 mmol) was added and stirred at room temperature for 28 h. After standard workup, the reaction product was isolated using column chromatography. 0.154 g (46%) of compound 44.1 was obtained. Synthesis of Compound 44.3 Compound 44.1 was dissolved in 5 mL of TFA and stirred at room temperature for 1 h. The volatile components were then removed in vacuo, and the dry residue was dissolved in 5 mL of ethanol. 3 mL of 3 M NaOH solution was added and stirred at room temperature for 1 hour, and the volatile components were removed. After standard workup, the product was purified by column chromatography. The residue containing compound 44.2 was then dissolved in 5 mL of DMF, and NaH (0.029 g, 0.720 mmol) was added at 0 °C and stirred for 30 minutes. Then, benzenesulfonyl chloride (0.134 g, 0.720 mmol) was added and stirred at room temperature for 16 h. After standard workup, the product was isolated using column chromatography. 0.054 g (34%) of compound 44.3 was obtained. Synthesis of Compound 44.4 Compound 44.4 was produced in a similar manner to compound 30.2. Synthesis of Compound 44.5 In a manner similar to compound 32.6, pyrimidine 31.1 was used to produce compound 44.5 in 54% yield. Synthesis of compound CDK7_1154 Compound CDK7_1154 was produced in a 12% yield in a similar manner to compound CDK7_1122.

[0353] Similarly, the following compounds were prepared:

[0354] [Table 8]

[0355] Example 45 Synthesis of compounds CDK7_1201 and CDK7_1277.

[0356] [ka]

[0357] Synthesis of Compound 45.1 In a similar manner to compound 44.1, compound 45.1 was produced using 2-iodopropane in 74% yield. Synthesis of Compound 45.2 Compound 45.2 was produced in a similar manner to compound 44.2 in 92% yield. Synthesis of Compound 45.3 Compound 45.3 was produced in a similar manner to compound 44.3 in 96% yield. Synthesis of Compound 45.4 Compound 45.4 was produced in a similar manner to compound 44.4 in 60% yield. Synthesis of Compound 45.6 Compound 45.6 was produced in 85% yield in a similar manner to compound 18.8. Synthesis of Compound 45.7 Compound 45.6 (1.55 g, 2.65 mmol) was dissolved in 15 ml of 4N HCl solution in 1,4-dioxane, and the reaction was stirred at 60 °C for 30 min. After standard workup, the product was filtered off and the volatile components were removed in vacuo, yielding 1.15 g (88%) of Compound 45.7. Synthesis of Compound 45.8 Compound 45.7 (0.470 g, 0.900 mmol) was dissolved in 36 ml of POCl and stirred at 90 °C for 30 min. After standard workup, the product was isolated using column chromatography. 0.367 g (79%) of compound 45.8 was obtained. Synthesis of compound CDK7_1277 A suspension of compound 45.8 (0.534 g, 1.04 mmol), amine 40.1 (0.171 g, 1.35 mmol), and TEA (0.916 mL, 6.24 mmol) in 30 mL of absolute ethanol was stirred at room temperature for 60 h. 2 mL of 3 M NaOH solution was added to the resulting mixture and stirred at room temperature for 2 h. After standard workup, the product was isolated using preparative HPLC. 0.170 g (35%) of product CDK7_1277 was obtained.

[0358] Similarly, compound CDK7_1201 was produced in an overall yield of 3%. Example 46 Synthesis of compound CDK7_1276.

[0359] [ka]

[0360] Synthesis of Compound 46.1 In a manner similar to compound 18.8, pyrimidine 45.5 was used to produce compound 46.1 in 75% yield. Synthesis of Compound 46.2 In a manner similar to compound 45.7, pyrimidine 45.5 was used to produce compound 46.2 in 75% yield. Synthesis of compound CDK7_1276 Compound 46.2 (0.075 g, 0.140 mmol) was dissolved in 0.5 ml of POCl3 and stirred at 90 °C for 30 min. After standard workup, the product was isolated using column chromatography. The residue containing compound 46.3, amine 40.1 (0.083 g, 1.70 mmol), and TEA (0.117 ml, 0.840 mmol) in 8 ml of absolute ethanol were mixed at room temperature for 72 h. 2 ml of 3 M NaOH solution was added to the resulting mixture and stirred at room temperature for 4 h. After standard workup, the product was isolated using preparative HPLC. 0.012 g of product CDK7_1276 (15%) was obtained.

[0361] Example 47 Analysis of the obtained compounds. The purity and structure of the obtained compounds were confirmed by chromatography / mass spectrometry (LC / MS-ESI and 1 Confirmation was achieved by 1 H NMR spectroscopy (Tables 3 and 4).

[0362] Device data:

[0363] [Table 9]

[0364] [Table 10]

[0365] [Table 11-1]

[0366]

Table 11-2

[0367]

Table 11-3

[0368]

Table 11-4

[0369]

Table 11-5

[0370]

Table 11-6

[0371]

Table 11-7

[0372]

Table 11-8

[0373]

Table 11-9

[0374]

Table 11-10

[0375]

Table 12-1

[0376] [Table 12-2]

[0377] Example 48 Inhibitory enzyme activity of CDK7-CycH, CDK2-CycA, CDK9-CycK, and CDK13-CycK.

[0378] Measurements were performed in a 5 μl reaction volume using a 384-well plate (Corning Inc., Cat. No. 4513). The substance to be analyzed was titrated at 4 and 11 concentration increments starting from 50 μM in normal strength kinase buffer A (Thermo Fisher Scientific Inc., Cat. No. PV3189) supplemented with DTT (Sigma, Cat. No. 646563-10X.5ML) and prepared with water (Panreac, Cat. No. 701074). Kinase was diluted in the same buffer, mixed with test compounds in plate wells, and pre-incubated at 25°C for 10 minutes. Following incubation, a mixture of reaction substrates (CDKtide (SignalChem, Cat. No. C06-58) or Histone H1 (SignalChem, Cat. No. H10-54N) or PDKtide (SignalChem, Cat. No. P10-58) and ATP (SignalChem, Cat. No. V915B) prepared in normal strength kinase buffer A was added. A 1% dimethyl sulfoxide (DMSO) solution (Sigma-Aldrich, Cat. No. D2438) was used as a negative control in the reaction volume. The final concentrations of all reaction components are shown in Table 5. The plate was centrifuged at 400 rcf for 1 minute (Eppendorf, 5804R) and incubated at 25°C for 40–60 minutes. The amount of ATP consumed in the kinase reaction was then measured using the ADP-Glo™ detection system. The luminescence signal was measured using a Spark 20M tablet multifunction reader (Tecan Group Ltd, Switzerland). IC 50Values ​​were calculated using Magellan 7.2 (Tecan Group Ltd, Switzerland) by fitting the experimental points with a four-parameter model using optimization according to Levenberg-Marquardt.

