Compounds and uses thereof

Abstract

Relates to a compound CDK4 / 6 inhibitor for targeted delivery to the gastrointestinal tract. The invention also relates to pharmaceutical compositions comprising such compounds, methods of using the compounds for treating, preventing or ameliorating side effects of the gastrointestinal tract caused by chemotherapy, and processes and intermediates for preparing such compounds.

Description

Compounds and uses thereof Technical Field

[0001] The present application relates to the field of biomedicine, and specifically to a CDK4 / 6 inhibitor and its use. Background Art

[0002] CDK (cyclin-dependent kinase) inhibitors have therapeutic potential for a variety of diseases, including cancer, diabetes, kidney disease, neurodegenerative diseases, infectious diseases, tumors, and side effects of cancer treatment. Oral administration of CDK inhibitors with systemic exposure often causes side effects such as neutropenia, leukopenia, and anemia.

[0003] Gastrointestinal side effects caused by chemotherapy are common adverse reactions in cancer treatment and significantly affect the survival and mortality rates of cancer patients. Gastrointestinal side effects caused by chemotherapy include diarrhea, constipation, nausea, vomiting, oral and small intestinal mucositis, colitis, proctitis, loss of appetite, etc. These gastrointestinal side effects reduce the patient's chance of recovery because it makes it difficult for patients to obtain the nutrition they need to optimize their ability to fight the disease. Because patients often find it difficult to tolerate these complications, gastrointestinal side effects caused by chemotherapy often lead to dose reductions, interruptions, or changes in treatment regimens, which in turn affect patient prognosis and overall survival.

[0004] For example, conventional chemotherapy regimens such as fluorouracil and irinotecan are reported to cause diarrhea in up to 50-80% of patients. (Stein, Ther. Adv. Med. Oncol. 2010, 2, 51-63; McQuade et al., Front Pharmacol. 2016, 7, 414.) Literature indicates that chemotherapy-induced diarrhea (CID) leads to treatment changes in approximately 60% of colorectal cancer patients, including dose reductions, treatment delays, and drug discontinuation. (Arbuckle et al., Oncologist 2000, 5, 250-9; Dranisaris et al., Can. J. Gastroenterol. 2005, 19, 83-7).

[0005] Current clinical guidelines recommend using loperamide first to control CID symptoms, but loperamide is less effective for treating severe diarrhea. For severe diarrhea (grade 3-4), the consensus is to use octreotide. Other treatments, such as budesonide, probiotics, or antibiotics, have not been shown to be effective in preventing or alleviating CID.

[0006] Although the incidence of chemotherapy-induced constipation (CIC) is difficult to estimate, it is reported to affect approximately 16% of cancer patients, and increasing evidence suggests that CIC significantly impacts patients' quality of life. Currently, therapeutic interventions for managing CIC include oral and / or rectal bulking, softening, osmotic, stimulant, and lubricating laxatives.

[0007] Overall, current treatments for CIC and CID aim to alleviate symptom severity rather than combat the underlying pathological mechanisms (Andreyev et al., Lancet Oncol. 2014, 15, e447-e60; McQuade et al., Front Pharmacol, 2016, 7, 414). A better mechanism for reducing gastrointestinal side effects in these patients would be to protect the primary lesions in the gastrointestinal epithelium and reduce the sensitivity of normal cells to chemotherapeutic drugs.

[0008] Therefore, there is an urgent need to develop effective drugs that can effectively treat, prevent or alleviate chemotherapy-induced gastrointestinal side effects, such as CIC and CID, while reducing damage to the gastrointestinal tract or other parts of the body; at the same time, the compounds have their effects at the site of action without significant systemic effects, and can be administered orally to achieve therapeutically relevant exposure in the gastrointestinal tract with minimal systemic exposure.

