Combination therapy of CDK7 inhibitors with other anticancer therapies

Abstract

The present disclosure relates to combinations of cyclin-dependent kinase 7 (CDK7) inhibitors with other therapeutic agents, particularly other anti-cancer agents, and the use of such combinations in the treatment of cancer.

Description

[Technical Field]

[0001] The present disclosure relates to combinations of cyclin-dependent kinase 7 (CDK7) inhibitors with other therapeutic treatments, particularly other anti-cancer agents, and the use of such combinations in the treatment of cancer. [Background technology]

[0002] CDK7 is a master regulator of cell cycle progression and a component of the general transcription factor TFIIH, which controls RNA polymerase II-mediated transcription. CDK7 inhibition can cause DNA damage and genomic instability by arresting the cell cycle and inducing replication stress. Due to its role as a master regulator of the cell cycle and transcription, CDK7 is an attractive therapeutic target for cancer treatment.

[0003] Various CDK7 inhibitors have been described in the art. For example, the inhibitor samuracilib has been described to target the proliferation pathway and inhibit advanced prostate cancer (Constantin et al., Oncogene 2022; http: / / doi.org / 101101 / 2022.06.29.497030).

[0004] Alvocidib (flavopiridol), a semisynthetic flavone derivative that inhibits CDKs 1, 2, 4, 6, 7, and 9, was the first CDK inhibitor to enter clinical trials. Most trials showed limited clinical activity, but demonstrated modest responses in chronic lymphocytic leukemia (CLL) and Mantel cell lymphoma (Byrd et al., 2006, Blood, 109(2), pp. 399-404).

[0005] WO2019 / 197546 describes pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives that are selective CDK7 inhibitors.

[0006] BS-181 is another example of a selective CDK7 inhibitor that is structurally related to the PAN-CDK inhibitor roscovitine [Ali et al., 2009, Cancer Research, 69(15), pp. 6208-6215].

[0007] Another selective CDK7 inhibitor, SY-1365, developed by Syros Pharmaceuticals, was used in a phase I clinical trial for the treatment of advanced solid tumors (Q et al. 2019, Cancer Research, https: / / doi.org / 10.1158 / 0008-5472), but this trial was discontinued.

[0008] There remains a need in the field for new therapeutic modalities that are effective in the treatment of proliferative diseases, particularly cancer.

[0009] Additionally, there remains a need in the field of cancer therapy to improve existing therapies and provide new therapies.

[0010] In a first aspect, the present invention relates to the combination of a cyclin-dependent kinase 7 inhibitor and an anti-cancer agent different from said cyclin-dependent kinase 7 inhibitor, wherein said cyclin-dependent kinase 7 inhibitor is represented by the general formula I

[0011] [ka]

[0012] (In the formula, X is independently selected at each occurrence from CH and N; Q is absent or, independently at each occurrence, is selected from the group consisting of: -NH-, -NH(CH2)-, -NH(CH2)2-, -NH(C=O)-, -NHSO2-, -O-, -O(CH2)-, -(C=O)-, -(C=O)NH-, and -(C=O)(CH2)-; Y, independently at each occurrence, is halogen, C1-C3 haloalkyl, C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclyl, -S(=O)2R 4 , C1-C6 alkyl and one or two -OR 6 , -N(R 6 )R 6 , C1-C6 alkyl substituted with aryl, heteroaryl, and heterocyclyl; C3-C8 cycloalkyl is one or two R 4 , R 5 and -(C=O)R 6 and heterocyclyl is optionally substituted with one or two R 4 , R 5 and -(C=O)R 6 The aryl or heteroaryl may be substituted with one or two R 4 , C1-C6 alkyl, -OR 6 , -N(R 6 )R 6 , -(C=O)R 6 , optionally substituted with halogen, heteroaryl and heterocyclyl; R 1 is independently selected at each occurrence from the group consisting of halogen, C1-C6 alkyl, C3-C10 cycloalkyl, —CN, —(C═O)CH3, and C1-C3 haloalkyl, any of which may be substituted; R 2 is independently selected in each occurrence from any one of the structures in Group A below:

[0013] [ka]

[0014] wherein m, at each occurrence, is independently selected from 1, 2, and 3; W is any one of the structures of Group B below;

[0015] [ka]

[0016] wherein L is absent or, independently at each occurrence, is selected from the group consisting of —O— and —NH—; n is independently selected in each occurrence from 1, 2 and 3); R 3 is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR 6 , -CN and -OH, -OR 6 Or -NHR 6 C1-C6 alkyl substituted with; R 4 is absent or, independently in each occurrence, hydrogen, -OR 6 , halogen, C1-C3 haloalkyl, -CN, -N(R 6 )R 6 , (=O), -NH(C=O)R 6 , -(C=O)NH2, -S(=O)2N(R 6 )R 6 , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and -OR 6 , -NH2 or -S(=O)2N(R 6 )R 6 C1-C6 alkyl substituted with; R 5 is independently in each occurrence hydrogen, halogen, C1-C3 haloalkyl, -CN, -OR 6 , -N(R 6 )R 6 , (=O), S(=O)2N(R 6 )R 6 , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and -OH, -NH2 or -S(=O)2N(R 6 )R 6 C1-C6 alkyl substituted with; R 4 and R 5are both attached to a single sulfur atom that forms part of a heterocycle, Y, then (=O); or R 4 and R 5 together with the structure to which they are attached form an aromatic ring, a heteroaromatic ring, a saturated or unsaturated heterocyclic ring, or a fused or bridged ring structure of either an aromatic ring, a heteroaromatic ring, a saturated or unsaturated heterocyclic ring; R 6 is independently, at each occurrence, hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, heteroaryl, heterocyclyl, one or two halogens, -OR 7 , -N(R 7 )R 7 , C1-C6 alkyl and heteroaryl substituted with C1-C6 alkyl substituted with -OH, -NH2; one or two halogens, -OR 7 , -N(R 7 )R 7 , C1-C6 alkyl, and heterocyclyl substituted with C1-C6 alkyl substituted with -OH or -NH2; R 7 is independently selected at each occurrence from the group consisting of hydrogen, C-C alkyl, C-C cycloalkyl, and W (as defined above); R 8 is independently selected at each occurrence from hydrogen and W (as defined above); R 7 W, R 8 If is hydrogen; R 9 is independently selected at each occurrence from hydrogen and W (as defined above); R 10 is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH2, -OR 6 -CN and W (as defined above); R 10 W, R 8 If is hydrogen; R 11 is independently selected at each occurrence from the group consisting of hydrogen, C-C alkyl, and C-C haloalkyl; R 12 is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH2, -OR 6 and -CN; R 13 is independently selected at each occurrence from the group consisting of hydrogen, C-C alkyl, C-C cycloalkyl, and W (as defined above); R 13 If W, then R 9 is hydrogen; R 14 and R 15 is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR 6 , heterocyclyl, and -CN; R 16 is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R 6 )2, -NR 13 R 14 , -NR 13 CH2(CO)NH2, heterocyclyl, -OR 6 and -CN), or an enantiomer, stereoisomeric form, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate, or pharmaceutically acceptable salt thereof.

[0017] In one embodiment, the anticancer agent is selected from: a) target-specific compounds selected from the group consisting of: immune checkpoint inhibitors, in particular monoclonal antibodies and antibody fragments that target immune checkpoints; poly ADP-ribose polymerase (PARP) inhibitors; monoclonal antibodies and antibody fragments that do not target immune checkpoints; tyrosine kinase inhibitors; immunotoxins; MEK inhibitors; KRAS inhibitors; c-MET inhibitors; FGFR inhibitors; proteasome inhibitors; cyclin-dependent kinase inhibitors; mTOR inhibitors; retinoids; immunomodulators; histone deacetylase inhibitors; proteolysis-targeted chimeric compounds (PROTACs); siRNAs; antibody-drug-conjugates (ADCs); antibody-siRNA-conjugates (ARCs); DNA damage response inhibitors, and target-specific fusion proteins; and b) cytotoxic nonspecific compounds selected from the following: taxanes, alkylating agents, nucleoside analogs, antifolates, topoisomerase inhibitors, anthracyclines, podophyllotoxins, vinca alkaloids, and platinum compounds; c) Hormonal anticancer agents selected from the following: hormones; hormone antagonists; hormone receptor antagonists; hormone receptor degraders and aromatase inhibitors; Preferably, the hormone is selected from medroxprogesterone; anastrozole, letrozole, exemestane; megestrol; raloxifene; estramustine; gonadotropin-releasing hormones such as leuprolide, goserelin, triptorelin, histrelin, abarelix; androgens such as testolactone, fluoxymesterone; antiandrogens such as enzalutamide, bicalutamide, apalutamide, darolutamide, nilutamide, flutamide; Preferably, the hormone antagonist is selected from a gonadotropin-releasing hormone antagonist, such as degarelix; Preferably, the hormone receptor antagonist is selected from fulvestrant, tamoxifen, toremifene; and Preferably, the hormone receptor degrader is selected from a selective estrogen receptor degrader and a selective androgen receptor degrader; more preferably selected from diledestrant, amsenestrant, fulvestrant, AZD9833, lindestrant, LSZ102, LY3484356, elacestrant, ZN-c5, D-0502, SHR9549, and benzalkonium chloride; Preferably, the aromatase inhibitor is selected from anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, testolactone, and aminoglutethimide; and d) Radiopharmaceuticals.

