Combination therapy of CDK7 inhibitors with other anti-cancer therapies

Abstract

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

[0002] CDK7 is a master regulator of the cell cycle process and is also a component of the general transcription factor TFIIH that regulates RNA polymerase II-mediated transcription. Inhibiting CDK7 can lead to DNA damage and genomic instability by blocking 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 therapy.

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

[0004] The semi-synthetic flavonoid derivative alvocidib (flavopiridol), which inhibits CDK1, 2, 4, 6, 7, and 9, was the first CDK inhibitor to enter clinical trials. Most trials showed limited clinical activity, but there was a modest response in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (Byrd et al., 2006, Blood, 109(2), pp. 399 - 404).

[0005] WO 2019 / 197546 describes selective CDK7 inhibitors, pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives.

[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, has been 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). However, this clinical trial has been aborted.

[0008] There is still a need in the art for new methods for the effective treatment of proliferative diseases, particularly cancer.

[0009] In the field of cancer treatment, there is still a need to improve existing therapies and provide new therapies. Summary of the Invention

[0010] In one aspect, the present application relates to a combination of a cyclin-dependent kinase 7 inhibitor and an anti-cancer agent different from the cyclin-dependent kinase 7 inhibitor, wherein the cyclin-dependent kinase 7 inhibitor is a compound having the general formula I

[0011]

[0012] wherein

[0013] X is independently selected from CH and N each time it appears;

[0014] Q is absent or is independently selected from the group consisting of:

[0015] -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 )- each time it appears;

[0016] Y is independently selected from the group consisting of halogen, C1-C3 haloalkyl, C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclic group, -S(=O) 2 R 4 , C1-C6 alkyl and C1-C6 alkyl substituted with one or two of -OR 6 , -N(R 6 )R 6 , aryl, heteroaryl and heterocyclic group each time it appears;

[0017] wherein the C3-C8 cycloalkyl is optionally substituted with one or two of R 4 , R 5 and -(C=O)R 6 , wherein the heterocyclic group is optionally substituted with one or two of R 4 , R 5 and -(C=O)R 6 , and wherein the aryl or heteroaryl is optionally substituted with R 4 , C1-C6 alkyl, -OR 6 , -N(R 6 )R6 、 -(C=O)R 6 、 substituted by one or two of halogen, heteroaryl and heterocyclic group;

[0018] R 1 independently selected from the group consisting of halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -CN, -(C=O)CH each time it appears 3 and C1-C3 haloalkyl, any of which is optionally substituted;

[0019] R 2 independently selected from any structure of the following Group A each time it appears:

[0020]

[0021] wherein m is independently selected from 1, 2 and 3 each time it appears;

[0022] W is any structure of the following Group B;

[0023]

[0024] L is absent, or independently selected from the group consisting of -O- and -NH- each time it appears;

[0025] wherein n is independently selected from 1, 2 and 3 each time it appears;

[0026] R 3 independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR each time it appears 6 , -CN and C1-C6 alkyl substituted by -OH, -OR 6 or -NHR 6 ;

[0027] R 4 is absent, or independently selected from the group consisting of hydrogen, -OR each time it appears 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, heterocyclic group, C1-C6 alkyl and C1-C6 alkyl substituted by -OR 6 , -NH 2 or S(=O) 2 N(R 6 )R 6The group consisting of substituted C1-C6 alkyls;

[0028] R 5 independently at each occurrence selected from the group consisting of hydrogen, halogen, C1-C3 haloalkyl, -CN, -OR 6 , -N(R 6 )R 6 , (=O), S(=O) 2 N(R 6 )R 6 , aryl, heteroaryl, heterocyclic group, C1-C6 alkyl, and C1-C6 alkyl substituted with -OH, -NH 2 or S(=O) 2 N(R 6 )R 6 the group consisting of substituted C1-C6 alkyls;

[0029] wherein R 4 and R 5 are both (=O) if they are attached to a single sulfur atom forming part of Y and Y is a heterocycle;

[0030] or wherein 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 any one of an aromatic ring, a heteroaromatic ring, and a saturated or unsaturated heterocyclic ring;

[0031] R 6 independently at each occurrence selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, heteroaryl, heterocyclic group, heteroaryl substituted with one or two of halogen, -OR 7 , -N(R 7 )R 7 , C1-C6 alkyl, and C1-C6 alkyl substituted with -OH, -NH 2 ; a heterocyclic group substituted with one or two of halogen, -OR 7 , -N(R 7 )R 7 , C1-C6 alkyl, and C1-C6 alkyl substituted with -OH or -NH 2 ; the group consisting of substituted C1-C6 alkyls;

[0032] R 7 independently at each occurrence selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, and W as defined above;

[0033] R 8 independently at each occurrence selected from hydrogen and W as defined above;

[0034] wherein if R 7If it is W, then R 8 is hydrogen;

[0035] R 9 is independently selected from hydrogen and W as defined above each time it appears;

[0036] R 10 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH 2 , -OR 6 , -CN and W as defined above each time it appears;

[0037] wherein if R 10 is W, then R 8 is hydrogen;

[0038] R 11 is independently selected from the group consisting of hydrogen, C1-C6 alkyl and C1-C3 haloalkyl each time it appears;

[0039] R 12 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH 2 , -OR 6 and -CN each time it appears;

[0040] R 13 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl and W as defined above each time it appears;

[0041] wherein if R 13 is W, then R 9 is hydrogen;

[0042] R 14 and R 15 are independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR 6 , heterocyclic group and -CN each time they appear;

[0043] R 16 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R 6 ) 2 , -NR 13 R 14 , -NR 13 CH 2 (CO)NH 2 , heterocyclic group, -OR 6 and -CN each time it appears.

[0044] or an enantiomer, stereoisomeric form, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate or pharmaceutically acceptable salt thereof of the above compounds.

[0045] In one embodiment, the anti-cancer agent is selected from

[0046] a) targeted specific compounds selected from the group consisting of immune checkpoint inhibitors, especially monoclonal antibodies and antibody fragments against immune checkpoints; poly ADP ribose polymerase (PARP) inhibitors; monoclonal antibodies and antibody fragments not against 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 targeting chimera compounds (PROTAC); siRNA; antibody-drug conjugates (ADC); antibody-siRNA conjugates (ARC); DNA damage response inhibitors and targeted specific fusion proteins; and

[0047] b) cytotoxic non-specific compounds selected from taxanes, alkylating agents, nucleoside analogs, folic acid antagonists, topoisomerase inhibitors, anthracyclines, podophyllotoxins, vinca alkaloids and platinum compounds;

[0048] c) hormonal anti-cancer agents selected from hormones; hormone antagonists; hormone receptor antagonists; hormone receptor degraders and aromatase inhibitors;

[0049] wherein, preferably, the hormones are selected from medroxyprogesterone; anastrozole, letrozole, exemestane; megestrol acetate; raloxifene; estramustine; gonadotropin-releasing hormones such as leuprolide, goserelin, triptorelin, histrelin, abarelix; androgens such as testolactone, fluoxymesterone; anti-androgens such as enzalutamide, bicalutamide, apalutamide, darolutamide, nilutamide, flutamide;

[0050] and wherein, preferably, the hormone antagonists are selected from gonadotropin-releasing hormone antagonists such as degarelix;

[0051] and wherein, preferably, the hormone receptor antagonists are selected from fulvestrant, tamoxifen, toremifene; and

[0052] Wherein, preferably, the hormone receptor degrader is selected from a selective estrogen receptor degrader and a selective androgen receptor degrader; more preferably, selected from giredestrant, amcenestrant, fulvestrant, AZD9833, rintodestrant, LSZ102, LY3484356, elastostrant, ZN-c5, D-0502, SHR9549 and bavdegalutamide;

[0053] And wherein, preferably, the aromatase inhibitor is selected from anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, testolactone and aminoglutethimide; and

[0054] d) Radiopharmaceuticals.

[0055] In one embodiment, the combination is a composition wherein the cyclin-dependent kinase 7 inhibitor and the anti-cancer agent are present together, physically mixed with each other or kept separated from each other by at least one physical isolation barrier between the cyclin-dependent kinase 7 inhibitor and the anti-cancer agent, wherein the at least one physical isolation barrier forms part of the combination, for example wherein the cyclin-dependent kinase 7 inhibitor and the anti-cancer agent are kept in separate containers or compartments or chambers or dosage units, and the separate containers, compartments, chambers and dosage units form part of the combination.