[0379]

number

[0380] (Where A is the upper asymptote, D is the lower asymptote, and C is the IC 50 is the concentration that half-maximally inhibits the kinase, nM, and B is the curvature (slope)

[0381] [Table 13]

[0382] [Table 14-1]

[0383] [Table 14-2]

[0384] [Table 14-3]

[0385] [Table 15]

[0386] The results of these experiments confirm the generation of a high affinity CDK7 inhibitor that is selective for CDK9, CDK13 and CDK2. Example 49 In vitro antiproliferative activity against sensitive cell lines The antiproliferative activity of the CDK7 inhibitors according to the present invention was evaluated in a cell assay using continuous culture cells: MDA-MB-468 (triple-negative breast cancer, ATCC® HTB-132™) and NCl-H82 (small cell lung cancer, ATCC® HTB-175™) using live cell AlamarBlue dye (Thermo Fisher Scientific Inc., Cat. No. DAL1100). Cells were cultured in DMEM (PanEco, Cat. No. C330p) and RPMI-1640 (PanEco, Cat. No. C330p), respectively. The basal culture medium was enriched with 2 mM L-glutamine (PanEco, Cat. No. C032) and 10% fetal bovine serum (Gibco, Cat. No. 16140-071). The night before the assay, MDA-MB-468 adherent cells were detached from the plastic using trypsin-EDTA (PanEco, catalog no. П039П) solution, then inactivated with DMEM complete medium and centrifuged at 1000 RPM (Eppendorf, 5804R). Cell suspensions were prepared in DMEM complete medium and transferred to 96-well culture plates (Corning Inc, catalog no. 3599) at 8 x 10 cells per well in 100 μl of medium. The following day, test compounds were dissolved in DMSO and diluted with DMEM complete medium to final concentrations ranging from 50 μM to 10 pM. Diluted compounds were transferred to plate wells in triplicate (final DMSO concentration was less than 1%) in a 50 μl volume and incubated for 96 hours in an incubator at 37°C and 5% CO2. NCl-H82 suspension cell line was prepared on the day of assay. 10x10^3 cells in 100μl of RPMI-1640 complete medium were added to each well of a 96-well plate. The sample dilution procedure was as described above. The cells were incubated with the test compounds in an incubator at 37℃, 5% CO2 for 120 hours.After incubation, 15 ml of AlamarBlue reagent (Thermo Fisher Scientific Inc., catalog number DAL1100) was added to the wells, and the plate contents were agitated on an orbital shaker (Biosan, Latvia) and then incubated for an additional 5.5–6 h at 37°C and 5% CO in an incubator. The number of viable cells was determined by measuring the fluorescence signal at an excitation wavelength (λEx) of 540 nm and an emission wavelength (λEm) of 590 nm using an Infinite M200Pro microplate spectrophotometer (Tecan Group Ltd, Switzerland).

[0387] I C 50 Values ​​were calculated by fitting the experimental points with a four-parameter model using Levenberg-Marquardt optimization using Magellan software (Tecan Group Ltd, Switzerland).

[0388] [Table 16-1]

[0389] [Table 16-2]

[0390] The results of these experiments confirm the generation of inhibitors capable of arresting the growth of triple-negative breast cancer and small cell lung cancer at nM concentrations. Example 50 Overall cytotoxicity against primary HepaRG hepatocytes in vitro.

[0391] The overall cytotoxicity of the CDK7 inhibitors according to the present invention was studied using primary differentiated HepaRG cells (Biopredic Int, Catalog No. HPR101). One week before the assay, cells were thawed and maintained in basal hepatocyte medium (Biopredic Int, Catalog No. MIL700079) supplemented with HepaRg Maintenance / Metabolism Medium Supplement with Antibiotics (Biopredic Int, Catalog No. ADD620C). The medium in the vials containing the cells was changed every 2–3 days. The night before the assay, cells were plated into wells of a 96-well plate (Corning Inc., Catalog No. 3599) at 25 × 10^3 cells per well in 100 μl of medium. The next day, test compounds were titrated at concentrations ranging from 200 μM to 0.2 nM and introduced into the plate wells together with the cells for 72 hours. Cell viability was assessed as described above.

[0392] [Table 17]

[0393] The results of these experiments confirm the generation of a CDK7 inhibitor that is non-toxic in a human hepatocyte model. Example 51 Determination of bromodeoxyuridine incorporation into DNA When bromodeoxyuridine (BrdU) is added to dividing cells, thymidine is replaced by its analog, BrdU, which is incorporated into DNA. Therefore, the BrdU incorporated into DNA characterizes the intensity of DNA replication and the ongoing S phase of the cell cycle. Under the action of the compound, a reduction in bromodeoxyuridine incorporation into DNA characterizes a slowdown of the cell cycle and DNA replication.

[0394] The ability of the CDK7 inhibitors according to the present invention to inhibit BrdU incorporation into DNA was evaluated in a cell assay using continuous cell culture: MDA-MB-468 (triple-negative breast cancer, ATCC® HTB-132™, using a BrdU detection kit (Roche, catalog number 11 669 915 001)). Cells were grown in DMEM medium (PanEco, catalog number C330p). The basal culture medium was enriched with 2 mM L-glutamine (PanEco, catalog number C032) and 10% fetal bovine serum (Gibco, catalog number 16140-071). Adherent MDA-MB-468 cells were detached from the plastic using trypsin-EDTA (PanEco, catalog no. П039П) solution, then inactivated with DMEM complete medium and centrifuged at 1000 RPM (Eppendorf, 5804R). Cell suspensions were prepared in DMEM complete medium and introduced into 96-well culture plates (Corning Inc, catalog no. 3599) at 4 x 10^3 cells per well in 75 μl of medium. Test compounds were dissolved in DMSO and diluted with DMEM complete medium to final concentrations ranging from 0.5 μM to 2 pM. Serum-free growth medium was removed from the plate wells, and a 100 μl volume of diluted compound in basal growth medium was added. Candidates were introduced into the cell-containing plate wells in triplicate (final DMSO concentration was ≤1%) and incubated for 24 hours in an incubator at 37°C and 5% CO2. After incubation, 10 μl of BrdU solution was added to the wells at a concentration of 10 μM. The plate contents were agitated on an orbital shaker (Biosan, Latvia) and incubated for an additional 72 hours in an incubator at 37°C and 5% CO2. Incorporated BrdU was then detected according to the kit manufacturer's instructions. The BrdU-containing medium was removed from the plate 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 added to each well and incubated for 90 minutes at room temperature (+15–25°C). The fixative solution was removed, and 100 ml of anti-BrdU-POD working solution was added, followed by 90 minutes of incubation at room temperature (+15–25°C).The anti-BrdU-POD antibody solution was removed from the plate wells, and the wells were washed three times with 200 ml of washing solution (10 min at room temperature (+15–25°C)). 100 μl of substrate solution was introduced into each assay well and incubated on an orbital shaker (Biosan, Latvia) at room temperature (+15–25°C) for 3 min, followed by an additional 5–7 min without agitation.

[0395] The amount of incorporated BrdU was detected by measuring the luminescence signal with an Infinite M200Pro microplate spectrophotometer (Tecan Group Ltd, Switzerland). 50 Values ​​were calculated by fitting the experimental points with a four-parameter model using Levenberg-Marquardt optimization using Magellan software (Tecan Group Ltd, Switzerland).

[0396] [Table 18]

[0397] The results of these experiments confirm the generation of CDK7 inhibitors, whose antiproliferative activity against the MDA-MB-468 model (Example 49) occurs via cell cycle arrest and slowing of DNA replication.

[0398] Example 52 Determination of passive membrane permeability through PAMPA artificial membranes The passive membrane permeability of the compounds described in this invention was determined at pH 7.4 using the PAMPA (Parallel Artificial Membrane Permeability Assay) model. We used a 96-well plate (Corning® BioCoat® Pre-Coated PAMPA Plate System, Catalog No. 353015) consisting of acceptor and donor sections with cell membrane model PVDF filters pre-impregnated with a lecithin-phospholipid bilayer. Substances (concentration: 10 μmol) in 0.01 M phosphate buffer at pH 7.4 were introduced into the donor wells of the plate, and pure buffer was introduced into the acceptor wells. Both sections were then combined and incubated at room temperature for 20 hours to allow the compounds to redistribute between the two wells and the membranes. Verapamil (USP, USA, Catalog No. 1711202) and propranolol (MCE LLC, USA, Catalog No. HY-B0573 / CS-2680) were used as control compounds with high and moderate permeability. The samples were analyzed by reversed-phase HPLC with UV detection (Agilent 1260 chromatograph with UV detector) by determining the peak areas in their donor and acceptor wells. The permeability (Pe, cm / s) and retention factor (R, %) in the lipid bilayer were calculated using the formula: P e =(-ln[1-C A (t) / C 平衡 ]) / (A×(1 / V D +1 / V A )×t) R=1-[C D (t) × V D +C A (t) × V A ] / (C o +V D ) was calculated using In the formula, C o is the substance concentration in the donor well at the starting time t (μM), C A (t) is the substance concentration (μM) in the acceptor well at time t; V d is the volume of the donor well (0.3 ml), Va is the volume of the acceptor well (0.15 ml). C 平衡 =[C D (t) × V D +C A (t) × V A ] / (V D +V A ) (A is the filter area (0.3 cm 2 ) and t is the incubation time (72000 s).