[0018] In one embodiment, the combination is a composition in which the cyclin-dependent kinase 7 inhibitor and the anti-cancer drug are present together and either physically mixed with each other or separated from each other by at least one physical separation barrier between the cyclin-dependent kinase 7 inhibitor and the anti-cancer drug, and the at least one physical separation barrier forms part of the combination, for example, the cyclin-dependent kinase 7 inhibitor and the anti-cancer drug are held in separate containers or compartments or chambers or dosage units, and the separate containers, compartments, chambers and dosage units form part of the combination.

[0019] In one embodiment, the anti-cancer agent is a target-specific compound selected from the following: immune checkpoint inhibitors, particularly monoclonal antibodies that target immune checkpoints; poly ADP-ribose polymerase (PARP) inhibitors; other monoclonal antibodies that do not target immune checkpoints; tyrosine kinase inhibitors; DNA damage response inhibitors; and antibody-cytokine fusion proteins.

[0020] In one embodiment, the target-specific compound is selected from: an anti-PD1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-VEGF antibody, an anti-VEGFR antibody, an anti-EGFR antibody, an anti-HER2 antibody, an anti-CD52 antibody, an anti-CD33 antibody, an anti-CD30 antibody, an anti-CD20 antibody, an anti-TIM3 antibody, an anti-TIGIT antibody, an anti-41BB antibody, an anti-OX40 antibody, an anti-CD40 antibody, an anti-CD27 antibody, an anti-GITR antibody, an anti-ICOS antibody, an anti-Siglec antibody, and an anti-PVRIG antibody.

[0021] In one embodiment, the target-specific compound is selected from the following: anti-human-PD1 antibodies, in particular pembrolizumab, nivolumab, cemiplimab, spartalizumab, atezolizumab, avelumab, durvalumab, ipilimumab, tremelimumab, relatolimab, bevacizumab, ramucirumab, cetuximab, panitumumab, pertuzumab, trastuzumab, trastuzumab-emtansine, alemtuzumab, gemtu ibritumomab, ibritumomab-tiuxetan, rituximab, obinutuzumab, tositumomab, ofatumumab, pidilizumab, toripalimab, centilimab, camrelizumab, tislelizumab, zimberelimab, progolimab, dostallimab; preferably, the target specific compound is pembrolizumab.

[0022] In one embodiment, the target-specific compounds are selected from: poly ADP-ribose polymerase (PARP) inhibitors, in particular olaparib, pamiparib, and niraparib; tyrosine kinase inhibitors, in particular afatinib, aflibercept, axitinib, bosutinib, cabozantinib, ceritinib, crizotinib, dasatinib, erlotinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, nilotinib, pazopanib, ponatinib, regorafenib, ruxolitinib MEK inhibitors, particularly cobimetinib and trametinib; KRAS inhibitors, particularly sotrasib and adagrasib; c-MET inhibitors, particularly savolitinib; FGFR inhibitors, particularly erdaftinib, pemigatinib, and bofatamab; DNA damage response inhibitors selected from WEE1 inhibitors and ATR inhibitors, particularly adavosertib, beruzosertib, and volasertib.

[0023] In one embodiment, the anti-cancer agent is a cytotoxic non-specific compound selected from: a) a taxane, preferably selected from docetaxel, carbazitaxel, and paclitaxel; b) alkylating agents, preferably selected from bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, fotemustine, ifosfamide, lomustine, melphalan, streptozotocin, and temozolomide; c) nucleoside analogs, preferably selected from azacitidine, capecitabine, carmofur, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, nelarabine, pentostatin, tegafur, and thioguanine; d) an antifolate, preferably selected from methotrexate, pemetrexed, and raltitrexed; e) topoisomerase inhibitors, preferably selected from irinotecan and topotecan; f) anthracyclines, preferably selected from daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, and valrubicin; g) podophyllotoxins, preferably selected from etoposide and teniposide; h) vinca alkaloids, preferably selected from vinblastine, vincristine, vindesine, vinflunine, and vinorelbine; i) Platinum compounds, preferably selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, heptaplatin, and lobaplatin.

[0024] In one embodiment, the compound has the general formula Ia

[0025] [ka]

[0026] (In the formula, X is independently selected at each occurrence from CH and N; Y 1 is independently selected at each occurrence from CH, C(OH), and N; Y 2 is independently selected at each occurrence from CH, C(OH), and N; Q is absent or, independently at each occurrence, selected from the group consisting of -NH-, -NH(CH2)-, -NH(C=O)-, -NHSO2-, -O-, -O(CH2)-, -(C=O)-, and -(C=O)(CH2)-; R 1 is independently selected at each occurrence from the group consisting of halogen, C1-C6 alkyl, C3-C10 cycloalkyl, —CN, —(C═O)CH3, and C1-C3 haloalkyl, any of which may be substituted; R 2 is independently selected in each occurrence from any one of the structures in Group A below:

[0027] [ka]

[0028] (m=1, 2 or 3; W is any one of the structures of the following group B';

[0029] [ka]

[0030] wherein L is absent or, independently at each occurrence, is selected from the group consisting of -O- and -NH-; R 3 is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR 6 , -CN and -OH, -OR 6 Or -NHR 6 C1-C6 alkyl substituted with; R 4 is absent or, independently in each occurrence, hydrogen, -OR 6 , halogen, C1-C3 haloalkyl, -CN, -N(R 6 )R 6 , (=O), -NH(C=O)R 6 , -(C=O)NH2, -S(=O)2N(R 6 )R 6 , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and -OR 6 , -NH2 or -S(=O)2N(R 6 )R 6 C1-C6 alkyl substituted with; R 5 is independently in each occurrence hydrogen, halogen, C1-C3 haloalkyl, -CN, -OR 6 , -N(R 6 )R 6 , (=O), S(=O)2N(R 6 )R 6, aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and -OH, -NH2 or -S(=O)2N(R 6 )R 6 C1-C6 alkyl substituted with; R 4 and R 5 are both connected to a single sulfur atom that forms part of the heterocyclic ring Y, then (=O); or R 4 and R 5 together with the structure to which they are attached form an aromatic ring, a heteroaromatic ring, a saturated or unsaturated heterocyclic ring, or a fused or bridged ring structure of either an aromatic ring, a heteroaromatic ring, a saturated or unsaturated heterocyclic ring; R 6 is independently, at each occurrence, hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, heteroaryl, heterocyclyl, one or two halogens, -OR 7 , -N(R 7 )R 7 , C1-C6 alkyl and heteroaryl substituted with C1-C6 alkyl substituted with -OH, -NH2; one or two halogens, -OR 7 , -N(R 7 )R 7 , C1-C6 alkyl, and heterocyclyl substituted with C1-C6 alkyl substituted with -OH or -NH2; R 7 is independently selected at each occurrence from the group consisting of hydrogen, C-C alkyl, C-C cycloalkyl, and W (as defined above); R 8 is independently selected at each occurrence from hydrogen and W (as defined above); R 7 If W, then R 8 is hydrogen; R 9 is independently selected at each occurrence from hydrogen and W (as defined above); R 10is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH2, -OR 6 -CN and W (as defined above); R 10 If W, then R 8 is hydrogen; R 11 is independently selected at each occurrence from the group consisting of hydrogen, C-C alkyl, and C-C haloalkyl; R 12 is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH2, -OR 6 and -CN; R 13 is independently selected at each occurrence from the group consisting of hydrogen, C-C alkyl, C-C cycloalkyl, and W (as defined above); R 13 If W, then R 9 is hydrogen; R 14 and R 15 is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR 6 , heterocyclyl, and -CN; R 16 is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R 6 )2, -NR 13 R 14 , heterocyclyl, -OR 6 and -CN); or an enantiomer, stereoisomeric form, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate, or pharmaceutically acceptable salt thereof of said compound.

[0031] In one embodiment, at least one or exactly one R 2 , R 7 , R 8 , R9 , R 10 and R 13 is W as defined in claim 1 or a structure containing W as defined in claim 1.

[0032] In one embodiment, R 1 is C1-C6 alkyl or C1-C3 haloalkyl.

[0033] In one embodiment, R 2 teeth,

[0034] [ka]

[0035] is.

[0036] In one embodiment, R 10 is hydrogen; m is 1; R 8 is W; W is (c-1) or (c-2) or (c-3), preferably (c-1); L is -NH-; R 14 and R 15 is independently in each occurrence hydrogen, halogen, or C1-C6 alkyl, preferably R 14 is a halogen; R 16 is hydrogen, halogen, C1-C6 alkyl, -N(R 6 )2, -NR 13 R 14 and preferably R 16 -N(R 6 )2 or -NR 13 R 14 is.

[0037] In one embodiment, the compound is a compound having a structure selected from structures 1-198 as defined in the column entitled "Structure" of Table 1 herein.

[0038] In one preferred embodiment, the compound is a compound having a structure selected from compounds 3, 14, 47, and 156, as defined herein.

[0039] In a further aspect, the present invention also relates to a combination of the invention as defined herein for use in a method for the prevention and / or treatment of cancer in a patient having or suspected of having cancer.

[0040] In one embodiment of this aspect of the invention, the prophylactic and / or therapeutic method comprises administering an effective amount of the cyclin-dependent kinase 7 inhibitor together with an effective amount of the anti-cancer agent to a patient having or suspected of having cancer.