[0056] In one embodiment, the anticancer agent is a targeting specific compound selected from immune checkpoint inhibitors, in particular monoclonal antibodies against immune checkpoints; poly ADP ribose polymerase (PARP) inhibitors; other monoclonal antibodies not against immune checkpoints; tyrosine kinase inhibitors; DNA damage response inhibitors; and antibody-cytokine fusion proteins.

[0057] In one embodiment, the targeting-specific compound is selected from anti-PD1 antibody, anti-PD-L1 antibody, anti-CTLA-4 antibody, anti-LAG-3 antibody, anti-VEGF antibody, anti-VEGFR antibody, anti-EGFR antibody, anti-HER2 antibody, anti-CD52 antibody, anti-CD33 antibody, anti-CD30 antibody, anti-CD20 antibody, anti-TIM3 antibody, anti-TIGIT antibody, anti-41BB antibody, anti-OX40 antibody, anti-CD40 antibody, anti-CD27 antibody, anti-GITR antibody, anti-ICOS antibody, anti-Siglec antibody and anti-PVRIG antibody.

[0058] In one embodiment, the target-specific compound is selected from anti-human-PD1 antibodies, in particular pembrolizumab, nivolumab, cemiplimab, spartalizumab, atezolizumab, avelumab, durvalumab, ipilimumab, tremelimumab, relatlimab, bevacizumab, ramucirumab, cetuximab, panitumumab, pertuzumab, trastuzumab, trastuzumab-emtansine, alemtuzumab, gemtuzumab, gemtuzumab-ozoamicin, brentuximab, brentuximab-vedotin, ibritumomab, ibritumomab-tiuxetan, rituximab, obinutuzumab, tositumomab, ofatumumab, pidilizumab, toripalimab, sintilimab, camrelizumab, tislelizumab, zimberelimab, prolgolimab, dostarlimab; wherein, preferably, the target-specific compound is pembrolizumab.

[0059] In one embodiment, the targeting specific compound is selected from: poly ADP ribose polymerase (PARP) inhibitors, particularly olaparib, pamiparib, and niraparib; tyrosine kinase inhibitors, particularly afatinib, aflibercept, axitinib, bosutinib, cabozantinib, ceritinib, crizotinib, dasatinib, erlotinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, nilotinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, anlotinib, apatinib, osimertinib, and alectinib; MEK inhibitors, particularly cobimetinib and trametinib; KRAS inhibitors, particularly sotorasib and adagrasib; c-MET inhibitors, particularly savolitinib; FGFR inhibitors, particularly erdafitinib, pemigatinib, and vofatamab; DNA damage response inhibitors selected from WEE1 inhibitors and ATR inhibitors, particularly adavosertib, berzosertib, and volasertib.

[0060] In one embodiment, the anticancer agent is a cytotoxic non-specific compound selected from the following:

[0061] a) Taxanes, preferably selected from docetaxel, carbazitaxel, and paclitaxel;

[0062] b) An alkylating agent, preferably selected from bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, fotemustine, ifosfamide, lomustine, melphalan, streptozotocin, and temozolomide;

[0063] c) A nucleoside analogue, preferably selected from azacitidine, capecitabine, carmofur, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, fluoruracil, gemcitabine, mercaptopurine, nelarabine, pentostatin, tegafur, and tioguanine;

[0064] d) A folic acid antagonist, preferably selected from methotrexate, pemetrexed, and raltitrexed;

[0065] e) A topoisomerase inhibitor, preferably selected from irinotecan and topotecan;

[0066] f) An anthracycline, preferably selected from daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, and valrubicin;

[0067] g) A podophyllotoxin, preferably selected from etoposide and teniposide;

[0068] h) Vinca alkaloids, preferably selected from vinblastine, vincristine, vindesine, vinflunine and vinorelbine;

[0069] i) Platinum compounds, preferably selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, heptaplatin and lobaplatin.

[0070] In one embodiment, the compound is a compound having the general formula Ia

[0071]

[0072] wherein

[0073] X is independently selected from CH and N each time it appears;

[0074] Y 1 is independently selected from CH, C(OH) and N each time it appears;

[0075] Y 2 is independently selected from CH, C(OH) and N each time it appears;

[0076] Q is absent or is independently selected from the group consisting of -NH-, -NH(CH 2 )-, -NH(C=O)-, -NHSO 2 -, -O-, -O(CH 2 )-, -(C=O)- and -(C=O)(CH 2 )- each time it appears;

[0077] R 1 is independently selected from the group consisting of halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -CN, -(C=O)CH 3 and C1-C3 haloalkyl, any of which is optionally substituted;

[0078] R 2 is independently selected from any structure of group A below,

[0079]

[0080] where m = 1, 2 or 3;

[0081] W is any structure of group B';

[0082]

[0083] L is absent or, each time it appears, is independently selected from the group consisting of -O- and -NH-;

[0084] R 3 is, each time it appears, independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR 6 , -CN, and C1-C6 alkyl substituted by -OH, -OR 6 or -NHR 6 ;

[0085] R 4 is absent or, each time it appears, is independently selected from the group consisting of 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, heterocyclic group, C1-C6 alkyl, and C1-C6 alkyl substituted by -OR 6 , -NH 2 or S(=O) 2 N(R 6 )R 6 ;

[0086] R 5 is, each time it appears, independently selected from the group consisting of hydrogen, halogen, C1-C3 haloalkyl, -CN, -OR 6 , -N(R 6 )R 6 , (=O), S(=O) 2 N(R 6 )R 6 , aryl, heteroaryl, heterocyclic group, C1-C6 alkyl, and C1-C6 alkyl substituted by -OH, -NH 2 or S(=O) 2 N(R 6 )R 6 ;

[0087] wherein both R 4 and R 5 are (=O) if they are attached to a single sulfur atom forming part of Y and Y is a heterocycle;

[0088] or wherein R 4 and R5 Together with the structures 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 any one of an aromatic ring, a heteroaromatic ring, and a saturated or unsaturated heterocyclic ring;

[0089] R 6 Each occurrence is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, heteroaryl, heterocyclic group, halogen, -OR 7 , -N(R 7 )R 7 , C1-C6 alkyl, and a heteroaryl substituted with one or two of -OH, -NH 2 ; a heterocyclic group substituted with halogen, -OR 7 , -N(R 7 )R 7 , C1-C6 alkyl, and a C1-C6 alkyl substituted with -OH or -NH 2 ;

[0090] R 7 Each occurrence is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, and W as defined above;

[0091] R 8 Each occurrence is independently selected from hydrogen and W as defined above;

[0092] Wherein if R 7 is W, then R 8 is hydrogen;

[0093] R 9 Each occurrence is independently selected from hydrogen and W as defined above;

[0094] R 10 Each occurrence is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH 2 , -OR 6 , -CN, and W as defined above;

[0095] Wherein if R 10 is W, then R 8 is hydrogen;

[0096] R 11 Each occurrence is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C3 haloalkyl;

[0097] R 12 Each occurrence is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH 2, -OR 6 and the group consisting of -CN;

[0098] R 13 independently at each occurrence is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, and W as defined above;

[0099] wherein if R 13 is W, then R 9 is hydrogen;

[0100] R 14 and R 15 independently at each occurrence is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR 6 , heterocyclic group, and -CN;

[0101] R 16 independently at each occurrence is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R 6 ) 2 , -NR 13 R 14 , heterocyclic group, -OR 6 , and -CN;

[0102] or an enantiomer, stereoisomeric form, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate, or a pharmaceutically acceptable salt thereof of the above compound.

[0103] In one embodiment, at least one or exactly one of R 2 , R 7 , R 8 , R 9 , R 10 , and R 13 is W as defined in claim 1, or is a structure containing W as defined in claim 1.

[0104] In one embodiment, R 1 is C1-C6 alkyl or C1-C3 haloalkyl.

[0105] In one embodiment, R 2 is

[0106]

[0107] 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 14and R 15 is, independently at each occurrence, hydrogen, halogen or C1-C6 alkyl, wherein preferably, R 14 is halogen; wherein R 16 is hydrogen, halogen, C1-C6 alkyl, -N(R 6 ), -NR 2 R 13 R 14 wherein, preferably, R 16 is -N(R 6 ) 2 or -NR 13 R 14 .

[0108] In one embodiment, the compound is a compound having a structure selected from Structures 1-198 as defined in the column headed "Structure" in Table 1 herein.