[0399] [Table 19]

[0400] The results of these experiments confirm the generation of a CDK7 inhibitor that has the ability to passively permeate lipid membranes. Example 53 In vitro microsomal stability studies of compounds in human, rat, and mouse microsomes Procedures to study the metabolism of selected compounds were carried out in the microsomal fraction of liver (rat, mouse, human) in the presence of phase I metabolic cofactor (NADPH).

[0401] In vitro assays to determine the rate of enzymatic degradation of compounds in liver microsomes were performed 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, Cat. No. NN108711101), and 0.1 M sodium phosphate buffer (pH 7.4) containing 1.5 mM magnesium chloride at 37°C in a solid-state thermostat (XenoTech, USA, Cat. No. H2610, Cat. No. R1000, Cat. No. M1000). Incubations were performed in triplicate.

[0402] To determine compound stability under sample preparation conditions, duplicate aliquots containing test compound and microsomal fraction but lacking NADPH cofactor were incubated at 37°C for 40 minutes.

[0403] The reaction was stopped at 0, 10, 20, 30 and 40 min by adding an ice-cold mixture of acetonitrile:methanol (3:1) containing an internal standard. The samples were then centrifuged to remove precipitated proteins, and the supernatants were analyzed using HPLC-MS / MS to determine the in vitro clearance (CL) of the compounds. int ) was determined. An Agilent 1260 Infinity II HPLC liquid chromatograph (Agilent, USA) and an Agilent 6410 mass spectrometer (Agilent, USA) coupled with a cooled autosampler controlled by MassHunter software (Agilent, USA) were used as the HPLC-MS / MS system. Chromatographic analysis was performed on a C18 reverse-phase HPLC column (Agilent, Waters, or equivalent) in gradient elution mode. Mobile phase: 0.1% formic acid in water / 0.1% formic acid in acetonitrile, flow rate: 0.5 ml / min, column T = 35 °C. Mass spectrometric detection was performed using electrospray ionization in multiple reaction monitoring mode. For each substance, precursor ions, fragment ions, and collision energy were experimentally selected.

[0404] A graph of the logarithmic ratio between the peak area of ​​the substance and that of the internal standard versus time was plotted. The coefficient of this line corresponds to the elimination rate constant k, from which the in vitro clearance CLint was calculated: Elimination rate constant (k) = (-slope)

[0405]

number

[0406]

number

[0407]

number

[0408] Based on the obtained in vitro clearance CLint values, the microsomal stability of selected compounds for humans, rats and mice was concluded. The results are shown in Tables 12 and 13.

[0409] [Table 20]

[0410] [Table 21]

[0411] The results of these experiments confirm the generation of CDK7 inhibitors that are resistant (B) and highly resistant (A) to activity of human, mouse, and rat liver microsomal enzymes. Example 54 Pharmacokinetic (PK) studies.

[0412] Dosage and Administration Pharmacokinetic studies of the compounds were performed on male CD-1 mice, approximately 8 weeks old and weighing 16-29 g. Animals received a single oral (PO) dose (intragastric) of 10 mg / kg, formulated in 0.2% hydroxypropylmethylcellulose (HPMC) solution in 5% glucose in water, and a single IV bolus (intravenous) of 1.0 mg / kg for 1277 and 2.0 mg / kg for substances CDK7_1187, CDK7_1225, CDK7_1229, and CDK7_1276, formulated in 0.2% DMSO in 5% glucose in water.

[0413] For each substance, 21-30 animals were used for each dose administered PO and IV. All mice were weighed and randomized prior to dosing. For each time point, 3-5 animals were used. Each animal was sampled at one time point. At least 12 h before the start of the experiment, animals were deprived of food but maintained free access to water.

[0414] Animals from the PO and IV groups were subjected to blood sampling before and 0.5, 2, 4, 8, 12 and 24 h after substance administration. blood sample Blood was collected by cardiac puncture using the closed-chest technique. Blood was collected in a volume of 0.2 ml into polypropylene tubes containing 20 μl of 5% EDTA. Plasma was isolated by centrifugation at 10,000 rpm for 10 minutes at 4 ± 2°C and transferred to clean, labeled tubes.

[0415] plasma analysis Test plasma samples from mice from the experimental groups were obtained in a volume of 50 μl. Then, 200 ml of an internal standard solution (tolbutamide (Sigma, T0891)) prepared at a concentration of 50 ng / ml in acetonitrile was pre-cooled in a refrigerator at 2-8°C and added to the samples. The samples were vortexed for 10 seconds using a vortex mixer (G560E, Scientific Industries) and incubated at 4°C for 15 minutes to precipitate proteins. The samples were then centrifuged at 1500 g for 10 minutes (5417R centrifuge, Eppendorf) while cooled to 4°C. 150 μl of the supernatant was transferred to a 96-well plate for HPLC-MS / MS analysis. The quantitative determination of the test compound in plasma was performed using the absolute calibration curve method. A calibration curve was constructed by analyzing plasma samples supplemented with known standard amounts of the compound to be determined. The lower limit of quantitative determination of the test compound in plasma was 1 ng / ml, and the analytical range of the method was 1 ng / ml to 2000 ng / ml. This method was partially validated in terms of selectivity, accuracy, precision, linearity, matrix effect, and stability.

[0416] An Agilent 1290 Infinity II HPLC liquid chromatograph (Agilent) and a Qtrap 5500 mass spectrometer (AB Sciex) coupled with a cooled multisampler (Agilent 1290 Infinity II Multisampler G7167B) were used as the HPLC-MS / MS system. Chromatographic analysis was performed on a C18 reverse-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 with a flow rate of 0.5 ml / min, column temperature at 40°C, autosampler temperature at 8°C, and analysis time of 2.8 min. Mass spectrometry detection was performed in multiple reaction monitoring (MRM) mode. For each substance, precursor ions, fragment ions, and collision energies were experimentally selected. MRM chromatograms of the analytes and internal standards were recorded using two transitions, Q1 / Q3; one transition was used for quantitative calculations, and the other was used to confirm that the extraction time matched the given substance. Based on the 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 internal standard signal, on the analyte concentration was constructed.

[0417] Pharmacokinetic analysis Pharmacokinetic analysis was performed using non-compartmental methods using the Phoenix WinNonlin 6.3 software package. Key mean PK parameters were determined: time to maximum blood concentration (Tmax), elimination half-life (T1 / 2), maximum blood concentration (Cmax), area under the pharmacokinetic curve from administration to the last measured concentration (AUClast), clearance (CL), steady-state volume of distribution (Vss), and also absolute systemic bioavailability (F). Pharmacokinetic parameters of the compounds of the present invention are shown in Tables 14-15.

[0418] [Table 22]

[0419] [Table 23]

[0420] The compound of the present invention meets the target pharmacokinetic properties: the compound is well absorbed and has sufficient oral absorption effect.According to the average area under the curve (AUClast), the absolute bioavailability of the compound is calculated to be more than 72.7%.Therefore, this demonstrates that oral administration of these compounds can achieve pharmacodynamic effect.

[0421] Example 55 Blood-brain barrier (BBB) ​​permeability The ability of a substance to penetrate the blood-brain barrier and enter the central nervous system (mouse brain) was assessed by the area under the pharmacokinetic curve ratio of the substance in rat brain and plasma following oral administration, which characterizes the tissue bioavailability relative to the rat brain, and was expressed as the AUC brain / AUC plasma coefficient.