[0041] In one embodiment of this aspect of the present invention, in the preventive and / or therapeutic method, the cyclin-dependent kinase 7 inhibitor is administered to the patient before or after administration of the anti-cancer agent, or both the cyclin-dependent kinase 7 inhibitor and the anti-cancer agent are administered to the patient concomitantly, synchronously, or with temporal overlap, or the cyclin-dependent kinase 7 inhibitor is administered to the patient concomitantly with the anti-cancer agent, or the anti-cancer agent is administered to the patient concomitantly with the cyclin-dependent kinase 7 inhibitor.

[0042] In one embodiment of this aspect of the invention, the method of prevention and / or treatment comprises administering said combination in combination with radiation therapy.

[0043] In one embodiment, the cancer is a cancer selected from the group comprising or consisting of: renal cell carcinoma (RCC), kidney cancer, hereditary papillary renal cancer, sporadic papillary renal cancer, non-squamous non-small cell lung cancer (non-squamous NSCLC), squamous non-small cell lung cancer (squamous NSCLC), small cell lung cancer (SCLC), triple-negative breast cancer, colorectal cancer, melanoma, pancreatic ductal adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma (HNSCC), urothelial carcinoma, adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, carcinoma of the cervix, anal carcinoma, astrocytoma, and basal cell carcinoma. , pancreatic cancer, desmoid tumor, bladder cancer, bronchial cancer, estrogen-dependent and -independent breast cancer, Burkitt's lymphoma, body cancer, cancer of unknown primary site (CUP syndrome), small intestine cancer, small intestine tumor, ovarian cancer, endometrial cancer, ependymoma, epithelial cancer type, Ewing's tumor, gastrointestinal tumor, stomach cancer, gallbladder cancer, gallbladder carcinoma, uterine cancer, head and neck cancer, cervix, glioblastoma, gynecological tumor, ear, nose and throat tumor, blood tumor, hairy cell leukemia, urethral cancer, skin cancer, skin testicular cancer, brain tumor (glioma), brain metastasis, testicular cancer, pituitary tumor, carcinoid, Kaposi's sarcoma, laryngeal cancer, germ cell tumor , bone cancer, head and neck tumors (tumors of the ear, nose and throat area), colon cancer, craniopharyngioma, oral cancer (cancer of the mouth area and lips), cancer of the central nervous system, liver cancer, liver metastases, leukemia, eyelid tumors, lung cancer, lymphoma, stomach cancer, malignant melanoma, malignant neoplasms, malignant tumors of the gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastoma, meningioma, Hodgkin's lymphoma / non-Hodgkin's lymphoma, mycosis fungoides, nasal cancer, schwannoma, neuroblastoma, oligodendroglioma, osteolytic and osteoplastic cancer, osteosarcoma, ovarian carcinoma, pancreatic carcinoma, penile cancer, plasmacytoma, prostate cancer, pharyngeal cancer, rectal carcinoma, retinal sarcoma, vaginal Endoscopic cancer, thyroid cancer, T-cell lymphoma, thymoma, tubular carcinoma, eye tumor, urethral cancer, urinary system tumor, urothelial carcinoma, vulvar cancer, wart-like symptoms, soft tissue tumor, soft cell sarcoma, nephroblastic carcinoma, cervical cancer, tongue cancer, invasive tubular carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, lobular carcinoma in situ, small cell lung carcinoma, non-small cell lung carcinoma, bronchial adenoma, pleuropulmonary blastoma, mesothelioma, brain stem glioma, hypothalamic glioma, cerebellar astrocytoma, cerebral astrocytoma, neuroectodermal tumor, pineal tumor, uterine sarcoma, salivary gland cancer, anal gland carcinoma, mast cell tumor, pelvic tumor, ureteral tumor, intraocular melanoma, hepatocellular carcinoma,Cholangiocarcinoma, mixed hepatocellular-cholangiocarcinoma, squamous cell carcinoma, Merkel cell skin cancer, non-melanoma skin cancer, hypopharyngeal cancer, nasopharyngeal carcinoma, oropharyngeal cancer, oral cancer, squamous cell carcinoma, oral melanoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, central nervous system lymphoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, malignant histiocytosis, fibroblastic sarcoma, hemangiosarcoma, hemangiopericytoma, leiomyosarcoma (LMS), canine mammary gland carcinoma, and feline mammary gland carcinoma.

[0044] In a further aspect, the present invention also relates to a cyclin-dependent kinase 7 inhibitor having general formula I as defined herein for use in a method for the prevention and / or treatment of cancer, wherein said cyclin-dependent kinase 7 inhibitor is administered to a patient having or suspected of having cancer, and wherein the administration of said cyclin-dependent kinase 7 inhibitor to said patient is combined with the administration of radiation therapy.

[0045] In a further aspect, the present invention also relates to a method for the prevention and / or treatment of cancer in a patient, said method comprising administering to a patient having or suspected of having cancer a combination of a cyclin-dependent kinase 7 inhibitor as defined herein and an anti-cancer agent.

[0046] In a further aspect, the present invention also relates to the use of a combination as defined herein for the manufacture of a medicament for the prevention and / or treatment of cancer in a patient.

[0047] In a further aspect, the present invention also relates to a pharmaceutical composition comprising a combination as defined herein for the prevention or treatment of cancer in a patient having or suspected of having cancer.

[0048] The present inventors have surprisingly found that combinations of highly specific CDK7 inhibitors of the pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine classes with other anticancer drugs are highly effective in improving antitumor efficacy compared to the respective monotherapies. In particular, the combination of such CDK7 inhibitors with other anticancer drugs has been found to significantly improve the therapeutic efficacy of such other anticancer drugs, which is unexpected given their seemingly unrelated mechanisms. As an example, the CDK7 inhibitors of the present invention significantly improve the efficacy of immune checkpoint inhibitors, such as PD1 inhibitors or PD-L1 inhibitors, and poly ADP-ribose polymerase (PARP) inhibitors. Furthermore, the combination of the CDK7 inhibitors of the present invention with non-specific cytotoxic compounds, such as taxanes, or hormonal anticancer drugs, such as hormone receptor antagonists, significantly improves the efficacy of the respective monotherapies of such other anticancer drugs. Surprisingly, such ameliorative effects appear to be independent of the specific type and properties of the other anti-cancer agent, such that the data of the present invention can be extrapolated to other anti-cancer agents and other anti-cancer treatment modalities. Furthermore, the inventors expect that such combinations according to embodiments of the present invention will restore sensitivity to cancer cells that would otherwise be resistant to each monotherapy.

[0049] In a preferred embodiment of the present invention, a cyclin-dependent kinase 7 inhibitor is combined with an immune checkpoint inhibitor, particularly an antibody or antibody fragment that targets an immune checkpoint. Preferably, such immune checkpoint is PD1 or PD-L1. In a preferred embodiment of this aspect of the present invention, such immune checkpoint inhibitor is an anti-PD1 antibody or an anti-PD-L1 antibody. By way of example, such an antibody may be an anti-human PD1 antibody. In a particularly preferred embodiment, such an anti-PD1 antibody is pembrolizumab, nivolumab, or cemiplimab. In another embodiment according to the present invention, a cyclin-dependent kinase 7 inhibitor is combined with an inhibitor of poly ADP-ribose polymerase (PARP), such as olaparib, pamiparib, or niraparib.

[0050] In another preferred embodiment, the CDK7 inhibitor according to the invention is combined with a cytotoxic non-specific compound, preferably a taxane, in particular docetaxel, carbacitaxel or paclitaxel, with docetaxel being particularly preferred.

[0051] In yet another preferred embodiment according to the present invention, the CDK7 inhibitor according to the present invention is combined with a hormonal anti-cancer agent, preferably a hormone, a hormone antagonist, a hormone receptor antagonist, a hormone receptor degrader or an aromatase inhibitor. More preferably, such a hormonal anti-cancer agent is a hormone receptor antagonist, even more preferably fulvestrant, tamoxifen, toremifene, letrozole or anastrozole.

[0052] As used herein, terms such as "of the invention," "in accordance with the invention," and "according to the present invention" are intended to refer to all aspects and embodiments of the invention described and / or claimed herein. As used herein, the term "comprising" is interpreted to encompass both "including" and "consisting of," with both meanings being specifically and explicitly intended as separately disclosed embodiments in accordance with the present invention. As used herein, "and / or" is interpreted as specifically disclosing each of the two specified features or components, regardless of order. For example, "A" and / or "B" is interpreted as specifically disclosing each of (i) A, (ii) B, and (iii) A and B, as if each were separately described herein. Where an indefinite or definite article is used, e.g., "a," "an," or "the," when referring to a singular noun, this includes the plural of that noun unless specifically stated otherwise. Similarly, such disclosure shall be construed as a specific disclosure of a single, individual entity preceded by "a," "an," or "the."

[0053] The term "CDK7 inhibitor" as used herein refers to an inhibitor of cyclin-dependent kinase 7, which is specific for such cyclin-dependent kinase 7 and does not inhibit, or inhibits to a much lesser extent, any other cyclin-dependent kinases. In other words, the CDK7 inhibitor according to the present invention is not an inhibitor having inhibitory activity against multiple cyclin-dependent kinases. More specifically, preferably, the CDK7 inhibitor according to the present invention is not a PAN-CDK inhibitor.