[0109] In a preferred embodiment, the compound is a compound having a structure selected from the structures of Compounds 3, 14, 47 and 156 as defined herein.

[0110] In another aspect, the present invention also relates to the use of the combination of the present invention as defined herein in a method for preventing and / or treating cancer in a patient suffering from or suspected of suffering from cancer.

[0111] In one embodiment of this aspect of the present invention, the method of prevention and / or treatment comprises administering to a patient suffering from or suspected of suffering from cancer an effective amount of the cyclin-dependent kinase 7 inhibitor and an effective amount of the anti-cancer agent.

[0112] In one embodiment of this aspect of the present invention, in the method of prevention and / or treatment, the cyclin-dependent kinase 7 inhibitor is administered before or after the anti-cancer agent is administered to the patient, or wherein the cyclin-dependent kinase 7 inhibitor and the anti-cancer agent are both administered to the patient concomitantly or synchronously or in a temporally overlapping manner, or wherein the cyclin-dependent kinase 7 inhibitor is administered adjunctively to the anti-cancer agent to the patient, or wherein the anti-cancer agent is administered adjunctively to the cyclin-dependent kinase 7 inhibitor to the patient.

[0113] In one embodiment of this aspect of the present invention, the method of prevention and / or treatment comprises administering the combination in conjunction with radiotherapy.

[0114] In one embodiment, the cancer is a cancer selected from or consisting of the group consisting of: renal cell carcinoma (RCC), kidney cancer, hereditary papillary renal cancer, sporadic papillary renal cancer, non-squamous non-small-cell lung carcinoma (non-squamous NSCLC), squamous non-small-cell lung carcinoma (squamous NSCLC), small-cell lung carcinoma (SCLC), triple-negative breast cancer, colorectal cancer, melanoma, pancreatic ductal adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma (HNSCC), urothelial cancer, adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer, bronchial carcinoma, estrogen-dependent and independent breast cancer, Burkitt's lymphoma, corpus cancer, carcinoma of unknown primary tumor (CUP-syndrome), small intestine cancerintestine cancer), small intestinal tumors, ovarian cancer, endometrial carcinoma, ependymoma, epithelial cancer types, Ewing’s tumors, gastrointestinal tumors, gastric cancer, gallbladder cancer, gall bladder carcinomas, uterine cancer, cervical cancer, cervix, glioblastomas, gynecologic tumors, ear, nose and throat tumors, hematologic tumor, hairy cell leukemia, urethral cancer, skin cancer, skin testis cancer, brain tumors (gliomas), brain metastases, testicle cancer, hypophysis tumor, carcinoids, Kaposi’s sarcoma, laryngeal cancer, germ cell tumor, bone cancer, head and neck tumors (tumors of the ear, nose and throat area), colon carcinoma, craniopharyngiomas, oral cancer (cancer in the mouth area and on lips), cancer of the central nervous system, liver cancer, liver metastasesmetastases), leukemia, eyelid tumor, lung cancer, lymphoma, stomach cancer, malignant melanoma, malignant neoplasia, malignant tumors of the gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastomas, meningiomas, Hodgkin’s / Non-Hodgkin’s lymphoma, mycosis fungoides, nasal cancer, neurinoma, neuroblastoma, oligodendroglioma, osteolytic carcinomas and osteoplastic carcinomas, osteosarcomas, ovarian carcinoma, pancreatic carcinoma, penile cancer, plasmacytoma, prostate cancer, pharyngeal cancer, rectal carcinoma, retinoblastoma, vaginal cancer, thyroid carcinoma, T-cell lymphoma, thymoma, tube carcinoma, eye tumors, urethral cancer, urologic tumors, urothelial carcinoma, vulva cancer, wart appearance, soft tissue tumors, soft tissue sarcoma, Nephroblastoma, cervical carcinoma, tonguecancer), invasive ductal 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 tumors, sarcoma of the uterus, salivary gland cancers, anal gland adenocarcinomas, mast cell tumors, pelvis tumor, ureter tumor, intraocular melanoma, hepatocellular carcinoma, cholangiocarcinoma, mixed hepatocellular cholangiocarcinoma, squamous cell carcinoma, Merkel cell skin cancer, non-melanoma skin cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, oral cavity cancer, squamous cell cancer, oralmelanoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, lymphoma of the central nervous system, malignant fibrous histiocytoma, lymph sarcoma, rhabdomyosarcoma, malignant histiocytosis, fibroblastic sarcoma, hemangiosarcoma, hemangiopericytoma, leiomyosarcoma (LMS), canine mammary carcinoma, and feline mammary carcinoma.

[0115] In another aspect, the present invention also relates to a method for preventing and / or treating cancer with a cyclin-dependent kinase 7 inhibitor of formula I as defined herein, wherein in said method, the cyclin-dependent kinase 7 inhibitor is administered to a patient suffering from or suspected of suffering from cancer, and wherein the administration of the cyclin-dependent kinase 7 inhibitor to the patient is carried out in combination with the administration of radiotherapy.

[0116] In another aspect, the present invention also relates to a method for preventing and / or treating cancer in a patient, said method comprising administering to a patient suffering from or suspected of suffering from cancer a combination of a cyclin-dependent kinase 7 inhibitor and an anti-cancer agent, said combination as defined herein.

[0117] In another aspect, the present invention also relates to the use of a combination as defined herein in the manufacture of a medicament for preventing and / or treating cancer in a patient.

[0118] In another aspect, the present invention also relates to a pharmaceutical composition comprising a combination as defined herein for preventing and / or treating cancer in a patient suffering from or suspected of suffering from cancer.

[0119] The present inventors have surprisingly found that highly specific CDK7 inhibitors of pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine classes, when used in combination with other anticancer agents, are very effective in enhancing antitumor efficacy, with a significant improvement in efficacy compared to their respective monotherapies / single-agent therapies. In particular, it has been found that, considering the seemingly completely unrelated mechanisms involved, it is not expected that combining such CDK7 inhibitors with other anticancer agents greatly enhances the efficacy of other anticancer agents. For example, the CDK7 inhibitors according to the present invention greatly enhance the efficacy of immune checkpoint inhibitors (such as PD1 inhibitors or PD-L1 inhibitors) and poly(ADP-ribose) polymerase (PARP) inhibitors. In addition, the combination of the CDK7 inhibitors according to the present invention with cytotoxic non-specific compounds (such as taxanes) or hormonal anticancer agents (such as hormone receptor antagonists) greatly enhances the efficacy of the respective monotherapies of such other anticancer agents. Surprisingly, this enhancing effect seems to be independent of the specific type and nature of the other anticancer agents, and thus, the data of the present invention can be extrapolated to other anticancer agents and other anticancer treatment modalities. In addition, the present inventors also expect that such combinations according to the embodiments of the present invention will restore the sensitivity of cancer cells resistant to the corresponding monotherapies.

[0120] In a preferred embodiment according to the present invention, the cyclin-dependent kinase 7 inhibitor is combined with an immune checkpoint inhibitor, particularly an antibody or antibody fragment directed against an immune checkpoint. Preferably, such an immune checkpoint is PD1 or PD-L1. In a preferred embodiment of this aspect of the present invention, such an immune checkpoint inhibitor is an anti-PD1 antibody or an anti-PD-L1 antibody. For example, such an antibody can 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, the cyclin-dependent kinase 7 inhibitor is combined with an inhibitor of poly(ADP-ribose) polymerase (PARP), such as olaparib, pamiparib or niraparib.

[0121] In another preferred embodiment, the CDK7 inhibitor according to the present invention is combined with a cytotoxic non-specific compound, preferably a taxane, particularly docetaxel, cabazitaxel or paclitaxel, with docetaxel being particularly preferred.

[0122] 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, which is 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, and even more preferably, it is fulvestrant, tamoxifen, toremifene, letrozole or anastrozole.

[0123] As used herein, the terms "[the] present invention", "according to the present invention", "in accordance with the present invention" and the like are intended to refer to all aspects and embodiments of the present invention described and / or claimed herein. As used herein, the term "comprising" shall be interpreted to cover both "including" and "consisting of", and is intended to specifically and expressly cover both meanings, and thus the embodiments disclosed separately according to the present invention. When used herein, "and / or" shall be regarded as a specific disclosure of each of the two designated features or components, regardless of order. For example, "A" and / or "B" shall be regarded as a specific disclosure of each of (i) A, (ii) B and (iii) A and B, as if each were listed separately herein. In the case of using an indefinite article or a definite article, when referring to a singular noun (such as "a", "an" or "the"), unless otherwise specifically stated, it includes the plural of that noun. Similarly, the present disclosure should also be regarded as a specific disclosure of a single individual entity introduced by "a", "an" or "the".