[0422] Dosage and Administration Pharmacokinetic studies of the compound were performed on male CD-1 mice, approximately 8 weeks old, weighing 16-29 g. Animals were administered a single oral (PO) dose (intragastric) of 10 mg / kg in a formulation in the form of a 0.2% hydroxypropylmethylcellulose (HPMC) solution in 5% aqueous glucose.

[0423] Twenty-one animals were used for each substance. All mice were weighed and randomized prior to dosing. Three animals were used for each time point. Biomaterials were collected from each animal at one time point. Animals were deprived of food at least 12 h before the start of the experiment, but had free access to water. Blood and brain samples were collected at 0.5, 2, 4, 6, 8, 12, and 16 h after substance administration.

[0424] blood sample All procedures were carried out in the same manner as in Example 54. Brain samples The mouse brain was perfused via the vascular system with saline. To this end, the chest was opened, the right atrium was opened with microsurgical scissors, and saline cooled to 4°C was administered into the left ventricle using a 10 ml syringe until the liver turned white. After washing, the skull was opened, the brain was removed, weighed, and transferred to a labeled 5 ml tube.

[0425] Analysis of brain samples Four volumes of water were added to the brain suspension and homogenized twice for 45 seconds using a homogenizer (Omni Bead Ruptor 24). Intact mouse brain homogenates were prepared in the same manner, and then used to prepare calibration and QC samples. A calibration curve was constructed by analyzing brain homogenate samples supplemented with known standard amounts of the compound to be determined.

[0426] The samples were precipitated with cold acetonitrile containing the internal standard tolbutamide (Sigma, T0891) at a ratio of 1:4 and a concentration of 50 ng / ml. The samples were vortexed for 10 seconds using a vortex mixer (G560E, Scientific Industries), held at 4°C for 15 minutes to precipitate proteins, and then centrifuged at 1500g for 10 minutes (5417R centrifuge, Eppendorf). 150 ml of the supernatant was collected and transferred to the corresponding wells of a 96-well plate for HPLC-MS / MS analysis. Quantitation of the test compound in the brain homogenate was performed in the same manner as in Example 54. The lower limit of quantitation of the test compound in the brain homogenate was 0.3 ng / ml.

[0427] Pharmacokinetic analysis of the data was performed similarly to the procedure described in Example 54. In addition to the main PK parameters, the brain and plasma concentration ratio (AUC brain / AUC plasma) at the time points of the study was calculated to assess bioavailability in the brain (permeability through the blood-brain barrier).

[0428] [Table 24]

[0429] The data obtained demonstrate the ability of the compounds according to the invention to penetrate across the BBB. Example 56 In vivo antitumor activity studies The antitumor activity of CDK7_1187 in vivo was evaluated in a subcutaneous xenograft model of NCl-H69 line (small cell lung carcinoma, ATCC® HTB-119™) implanted in BALB / c nude mice.

[0430] The NCl-H69 cell line was cultured in RPMI-1640 medium (PanEco, Russia) enriched with basal growth medium with a concentration of 2 mM L-glutamine (PanEco, Russia) and 10% fetal bovine serum (Gibco, Thermo Fisher Scientific, USA).

[0431] Twenty BALB / c nude mice (female) obtained from the Federal State Budgetary Scientific Institution "Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences" (ICG SB RAS) were used in the study.

[0432] BALB / c nude mice, 5 × 10 6 200 ml of a suspension containing 1:1 NCI-H69 tumor cells and Matrigel (Corning® Matrigel® Basement Membrane Matrix) was administered subcutaneously to the right lateral side of the body.

[0433] The tumor dimensions were determined using electronic calipers. The volume of the tumor nodule was determined by the formula (1): V=L×W 2 / twenty one) (where L and W are the major and minor diameters of the tumor nodule, respectively).

[0434] The efficacy of the test products was measured by the Tumor Growth Inhibition Index (TGI, %) calculated according to formula (2):

[0435]

number

[0436] (where Vc and Vp are the mean tumor nodule volumes of the control group and the group of animals receiving the test substance, respectively). Average tumor volume: 130mm 3 After achieving this, the animals were divided into two groups of 10, and tumor nodule volume was used as the randomization criterion. The day of the first administration of the product was designated as day 0.

[0437] The test substance CDK7_1187 was intragastrically administered at a dose of 6 mg / kg per day for 21 days. Before each administration, CDK7_1187 was diluted with 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.

[0438] Statistical analysis was performed using the GraphPad Prism 9 software package. The Mann-Whitney U test was used to assess the significance of differences when comparing tumor nodule volumes. Differences were identified as significant when p<0.05.

[0439] The kinetics of tumor growth are shown in Figure 1. The TGI index, % is shown in Table 17.

[0440] [Table 25]

[0441] The study results showed that tumor volumes following administration of CDK7_1187 to BALB / c nude mice were statistically significantly smaller than those in the control group on days 17 and 21 of the experiment. The tumor growth inhibition index was 48% at the end of the observation period.