[0054] As used herein in the context of a compound, the term "target specificity" relates to the ability of such a compound and / or a molecular structure forming part of such a compound to bind to a particular structure, such as a ligand, an antigen, particularly an epitope, through a specific interaction. For example, the term target specificity may be used in conjunction with an antibody, an antigen-binding peptide, an antigen-binding protein, or a surface molecule of an immune cell, such as a cytotoxic T cell.

[0055] As used herein, the term "combination" preferably refers to a composition in which the cyclin-dependent kinase 7 inhibitor and the anticancer drug are present together and physically mixed with each other, or are separated from each other by at least one physical separation barrier between the inhibitor and the anticancer drug, and the at least one physical separation barrier forms part of the combination. As an example, the cyclin-dependent kinase 7 inhibitor and the anticancer drug may be stored in separate containers, compartments, chambers, or dosage units, and the separate containers, compartments, chambers, and dosage units still form part of the combination. In another embodiment, the term "combination" refers to a scenario in which the cyclin-dependent kinase 7 inhibitor and the anticancer drug are stored separately in different separate containers, compartments, chambers, or dosage units designed or arranged to be separated by multiple physical separation barriers, but are still intended to be administered in combination with each other.

[0056] As used herein, the term "in combination with each other" preferably refers to the administration of two agents or therapeutic modalities, or one agent and one therapeutic modality, to a patient together, preferably simultaneously, either sequentially in any desired and useful order, or overlapping. Such combined administration is intended to achieve elevated levels of each agent or effective treatment with each therapeutic modality simultaneously, or at least overlapping, so that both agents or therapeutic modalities, or one agent and one therapeutic modality, can exert an anti-cancer effect together.

[0057] As used herein, the term "antibody" refers to substantially intact antibodies, antibody fragments, e.g., Fab fragments, F(ab')2 fragments, single-chain Fv fragments, diabodies, triabodies, tetrabodies, diabodies, nanobodies, and other peptide / proteinaceous molecules in which such "antibodies" retain binding affinity for their specific ligands. In one embodiment, the antibody is a monoclonal antibody. In one embodiment, the antibody is a human or humanized antibody, or a rodent antibody, such as a murine antibody, which may or may not be further humanized.

[0058] As used herein, the term "fusion protein" preferably specifically refers to an antibody-cytokine fusion protein. In one embodiment, such a fusion protein comprises a complete antibody or antibody fragment (e.g., complete IgG, Fc fragment, Fab fragment, or scFv fragment) linked to a cytokine monomer (e.g., IL-2, IFN-alpha, or GM-CSF) or cytokine homomultimer (IFN-gamma or TNF) or cytokine heteromultimer (e.g., IL-12 or IL-27). Examples of suitable antibody-cytokine fusion proteins that can be used in embodiments of the present invention are disclosed in Jin et al., 2022; Signal Transduction and Targeted Therapy; 7: 39; https: / / doi.org / 10.1038 / s41392-021-00868-x.

[0059] As used herein, the term "radiopharmaceutical" refers to a drug containing a radioisotope, more specifically, a target-specific drug containing a radioisotope. Typically, target-specific drugs are specific to a particular cell type or tissue type, more specifically, cancer cells or cancer tissues, and specifically bind to or interact with them. The radioisotope forming part of the radiopharmaceutical is thus transported to the vicinity of such cells or tissues and damages them by emitting radiation thereto. Examples of target-specific drugs within radiopharmaceuticals include antibodies and antibody fragments, particularly monoclonal antibodies and antibody fragments, poly ADP-ribose polymerase (PARP) inhibitors; tyrosine kinase inhibitors; and immunotoxins. Specific examples of radiopharmaceuticals include Metastrone, Zevalin, Xofigo, Lutathera, Azedra, and Pulvict.

[0060] As used herein, the term "radiotherapy" includes external beam radiotherapy, brachytherapy, and radiopharmaceutical treatment, as well as combinations thereof. Thus, according to one aspect of the present invention as defined in claim 21, when a cyclin-dependent kinase 7 inhibitor as defined herein is administered to a patient "in combination with radiotherapy," such combined administration includes scenarios in which the inhibitor is administered in combination with either a) external beam radiotherapy, or b) brachytherapy, or c) radiopharmaceutical treatment, or d) any combination of a) to c). In one embodiment, such combined administration refers to the administration of the inhibitor together with external beam radiotherapy (without brachytherapy and radiopharmaceutical treatment). In another embodiment, such combined administration refers to the administration of the inhibitor together with brachytherapy (without external beam radiotherapy and radiopharmaceutical treatment). In yet another embodiment, such combined administration refers to the administration of the inhibitor together with radiopharmaceutical treatment (without brachytherapy and external beam radiotherapy).

[0061] As used herein, "external beam radiation therapy" is distinct from and does not include therapies based on or involving the administration of radiopharmaceuticals or other radioactive substances into a patient's body. Rather, as used herein, "external beam radiation therapy" refers to the use of collimated or focused radiation, preferably ionizing radiation, from outside the patient's body into the patient's body to treat disorders or diseases, preferably cancerous diseases. In a preferred embodiment, "external beam radiation therapy" includes irradiation with X-rays, gamma rays, protons, neutrons, electrons, or heavy ions, preferably X-rays. In a more preferred embodiment, "external beam radiation therapy" is selected from treatment modalities such as, but not limited to, three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), image-guided radiation therapy (IGRT), and stereotactic radiation therapy (SRT).

[0062] As used herein, the term "brachytherapy" refers to a type of internal radiation therapy in which a suitable implant, such as a seed, capsule, bolus, ribbon, strip, stick, needle, bar, plaster, or wire, is placed inside a patient's body, preferably at or near a tumor or cancerous tissue, and the implant contains a radiation source. Once the implant is placed inside the patient's body, it emits radiation toward the part of the body where it is placed. The placement of the implant can be temporary or permanent, depending on the desired type, intensity, and duration of treatment. Examples of brachytherapy include, but are not limited to, low-dose-rate (LDR) implants, high-dose-rate (HDR) implants, and permanent implants.

[0063] As used herein, the term "optionally substituted" is intended to indicate that the hydrogen atoms present and connected to member atoms within a group, or some of such hydrogen atoms, may be replaced with a suitable group such as a halogen such as fluorine, C-C alkyl, C-C haloalkyl, methylhydroxyl, COOMe, C(O)H, COOH, OMe, or OCF.

[0064] The term "alkyl" refers to a monovalent straight-, branched-, or cyclic-chain saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range. Thus, for example, "C1-C6 alkyl" refers to any of the hexyl alkyl and pentyl alkyl isomers, as well as n-, iso-, sec-, and t-butyl, n- and isopropyl, cyclic propyl, ethyl, and methyl.

[0065] The term "alkenyl" refers to a monovalent straight- or branched-chain aliphatic hydrocarbon radical containing one carbon-carbon double bond and having a number of carbon atoms in the specified range. Thus, for example, "C2-C6 alkenyl" refers to all isomers of hexenyl and pentenyl, as well as 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-propenyl, 2-propenyl, and ethenyl (or vinyl).

[0066] The term "cycloalkyl," by itself or in combination with other terms, refers, unless otherwise defined, to an optionally substituted or unsubstituted cyclic hydrocarbon, etc. group having 3 to 8 carbon atoms. Thus, for example, "C3-C8 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0067] The term "haloalkyl" refers to an alkyl group, as defined herein, substituted with at least one halogen. Examples of linear or branched "haloalkyl" groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl, each independently substituted with one or more halogens. The term "haloalkyl" should be interpreted to include such substituents as -CHF, -CF, -CH-CH-F, and -CH-CF.

[0068] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced with a heteroatom, such as O, N, or S. For example, when a carbon atom of an alkyl group attached to a parent molecule is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkoxy group (e.g., -OCH), an amine (e.g., -NHCH, -N(CH), or a thioalkyl group (e.g., -SCH), respectively. When a non-terminal carbon atom of an alkyl group not attached to a parent molecule is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkyl ether (e.g., -CHCH-O-CH), an alkylamine (e.g., -CHNHCH, -CHN(CH), or a thioalkyl ether (e.g., -CH-S-CH), respectively.

[0069] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0070] As used herein, the term "phenyl" is intended to refer to optionally substituted or unsubstituted phenyl.

[0071] As used herein, the term "benzyl" is intended to refer to an optionally substituted or unsubstituted benzyl group.

[0072] The term "heteroaryl" refers to (i) optionally substituted 5- and 6-membered heteroaromatic rings and (ii) optionally substituted 9- and 10-membered bicyclic fused ring systems in which at least one ring is aromatic, wherein the heteroaromatic ring or bicyclic fused ring system contains from 1 to 4 heteroatoms independently selected from N, O, and S, each N optionally in the form of an oxide, and each S in a non-aromatic ring is optionally S(O) or S(O). Suitable 5- and 6-membered heteroaromatic rings include, for example, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Suitable 9- and 10-membered heterobicyclic fused ring systems include, for example, benzofuranyl, indolyl, indazolyl, naphthyridinyl, isobenzofuranyl, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, chromenyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolyl, benzodioxolyl, benzofuranyl, imidazo[1,2-a]pyridinyl, benzotriazolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, 2,3-dihydrobenzofuranyl, and 2,3-dihydrobenzo-1,4-dioxinyl.