[0124] As used herein, the term "CDK7 inhibitor" refers to an inhibitor of cyclin-dependent kinase 7, which is specific for such cyclin-dependent kinase 7 and has no or little inhibitory effect on other cyclin-dependent kinases. In other words, according to the present invention, a CDK7 inhibitor is not an inhibitor having inhibitory activity against a plurality of cyclin-dependent kinases. More specifically, and preferably, the CDK7 inhibitor according to the present invention is not a PAN-CDK inhibitor.

[0125] When referring to a compound herein, the term "targeting specificity" relates to the ability of such a compound and / or the molecular structure forming part of such a compound to bind to a certain structure (such as a ligand, an antigen, especially an epitope) through specific interaction. For example, the term "targeting specificity" can be used in combination with the surface molecules of an antibody, an antigen-binding peptide, an antigen-binding protein or an immune cell (such as a cytotoxic T cell).

[0126] As used herein, the term "combination" preferably refers to a combination in which the cyclin-dependent kinase 7 inhibitor and the anti-cancer agent are present together, either physically mixed with each other or kept separate from each other by at least one physical barrier between the inhibitor and the anti-cancer agent, wherein the at least one physical barrier forms part of the combination. For example, the cyclin-dependent kinase 7 inhibitor and the anti-cancer agent can be separately stored in separate containers or compartments or chambers or dosage units, and these separate containers, compartments, chambers and dosage units form part of the combination. In another embodiment, such "combination" refers to a situation where the cyclin-dependent kinase 7 inhibitor and the anti-cancer agent are separately kept in different, separate containers, compartments, chambers or dosage units, and the different, separate containers, compartments, chambers or dosage units are made or arranged in such a way that they are separated by more than one physical barrier but are still intended to be co-administered to each other.

[0127] As used herein, the term "in conjunction with each other" preferably refers to a mode of administration in which two agents or treatment modalities, or one agent and one treatment modality, are co-administered to a patient, preferably simultaneously, sequentially in any desired useful order, or in an overlapping manner. Such co-administration is intended to achieve a higher effective treatment level of the respective formulations or the respective treatment modalities simultaneously or at least in an overlapping manner, so that the two formulations or treatment modalities, or one formulation and one treatment modality, jointly exert an anti-cancer effect.

[0128] As used herein, the term "antibody" means a substantially intact antibody, antibody fragments, e.g., Fab fragments, F(ab') 2 fragments, single-chain Fv fragments, diabodies, triabodies, tetra-bodies, bispecific antibodies, nanobodies and other peptide / protein molecules that maintain binding affinity with a ligand specific to "antibody". In one embodiment, the antibody is a monoclonal antibody. In one embodiment, such antibody is a human antibody or a humanized antibody or a rodent antibody, e.g., a mouse antibody, which may or may not be further humanized.

[0129] As used herein, the term "fusion protein" preferably and specifically refers to an antibody-cytokine fusion protein. In one embodiment, in such a fusion protein, a full-length antibody or antibody fragment (e.g., full-length IgG, Fc fragment, Fab fragment or scFv fragment) is linked to a cytokine monomer (e.g., IL-2 or IFN-α or GM-CSF) or a cytokine homopolymer (IFN-γ or TNF) or a cytokine heteropolymer (e.g., IL-12 or IL-27). Examples of suitable antibody-cytokine fusion proteins useful 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.

[0130] As used herein, the term "radiopharmaceutical" refers to a drug containing a radioisotope, and more specifically, a targeted specific drug containing a radioisotope. Generally, a targeted specific drug is specific for a particular cell type or tissue type, more specifically for cancer cells or cancer tissue, and specifically binds to or specifically interacts with the same, and the radioisotope that forms part of the radiopharmaceutical is thus brought near such cells or tissues and damages such cells or tissues by emitting radiation thereto. Examples of targeted specific drugs in radiopharmaceuticals are antibodies and antibody fragments, especially monoclonal antibodies and antibody fragments, poly ADP ribose polymerase (PARP) inhibitors; tyrosine kinase inhibitors; and immunotoxins. Specific examples of radiopharmaceuticals are metastron, zevalin, xofigo, lutathera, azedra and pluvicto.

[0131] As used herein, the term "radiation therapy" is intended to include external beam radiation therapy, brachytherapy, and treatment with radiopharmaceuticals and combinations thereof. Thus, when a cyclin-dependent kinase 7 inhibitor as defined herein is administered "in combination with radiation therapy" to a patient, according to one aspect of the invention, as defined in claim 21, such co-administration is intended to include the situation where such inhibitor is co-administered with a) external beam radiation therapy or b) brachytherapy or c) a radiopharmaceutical, or d) a combination of any of a)-c). In one embodiment, such co-administration refers to administering the inhibitor together with external beam radiation therapy (and not using brachytherapy or treatment with radiopharmaceuticals). In another embodiment, such co-administration refers to administering the inhibitor together with brachytherapy (and not using external beam radiation therapy or treatment with radiopharmaceuticals). In yet another embodiment, such co-administration refers to administering the inhibitor together with treatment with a radiopharmaceutical (and not using brachytherapy or external beam radiation therapy).

[0132] 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. Instead, as used herein, "external beam radiation therapy" refers to the use of an ionizing radiation beam (preferably a collimated or focused beam) that is directed onto or into a patient's body from outside the patient's body to treat a disorder or disease, preferably a cancerous disease. In a preferred embodiment, "external beam radiation therapy" includes irradiation with X-rays, γ-rays, protons, neutrons, electrons, or heavy ions (preferably X-rays). In another preferred embodiment, "external beam radiation therapy" is selected from treatment modalities including 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).

[0133] As used herein, the term "brachytherapy" refers to a type of internal radiotherapy in which a suitable implant (such as a seed, capsule, bolus, ribbon, strip, stick, needle, bar, plaster or wire) is placed into a patient, preferably into or near a tumor or cancerous tissue, and such an implant contains a radiation source. Since the implant is placed into the patient, radiation is released from the implant and enters the body part where the implant is located. 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.

[0134] As used herein, the term "optionally substituted" means that a hydrogen atom or multiple such hydrogen atoms present and attached to a member atom within a group can be replaced by a suitable group, such as a halogen (including fluorine), C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, methyl hydroxy, COOMe, C(O)H, COOH, OMe or OCF 3 .

[0135] The term "alkyl" refers to a monovalent straight-chain, branched-chain or cyclic-chain saturated aliphatic hydrocarbon group having a specified number of carbon atoms. Thus, for example, "C 1 -C 6 alkyl" refers to any hexylalkyl and pentylalkyl isomers, as well as n-butyl, isobutyl, sec-butyl and tert-butyl, n-propyl and isopropyl, cyclopropyl, ethyl and methyl.

[0136] The term "alkenyl" refers to a monovalent straight-chain or branched-chain aliphatic hydrocarbon group containing one carbon-carbon double bond and having a specified number of carbon atoms. Thus, for example, "C 2 -C 6 alkenyl" refers to all hexenyl and pentenyl isomers, as well as 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-propenyl, 2-propenyl and vinyl (or ethenyl).

[0137] Unless otherwise defined, the term "cycloalkyl", when used alone or in combination with any other term, refers to a group having 3 - 8 carbon atoms, such as an optionally substituted or unsubstituted cyclic hydrocarbon. Thus, for example, "C 3 -C 8 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0138] The term "haloalkyl" refers to an alkyl group as defined herein that is substituted by at least one halogen. Examples of straight-chain or branched "haloalkyl" groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and tert-butyl independently substituted by one or more halogens. The term "haloalkyl" should be construed to include, for example, -CHF 2 、-CF 3 、-CH 2 -CH 2 -F, -CH 2 -CF 3 and such substituents as etc.

[0139] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by heteroatoms (such as O, N, or S). For example, if a carbon atom of an alkyl group attached to the parent molecule is replaced by a heteroatom (such as O, N, or S), the resulting heteroalkyls are respectively alkoxy groups (e.g., -OCH 3 etc.), amines (e.g., -NHCH 3 , -N(CH 3 ) 2 etc.), or alkylthio groups (e.g., -SCH 3 etc.). If a non-terminal carbon atom of an alkyl group is not attached to the parent molecule and is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyls are respectively alkyl ethers (such as -CH 2 CH 2 -O-CH 3 etc.), alkylamines (such as -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 etc.), or thioalkyl ethers (such as -CH 2 -S-CH 3 ).