Claims

1. Compounds of Formula I 【Chemical 1】 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof (In the formula, R １ is -C(Hal) ３ , —CH(Hal) ２ , -CH ２ Hal, -Hal, -H, -NO ２ , unsubstituted or substituted by one or several Hal atoms -(C １ ~C ６ ) alkyl, unsubstituted or substituted by one or several Hal atoms -O-(C １ ~C ６ ) alkyl, unsubstituted or substituted by one or several Hal atoms -S-(C １ ~C ６ ) alkyl, R ２ , R ３ are each independently H, -(C １ ~C ６ ) alkyl, or R ２ , R ３ is unsubstituted or has one or several -(C １ ~C ６ ) alkyl-substituted —(C ３ ~C ６ ) together form a cycloalkyl, L １ , L ２ are each independently a chemical bond, -NR ５ -, -O-, -S-, -S(O)-, -S(O) ２ -, -C(O)-, -C(O)O-, -C(S)-, -C(=NH)-, -(CR ６ａ R ６ｂ ) １～３ -, -Р(O)(CH ３ ) -, -O-(CH ２ ) １～３ -, -(CH ２ ) １～３ —O—, —NR ５ａ - (CH ２ ) １～３ -, -(CH ２ ) １～３ -NR ５ａ -, -C(O)-(CH ２ ) １～３ -, -(CH ２ ) １～３ -C(O)-, -C(O)-NH- or -NH-C(O)-; A is unsubstituted or substituted with one or several R ７ 6-10 membered aryl substituted by ７ａ and is unsubstituted or substituted with one or several R ８ａ -(C ３ ~C ６ ) 6-10 membered aryl fused to cycloalkyl; unsubstituted or one or several R ７ｂ and containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, and is unsubstituted or substituted with one or several R ８ｂ a 6- to 10-membered aryl fused to a 4- to 10-membered heterocyclyl substituted by ７ｃ and containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, and is unsubstituted or substituted with one or several R ８ｃ a 6- to 10-membered aryl fused to a 5- to 6-membered heteroaryl substituted by one, two, three or four N atoms, unsubstituted or one or several R ７ｄ 5-6 membered heteroaryl substituted by: ７ｅ and is unsubstituted or substituted with one or several R ８ｅ (C ３ ~C ６ ) 5-6 membered heteroaryl fused to cycloalkyl; containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, unsubstituted or containing one or several R ７ｆ and containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, and is unsubstituted or substituted with one or several R ８ｆ a 5- to 6-membered heteroaryl fused to a 4- to 10-membered heterocyclyl substituted by ７ｇ 5-6 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R ７ｈ and containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, and is unsubstituted or substituted with one or several R ８ｈ a 5- to 6-membered heterocyclyl fused to a 4- to 10-membered heterocyclyl substituted by R ４ is -H, -Hal, (=O), -OH, -C(O)OH, -NR ４ａ R ４ｂ , -P(O)(C １ ~C ６ alkyl) ２ , -S(O) ２ NH ２ , -S(O) ２ C １ ~C ６ Alkyl, unsubstituted or one or several R ４ｃ -(C １ ~C ６ ) alkyl; unsubstituted or with one or several R ４ｄ -O-C substituted by １ ~C ６ alkyl; unsubstituted or one or several R ４ｅ phenyl containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted with one or several R ４ｆ 4- to 7-membered heterocyclyl substituted by ４ｇ -(C ３ ~C ６ ) cycloalkyl; unsubstituted or with one or several R ４ｈ -C substituted by ２ ~C ６ Alkenyl; containing 1, 2, 3 or 4 N atoms and unsubstituted or containing one or several R ４ｉ 5-6 membered heteroaryl containing one or two heteroatoms selected from N, S or O and unsubstituted or one or several R ４ｊ and is unsubstituted or substituted with one or several R ４ｋ 4- to 7-membered heterocyclyl fused to phenyl substituted by ４ｌ and is unsubstituted or substituted with one or several R ４ｍ is a 5-6 membered heteroaryl fused to a phenyl substituted by 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 are each independently —H, (═O), —OH, or —NH ２ , -Hal, -CN, unsubstituted or -Hal, -OH, -NH ２ , —CN, —C substituted by one or several radicals selected from phenyl １ ~C ６ Alkyl; unsubstituted or -Hal, -OH, -NH ２ -OC substituted by one or several radicals selected from: -CN, phenyl １ ~C ６ Alkyl; unsubstituted or -Hal, -OH, -NH ２ , -CN, phenyl, -C １ ~C ６ -C substituted by one or several radicals selected from alkyl ３ ~C ６ Cycloalkyl; -S(O) ２ C １ ~C ６ Alkyl, —S(O) ２ NH ２ , —NH(C １ ~C ６ alkyl), -N(C １ ~C ６ alkyl) ２ , -P(O)(C １ ~C ６ alkyl) ２ , morpholinyl, thiazolyl, phenyl; R ５ , R ５ａ are each independently —H, C １ ~C ６ is alkyl, R ６ａ , R ６ｂ are each independently —H, C １ ~C ６ alkyl, -Hal; Or, R ６ａ and R ６ｂ are unsubstituted or some -(C １ ~C ６ ) C substituted with alkyl ３ ~C ６ forming a cycloalkyl, R ７ , R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , R ７ｈ are each independently -Hal, -OH, or -NH ２ , —CN, (═O), unsubstituted or substituted by one or several —Hal, —(C １ ~C ６ ) alkyl; unsubstituted or substituted by one or several -Hal; １ ~C ６ ) alkyl, R ８ａ , R ８ｂ , R ８ｃ , R ８ｄ , R ８ｅ , R ８ｆ , R ８ｈ are each independently -Hal, -OH, or -NH ２ , —CN, (═O), unsubstituted or substituted by one or several —Hal, —(C １ ~C ６ ) alkyl, Hal is an atom of F, Cl, Br, or I).

2. -A-L ２ -R ４ but, 【Chemistry 2-1】 【Chemistry 2-2】 【Chemistry 2-3】 (In the formula, k and m each independently represent 0, 1, 2, or 3; X １ , X ２ , X ３ , X ４ , X ５ , X ６ are each independently C, N, CH, or CH ２ , NH, S or O; Y １ , Y ２ , Y ３ , Y ４ , Y ５ are each independently C, N, or CH; L ２ is a chemical bond, -NR ５ -, -O-, -S-, -S(O)-, -S(O) ２ -, -C(O)-, -C(O)O-, -C(S)-, -C(=NH)-, -(CR ６ａ R ６ｂ ) １～３ -, -Р(O)(CH ３ ) -, -O-(CH ２ ) １～３ -, -(CH ２ ) １～３ —O—, —NR ５ａ - (CH ２ ) １～３ -, -(CH ２ ) １～３ -NR ５ａ -, -C(O)-(CH ２ ) １～３ -, -(CH ２ ) １～３ -C(O)-, -C(O)-NH- or -NH-C(O)-; R ４ is -H, -Hal, (=O), -OH, -C(O)OH, -NR ４ａ R ４ｂ , -P(O)(C １ ~C ６ alkyl) ２ , -S(O) ２ NH ２ , -S(O) ２ C １ ~C ６ Alkyl, unsubstituted or one or several R ４ｃ -(C １ ~C ６ ) alkyl; unsubstituted or with one or several R ４ｄ -O-C substituted by １ ~C ６ alkyl; unsubstituted or one or several R ４ｅ phenyl containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted with one or several R ４ｆ 4- to 7-membered heterocyclyl substituted by ４ｇ -(C ３ ~C ６ ) cycloalkyl; unsubstituted or with one or several R ４ｈ -C substituted by ２ ~C ６ Alkenyl; containing 1, 2, 3 or 4 N atoms and unsubstituted or containing one or several R ４ｉ 5-6 membered heteroaryl containing one or two heteroatoms selected from N, S or O and unsubstituted or one or several R ４ｊ and is unsubstituted or substituted with one or several R ４ｋ 4- to 7-membered heterocyclyl fused to phenyl substituted by ４ｌ and is unsubstituted or substituted with one or several R ４ｍ is a 5-6 membered heteroaryl fused to a phenyl substituted by 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 are each independently —H, (═O), —OH, or —NH ２ , -Hal, -CN, unsubstituted or -Hal, -OH, -NH ２ , —CN, —C substituted by one or several radicals selected from phenyl １ ~C ６ Alkyl; unsubstituted or -Hal, -OH, -NH ２ -OC substituted by one or several radicals selected from: -CN, phenyl １ ~C ６ Alkyl; unsubstituted or -Hal, -OH, -NH ２ , -CN, phenyl, -C １ ~C ６ -C substituted by one or several radicals selected from alkyl ３ ~C ６ Cycloalkyl; -S(O) ２ C １ ~C ６ Alkyl, —S(O) ２ NH ２ , —NH(C １ ~C ６ alkyl), -N(C １ ~C ６ alkyl) ２ , -P(O)(C １ ~C ６ alkyl) ２ , morpholinyl, thiazolyl, phenyl; R ５ , R ５ａ are each independently —H, C １ ~C ６ is alkyl, R ６ａ , R ６ｂ are each independently —H, C １ ~C ６ alkyl, -Hal; Or, R ６ａ and R ６ｂ are unsubstituted or some -(C １ ~C ６ ) C substituted with alkyl ３ ~C ６ forming a cycloalkyl, R ７ , R ７ｂ , R ７ｄ , R ７ｆ are each independently -Hal, -OH, or -NH ２ , —CN, (═O), unsubstituted or substituted by one or several —Hal, —(C １ ~C ６ ) alkyl; unsubstituted or substituted by one or several -Hal; １ ~C ６ ) alkyl, R ８ｂ , R ８ｄ , R ８ｆ are each independently -Hal, -OH, or -NH ２ , —CN, (═O), unsubstituted or substituted by one or several —Hal, —(C １ ~C ６ ) alkyl, 2. The compound of claim 1, wherein Hal is an atom of F, Cl, Br, or I.