[0073] The term "heterocyclyl" refers to (i) optionally substituted 4- to 8-membered saturated and unsaturated but non-aromatic monocyclic rings containing at least one carbon atom and one to four heteroatoms, (ii) optionally substituted bicyclic ring systems containing one to six heteroatoms, and (iii) optionally substituted tricyclic ring systems, wherein each ring in (ii) or (iii) is independently fused to or bridged with another ring or rings, each ring is saturated or unsaturated but non-aromatic, and each heteroatom in (i), (ii), and (iii) is independently selected from N, O, and S, wherein each N is optionally in the form of an oxide and each S is optionally oxidized to S(O) or S(O). Suitable 4- to 8-membered saturated heterocycles include, for example, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanyl, and azacyclooctyl.Suitable unsaturated heterocycles include those corresponding to the saturated heterocycles listed above, in which a single bond is replaced with a double bond.It is understood that the specific rings and ring systems suitable for use in the present invention are not limited to those listed in this and the preceding paragraphs.These rings and ring systems are merely representative.

[0074] Pharmaceutically acceptable salts Examples of pharmaceutically acceptable addition salts include, but are not limited to, non-toxic inorganic and organic acid addition salts, such as acetate from acetic acid, aconitate from aconitic acid, ascorbate from ascorbic acid, benzenesulfonate from benzenesulfonic acid, benzoate from benzoic acid, cinnamate from cinnamic acid, citrate from citric acid, embonate from embonic acid, enanthate from enanthic acid, formate from formic acid, fumarate from fumaric acid, glutamate from glutamic acid, glycolate from glycolic acid, hydrochloride from hydrochloric acid, and hydrobromide from hydrobromic acid. , lactate from lactic acid, maleate from maleic acid, malonate from malonic acid, mandelate from mandelic acid, methanesulfonate from methanesulfonic acid, naphthalene-2-sulfonate from naphthalene-2-sulfonic acid, nitrate from nitric acid, perchlorate from perchloric acid, phosphate from phosphoric acid, phthalate from phthalic acid, salicylate from salicylic acid, sorbate from sorbic acid, stearic acid from stearic acid, succinate from succinic acid, sulfate from sulfuric acid, tartrate from tartaric acid, toluene-p-sulfonate from p-toluenesulfonic acid, etc. Such salts can be formed by procedures well known and described in the art.

[0075] Other acids, such as oxalic acid, although not considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates to obtain the chemical compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0076] In another embodiment, the compounds of the present invention are used in accordance with the present invention in their free base form.

[0077] Metal salts of chemical compounds of the present invention include alkali metal salts, such as sodium salts, of chemical compounds of the present invention that contain a carboxy group.

[0078] The chemical compounds included in the combinations of the present invention can be provided in unsolvated or solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. Solvated forms can include hydrated forms such as the monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, etc. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

[0079] Preferred CDK7 inhibitors that form part of the combination according to the invention are those listed and shown in the column entitled "Structure" in Table 1 herein:

[0080] Table 1. Summary of structures and corresponding exemplary properties of compounds 1-198

[0081] [Table 1-1]

[0082] [Table 1-2]

[0083] [Table 1-3]

[0084] [Table 1-4]

[0085] [Table 1-5]

[0086] [Table 1-6]

[0087] [Table 1-7]

[0088]

Table 1-8

[0089]

Table 1-9

[0090]

Table 1-10

[0091]

Table 1-11

[0092]

Table 1-12

[0093]

Table 1-13

[0094]

Table 1-14

[0095]

Table 1-15

[0096]

Table 1-16

[0097]

Table 1-17

[0098]

Table 1-18

[0099]

Table 1-19

[0100]

Table 1-20

[0101]

Table 1-21

[0102]

Table 1-22

[0103]

Table 1-23

[0104]

Table 1-24

[0105]

Table 1-25

[0106]

Table 1-26

[0107]

Table 1-27

[0108]

Table 1-28

[0109]

Table 1-29

[0110]

Table 1-30

[0111]

Table 1-31

[0112]

Table 1-32

[0113]

Table 1-33

[0114]

Table 1-34

[0115]

Table 1-35

[0116]

Table 1-36

[0117]

Table 1-37

[0118]

Table 1-38

[0119]

Table 1-39

[0120]

Table 1-40

[0121]

Table 1-41

[0122]

Table 1-42

[0123]

Table 1-43

[0124]

Table 1-44

[0125]

Table 1-45

[0126]

Table 1-46

[0127] This patent application demonstrates the usefulness and excellent activity achieved by combining CDK7 inhibitors with other anti-cancer therapies, particularly other anti-cancer drugs. Considering the cell cycle arrest, replication stress, and genomic instability-inducing effects of CDK7 inhibitors, the combination of CDK7 inhibitors with other anti-cancer therapies improves anti-tumor effects as a new approach to cancer treatment.

[0128] Additionally, see the diagram: [Brief explanation of the drawings]

[0129] [Figure 1A] 1A, 1B, and 1C show the effect of a CDK7 inhibitor on RENCA cells. Figure 1A shows the results of examining the viability of RENCA cells in the presence of a CDK7 inhibitor. [Figure 1B] FIG. 1B shows the results of an analysis of CDK7 engagement by a CDK7 inhibitor. [Figure 1C] FIG. 1C shows the results of Western blot of the phosphorylated form of H2AX in RENCA cells treated with a CDK7 inhibitor. [Figure 2A] Figures 2A and 2B show the effect of combined treatment with a CDK7 inhibitor and an anti-PD-1 antibody in the RENCA syngenic mouse tumor model. Figure 2A shows tumor growth of RENCA cells in each treatment group as mean ± SEM. [Figure 2B] Figure 2B shows the tumor volume data at day 21. [Figure 3A] Figures 3A and 3B show the effect of combined treatment with a CDK7 inhibitor and olaparib in a xenograft model derived from the OVCAR3 high-grade serous ovarian cancer cell line. Figure 3A shows tumor growth of OVCAR3 cells in each treatment group as mean ± SEM. [Figure 3B] Figure 3B shows the tumor size data at day 27. [Figure 4A]Figures 4A and 4B show the effect of combined treatment with a CDK7 inhibitor and docetaxel in a xenograft model derived from the DU145 castration-resistant prostate cancer cell line. Figure 4A shows tumor growth of DU145 cells in each treatment group as mean ± SEM. [Figure 4B] Figure 4B shows the tumor size data at day 26. [Figure 5A] Figures 5A and 5B show the effect of combined treatment with a CDK7 inhibitor and fulvestrant in a xenograft model derived from the MCF7 breast cancer cell line. Figure 5A shows tumor growth of MCF7 cells in each treatment group as mean ± SEM. [Figure 5B] Figure 5B shows the tumor volume data at day 28. [Figure 6] FIG. 6 shows the mean percentage of g-H2AX positive OVCAR3 cells treated with a combination of compound 47 and cisplatin. [Figure 7] FIG. 7 shows the average number of g-H2AX (FIGS. 7A to 7C) or 53BP1 (FIGS. 7D to 7F) granules in PC3 cells treated with a combination of compound 47 and X-ray radiation. [Example]

[0130] Example 1. Effect of CDK7 inhibitor on RENCA cells Cell viability assay RENCA renal adenocarcinoma cells were treated with various concentrations of compound 47 for 72 hours. Cell viability was measured using the CellTiter-Glo assay system (Promega). Luminescence units were normalized to those of untreated cells and are presented as a percentage of cell viability. IC 50 was calculated using a dose-response curve generated by GraphPad Prism. Figure 1A shows the effect of compound 47 on RENCA cell viability. Compound 47 inhibited RENCA cell proliferation in a dose-dependent manner, with an IC 50 was 20 nM.

[0131] Target occupancy assay RENCA cells were treated with various concentrations of compound 47 for 4 hours. Cells were washed twice with ice-cold PBS and lysed in ice-cold lysis buffer (0.025 M Tris, 0.15 M NaCl, 0.001 M EDTA, 1% NP-40, 5% glycerol, pH 7.4) containing a protease and phosphatase cocktail (Sigma-Aldrich). Lysed cells were centrifuged at 12,000 rpm for 10 minutes at 4°C, and the supernatant was collected. Protein concentration was determined using a BCA protein quantification kit (Thermo Fisher Scientific, #23227). Equal amounts of protein were incubated overnight at 4°C with 1 μM biotinylated compound 3 (biocompound 3, a biotinylated analog of compound 47) and immunoprecipitated with streptavidin agarose beads. The pulled-down proteins were eluted, loaded onto SDS-PAGE, transferred to a PVDF membrane (MilliporeSigma), and treated with anti-CDK7 antibody. CDK7 protein was detected with an HRP-conjugated secondary antibody. Images were acquired using an ImageQuant™ LAS4000. Figure 1B shows the dose-dependent CDK7 occupancy of compound 47 in RENCA cells.

[0132] Western blot analysis RENCA cells were treated with various concentrations of compound 47 for 48 hours at 37°C in 5% CO2. The cells were washed twice with ice-cold PBS and lysis buffer was added. The cells were harvested and placed on ice for 30 minutes. Lysed cells were centrifuged at 12,000 rpm at 4°C for 10 minutes, and the supernatant was collected. Protein concentration was quantified using a BCA protein quantification kit. Equal amounts of protein were fractionated by SDS-PAGE, transferred to PVDF membranes, and treated with anti-phosphorylated H2AX (Ser139) antibody. The phosphorylated form of H2AX protein was detected with an HRP-conjugated secondary antibody, and the signal was obtained using Super Signal Western Blot Enhancer. Images were acquired on an ImageQuant™ LAS 4000. Figure 1C shows the effect of compound 47 on the phosphorylated form of the histone variant H2AX, a marker of the early cellular response to DNA double-strand breaks. Compound 47 induced the phosphorylation of H2AX at serine 139 residue in a dose-dependent manner, suggesting that compound 47 induces DNA double-strand breaks in RENCA cells by inhibiting the homology-directed repair and DNA mismatch repair pathways.