[0140] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0141] The term "phenyl" as used herein refers to a phenyl group optionally substituted or unsubstituted.

[0142] The term "benzyl" as used herein refers to a benzyl group optionally substituted or unsubstituted.

[0143] The term "heteroaryl" refers to (i) an optionally substituted 5- and 6-membered heteroaromatic ring, and (ii) an optionally substituted 9- and 10-membered bicyclic fused ring system, wherein at least one ring is aromatic, wherein the heteroaromatic ring or bicyclic fused ring system contains 1-4 heteroatoms independently selected from N, O, and S, wherein each N is optionally in the form of an oxide, and each S in a non-aromatic ring is optionally S(O) or S(O) 2 form. Suitable 5- and 6-membered heteroaromatic rings include, for example, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Suitable 9- and 10-membered hetero-bicyclic fused ring systems include, for example, benzofuryl, indolyl, indazolyl, naphthyridinyl, isobenzofuryl, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolyl, benzodioxolyl, benzodioxolyl, imidazo[1,2-a]pyridyl, benzotriazolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, 2,3-dihydrobenzofuryl, and 2,3-dihydrobenzo-1,4-dioxinyl.

[0144] The term "heterocyclic group" refers to (i) an optionally substituted 4- to 8-membered, saturated and unsaturated non-aromatic monocyclic ring containing at least one carbon atom and 1 to 4 heteroatoms, (ii) an optionally substituted bicyclic ring system containing 1 to 6 heteroatoms, and (iii) an optionally substituted tricyclic ring system, wherein each ring in (ii) or (iii) is independently fused or bridged to one or more other rings, and each ring is a saturated or unsaturated non-aromatic ring, and wherein 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) 2Suitable 4- to 8-membered saturated heterocyclic groups include, for example, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuryl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinyl, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxolanyl, and azocanyl. Suitable unsaturated heterocycles include those corresponding to the saturated heterocycles listed in the previous sentence, in which a single bond is replaced by a double bond. It should be understood that the specific rings and ring systems applicable to the present invention are not limited to those listed in this paragraph and the previous paragraph. These rings and ring systems are merely representative.

[0145] Pharmaceutically acceptable salts

[0146] Examples of pharmaceutically acceptable addition salts include, but are not limited to, non-toxic inorganic acid addition salts and organic acid addition salts, such as acetates derived from acetic acid, aconitates derived from aconitic acid, ascorbates derived from ascorbic acid, benzenesulfonates derived from benzenesulfonic acid, benzoates derived from benzoic acid, cinnamates derived from cinnamic acid, citrates derived from citric acid, embonates derived from embonic acid, heptanoates derived from heptanoic acid, formates derived from formic acid, fumarates derived from fumaric acid, glutamates derived from glutamic acid, glycolates derived from glycolic acid, hydrochlorides derived from hydrochloric acid, hydrobromides derived from hydrobromic acid, lactates derived from lactic acid, maleates derived from maleic acid, malonates derived from malonic acid, mandelates derived from mandelic acid, mesylates derived from methanesulfonic acid, naphthalene-2-sulfonates derived from naphthalene-2-sulfonic acid, nitrates derived from nitric acid, perchlorates derived from perchloric acid, phosphates derived from phosphoric acid, phthalates derived from phthalic acid, salicylates derived from salicylic acid, sorbates derived from sorbic acid, stearates derived from stearic acid, succinates derived from succinic acid, sulfates derived from sulfuric acid, tartrates derived from tartaric acid, p-toluenesulfonates derived from p-toluenesulfonic acid, and the like. Such salts can be formed by processes well known and described in the art.

[0147] Other acids such as oxalic acid (which may not be considered pharmaceutically acceptable) can be used as salts in the preparation of intermediates useful for obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0148] In another embodiment, according to the present invention, the compounds of the present invention are used in their respective free base forms.

[0149] The metal salts of the compounds of the present invention include alkali metal salts, such as the sodium salts of the compounds of the present invention containing a carboxyl group.

[0150] The compounds within the combination of the present invention can be provided in non-solvated or solvated forms together with pharmaceutically acceptable solvents such as water, ethanol, etc. Solvated forms can also include hydrated forms, such as monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, etc. Generally, for the purposes of the present invention, solvated forms are considered equivalent to non-solvated forms.

[0151] According to the present invention, the preferred CDK7 inhibitors that form part of the combination are those listed and shown in the column headed "Structure" in Table 1:

[0152] Table 1. Overview of the structures and exemplary corresponding characteristics of Compounds 1 - 198

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189] This patent application provides utilities and outstanding activities achieved through combinations of CDK7 inhibitors with other anti-cancer therapies, particularly other anti-cancer agents. Considering the effects of CDK7 inhibitors on blocking the cell cycle and inducing replication stress and genomic instability, the combination of CDK7 inhibitors with other anti-cancer therapies improves anti-tumor efficacy as a new cancer treatment method. BRIEF DESCRIPTION OF THE DRAWINGS

[0190] In addition, reference is made to the accompanying drawings, in which:

[0191] Figure 1A 、 1B and FIG. 1C show the effects of the CDK7 inhibitor on RENCA cells.

[0192] Figure 1AShows the results of examining the viability of RENCA cells in the presence of a CDK7 inhibitor.

[0193] Figure 1B Shows the results of the CDK7 binding assay of the CDK7 inhibitor.

[0194] Figure 1C Shows the immunoblotting results of the phosphorylated form of H2AX in RENCA cells treated with a CDK7 inhibitor.

[0195] Figure 2A and 2B Shows the effect of combined treatment with a CDK7 inhibitor and an anti-PD-1 antibody in a RENCA syngeneic mouse tumor model.

[0196] Figure 2A Shows the MEAN±SEM of tumor growth of RENCA cells in each treatment group.

[0197] Figure 2B Shows the tumor volume data on day 21.

[0198] Figure 3A and 3B Shows 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.

[0199] Figure 3A Shows the MEAN±SEM of tumor growth of OVCAR3 cells in each treatment group.

[0200] Figure 3B Shows the tumor size data on day 27.

[0201] Figure 4A and 4B Shows 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.

[0202] Figure 4A Shows the MEAN±SEM of tumor growth of DU145 cells in each treatment group.

[0203] Figure 4B Shows the tumor size data on day 26.

[0204] Figure 5A and 5B Shows the effect of combined treatment with a CDK7 inhibitor and fulvestrant in a xenograft model derived from the MCF7 breast cancer cell line.

[0205] Figure 5AShows the MEAN±SEM of MCF7 cell tumor growth in each treatment group.

[0206] Figure 5B Shows the tumor volume data on day 28.

[0207] Figure 6 Shows the average percentage of g-H2AX-positive OVCAR3 cells treated with the combination of compound 47 and cisplatin.

[0208] Figure 7 shows PC3 cells g-H2AX ( Figures 7A to 7C ) or 53BP1 ( Figures 7D to 7F ) average granule number treated with the combination of compound 47 and X-ray radiation. Example

[0209] Example 1. Effect of CDK7 inhibitor on RENCA cells

[0210] Cell viability assay

[0211] RENCA renal adenocarcinoma was treated with different concentrations of compound 47 for 72 hours. Cell viability was measured using the CellTiter-Glo assay system (Promega). Luminescence units were normalized to the luminescence units of untreated cells and presented as a percentage of cell viability. The IC 50 . Figure 1A Shows the effect of compound 47 on RENCA cell viability. Compound 47 inhibited the growth of RENCA cells in a dose-dependent manner with an IC 50 of 20 nM.

[0212] Target occupancy assay

[0213] RENCA cells were treated with compound 47 at different concentrations for 4 hours. The cells were washed twice with ice-cold PBS and then lysed with 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 mixture (Sigma-Aldrich). The lysed cells were centrifuged at 12,000 rpm for 10 minutes at 4 °C, and then 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 (Bio-compound 3; biotinylated analogue of compound 47) and then immunoprecipitated with streptavidin agarose beads. The pulled-down proteins were eluted, loaded onto SDS-PAGE, transferred to a PVDF membrane (MilliporeSigma), and then treated with an anti-CDK7 antibody. The CDK7 protein was detected by an HRP-conjugated secondary antibody. Images were obtained by ImageQuantTM LAS4000. Figure 1B Compound 47 was shown to occupy CDK7 in a dose-dependent manner in RENCA cells.