[0009] Summary of the Invention

[0010] The present application provides a CDK inhibitor. The CDK inhibitor is a CDK4 / 6 inhibitor. The CDK inhibitor is a compound shown in formula (I), a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof. In the present application, the compound of formula (I) has properties that are different from other CDK4 / 6 inhibitors, and the concentration of the compound in the gastrointestinal tissue is much higher than the concentration of CDK4 / 6 inhibitors in the blood. This property is conducive to playing a therapeutic role in the gastrointestinal tract while greatly reducing the physiological effects of CDK4 / 6 inhibitors on systemic systems other than the gastrointestinal tract, and the related side effects caused by them. Ultimately, only the gastrointestinal tract is treated, no additional physiological effects are produced on the human body, and the safety of medication is improved.

[0011] In one aspect, the present application provides a compound of formula (I), a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof,

[0012] in,

[0013] n is 1, 2 or 3,

[0014] R1 is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl;

[0015] R2, R3, R4, and R5 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted alkenyl;

[0016] Or any two groups among R2, R3, R4 and R5 are connected to form a ring.

[0017] In certain embodiments, the substitution comprises heteroatom substitution.

[0018] In certain embodiments, the substitution includes alkyl, cycloalkyl, and alkenyl substitution.

[0019] In certain embodiments, R2, R3, R4, and R5 are each independently selected from: 1-10 Substituted or unsubstituted alkyl, C 1-10 Substituted or unsubstituted cycloalkyl, C 1-10 Substituted or unsubstituted alkenyl.

[0020] In certain embodiments, R2, R3, R4, and R5 are each independently selected from C 1-5 a substituted or unsubstituted alkyl group.

[0021] In certain embodiments, each R4 is the same or different.

[0022] In certain embodiments, each R5 is the same or different.

[0023] In certain embodiments, any two groups among R2, R3, R4 and R5 are linked to form an alkane ring.

[0024] In certain embodiments, the compound of formula (I) comprises a structure selected from the group consisting of:

[0025] as well as

[0026] In certain embodiments, the R1 is selected from: C 1-10 Substituted or unsubstituted alkyl, C 1-10 Substituted or unsubstituted cycloalkyl, C 1-10 a substituted or unsubstituted alkenyl group.

[0027] In certain embodiments, the R1 is a substituted or unsubstituted cycloalkyl group.

[0028] In certain embodiments, the R1 is cyclopentyl.

[0029] In certain embodiments, n is 1.

[0030] In certain embodiments, n is 2.

[0031] In certain embodiments, n is 3.

[0032] In certain embodiments, the compound of formula (I) comprises a structure selected from the group consisting of:

[0033] as well as

[0034] In certain embodiments, the compound, its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer is a cyclin-dependent kinase (CDK) inhibitor.

[0035] In certain embodiments, the CDK inhibitor is a CDK4 / 6 inhibitor.

[0036] In another aspect, the present application provides a method for preparing the compound, its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer.

[0037] In another aspect, the present application provides a composition comprising the compound, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof.

[0038] In certain embodiments, the composition further comprises, optionally, a pharmaceutically acceptable carrier.

[0039] In certain embodiments, the composition further comprises one or more additional active ingredients.

[0040] In certain embodiments, the composition is an oral formulation.

[0041] On the other hand, the present application also provides the compound, its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer, or the use of the composition in the preparation of a medicament for preventing, alleviating and / or treating a disease and / or condition.

[0042] In certain embodiments, the disease and / or condition comprises gastrointestinal side effects associated with chemotherapy.

[0043] In certain embodiments, the chemotherapy comprises administering a chemotherapeutic agent.

[0044] In certain embodiments, the chemotherapeutic agent is a cytotoxic agent.

[0045] In certain embodiments, the chemotherapeutic agent is selected from one or more of the following groups: DNA synthesis inhibitors, RNA synthesis inhibitors, protein synthesis inhibitors, cell division inhibitors, DNA base analogs, topoisomerase inhibitors and / or telomerase synthesis inhibitors.

[0046] In certain embodiments, the chemotherapeutic agent is selected from fluorouracil, oxaliplatin, topotecan, irinotecan, folinic acid, docetaxel, gemcitabine, carboplatin, cisplatin, etoposide, methotrexate, doxorubicin, cytarabine, vinorelbine and capecitabine, and combinations thereof.

[0047] In certain embodiments, the chemotherapeutic agent is administered continuously and / or discontinuously.