[0133] Example 2. Effect of a CDK7 inhibitor and anti-PD1 combination in the RENCA syngenic kidney tumor mouse model RENCA cells (1 x 10 5 ) were implanted subcutaneously into the right flank of BALB / c mice. Tumor-bearing mice were randomized and the mean tumor volume was 31 mm. 3At day 21, mice were treated with compound 47 (10 mg / kg, intraperitoneally, daily), anti-PD-1 antibody (10 mg / kg, intraperitoneally, twice weekly, clone: RMP1-14, Bio X Cell), or both compound 47 and anti-PD-1 antibody (N = 7 or 8 per group). Control mice were treated with vehicle or a rat IgG2a isotype control antibody (clone: 2A3, Bio X Cell). Tumor volume and body weight were measured twice weekly. Figure 2A shows the growth of RENCA tumor cells in each treatment group. Compound 47 treatment induced a 50.2% tumor growth inhibition (TGI), while the anti-PD-1 treatment group showed a 13.2% TGI. However, the combination of compound 47 and anti-PD-1 antibody improved TGI (66%). Figure 2B shows the tumor volume at day 21. On day 21, tumor volume was significantly reduced in the compound 47 and anti-PD-1 antibody combination group.

[0134] Example 3. Effect of a CDK7 inhibitor in combination with olaparib in a xenograft model derived from the OVCAR3 high-grade serous ovarian cancer cell line OVCAR3 cells (1 × 10) mixed with Matrigel 7 ) (50:50) were implanted subcutaneously into the right flank of female BALB / c nude mice. Tumor-bearing mice were randomized and grafted to a mean tumor volume of 173 mm. 3 At day 27, the mice were treated with compound 47 (3 mg / kg intraperitoneally daily), olaparib (100 mg / kg orally daily), or both compound 47 and olaparib (n=8 per group). Tumor volume and body weight were measured twice weekly. Figure 3A shows the growth of OVCAR3 tumor cells in each treatment group. Compound 47 treatment induced a 36% TGI, while the olaparib treatment group showed a 38% TGI. However, the combination of compound 47 and olaparib improved TGI (65%). Figure 3B shows tumor volume at day 27. At day 27, the combination of compound 47 and olaparib significantly reduced tumor volume compared with either the olaparib or compound 47 alone groups.

[0135] Example 4. Effect of a CDK7 inhibitor in combination with docetaxel in a DU145 castration-resistant prostate cancer cell line-derived xenograft model DU145 cells (1 × 10 7 ) (50:50) were implanted subcutaneously into the right flank of male BALB / c nude mice. Tumor-bearing mice were randomized and the mean tumor volume was 154 mm. 3 At day 26, the mice were treated with compound 47 (3 mg / kg, intraperitoneally, daily), docetaxel (15 mg / kg, intraperitoneally, weekly), or both compound 47 and docetaxel (n=8 per group). Tumor volume and body weight were measured twice weekly. Figure 4A shows the growth of DU145 tumor cells in each treatment group. Compound 47 treatment induced a 61% TGI, while the docetaxel treatment group showed a 25% TGI. However, the combination of compound 47 and docetaxel improved TGI (81%). Figure 4B shows tumor volume measurements on day 26. On day 26, the compound 47 and docetaxel combination group showed a significant reduction in tumor size compared to the docetaxel alone group.

[0136] Example 5. Effect of a CDK7 inhibitor in combination with fulvestrant in an MCF7 human breast cancer xenograft model MCF7 cells (1 × 10) mixed with Matrigel 7 ) (50:50) were implanted subcutaneously into the right flank of female BALB / c nude mice. Tumor-bearing mice were randomized and grafted to a mean tumor volume of 117 mm. 3 At the time of tumor growth, mice were treated with compound 47 (3 mg / kg intraperitoneally, daily), fulvestrant (2.5 mg / dose, subcutaneously, daily), or both compound 47 and fulvestrant (N=8 per group). Tumor volume and body weight were measured twice weekly. Figure 5A shows the growth of MCF7 tumor cells in each treatment group. Both the compound 47-treated group and the fulvestrant-treated group each showed a TGI of 81%. However, the combination of compound 47 and fulvestrant improved TGI (101%). Figure 5B shows tumor size at day 28. On day 28, tumor volume in the compound 47 and fulvestrant combination group was reduced compared to the compound 47 alone or fulvestrant-treated group.

[0137] Example 6. Effect of a CDK7 inhibitor in combination with cisplatin in the OVCAR3 human high-grade serous ovarian cancer cell line OVCAR3 cells were treated with DMSO or 100 nM cisplatin for 24 hours. Then, cells were washed with culture medium and treated with various concentrations of compound 47. Cells were harvested 24, 48, and 72 hours after cisplatin washing and stained with 4',6-diamidino-2-phenylindole (DAPI) and anti-phosphorylated histone H2AX (Ser129). Nucleus g-H2AX foci were identified by Alexa-568 staining. Fluorescent images of g-H2AX foci were captured using a CQ1 confocal imaging system (x40 objective). Figure 6 shows the mean percentage of g-H2AX-positive cells ± SD. Compound 47 increased the percentage of g-H2AX foci in a time- and dose-dependent manner, indicating that compound 47 sustains DNA damage induced by cisplatin treatment.

[0138] Example 7. Effect of a CDK7 inhibitor in combination with X-irradiation in the PC3 human castration-resistant prostate cancer cell line. PC3 cells were treated with DMSO or various concentrations of compound 47 for 1 hour. They were then irradiated for 5 minutes at 225 kV and 17.7 mA using a Faxitron specimen radiography system (8 Gy, 4 Gy, and 2 Gy, respectively; Figures 7A-7C and 7D-7F). Cells were collected at 1, 4, 6, 24, and 48 hours after X-ray irradiation and stained with HOECHST and anti-phosphorylated histone H2AX (Ser129) or 53BP1. Nuclei containing g-H2AX or 53BP1 foci were identified using Alexa Flour 488. Fluorescent images of the foci were acquired using an Opera Phenix3 high-content screening system (x40 objective), and the mean number of g-H2AX (Figures 7A-7C) or 53BP1 (Figures 7D-7F) granules per cell ± SD was determined using MetaXpress software. As shown in Figures 7A to 7F, compound 47 exhibited a significant DNA damage sustaining effect 24 hours after X-ray irradiation, depending on the irradiation dose or compound concentration.

Claims

1. A combination of a cyclin-dependent kinase 7 inhibitor and an anticancer drug different from the cyclin-dependent kinase 7 inhibitor, The cyclin-dependent kinase 7 inhibitor is represented by the general formula I 【Chemical 1】 (In the formula, X, at each occurrence, is independently selected from CH and N; Q is absent or, independently in each occurrence, -NH-, -NH(CH ２ ) -, -NH(CH ２ ) ２ -, -NH(C=O)-, -NHSO ２ -, -O-, -O(CH ２ )—, —(C═O)—, —(C═O)NH—, and —(C═O)(CH ２ )-selected from the group consisting of; Y, independently at each occurrence, is halogen, C1-C3 haloalkyl, C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclyl, -S(=O) ２ R ４ , C1-C6 alkyl and one or two -OR ６ , -N(R ６ ) R ６ , C1-C6 alkyl substituted with aryl, heteroaryl, and heterocyclyl; C3-C8 cycloalkyl is one or two R ４ , R ５ and —(C═O)R ６ and the heterocyclyl may be substituted with one or two R ４ , R ５ and —(C═O)R ６ and the aryl or heteroaryl may be substituted with one or two R ４ , C1-C6 alkyl, —OR ６ , -N(R ６ ) R ６ , -(C=O)R ６ , optionally substituted with halogen, heteroaryl, and heterocyclyl; R １ is independently in each occurrence halogen, C1-C6 alkyl, C3-C10 cycloalkyl, —CN, —(C═O)CH ３ and C1-C3 haloalkyl, any of which may be substituted; R ２ is independently in each occurrence the following Group A: 【Chemistry 2】 m is independently selected at each occurrence from 1, 2, and 3; W is Group B below; 【Chemistry 3】 wherein L is absent or, independently at each occurrence, is selected from the group consisting of —O— and —NH—; n is independently at each occurrence selected from 1, 2, and 3; R ３ is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, —OR ６ , —CN and —OH, —OR ６ Or -NHR ６ C1-C6 alkyl substituted with; R ４ is absent or, independently in each occurrence, hydrogen, -OR ６ , halogen, C1-C3 haloalkyl, —CN, —N(R ６ ) R ６ , (=O), -NH(C=O)R ６ , -(C=O)NH ２ , -S(=O) ２ N (R ６ ) R ６ , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and -OR ６ , -NH ２ Or -S(=O) ２ N (R ６ ) R ６ C1-C6 alkyl substituted with; R ５ is independently in each occurrence hydrogen, halogen, C1-C3 haloalkyl, —CN, —OR ６ , -N(R ６ ) R ６ , (=O), S(=O) ２ N (R ６ ) R ６ , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and —OH, —NH ２ Or -S(=O) ２ N (R ６ ) R ６ C1-C6 alkyl substituted with; R ４ and R ５ are both attached to a single sulfur atom that forms part of the heterocycle Y, then (=O); or R ４ and R ５ together with the structure to which they are attached form an aromatic ring, a heteroaromatic ring, a saturated or unsaturated heterocyclic ring, or a fused or bridged ring structure of either an aromatic ring, a heteroaromatic ring, a saturated or unsaturated heterocyclic ring; R ６ is independently at each occurrence hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, heteroaryl, heterocyclyl, one or two halogens, —OR ７ , -N(R ７ ) R ７ , C1-C6 alkyl and —OH, —NH ２ heteroaryl substituted with C1-C6 alkyl substituted with one or two halogens, -OR ７ , -N(R ７ ) R ７ , C1-C6 alkyl and —OH or —NH ２ heterocyclyl substituted with C1-C6 alkyl substituted with; R ７ is independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, and W (as defined above); R ８ is independently selected at each occurrence from hydrogen and W (as defined above); R ７ If W, then R ８ is hydrogen; R ９ is independently selected at each occurrence from hydrogen and W (as defined above); R １０ is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, —NH ２ , -OR ６ -CN and W (as defined above); R １０ If W, then R ８ is hydrogen; R １１ is independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, and C1-C3 haloalkyl; R １２ is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, —NH ２ , -OR ６ and -CN; R １３ is independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, and W (as defined above); R １３ If W, then R ９ is hydrogen; R １４ and R １５ is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, —OR ６ , heterocyclyl, and —CN; R １６ is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C3-C10 cycloalkyl, —N(R ６ ) ２ , -NR １３ R １４ , -NR １３ CH ２ (CO)NH ２ , heterocyclyl, -OR ６ and —CN), or an enantiomer, stereoisomeric form, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate, or pharmaceutically acceptable salt thereof of said compound.