[0214] Immunoblot analysis

[0215] RENCA cells were treated with compound 47 at different concentrations for 48 hours at 37 °C in 5% CO 2 The cells were washed twice with ice-cold PBS, and lysis buffer was added. The cells were collected and kept on ice for 30 minutes. The lysed cells were centrifuged at 12,000 rpm for 10 minutes at 4 °C, and then 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 a PVDF membrane, and then treated with an anti-phospho-H2AX (Ser139) antibody. The phosphorylated form of the H2AX protein was detected by an HRP-conjugated secondary antibody, and the signal was obtained using a Super Signal Western blot enhancer. Images were acquired by ImageQuantTM LAS 4000. Figure 1C The effect of compound 47 on the phosphorylated form of histone variant H2AX, a marker of the early cellular response to DNA double-strand breaks, was shown. Compound 47 induced phosphorylation of H2AX at the serine-139 residue in a dose-dependent manner, indicating that compound 47 induces DAN double-strand breaks in RENCA cells by blocking the homologous recombination repair and DNA mismatch repair pathways.

[0216] Example 2. Effect of the combination of a CDK7 inhibitor and anti-PD1 in a mouse model of RENCA syngeneic renal tumors

[0217] RENCA cells (1x10 5 ) were subcutaneously implanted into the right flank of BALB / c mice. The tumor-bearing mice were randomized and then, when the average tumor volume reached 31 mm 3 , they were treated with compound 47 (10 mg / kg, intraperitoneal injection daily), anti-PD-1 antibody (10 mg / kg, intraperitoneal injection twice a week, clone: RMP1-14, Bio X Cell), or both compound 47 and anti-PD-1 antibody simultaneously (N = 7 or 8 per group). Control mice were treated with vehicle and rat IgG2a isotype control antibody (clone: 2A3, Bio X Cell). Tumor volume and body weight were measured twice a week. Figure 2A RENCA tumor cell growth in each treatment group is shown. The tumor growth inhibition rate (TGI) in the compound 47 treatment group was 50.2%, while that in the anti-PD-1 treatment group was 13.2% TGI. However, the combination of compound 47 and anti-PD-1 antibody increased the TGI (66%).

[0218] Figure 2B Tumor volume on day 21 is shown. On day 21, the tumor volume was significantly reduced in the group treated with the combination of compound 47 and anti-PD-1 antibody.

[0219] Example 3. Effect of the combination of a CDK7 inhibitor and olaparib in a xenograft model derived from the OVCAR3 high-grade serous ovarian cancer cell line

[0220] OVCAR3 cells (1x10 7 ) were mixed with Matrigel (50:50) and subcutaneously implanted into the right flank of female BALB / c nude mice. The tumor-bearing mice were randomized and then, when the average tumor volume reached 173 mm 3 , they were treated with compound 47 (3 mg / kg, intraperitoneal injection daily), olaparib (100 mg / kg, oral administration daily), or both compound 47 and olaparib simultaneously (N = 8 per group). Tumor volume and body weight were measured twice a week. Figure 3A OVCAR3 tumor cell growth in each treatment group is shown. Treatment with compound 47 induced a 36% TGI, and the olaparib treatment group showed a 38% TGI. However, the combination of compound 47 and olaparib increased the TGI (65%). Figure 3B Tumor volume on day 27 is shown. On day 27, treatment with the combination of compound 47 and olaparib significantly reduced the tumor volume compared to olaparib alone or compound 47 alone.

[0221] Example 4. Effect of the combination of a CDK7 inhibitor and docetaxel in a xenograft model derived from the DU145 castration-resistant prostate cancer cell line

[0222] DU145 cells (1x10 7 ) were mixed with Matrigel (50:50) and subcutaneously implanted into the right flank of male BALB / c nude mice. The tumor-bearing mice were randomized and then, when the average tumor volume reached 154 mm 3 , they were treated separately with compound 47 (3 mg / kg, intraperitoneal injection daily), docetaxel (15 mg / kg, intraperitoneal injection once a week), or both compound 47 and docetaxel simultaneously (N = 8 per group). Tumor volume and body weight were measured twice a week. Figure 4A DU145 tumor cell growth in each treatment group is shown. Treatment with compound 47 induced 61% TGI, and the docetaxel treatment group showed 25% TGI. However, the combination of compound 47 and docetaxel increased the TGI (81%). Figure 4B Tumor volume measurements on day 26 are shown. On day 26, the tumor size was significantly reduced in the group treated with the combination of compound 47 and docetaxel compared to docetaxel alone.

[0223] Example 5. Effect of the combination of a CDK7 inhibitor and fulvestrant in an MCF7 human breast cancer xenograft model

[0224] MCF7 cells (1x10 7 ) were mixed with Matrigel (50:50) and subcutaneously implanted into the right flank of female BALB / c nude mice. The tumor-bearing mice were randomized and then, when the average tumor volume reached 117 mm 3 , they were treated separately with compound 47 (3 mg / kg, intraperitoneal injection daily), fulvestrant (2.5 mg / dose, subcutaneous injection daily), or both compound 47 and fulvestrant simultaneously (N = 8 per group). Tumor volume and body weight were measured twice a week. Figure 5A MCF7 tumor cell growth in each treatment group is shown. The compound 47 treatment group and the fulvestrant treatment group showed 81% TGI, respectively. However, the combination of compound 47 and fulvestrant increased the TGI (101%). Figure 5B Tumor size on day 28 is shown. On day 28, the tumor volume was reduced in the group treated with the combination of compound 47 and fulvestrant compared to the group treated with compound 47 alone or the group treated with fulvestrant alone.

[0225] Example 6. Combined effect of a CDK7 inhibitor and cisplatin in the OVCAR3 human high-grade serous ovarian cancer cell line

[0226] OVCAR3 cells were treated with DMSO or 100 nM cisplatin for 24 h. Then the cells were washed with medium and treated with compound 47 at different concentrations. Cells were collected at 24 h, 48 h, and 72 h after cisplatin washout and then stained with 4′,6-diamidino-2-phenylindole (DAPI) and anti-phospho-histone H2AX (Ser129). g-H2AX foci in the nucleus were identified by Alexa-568 staining. Fluorescent images of g-H2AX foci were captured using a confocal imaging system CQ1 (x40 objective). Figure 6 The mean percentage ± SD of g-H2AX positive cells was shown, and it was obvious that compound 47 increased the percentage of g-H2AX foci in a time- and dose-dependent manner, indicating that compound 47 maintained the DNA damage induced by cisplatin treatment.

[0227] Example 7. Combinatorial effect of a CDK7 inhibitor and X-ray irradiation in the PC3 human castration-resistant prostate cancer cell line

[0228] PC3 cells were treated with DMSO or different concentrations of compound 47 for 1 h. Then, using a Faxitron specimen radiography system, the cells were irradiated with X-rays at 225 kV, 17.7 mA for 5 min (8 Gy, 4 Gy, and 2 Gy radiation, respectively, Figures 7A-7C and 7D-7F). Cells were collected at 1 h, 4 h, 6 h, 24 h, and 48 h after X-ray irradiation and stained with HOECHST and anti-phospho-histone H2AX (Ser129) or 53BP1. g-H2AX or 53BP1 foci in the nucleus were identified with Alexa Flour488. Fluorescent images of the foci were obtained using an Opera Phenix 3 high-content screening system (x40 objective), and the mean number of particles ± SD of g-H2AX ( Figures 7A to 7C ) or 53BP1 ( Figures 7D to 7F ) per cell was determined using MetaXpress software. As Figures 7A to 7F shown, compound 47 showed a significant DNA damage maintenance effect at 24 h after X-ray irradiation in a manner depending on the irradiation dose or compound concentration.