[0048] In certain embodiments, the chemotherapy is used in combination with one or more other therapies.

[0049] In certain embodiments, the chemotherapy-related gastrointestinal side effects include gastrointestinal side effects caused by chemotherapy.

[0050] In certain embodiments, the chemotherapy-related gastrointestinal side effects include gastrointestinal adverse events that occur or worsen after administration of a chemotherapeutic agent.

[0051] In certain embodiments, the gastrointestinal adverse event, in the absence of prophylaxis or treatment, occurs or worsens after about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 1 day, about 2 days, about 4 days, about 7 days, about 2 weeks, about 3 weeks, about 1 month, about 2 months, or more after administration of the chemotherapeutic agent.

[0052] In certain embodiments, the gastrointestinal side effects include gastric mucosal damage disease and / or intestinal mucosal damage disease.

[0053] In certain embodiments, the gastrointestinal side effects include diarrhea, abdominal pain, nausea, vomiting, mucositis, loss of appetite, gastric ulcer, gastritis, constipation, enteritis, intestinal perforation, intestinal bleeding, ulcer and / or intestinal necrosis.

[0054] In certain embodiments, the gastrointestinal side effects include diarrhea and / or constipation.

[0055] In certain embodiments, the severity of the gastrointestinal side effect is grade 1 or higher, grade 2 or higher, grade 3 or higher, grade 4 or higher, or grade 5 according to NCI-CTCAE.

[0056] In certain embodiments, the drug does not substantially affect the therapeutic effect of the chemotherapy.

[0057] In certain embodiments, the drug is administered about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, or more prior to administration of the chemotherapy.

[0058] In certain embodiments, the drug is administered about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, or more after administration of the chemotherapy.

[0059] In certain embodiments, the drug is administered concurrently with the chemotherapy.

[0060] In certain embodiments, the drug is administered one or more times.

[0061] In certain embodiments, the medicament is prepared for oral administration, intravenous injection, subcutaneous injection, intraperitoneal injection and / or intramuscular injection.

[0062] In certain embodiments, the medicament is prepared as a tablet and / or capsule.

[0063] On the other hand, the present application provides a method for preventing, alleviating and / or treating a disease and / or condition in a subject, comprising administering to a subject in need thereof the compound, its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer, or the composition.

[0064] In certain embodiments, the disease and / or condition comprises gastrointestinal side effects associated with chemotherapy.

[0065] In certain embodiments, the chemotherapy comprises administering a chemotherapeutic agent.

[0066] In certain embodiments, the chemotherapeutic agent is a cytotoxic agent.

[0067] In certain embodiments, the chemotherapeutic agent is selected from one or more of the following groups: DNA synthesis inhibitors, RNA synthesis inhibitors, protein synthesis inhibitors, cell division inhibitors, DNA base analogs, topoisomerase inhibitors and / or telomerase synthesis inhibitors.

[0068] In certain embodiments, the chemotherapeutic agent is selected from fluorouracil, oxaliplatin, topotecan, irinotecan, folinic acid, docetaxel, gemcitabine, carboplatin, cisplatin, etoposide, methotrexate, doxorubicin, cytarabine, vinorelbine and capecitabine, and combinations thereof.

[0069] In certain embodiments, the chemotherapeutic agent is administered continuously and / or discontinuously.

[0070] In certain embodiments, the chemotherapy is used in combination with one or more other therapies.

[0071] In certain embodiments, the chemotherapy-related gastrointestinal side effects include gastrointestinal side effects caused by chemotherapy.

[0072] In certain embodiments, the chemotherapy-related gastrointestinal side effects include gastrointestinal adverse events that occur or worsen after administration of a chemotherapeutic agent.

[0073] In certain embodiments, the gastrointestinal adverse event, in the absence of prophylaxis or treatment, occurs or worsens after about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 1 day, about 2 days, about 4 days, about 7 days, about 2 weeks, about 3 weeks, about 1 month, about 2 months, or more after administration of the chemotherapeutic agent.

[0074] In certain embodiments, the gastrointestinal side effects include gastric mucosal damage disease and / or intestinal mucosal damage disease.