3. -A-L ２ -R ４ but, 【Chemistry 3-1】 【Chemistry 3-2】 【Chemistry 3-3】 (In the formula, k and m each independently represent 0, 1, 2, or 3; L ２ is a chemical bond, -NR ５ -, -O-, -S-, -S(O)-, -S(O) ２ -, -C(O)-, -C(O)O-, -C(S)-, -C(=NH)-, -(CR ６ａ R ６ｂ ) １～３ -, -Р(O)(CH ３ ) -, -O-(CH ２ ) １～３ -, -(CH ２ ) １～３ —O—, —NR ５ａ - (CH ２ ) １～３ -, -(CH ２ ) １～３ -NR ５ａ -, -C(O)-(CH ２ ) １～３ -, -(CH ２ ) １～３ -C(O)-, -C(O)-NH-, or -NH-C(O)-; R ４ is -H, -Hal, (=O), -OH, -C(O)OH, -NR ４ａ R ４ｂ , -P(O)(C １ ~C ６ alkyl) ２ , -S(O) ２ NH ２ , -S(O) ２ C １ ~C ６ Alkyl, unsubstituted or one or several R ４ｃ -(C １ ~C ６ ) alkyl; unsubstituted or with one or several R ４ｄ -O-C substituted by １ ~C ６ alkyl; unsubstituted or one or several R ４ｅ phenyl containing 1, 2, 3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted with one or several R ４ｆ 4- to 7-membered heterocyclyl substituted by ４ｇ -(C ３ ~C ６ ) cycloalkyl; unsubstituted or with one or several R ４ｈ -C substituted by ２ ~C ６ Alkenyl; containing 1, 2, 3 or 4 N atoms and unsubstituted or containing one or several R ４ｉ 5-6 membered heteroaryl containing one or two heteroatoms selected from N, S or O and unsubstituted or one or several R ４ｊ and is unsubstituted or substituted with one or several R ４ｋ 4- to 7-membered heterocyclyl fused to phenyl substituted by ４ｌ and is unsubstituted or substituted with one or several R ４ｍ is a 5-6 membered heteroaryl fused to a phenyl substituted by 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 are each independently —H, (═O), —OH, or —NH ２ , -Hal, -CN, unsubstituted or -Hal, -OH, -NH ２ , -CN, phenyl, -C １ ~C ６ -C substituted by one or several radicals selected from alkyl １ ~C ６ Alkyl; unsubstituted or -Hal, -OH, -NH ２ -OC substituted by one or several radicals selected from: -CN, phenyl １ ~C ６ Alkyl; unsubstituted or -Hal, -OH, -NH ２ , —CN, —C substituted by one or several radicals selected from phenyl ３ ~C ６ Cycloalkyl; -S(O) ２ C １ ~C ６ Alkyl, —S(O) ２ NH ２ , —NH(C １ ~C ６ alkyl), -N(C １ ~C ６ alkyl) ２ , -P(O)(C １ ~C ６ alkyl) ２ , morpholinyl, thiazolyl, phenyl; R ５ , R ５ａ are each independently —H, C １ ~C ６ is alkyl, R ６ａ , R ６ｂ are each independently —H, C １ ~C ６ alkyl, -Hal; Or, R ６ａ and R ６ｂ are unsubstituted or some -(C １ ~C ６ ) C substituted with alkyl ３ ~C ６ forming a cycloalkyl, R ７ , R ７ｂ , R ７ｄ , R ７ｆ are each independently -Hal, -OH, or -NH ２ , —CN, (═O), unsubstituted or substituted by one or several —Hal, —(C １ ~C ６ ) alkyl; unsubstituted or substituted by one or several -Hal; １ ~C ６ ) alkyl, R ８ｂ , R ８ｄ , R ８ｆ are each independently -Hal, -OH, or -NH ２ , —CN, (═O), unsubstituted or substituted by one or several —Hal, —(C １ ~C ６ ) alkyl; unsubstituted or substituted by one or several -Hal; １ ~C ６ ) alkyl, 3. The compound according to claim 1 or 2, wherein Hal is an atom of F, Cl, Br, I.

4. L １ , L ２ are each independently a chemical bond, —C(O)—, or —CH ２ -, -CH(CH ３ ) -, -C(CH ３ ) ２ -, -C(CH ２ ) ２ -, -CF ２ -, -S-, -S(O)-, -S(O) ２ -, -O-, -NH-, -NCH ３ -, -Р(O)(CH ３ 4. The compound according to claim 1, wherein the aryl group is —C(O)—, —C(O)O—, —C(O)—NH—, or —NHC(O)—.

5. R １ -H, -CF ３ , -CCl ３ , -CHF ２ , -CH ２ F, —CHCl ２ , -CH ２ Cl, -NO ２ 4. The compound of claims 1 to 3, wherein

6. R ２ , R ３ are each independently —H, methyl, ethyl, or propyl, or R ２ and R ３ 4. Compounds according to claims 1 to 3, wherein together with the C atom to which they are attached form cyclopropyl, cyclobutyl or cyclopentyl.

7. R ４ is -H, (=O), -OH, -F, -Cl, -Br, -P(O)(C １ ~C ６ alkyl) ２ -S(O) ２ NH ２ -S(O) ２ -(C １ ~C ６ ) alkyl; unsubstituted or one or several (=O), -Hal, -CN, -S(O) ２ -(C １ ~C ６ ) alkyl-substituted —(C １ ~C ６ ) alkyl; unsubstituted or substituted with one or several (=O), -CN, -Hal; １ ~C ６ ) alkyl; unsubstituted or substituted with one or several (=O), -OH, -Hal, -CN; ３ ~C ６ ) cycloalkyl; unsubstituted or one or several -Hal, -CN, morpholine, -P(O)(CH ３ ) ２ phenyl containing 1, 2 or 3 heteroatoms selected from N or O, unsubstituted or -(C １ ~C ６ ) alkyl, (=O), -Hal, 5-6 membered heterocyclyl substituted with -CN; having 1, 2, 3 or 4 heteroatoms selected from N, O or S, unsubstituted or (=O), -(C １ ~C ６ ) alkyl, -(C ３ ~C ６ )cycloalkyl, -Hal, 5-6 membered heteroaryl substituted with -CN; containing one or two N atoms and unsubstituted or with one or several (=O), -(C １ ~C ６ ) a 5-6 membered heteroaryl substituted with alkyl and fused to phenyl; -NR ４ａ R ４ｂ and R ４ａ , R ４ｂ are each independently —H, (═O), morpholinyl, —F, or —S(O) ２ CH ３ , -CN, -one, cyclopropyl, thiazolyl, unsubstituted or phenyl, -P(O)(CH ３ ) ２ -C substituted by １ ~C ３ 4. The compound of claims 1 to 3, wherein the compound is alkyl.

8. R ４ -H, -O, (=O), -P(O)(CH ３ ) ２ , -CH ３ , -CH ２ CN ３ , tert-butyl, —CH ２ CF ３ , -CH ２ CH ２ S (O) ２ CH ３ , -CF ３ , -Cl, -OCF ３ , -S(O) ２ NH ２ , -S(O) ２ CH ３ phenyl, unsubstituted or substituted by one or several -Hal, -CN; methylpiperazinyl, piperazinyl, imidazolyl, thiazolyl, methylpyrazolyl, pyrazolyl, pyridinyl, pyrimidinyl, morpholine, oxanyl, oxolanyl, cyclohexyl, cyclopentyl, cyclopropyl, oxazolyl, methyloxazolyl, dimethyloxazolyl, dihydropyridinyl, methyldihydropyridinyl, -NR ４ａ R ４ｂ and R ４ａ , R ４ｂ are each independently —H, (═O), morpholinyl, —F, or —S(O) ２ CH ３ , -CN, -one, cyclopropyl, thiazolyl, unsubstituted or phenyl, -P(O)(CH ３ ) ２ -C substituted by １ ~C ３ The compound of claim 7, wherein the compound is alkyl.

9. 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 are each independently —H, (═O)—CH ３ , morpholinyl, -F, -S(O) ２ CH ３ , -CN, -one, cyclopropyl, thiazolyl, unsubstituted or phenyl, -P(O)(CH ３ ) ２ -C substituted by １ ~C ３ 8. The compound according to claim 1, wherein the aryl group is alkyl.

10. R ５ -H, -CH ３ 4. The compound of claims 1 to 3, wherein

11. R ６ａ and R ６ｂ are each independently —H, —F, or —CH ３ or R ６ａ and R ６ｂ 4. A compound according to claim 1, wherein together with the C atom to which they are attached, is cyclopropyl.