Claims

1. A combination of a cyclin-dependent kinase 7 inhibitor and an anti-cancer agent different from the cyclin-dependent kinase 7 inhibitor, wherein the cyclin-dependent kinase 7 inhibitor is a compound having the general formula I wherein X is independently selected from CH and N each time it appears; Q is absent or is independently selected, each time it appears, from the group consisting of -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 )-; Y is independently selected, each time it appears, from the group consisting of halogen, C1-C3 haloalkyl, C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclic group, -S(=O) 2 R 4 , C1-C6 alkyl and C1-C6 alkyl substituted by one or two substituents selected from -OR 6 , -N(R 6 )R 6 , aryl, heteroaryl and heterocyclic group; wherein the C3-C8 cycloalkyl is optionally substituted by one or two of R 4 , R 5 and -(C═O)R 6 , wherein the heterocyclic group is optionally substituted by one or two of R 4 , R 5 and -(C═O)R 6 , and wherein the aryl or heteroaryl is optionally substituted by one or two of R 4 , C1-C6 alkyl, -OR 6 , -N(R 6 )R 6 , -(C═O)R 6 , halogen, heteroaryl and heterocyclic group; R 1 Each occurrence is independently selected from the group consisting of halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -CN, -(C=O)CH 3 and C1-C3 haloalkyl, any of which is optionally substituted; R 2 independently selected from any structure of the following Group A each time it appears: Group A wherein m is independently selected from 1, 2, and 3 each time it appears; W is any structure of the following Group B; Group B L is absent or is independently selected from the group consisting of -O- and -NH- each time it appears; wherein n is independently selected from 1, 2, and 3 each time it appears; R 3 independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR 6 , -CN and C1-C6 alkyl substituted by -OH, -OR 6 or -NHR 6 each time it appears; R 4 is absent or, each occurrence independently, is selected from the group consisting of 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, heterocyclic group, C1-C6 alkyl, and C1-C6 alkyl substituted with -OR 6 , -NH 2 or S(=O) 2 N(R 6 )R 6 ; R 5 independently selected from the group consisting of hydrogen, halogen, C1-C3 haloalkyl, -CN, -OR 6 , -N(R 6 )R 6 , (=O), S(=O) 2 N(R 6 )R 6 , aryl, heteroaryl, heterocyclic group, C1-C6 alkyl and C1-C6 alkyl substituted by -OH, -NH 2 or S(=O) 2 N(R 6 )R 6 ; each occurrence wherein R 4 and R 5 are both (=O), if they are attached to a single sulfur atom forming part of Y and Y is a heterocycle; or wherein R 4 and R 5 together with the structures 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 any one of an aromatic ring, a heteroaromatic ring, and a saturated or unsaturated heterocyclic ring; R 6 Independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, heteroaryl, heterocyclic group, halogen, -OR 7 , -N(R 7 )R 7 , C1-C6 alkyl, and heteroaryl substituted with one or two of -OH, -NH 2 -substituted C1-C6 alkyl; halogen, -OR 7 , -N(R 7 )R 7 , C1-C6 alkyl, and heterocyclic group substituted with -OH or -NH 2 -substituted C1-C6 alkyl each time it appears; R 7 independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl and W as defined above each time it appears; R 8 independently selected from hydrogen and W as defined above each time it appears; wherein if R 7 is W, then R 8 is hydrogen; R 9 independently selected from hydrogen and W as defined above each time it appears; R 10 each occurrence independently is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH 2 , -OR 6 , -CN and W as defined above; Wherein if R 10 is W, then R 8 is hydrogen; R 11 independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C3 haloalkyl each time it appears; R 12 each occurrence independently is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH 2 , -OR 6 and -CN; R 13 independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl and W as defined above each time it appears; wherein if R 13 is W, then R 9 is hydrogen; R 14 and R 15 each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR 6 , heterocyclic group, and -CN each time it appears; R 16 Each occurrence is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R 6 ) 2 , -NR 13 R 14 , -NR 13 CH 2 (CO)NH 2 , heterocyclic group, -OR 6 and -CN; or an enantiomer, stereoisomeric form, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate, or pharmaceutically acceptable salt of the above compound.

2. The combination according to claim 1, wherein the anti-cancer agent is selected from a) targeted specific compounds selected from the group consisting of immune checkpoint inhibitors, especially monoclonal antibodies and antibody fragments against immune checkpoints; poly ADP ribose polymerase (PARP) inhibitors; monoclonal antibodies and antibody fragments not against 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 targeting chimera compounds (PROTAC); siRNA; antibody-drug conjugates (ADC); antibody-siRNA conjugates (ARC); DNA damage response inhibitors; and targeted specific fusion proteins; and b) cytotoxic non-specific compounds selected from taxanes, alkylating agents, nucleoside analogs, folic acid antagonists, topoisomerase inhibitors, anthracyclines, podophyllotoxins, vinca alkaloids, and platinum compounds; c) hormonal anti-cancer agents selected from hormones; hormone antagonists; hormone receptor antagonists; hormone receptor degraders; and aromatase inhibitors; wherein, preferably, the hormone is selected from medroxyprogesterone; anastrozole, letrozole, exemestane; megestrol acetate; raloxifene; estramustine; gonadotropin-releasing hormones such as leuprolide, goserelin, triptorelin, histrelin, abarelix; androgens such as testolactone, fluoxymesterone; anti-androgens such as enzalutamide, bicalutamide, apalutamide, darolutamide, nilutamide, flutamide; and wherein, preferably, the hormone antagonist is selected from gonadotropin-releasing hormone antagonists such as degarelix; and wherein, preferably, the hormone receptor antagonist is selected from fulvestrant, tamoxifen, toremifene; and Among them, preferably, the hormone receptor degrader is selected from selective estrogen receptor degrader and selective androgen receptor degrader; more preferably, selected from giredestrant, amcenestrant, fulvestrant, AZD9833, rintodestrant, LSZ102, LY3484356, elacestrant, ZN-c5, D-0502, SHR9549 and bavdegalutamide; And among them, preferably, the aromatase inhibitor is selected from anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, testolactone and aminoglutethimide; and d) Radiopharmaceuticals.

3. The combination according to any one of claims 1 to 2, wherein, the combination is a composition, wherein the cyclin-dependent kinase 7 inhibitor and the anti-cancer agent are present together, physically mixed with each other or separated from each other by at least one physical isolation barrier between the cyclin-dependent kinase 7 inhibitor and the anti-cancer agent, wherein the at least one physical isolation barrier forms part of the combination, for example, wherein the cyclin-dependent kinase 7 inhibitor and the anti-cancer agent 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. The combination according to 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 against immune checkpoints; poly ADP ribose polymerase (PARP) inhibitors; other monoclonal antibodies not against immune checkpoints; tyrosine kinase inhibitors; DNA damage response inhibitors; and target-specific compounds of antibody-cytokine fusion proteins.

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

6. The combination according to claim 5, wherein, The targeted specific compound is selected from anti-human-PD1 antibodies, especially pembrolizumab, nivolumab, cemiplimab, spartalizumab, atezolizumab, avelumab, durvalumab, ipilimumab, tremelimumab, relatlimab, bevacizumab, ramucirumab, cetuximab, panitumumab, pertuzumab, trastuzumab, ado-trastuzumab emtansine, alemtuzumab, gemtuzumab, gemtuzumab ozogamicin, brentuximab vedotin, polatuzumab vedotin, ibritumomab, ibritumomab tiuxetan, rituximab, ofatumumab, tositumomab, ocrelizumab, pidilizumab, toripalimab, sintilimab, camrelizumab, tislelizumab, sepacatlizumab, palovarotene, dostarlimab; wherein, preferably, the targeted specific compound is pembrolizumab.

7. The combination according to claim 4, wherein, the targeted specific compound is selected from: poly(ADP-ribose) polymerase (PARP) inhibitors, especially olaparib, pamiparib and niraparib; tyrosine kinase inhibitors, especially afatinib, aflibercept, axitinib, bosutinib, cabozantinib, ceritinib, crizotinib, dasatinib, erlotinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, nilotinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, anlotinib, apatinib, osimertinib and alectinib; MEK inhibitors, especially cobimetinib and trametinib; KRAS inhibitors, especially sotorasib and adagrasib; c-MET inhibitors, especially savolitinib; FGFR inhibitors, especially erdafitinib, pemigatinib and votioxazumab; DNA damage response inhibitors selected from WEE1 inhibitors and ATR inhibitors, especially adavosertib, berzosertib and volasertib.

8. The combination according to any one of claims 1-3, wherein the anti-cancer agent is a cytotoxic non-specific compound selected from the following: a) taxanes, preferably selected from docetaxel, cabazitaxel and paclitaxel; b) alkylating agents, preferably selected from bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, fotemustine, ifosfamide, lomustine, melphalan, streptozocin 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) folic acid antagonists, 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) Podophyllotoxin, 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, iproplatin and lobaplatin.