[0075] In certain embodiments, the gastrointestinal side effects include diarrhea, abdominal pain, nausea, vomiting, mucositis, loss of appetite, gastric ulcer, gastritis, constipation, enteritis, intestinal perforation, intestinal bleeding, ulcer and / or intestinal necrosis.

[0076] In certain embodiments, the gastrointestinal side effects include diarrhea and / or constipation.

[0077] In certain embodiments, the severity of the gastrointestinal side effect is grade 1 or higher, grade 2 or higher, grade 3 or higher, grade 4 or higher, or grade 5 according to NCI-CTCAE.

[0078] In certain embodiments, the drug does not substantially affect the therapeutic effect of the chemotherapy.

[0079] In certain embodiments, the drug is administered about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, or more prior to administration of the chemotherapy.

[0080] In certain embodiments, the drug is administered about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, or more after administration of the chemotherapy.

[0081] In certain embodiments, the drug is administered concurrently with the chemotherapy.

[0082] In certain embodiments, the drug is administered one or more times.

[0083] In certain embodiments, the compound, its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer, or the composition is administered at a dose of about 10-1000 mg / kg.

[0084] In certain embodiments, the subject is a cancer patient.

[0085] In another aspect, the present application provides a kit comprising a compound described herein, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer, or stereoisomer thereof.

[0086] In certain embodiments, the kit further comprises instructions for use of the compound, its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer.

[0087] In certain embodiments, the kit further comprises one or more pharmaceutically acceptable carriers.

[0088] Those skilled in the art can easily discern other aspects and advantages of the present application from the detailed description below. In the detailed description below, only exemplary embodiments of the present application are shown and described. As will be appreciated by those skilled in the art, the content of the present application enables those skilled in the art to modify the disclosed specific embodiments without departing from the spirit and scope of the invention to which the present application relates. Accordingly, the description in the specification of the present application is merely exemplary and not restrictive. DETAILED DESCRIPTION

[0089] The following describes the implementation of the present invention through specific embodiments. People familiar with this technology can easily understand other advantages and effects of the present invention from the contents disclosed in this specification.

[0090] Definition of terms

[0091] In this application, the term "prodrug" is also referred to as "prodrug", and generally refers to an agent or compound that is converted into a parent drug or active drug molecule in vivo. For example, the "prodrug" can be a precursor of another pharmaceutically active molecule, which, after administration to a subject, produces the other pharmaceutically active molecule in vivo through chemical or physiological processes such as solvolysis or enzymatic cleavage, or under physiological conditions.

[0092] As used herein, the term "substituted or unsubstituted alkyl" includes straight or branched chain alkyl groups that do not contain any substituents, and also includes straight or branched chain alkyl groups that contain one or more non-hydrogen substituents. For example, the alkyl group generally includes a saturated aliphatic hydrocarbon group having a specified number of carbon atoms, which may be branched or straight chain. The term "alkyl" also refers to non-aromatic cycloalkyl groups. For example, the alkyl group may have 1-20 carbon atoms (i.e., C1-C 20 ). For example, if "C1-C 10 C1-C 10 It is defined as including groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in a straight chain, branched chain or cyclic arrangement (i.e., cycloalkyl). The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., as well as cycloalkyl, including cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, etc.

[0093] In this application, the term "biologically active metabolite" generally refers to a compound (e.g., a compound of the present application) that is metabolized in the human or animal body or cell and processed in vivo to produce a metabolite. For example, the "biologically active metabolite" may include derivatives of any structural formula produced in an individual after administration of the parent compound. These derivatives may be produced from the parent compound by various biochemical transformations in the individual, such as oxidation, reduction, hydrolysis, or conjugation, and include, for example, oxides and demethylated derivatives. Metabolites of the compounds of the present invention can be identified using conventional techniques known in the art. See, e.g., Bertolini, G. et al., J. Med. Chem. 40:2011-2016 (1997); Shan, D. et al., J. Pharm. Sci. 86(7):765-767; Bagshawe K., Drug Dev. Res. 34:220-230 (1995); Bodor, N., Advances in Drug Res. 13:224-331 (1984); Bundgaard, H., Design of Prodrugs (Elsevier Press 1985); and Larsen, IK, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991). It should be understood that chemical compounds that are metabolites of compounds of formula (I) or their tautomers, prodrugs and stereoisomers, as well as pharmaceutically acceptable salts, esters and prodrugs of any of them, are encompassed by the present application.