12. R ７ , R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ７ｇ , R ７ｈ each independently represents (═O), —Hal, or —CH ３ ;-OCH ３ ;-CHal ３ ;-OCHal ３ 4. The compound of claims 1 to 3, wherein

13. R ８ａ , R ８ｂ , R ８ｃ , R ８ｄ , R ８ｅ , R ８ｆ , R ８ｈ each independently represents (═O), —Hal, or —CH ３ ;-OCH ３ ;-CHal ３ ;-OCHal ３ 4. The compound of claims 1 to 3, wherein

14. 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)sulfanyl]-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_545); 4-[(2-aminophenyl)sulfanyl]-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-methylsulfonylphenoxy)-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_894); 4-(3-methylsulfonylphenoxy)-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-methanesulfonylethyl)-4-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (CDK7_848); N-(2-methanesulfonylethyl)-4-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrrole-2-carboxamide (CDK7_848_a); 4-[5-(morpholine-4-carbonyl)-1H-pyrrol-3-yl]-N-[(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]azocin-9-one (CDK7_932); 3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H,7H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_932_a); 8-methyl-3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_933); 8-methyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H,7H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_933_a); 3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_934); 3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,8H,9H-pyrrolo[2,3-c]azocin-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]azocin-9-one (CDK7_935); 8-methyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_935_a); 3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,7H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_936); 3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,7H,8H,9H-pyrrolo[2,3-c]azocin-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]azocin-9-one (CDK7_937); 8-methyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,7H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_937_a); 3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,6H,7H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_938); 3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,6H,7H,8H,9H-pyrrolo[2,3-c]azocin-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]azocin-9-one (CDK7_939); 8-methyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,6H,7H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_939_a); 3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_940); 3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,8H,9H-pyrrolo[2,3-c]azocin-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]azocin-9-one (CDK7_941); 8-methyl-3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,8H,9H-pyrrolo[2,3-c]azocin-9-one (CDK7_941_a); 3-(2-{[(3S)-piperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-9H-pyrrolo[2,3-c]azocin-9-one (CDK7_942); 3-{2-[(piperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-9H-pyrrolo[2,3-c]azocin-9-one (CDK7_942_a); 3-(2-{[(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_a); 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_a); 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]octan-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]octan-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]nonan-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]nonan-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-(oxanyl-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]octan-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]octan-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]octan-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]octan-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]octan-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]octan-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); -(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 ]trideca-1(10),2,4,11-tetraen-11-yl}-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (CDK7_1236_a); 4-{5-cyclopropyl-3,4,6,13-tetraazatricyclo[8.3.0.0 ２ , ６ ]trideca-1(10),2,4,11-tetraen-11-yl}-N-[(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 ]undeca-3(7),5-dien-2-one (CDK7_1261); 6-{2-[(6,6-dimethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1,4-diazatricyclo[7.1.1.0 ３ , ７ ]undeca-3(7),5-dien-2-one (CDK7_1261_a); 7-methyl-3-(2-{[(3S,6S)-6-methylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1264); 7-methyl-3-{2-[(6-methylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1264_a); 3-(2-{[(3S,6S)-6-ethylpiperidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-methyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1265); 3-{2-[(6-ethylpiperidin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-7-methyl-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1265_a); 3-(2-{[(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]octan-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]octan-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]octan-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]octan-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]octan-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]octan-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]octan-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]octan-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]octan-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]octan-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]octan-6-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-(propan-2-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1277); 3-[2-({4-azaspiro[2.5]octan-6-yl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]-7-(propan-2-yl)-1H,4H,5H,6H,7H,8H-pyrrolo[2,3-c]azepin-8-one (CDK7_1277_a) 2. The compound of claim 1, wherein:

15. A method for inhibiting the biological activity of cyclin-dependent protein kinase CDK7 in a subject, comprising the step of contacting cyclin-dependent protein kinase CDK7 with a compound described in any one of claims 1 to 13.

16. 14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

17. 16. A pharmaceutical composition according to claim 15, intended for the prevention or treatment of a disease or disorder associated with increased cyclin-dependent protein kinase CDK7 activity.

18. 17. The pharmaceutical composition according to claim 16, intended for the prevention or treatment of a disease or disorder associated with increased cyclin-dependent protein kinase CDK7 activity, wherein the disease or disorder associated with increased cyclin-dependent protein kinase CDK7 activity is a neoplastic, infectious or non-infectious inflammatory, autoinflammatory, or autoimmune disease.

19. The neoplastic disease is selected from the group consisting of breast cancer, metastatic breast cancer, HER2-positive breast cancer, estrogen receptor-expressing breast cancer, progesterone receptor-expressing breast cancer, triple-negative breast cancer (TNBC), estrogen and / or progesterone receptor-expressing HER2-negative breast cancer, 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, and rectal cancer. selected from the group comprising squamous cell carcinoma of the lining of the mouth, hepatobiliary cancer, hepatocellular carcinoma, urothelial carcinoma, prostate cancer, castration-resistant prostate cancer, thyroid cancer, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, lymphoma, T-cell lymphoma, B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, uterine cancer, fallopian tube cancer, sarcoma, Ewing's sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, multiple myeloma; the autoimmune disease is selected from the group comprising axial spondyloarthritis, antiphospholipid syndrome, vasculitis (Wegener's granulomatosis and related forms of vasculitis, temporal arteritis and polyarteritis nodosa, ANCA-associated vasculitis including necrotizing vasculitis), Goodpasture's syndrome, autoimmune thyroiditis, Graves' disease, bronchial asthma, cardiomyopathy, Crohn's disease, dermatomyositis, polymyositis, mixed connective tissue disease, glomerulonephritis, Guillain-Barré syndrome, Lyme arthritis, psoriasis, pemphigus, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis and uveitis; Autoinflammatory diseases include Behçet's disease, Blau syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, cryopyrin-associated periodic syndromes (CAPS), interleukin-1 receptor antagonist molecule deficiency (DIRA), familial Mediterranean fever (FMF), NLRP12-associated autoinflammatory disease, neonatal-onset multisystem inflammatory disease (NOMID), and chronic neonatal neurocutaneous and articular (CINCA) syndrome. , Majeed syndrome, mevalonate kinase deficiency (hyperimmunoglobulin D syndrome), periodic fever, aphthous stomatitis, pharyngitis and cervical lymphadenitis (PFAPA) syndrome, septic 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 include, but are not limited to, allergies (including delayed hypersensitivity reactions, immediate hypersensitivity reactions, and anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, osteitis, adult respiratory distress syndrome, airway inflammation (bronchiolitis, bronchitis, bronchiectasis, interstitial pneumonia, giant cell lung disease, etc.), and (including but not limited to) alveolar interstitial pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonitis, laryngitis, pneumonitis, pharyngitis, pleuritis, pneumonia, pneumoconiosis, asbestosis, beryllium disease, silicosis, tallithiasis, and usual interstitial pneumonia), tonsillitis, bursitis, cellulitis, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes mellitus, encephalitis, and endocardial Meningitis, 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, and inflammatory skin diseases), myelitis, myocarditis, nephritis, pyelonephritis, osteitis, osteomyelitis, optic neuritis, otitis, pancreatitis, mumps, pemphigoid, pericarditis, pernicious anemia, and phlebitis , polymyalgia rheumatica, hepatitis, cholangitis, progressive systemic sclerosing cholangitis, reperfusion injury, acute rheumatic fever, rhinitis, sinusitis, synovitis, tendonitis, necrotizing fasciitis, prostatitis, cystitis, epididymitis, omphalitis, oophoritis, orchitis, orchitis, transverse myelitis, urethritis, cystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis, 18. The pharmaceutical composition of claim 17.