2. 2. The combination of claim 1, wherein the anti-cancer agent is selected from: a) target-specific compounds selected from the group consisting of immune checkpoint inhibitors, in particular monoclonal antibodies and antibody fragments that target immune checkpoints; poly ADP-ribose polymerase (PARP) inhibitors; monoclonal antibodies and antibody fragments that do not target immune checkpoints; tyrosine kinase inhibitors; immunotoxins; MEK inhibitors; KRAS inhibitors; c-MET inhibitors; FGFR inhibitors; proteasome inhibitors; cyclin-dependent kinase inhibitors; mTOR inhibitors; retinoids; immunomodulators; histone deacetylase inhibitors; protein hydrolysis-targeted chimeric compounds (PROTACs); siRNA; antibody-drug-conjugates (ADCs); antibody-siRNA-conjugates (ARCs); DNA damage response inhibitors, and target-specific fusion proteins; and b) a cytotoxic nonspecific compound selected from the following: taxanes, alkylating agents, nucleoside analogs, antifolates, topoisomerase inhibitors, anthracyclines, podophyllotoxins, vinca alkaloids, and platinum compounds; c) a hormonal anticancer agent selected from the following: hormones; hormone antagonists; hormone receptor antagonists; hormone receptor degraders and aromatase inhibitors; Preferably, the hormone is selected from medroxprogesterone; anastrozole, letrozole, exemestane; megestrol; raloxifene; estramustine; gonadotropin-releasing hormones such as leuprolide, goserelin, triptorelin, histrelin, abarelix; androgens such as testolactone, fluoxymesterone; antiandrogens such as enzalutamide, bicalutamide, apalutamide, darolutamide, nilutamide, flutamide; Preferably, the hormone antagonist is selected from a gonadotropin-releasing hormone antagonist, such as degarelix; Preferably, the hormone receptor antagonist is selected from fulvestrant, tamoxifen, toremifene; and Preferably, the hormone receptor degrader is selected from a selective estrogen receptor degrader and a selective androgen receptor degrader; more preferably selected from diledestrant, amsenestrant, fulvestrant, AZD9833, lintodestrant, LSZ102, LY3484356, elacestrant, ZN-c5, D-0502, SHR9549, and babdegalutamide; Preferably, the aromatase inhibitor is selected from anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, testolactone, and aminoglutethimide; and d) Radiopharmaceuticals.

3. The combination described in any one of claims 1 to 2, wherein the combination is a composition in which the cyclin-dependent kinase 7 inhibitor and the anti-cancer drug are present together and physically mixed with each other, or are separated from each other by at least one physical separation barrier between the cyclin-dependent kinase 7 inhibitor and the anti-cancer drug, and the at least one physical separation barrier forms part of the combination, for example, the cyclin-dependent kinase 7 inhibitor and the anti-cancer drug are held in separate containers or compartments or chambers or dosage units, and the separate containers, compartments, chambers and dosage units form part of the combination.

4. 4. The combination of any one of claims 1 to 3, wherein the anti-cancer agent is a target-specific compound selected from immune checkpoint inhibitors, in particular monoclonal antibodies that target immune checkpoints; poly ADP-ribose polymerase (PARP) inhibitors; other monoclonal antibodies that do not target immune checkpoints; tyrosine kinase inhibitors; DNA damage response inhibitors; and antibody-cytokine fusion proteins.

5. 5. The combination of claim 4, wherein the target-specific compound is selected from an anti-PD1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-VEGF antibody, an anti-VEGFR antibody, an anti-EGFR antibody, an anti-HER2 antibody, an anti-CD52 antibody, an anti-CD33 antibody, an anti-CD30 antibody, an anti-CD20 antibody, an anti-TIM3 antibody, an anti-TIGIT antibody, an anti-41BB antibody, an anti-OX40 antibody, an anti-CD40 antibody, an anti-CD27 antibody, an anti-GITR antibody, an anti-ICOS antibody, an anti-Siglec antibody, and an anti-PVRIG antibody.

6. The target-specific compound is an anti-human PD1 antibody, in particular pembrolizumab, nivolumab, cemiplimab, spartalizumab, atezolizumab, avelumab, durvalumab, ipilimumab, tremelimumab, leratolimab, bevacizumab, ramucirumab, cetuximab, panitumumab, pertuzumab, trastuzumab, trastuzumab-emtansine, alemtuzumab, gemtuzumab, gemtuzumab-ozoamycin 6. The combination of claim 5, wherein the target specific compound is selected from the group consisting of brentuximab, brentuximab-vedotin, ibritumomab, ibritumomab-tiuxetan, rituximab, obinutuzumab, tositumomab, ofatumumab, pidilizumab, toripalimab, centilimab, camrelizumab, tislelizumab, zimberelimab, prorugolimab, dostarlimab; preferably wherein the target specific compound is pembrolizumab.

7. The target-specific compounds are selected from the group consisting of poly ADP-ribose polymerase (PARP) inhibitors, in particular olaparib, pamiparib, and niraparib; tyrosine kinase inhibitors, in particular afatinib, aflibercept, axitinib, bosutinib, cabozantinib, ceritinib, crizotinib, dasatinib, erlotinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, nilotinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, and bantam.

5. The combination of claim 4 selected from: detanib, anlotinib, apatinib, osimertinib, and alectinib; MEK inhibitors, particularly cobimetinib and trametinib; KRAS inhibitors, particularly sotrasib and adagrasib; c-MET inhibitors, particularly savolitinib; FGFR inhibitors, particularly erdaftinib, pemigatinib, and bofatamab; DNA damage response inhibitors selected from WEE1 inhibitors and ATR inhibitors, particularly adavosertib, beruzosertib, and volasertib.

8. The anticancer drug is a) a taxane, preferably selected from docetaxel, carbazitaxel, and paclitaxel; b) alkylating agents, preferably selected from bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, fotemustine, ifosfamide, lomustine, melphalan, streptozotocin, and temozolomide; c) nucleoside analogs, preferably selected from azacitidine, capecitabine, carmofur, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, nelarabine, pentostatin, tegafur, and thioguanine; d) an antifolate, preferably selected from methotrexate, pemetrexed, and raltitrexed; e) a topoisomerase inhibitor, preferably selected from irinotecan and topotecan; f) anthracyclines, preferably selected from daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, and valrubicin; g) podophyllotoxins, preferably selected from etoposide and teniposide; h) vinca alkaloids, preferably selected from vinblastine, vincristine, vindesine, vinflunine, and vinorelbine; i) platinum compounds, preferably selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, heptaplatin, and lobaplatin; The combination of any one of claims 1 to 3, wherein the cytotoxic non-specific compound is selected from the group consisting of:

9. The compound has the general formula Ia 【Chemistry 4】 (In the formula, X, at each occurrence, is independently selected from CH and N; Y １ is independently selected at each occurrence from CH, C(OH), and N; Y ２ is independently selected at each occurrence from CH, C(OH), and N; Q is absent or, independently in each occurrence, -NH-, -NH(CH ２ )-, -NH(C=O)-, -NHSO ２ -, -O-, -O(CH ２ )-, -(C=O)- and -(C=O)(CH ２ )-selected from the group consisting of; R １ is independently in each occurrence halogen, C1-C6 alkyl, C3-C10 cycloalkyl, —CN, —(C═O)CH ３ and C1-C3 haloalkyl, any of which may be substituted; R ２ is independently in each case the following Group A 【Chemistry 5】 (Wherein m=1, 2 or 3; W is the following group B'; 【Chemistry 6】 (L is absent or, independently at each occurrence, selected from the group consisting of —O— and —NH—); R ３ is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, —OR ６ , —CN and —OH, —OR ６ Or -NHR ６ C1-C6 alkyl substituted with; R ４ is absent or, independently in each occurrence, hydrogen, -OR ６ , halogen, C1-C3 haloalkyl, —CN, —N(R ６ ) R ６ , (=O), -NH(C=O)R ６ , -(C=O)NH ２ , -S(=O) ２ N (R ６ ) R ６ , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and -OR ６ , -NH ２ Or -S(=O) ２ N (R ６ ) R ６ C1-C6 alkyl substituted with; R ５ is independently in each occurrence hydrogen, halogen, C1-C3 haloalkyl, —CN, —OR ６ , -N(R ６ ) R ６ , (=O), S(=O) ２ N (R ６ ) R ６ , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and —OH, —NH ２ Or -S(=O) ２ N (R ６ ) R ６ C1-C6 alkyl substituted with; R ４ and R ５ are both attached to a single sulfur atom that forms part of the heterocycle Y, then (=O); Or R ４ and R ５ together with the structure to which they are attached form an aromatic ring, a heteroaromatic ring, a saturated or unsaturated heterocyclic ring, or a fused or bridged ring structure of either an aromatic ring, a heteroaromatic ring, a saturated or unsaturated heterocyclic ring; R ６ is independently at each occurrence hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, heteroaryl, heterocyclyl, one or two halogens, —OR ７ , -N(R ７ ) R ７ , C1-C6 alkyl and —OH, —NH ２ heteroaryl substituted with C1-C6 alkyl substituted with one or two halogens, -OR ７ , -N(R ７ ) R ７ , C1-C6 alkyl and —OH or —NH ２ heterocyclyl substituted with C1-C6 alkyl substituted with; R ７ is independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, and W (as defined above); R ８ is independently selected at each occurrence from hydrogen and W (as defined above); R ７ If W, then R ８ is hydrogen; R ９ is independently selected at each occurrence from hydrogen and W (as defined above); R １０ is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, —NH ２ , -OR ６ -CN and W (as defined above); R １０ If W, then R ８ is hydrogen; R １１ is independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, and C1-C3 haloalkyl; R １２ is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, —NH ２ , -OR ６ and -CN; R １３ is independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, and W (as defined above); R １３ If W, then R ９ is hydrogen; R １４ and R １５ is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, —OR ６ , heterocyclyl, and —CN; R １６ is independently in each occurrence hydrogen, halogen, C1-C6 alkyl, C3-C10 cycloalkyl, —N(R ６ ) ２ , -NR １３ R １４ , heterocyclyl, -OR ６ and —CN) or an enantiomer, stereoisomeric form, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate, or a pharmaceutically acceptable salt thereof of said compound.

10. R ２ , R ７ , R ８ , R ９ , R １０ and R １３ 10. The combination of any of the preceding claims, wherein at least one or exactly one of is W as defined in claim 1 or a structure comprising W as defined in claim 1.

11. R １ The combination of any of the preceding claims, wherein is C1-C6 alkyl or C1-C3 haloalkyl.

12. R ２ but, 【Chemistry 7】 2. The combination of any of the preceding claims,

13. R １０ is hydrogen; m is 1; R ８ is W; W is (c-1) or (c-2) or (c-3), preferably (c-1); L is -NH-; R １４ and R １５ is independently in each occurrence hydrogen, halogen, or C1-C6 alkyl, preferably R １４ is halogen; R １６ is hydrogen, halogen, C1-C6 alkyl, —N(R ６ ) ２ , -NR １３ R １４ and preferably R １６ -N (R ６ ) ２ or -NR １３ R １４ 13. The combination of claim 12, wherein:

14. The combination of any of the preceding claims, wherein said compound is a compound having a structure selected from structures 1 to 198 as defined in the column entitled "Structure" of Table 1 of the specification.

15. 14. The combination of any of the preceding claims, wherein the compound is a compound having a structure selected from compounds 3, 14, 47, and 156 defined in claim 14.

16. 10. The combination of any of the preceding claims for use in a method for the prevention and / or treatment of cancer in a patient having or suspected of having cancer.

17. The combination for use described in claim 16, wherein the method of prevention and / or treatment comprises administering an effective amount of the cyclin-dependent kinase 7 inhibitor together with an effective amount of the anti-cancer agent to a patient having or suspected of having cancer.

18. The combination for use according to any of claims 16 to 17, wherein in the method for prevention and / or treatment, the cyclin-dependent kinase 7 inhibitor is administered before or after administration of the anticancer drug to the patient, or both the cyclin-dependent kinase 7 inhibitor and the anticancer drug are administered to the patient concomitantly, synchronously, or with a temporal overlap, or the cyclin-dependent kinase 7 inhibitor is administered to the patient concomitantly with the anticancer drug, or the anticancer drug is administered to the patient concomitantly with the cyclin-dependent kinase 7 inhibitor.

19. The combination for use according to any of claims 16 to 18, wherein said method of prevention and / or treatment comprises administering said combination in combination with radiation therapy.

20. The cancers include: renal cell carcinoma (RCC), kidney cancer, hereditary papillary renal cancer, sporadic papillary renal cancer, non-squamous non-small cell lung cancer (non-squamous NSCLC), squamous non-small cell lung cancer (squamous NSCLC), small cell lung cancer (SCLC), triple-negative breast cancer, colorectal cancer, melanoma, pancreatic ductal adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma (HNSCC), urothelial carcinoma, adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampulla carcinoma, anal cancer, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer, bronchial cancer, estrogen-dependent and and non-dependent breast cancer, Burkitt's lymphoma, body cancer, cancer of unknown primary site (CUP syndrome), small intestine cancer, small intestine tumors, ovarian cancer, endometrial cancer, ependymoma, epithelial cancer type, Ewing's tumor, gastrointestinal tumors, stomach cancer, gallbladder cancer, gallbladder carcinoma, uterine cancer, head and neck cancer, cervix, glioblastoma, gynecological tumors, ear, nose and throat tumors, blood tumors, hairy cell leukemia, urethral cancer, skin cancer, skin testicular cancer, brain tumors (gliomas), brain metastases, testicular cancer, pituitary tumors, carcinoid, Kaposi's sarcoma, laryngeal cancer, germ cell tumors, bone cancer, head and neck tumors (tumors of the ear, nose and throat area), colon cancer, craniopharyngioma , oral cancer (cancer of the mouth area and lips), cancer of the central nervous system, liver cancer, liver metastases, leukemia, eyelid tumors, lung cancer, lymphoma, stomach cancer, malignant melanoma, malignant neoplasms, malignant tumors of the gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastoma, meningioma, Hodgkin's lymphoma / non-Hodgkin's lymphoma, mycosis fungoides, nasal cancer, schwannoma, neuroblastoma, oligodendroglioma, osteolytic and osteoplastic carcinoma, osteosarcoma, ovarian carcinoma, pancreatic carcinoma, penile cancer, plasmacytoma, prostate cancer, pharyngeal cancer, rectal carcinoma, retinal sarcoma, vaginal carcinoma, thyroid cancer, T-cell lymphoma, thymoma, tubular carcinoma, eye tumors, urethral cancer , urinary tumors, urothelial carcinoma, vulvar cancer, wart-like symptoms, soft tissue tumors, soft cell sarcoma, nephroblastic carcinoma, cervical cancer, tongue cancer, invasive tubular carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, lobular carcinoma in situ, small cell lung carcinoma, non-small cell lung carcinoma, bronchial adenoma, pleuropulmonary blastoma, mesothelioma, brain stem glioma, hypothalamic glioma, cerebellar astrocytoma, cerebral astrocytoma, neuroectodermal tumor, pineal tumor, uterine sarcoma, salivary gland cancer, anal gland carcinoma, mast cell tumor, pelvic tumor, ureter tumor, intraocular melanoma, hepatocellular carcinoma, cholangiocarcinoma, mixed hepatocellular-cholangiocarcinoma, squamous cell carcinoma, Merkel cell skin cancer,The combination for use according to any one of claims 16 to 19, wherein the cancer is selected from the group comprising or consisting of non-melanoma skin cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, oral cancer, squamous cell carcinoma, oral melanoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, central nervous system lymphoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, malignant histiocytosis, fibroblastic sarcoma, hemangiosarcoma, hemangiopericytoma, leiomyosarcoma (LMS), canine mammary gland carcinoma, and feline mammary gland carcinoma.

21. 16. A cyclin-dependent kinase 7 inhibitor having general formula I as defined in any of claims 1, 9 to 15, for use in a method for the prevention and / or treatment of cancer, wherein said cyclin-dependent kinase 7 inhibitor is administered to a patient having or suspected of having cancer, and wherein the administration of said cyclin-dependent kinase 7 inhibitor to said patient is combined with the administration of radiotherapy.

22. 16. A method for preventing and / or treating cancer in a patient, said method comprising administering to a patient having or suspected of having cancer a combination of a cyclin-dependent kinase 7 inhibitor and an anti-cancer agent, said combination being defined in any one of claims 1 to 15.

23. Use of a combination as defined in any of claims 1 to 15 for the manufacture of a medicament for the prevention and / or treatment of cancer in a patient.

24. A pharmaceutical composition comprising a combination as defined in any one of claims 1 to 15 for the prevention and / or treatment of cancer in a patient having or suspected of having cancer.

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