9. The combination according to any one of the preceding claims, wherein the compound is a compound having the general formula Ia wherein X is independently selected from CH and N at each occurrence; Y 1 each independently selected from CH, C(OH), and N each time it appears; Y 2 each independently selected from CH, C(OH), and N each time it appears; Q is absent or, independently at each occurrence, is selected from the group consisting of -NH-, -NH(CH 2 )-, -NH(C=O)-, -NHSO 2 -, -O-, -O(CH 2 )-, -(C=O)- and -(C=O)(CH 2 )-; R 1 Each occurrence is independently selected from the group consisting of halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -CN, -(C=O)CH 3 and C1-C3 haloalkyl, any of which is optionally substituted; R 2 any structure independently selected from the following group A each time it appears, Group A where m = 1, 2 or 3; W is any structure of the following Group B'; Group B' L is absent or is independently selected from the group consisting of -O- and -NH- at each occurrence; R 3 independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR 6 , -CN and C1-C6 alkyl substituted by -OH, -OR 6 or -NHR 6 each time it appears; R 4 is absent or, each time it appears, is independently selected from the group consisting of 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, heterocyclic group, C1-C6 alkyl, and C1-C6 alkyl substituted with -OR 6 , -NH 2 or S(=O) 2 N(R 6 )R 6 ; R 5 independently selected from the group consisting of hydrogen, halogen, C1-C3 haloalkyl, -CN, -OR 6 , -N(R 6 )R 6 , (=O), S(=O) 2 N(R 6 )R 6 , aryl, heteroaryl, heterocyclic group, C1-C6 alkyl and C1-C6 alkyl substituted with -OH, -NH 2 or S(=O) 2 N(R 6 )R 6 at each occurrence; wherein R 4 and R 5 are both (=O), if they are attached to a single sulfur atom forming part of Y and Y is a heterocycle; or wherein R 4 and R 5 together with the structures 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 any one of an aromatic ring, a heteroaromatic ring, and a saturated or unsaturated heterocyclic ring; R 6 Each occurrence is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, heteroaryl, heterocyclic group, halogen, -OR 7 , -N(R 7 )R 7 , C1-C6 alkyl, and heteroaryl substituted with one or two of -OH, -NH 2 ; heterocyclic group substituted with halogen, -OR 7 , -N(R 7 )R 7 , C1-C6 alkyl, and C1-C6 alkyl substituted with -OH or -NH 2 ; R 7 independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, and W as defined above, each time it appears; R 8 independently selected from hydrogen and W as defined above at each occurrence; Wherein if R 7 is W, then R 8 is hydrogen; R 9 independently selected from hydrogen and W as defined above each time it appears; R 10 independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH 2 , -OR 6 , -CN and W as defined above, each time it appears; Wherein if R 10 is W, then R 8 is hydrogen; R 11 independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C3 haloalkyl each time it appears; R 12 each occurrence independently is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH 2 , -OR 6 and -CN; R 13 independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, and W as defined above each time it appears; Wherein if R 13 is W, then R 9 is hydrogen; R 14 and R 15 each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR 6 , heterocyclic group, and -CN each time it appears; R 16 Independently at each occurrence, selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R 6 ) 2 , -NR 13 R 14 , heterocyclic group, -OR 6 and -CN; or an enantiomer, stereoisomeric form, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate or pharmaceutically acceptable salt of the above compound.

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

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

12. The combination according to any one of the preceding claims, wherein R 2 is 13. The combination according to claim 12, wherein 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 are each independently hydrogen, halogen or C1-C6 alkyl each time they appear, wherein, Preferably, R 14 is a halogen; wherein, R 16 is hydrogen, a halogen, a C1-C6 alkyl group, -N(R 6 ) 2 , -NR 13 R 14 , wherein, preferably, R 16 is -N(R 6 ) 2 or -NR 13 R 14 .

14. The combination according to any one of the preceding claims, wherein the compound is a compound having a structure selected from Structures 1 - 198 as defined in the column headed "Structure" of Table 1 of the specification.

15. The combination according to any one of the preceding claims, wherein the compound is a compound having a structure selected from Compounds 3, 14, 47 and 156 as defined in Claim 14.

16. The combination according to any one of the preceding claims, for use in a method for preventing and / or treating cancer in a patient suffering from or suspected of suffering from cancer.

17. The combination according to the use of Claim 16, wherein the method of prevention and / or treatment comprises administering to a patient suffering from or suspected of suffering from cancer an effective amount of the cyclin - dependent kinase 7 inhibitor and an effective amount of the anti - cancer agent.

18. The combination according to the use of any one of Claims 16 - 17, wherein, in the method of prevention and / or treatment, the cyclin - dependent kinase 7 inhibitor is administered before or after the anti - cancer agent is administered to the patient, or wherein both the cyclin - dependent kinase 7 inhibitor and the anti - cancer agent are administered to the patient simultaneously or synchronously or in a temporally overlapping manner, or wherein the cyclin - dependent kinase 7 inhibitor is administered adjunctively to the anti - cancer agent to the patient, or wherein the anti - cancer agent is administered adjunctively to the cyclin - dependent kinase 7 inhibitor to the patient.

19. The combination according to the use of any one of Claims 16 - 18, wherein the method of prevention and / or treatment comprises administering the combination in combination with radiotherapy.

20. The combination according to the use of any one of Claims 16 - 19, wherein, The cancer is a cancer selected from or consisting of the group consisting of: renal cell carcinoma, kidney cancer, hereditary papillary renal carcinoma, sporadic papillary renal carcinoma, 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 neuroma, ampullary cancer, anal cancer, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer, bronchial cancer, estrogen-dependent and non-estrogen-dependent breast cancers, Burkitt lymphoma, corpus cancer, cancer of unknown primary site (CUP-syndrome), small intestine cancer, small intestine tumor, ovarian cancer, endometrial cancer, ependymoma, epithelial cancer type, Ewing sarcoma, gastrointestinal tumor, gastric cancer, gallbladder cancer, gallbladder carcinoma, uterine cancer, cervical cancer, cervix, glioblastoma, gynecological tumor, ENT tumor, hematological tumor, hairy cell leukemia, urethral cancer, skin cancer, skin testicular cancer, brain tumor (glioma), brain metastasis, testicular cancer, pituitary tumor, carcinoid, Kaposi sarcoma, laryngeal cancer, germ cell tumor, bone cancer, head and neck cancer (tumors in the ear, nose, and throat area), colon cancer, craniopharyngioma, oral cancer (cancers in the oral cavity and lips), central system tumor, liver cancer, liver metastasis, leukemia, eyelid tumor, lung cancer, lymphoma, gastric cancer, malignant melanoma, malignant tumor, gastrointestinal malignant tumor, breast cancer, rectal cancer, medulloblastoma, meningioma, Hodgkin / non-Hodgkin lymphoma, mycosis fungoides, nasal cavity cancer, schwannoma, neuroblastoma, oligodendroglioma, osteolytic cancer and osteoblastic cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, plasmacytoma, prostate cancer, pharyngeal cancer, rectal cancer, retinoblastoma, vaginal cancer, thyroid cancer, T cell lymphoma, thymoma, ductal cancer, eye tumor, urethral cancer, urinary system tumor, urothelial carcinoma, vulvar cancer, wart, soft tissue tumor, soft tissue sarcoma, nephroblastoma, cervical cancer, tongue cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, lobular carcinoma in situ, small cell lung cancer, non-small cell lung cancer, bronchial adenoma, pleuropulmonary blastoma, mesothelioma, brainstem glioma, hypothalamic glioma, cerebellar astrocytoma, cerebral astrocytoma, neuroectodermal tumor, pineal tumor, uterine sarcoma, salivary gland adenocarcinoma, anal adenocarcinoma, 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 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, angiosarcoma, hemangiopericytomaLeiomyosarcoma (LMS), canine breast cancer, and feline breast cancer.

21. A cyclin - dependent kinase 7 inhibitor having the general formula I as defined in any one of Claims 1, 9 - 15, for use in a method for preventing and / or treating cancer, wherein, in the method, the cyclin - dependent kinase 7 inhibitor is administered to a patient suffering from or suspected of suffering from cancer, and wherein the administration of the cyclin - dependent kinase 7 inhibitor to the patient is carried out in combination with the administration of radiotherapy.

22. A method for preventing and / or treating cancer in a patient, the 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, the combination being defined as in any one of claims 1-15.

23. Use of the combination according to any one of claims 1 to 15 in the manufacture of a medicament for preventing and / or treating cancer in a patient.

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

Images