20. 19. A method for the treatment of a disease or disorder associated with increased cyclin-dependent protein kinase CDK7 activity, comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to claim 15.

21. 20. A method for treating a disease or disorder according to claim 19, wherein the disease or disorder associated with increased activity of cyclin-dependent protein kinase CDK7 is a neoplastic, infectious or non-infectious inflammatory, autoinflammatory, or autoimmune disease.

22. The neoplastic disease is selected from the group consisting of breast cancer, metastatic breast cancer, HER2-positive breast cancer, estrogen receptor-expressing breast cancer, progesterone receptor-expressing breast cancer, triple-negative breast cancer (TNBC), estrogen and / or progesterone receptor-expressing HER2-negative breast cancer, 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, and rectal cancer. selected from the group comprising squamous cell carcinoma of the lining of the mouth, hepatobiliary cancer, hepatocellular carcinoma, urothelial carcinoma, prostate cancer, castration-resistant prostate cancer, thyroid cancer, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, lymphoma, T-cell lymphoma, B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, uterine cancer, fallopian tube cancer, sarcoma, Ewing's sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, multiple myeloma; the autoimmune disease is selected from the group comprising axial spondyloarthritis, antiphospholipid syndrome, vasculitis (Wegener's granulomatosis and related forms of vasculitis, temporal arteritis and polyarteritis nodosa, ANCA-associated vasculitis including necrotizing vasculitis), Goodpasture's syndrome, autoimmune thyroiditis, Graves' disease, bronchial asthma, cardiomyopathy, Crohn's disease, dermatomyositis, polymyositis, mixed connective tissue disease, glomerulonephritis, Guillain-Barré syndrome, Lyme arthritis, psoriasis, pemphigus, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis and uveitis; Autoinflammatory diseases include Behçet's disease, Blau syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, cryopyrin-associated periodic syndromes (CAPS), interleukin-1 receptor antagonist molecule deficiency (DIRA), familial Mediterranean fever (FMF), NLRP12-associated autoinflammatory disease, neonatal-onset multisystem inflammatory disease (NOMID), and chronic neonatal neurocutaneous and articular (CINCA) syndrome. , Majeed syndrome, mevalonate kinase deficiency (hyperimmunoglobulin D syndrome), periodic fever, aphthous stomatitis, pharyngitis and cervical lymphadenitis (PFAPA) syndrome, septic 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 include, but are not limited to, allergies (including delayed hypersensitivity reactions, immediate hypersensitivity reactions, and anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, osteitis, adult respiratory distress syndrome, airway inflammation (bronchiolitis, bronchitis, bronchiectasis, interstitial pneumonia, giant cell lung disease, etc.), and (including but not limited to) alveolar interstitial pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonitis, laryngitis, pneumonitis, pharyngitis, pleuritis, pneumonia, pneumoconiosis, asbestosis, beryllium disease, silicosis, tallithiasis, and usual interstitial pneumonia), tonsillitis, bursitis, cellulitis, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes mellitus, encephalitis, and endocardial Meningitis, 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, and inflammatory skin diseases), myelitis, myocarditis, nephritis, pyelonephritis, osteitis, osteomyelitis, optic neuritis, otitis, pancreatitis, mumps, pemphigoid, pericarditis, pernicious anemia, and phlebitis , polymyalgia rheumatica, hepatitis, cholangitis, progressive systemic sclerosing cholangitis, reperfusion injury, acute rheumatic fever, rhinitis, sinusitis, synovitis, tendonitis, necrotizing fasciitis, prostatitis, cystitis, epididymitis, omphalitis, oophoritis, orchitis, orchitis, transverse myelitis, urethritis, cystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis, 21. A method for treating the disease or disorder of claim 20.

23. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition according to claim 15, for the treatment of a disease or disorder associated with increased cyclin-dependent protein kinase CDK7 activity, in a subject in need of such treatment.

24. The use according to claim 22, wherein the disease or disorder associated with increased cyclin-dependent protein kinase CDK7 activity is a neoplastic, infectious or non-infectious inflammatory, autoinflammatory, or autoimmune disease.

25. The neoplastic disease is selected from the group consisting of breast cancer, metastatic breast cancer, HER2-positive breast cancer, estrogen receptor-expressing breast cancer, progesterone receptor-expressing breast cancer, triple-negative breast cancer (TNBC), estrogen and / or progesterone receptor-expressing HER2-negative breast cancer, 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, and rectal cancer. selected from the group comprising squamous cell carcinoma of the lining of the mouth, hepatobiliary cancer, hepatocellular carcinoma, urothelial carcinoma, prostate cancer, castration-resistant prostate cancer, thyroid cancer, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, lymphoma, T-cell lymphoma, B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma, neuroblastoma, skin cancer, melanoma, cervical cancer, uterine cancer, fallopian tube cancer, sarcoma, Ewing's sarcoma, soft tissue sarcoma, primary peritoneal cancer, retinoblastoma, multiple myeloma; the autoimmune disease is selected from the group comprising axial spondyloarthritis, antiphospholipid syndrome, vasculitis (Wegener's granulomatosis and related forms of vasculitis, temporal arteritis and polyarteritis nodosa, ANCA-associated vasculitis including necrotizing vasculitis), Goodpasture's syndrome, autoimmune thyroiditis, Graves' disease, bronchial asthma, cardiomyopathy, Crohn's disease, dermatomyositis, polymyositis, mixed connective tissue disease, glomerulonephritis, Guillain-Barré syndrome, Lyme arthritis, psoriasis, pemphigus, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, sarcoidosis, ulcerative colitis, multiple sclerosis, myasthenia gravis and uveitis; Autoinflammatory diseases include Behçet's disease, Blau syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, cryopyrin-associated periodic syndromes (CAPS), interleukin-1 receptor antagonist molecule deficiency (DIRA), familial Mediterranean fever (FMF), NLRP12-associated autoinflammatory disease, neonatal-onset multisystem inflammatory disease (NOMID), and chronic neonatal neurocutaneous and articular (CINCA) syndrome. , Majeed syndrome, mevalonate kinase deficiency (hyperimmunoglobulin D syndrome), periodic fever, aphthous stomatitis, pharyngitis and cervical lymphadenitis (PFAPA) syndrome, septic 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 include, but are not limited to, allergies (including delayed hypersensitivity reactions, immediate hypersensitivity reactions, and anaphylactic shock), allograft rejection, graft-versus-host disease, atherosclerosis, arteritis, arthritis, osteitis, adult respiratory distress syndrome, airway inflammation (bronchiolitis, bronchitis, bronchiectasis, interstitial pneumonia, giant cell lung disease, etc.), and (including but not limited to) alveolar interstitial pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, hypersensitivity pneumonitis, laryngitis, pneumonitis, pharyngitis, pleuritis, pneumonia, pneumoconiosis, asbestosis, beryllium disease, silicosis, tallithiasis, and usual interstitial pneumonia), tonsillitis, bursitis, cellulitis, chorioamnionitis, blepharitis, iritis, conjunctivitis, dacryoadenitis, chronic cholecystitis, cystic fibrosis, diabetes mellitus, encephalitis, and endocardial Meningitis, 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, and inflammatory skin diseases), myelitis, myocarditis, nephritis, pyelonephritis, osteitis, osteomyelitis, optic neuritis, otitis, pancreatitis, mumps, pemphigoid, pericarditis, pernicious anemia, and phlebitis , polymyalgia rheumatica, hepatitis, cholangitis, progressive systemic sclerosing cholangitis, reperfusion injury, acute rheumatic fever, rhinitis, sinusitis, synovitis, tendonitis, necrotizing fasciitis, prostatitis, cystitis, epididymitis, omphalitis, oophoritis, orchitis, orchitis, transverse myelitis, urethritis, cystitis, uveitis, cervicitis, salpingitis, endometritis, vaginitis, vulvitis, vulvovaginitis, 24. The use according to claim 23.

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