[0094] As used herein, the term "pharmaceutically acceptable salt" generally refers to a salt that retains the biological effectiveness and properties of the free base or free acid and is otherwise biologically or otherwise desirable. The salt may be a salt formed with an inorganic acid or an organic acid. In addition, the pharmaceutically acceptable salt may be prepared by adding an inorganic base or an organic base to the free acid.

[0095] In this application, the term "CDK inhibitor" generally refers to any molecule known in the art or discovered in the future that can block, reduce or inhibit the activity or function of CDK (cyclin-dependent kinase), including but not limited to small molecule compounds, polynucleotides (such as DNA or RNA), and / or polypeptides (such as antibodies or antigen-binding portions thereof). CDK inhibitors can act directly on CDK, for example by binding to CDK, or can act indirectly, for example by interfering with the interaction between CDK and its ligand, inhibiting cell cycle proteins (cyclin) or by inhibiting the activity of substrates. CDK is a class of kinases in the protein kinase family that can be used to regulate the cell cycle and is also involved in regulating transcription, mRNA processing and neural cell differentiation. The CDK described in this application can refer to a complete CDK or a kinase domain fragment, and also covers CDKs from various vertebrates (such as humans, monkeys, mice, dogs, rabbits, etc.). CDKs can be divided into different types depending on the cyclin they bind to. For example, there are four CDKs that are clearly involved in cell proliferation: CDK1, which primarily regulates the transition from G2 to M phase, and CDK2, CDK4, and CDK6, which regulate the transition from G1 to S phase.

[0096] In this application, the term "CDK4 / 6 inhibitor" generally refers to an inhibitor that acts on both CDK4 and CDK6 in the CDK family. Among all members of the CDK family, it mainly has an inhibitory effect on CDK4 and CDK6, and does not exclude the possibility of having an inhibitory effect on other CDK family members besides CDK4 and CDK6, nor does it exclude the possibility of having an inhibitory effect on other molecules outside the CDK family. CDK4 / 6 inhibitors are not required to have the same or similar effects on CDK4 and CDK6.

[0097] In this application, the term "chemotherapy" generally refers to a therapy using chemotherapeutic agents to treat tumors, which can cause cancer cell death or interfere with the division, repair, growth and / or function of cancer cells. The agent used in chemotherapy is a chemotherapeutic agent. The chemotherapeutic agent includes a chemical or biological substance that can cause cancer cell death or interfere with the growth, division, repair and / or function of cancer cells. For example, the chemotherapy can include cytotoxic agents, cytostatics and antitumor agents that kill, inhibit the growth of tumor cells or inhibit the metastasis of tumor cells or disrupt the cell cycle of rapidly proliferating cells. Chemotherapeutic agents include natural compounds found in animals and plants, or artificial chemicals. In this application, the chemotherapy or chemotherapeutic agent has low selectivity for tumor cells and normal cells, and therefore can also interfere with the growth, division, repair and / or function of normal cells (such as bone marrow cells, hair follicle cells or digestive tract cells), leading to the death of normal cells.

[0098] In this application, the term "pharmaceutically acceptable" generally refers to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic reaction or other problems or complications within the scope of reasonable medical judgment, with a reasonable benefit / risk ratio. In some embodiments, pharmaceutically acceptable compounds, materials, compositions and / or dosage forms refer to those approved by regulatory agencies (such as the U.S. Food and Drug Administration, the China Food and Drug Administration or the European Medicines Agency) or listed in generally recognized pharmacopoeias (such as the U.S. Pharmacopoeia, the Chinese Pharmacopoeia or the European Pharmacopoeia) for use in animals (more particularly in humans).

[0099] In the present application, examples of chemotherapeutic agents may include, but are not limited to, alkylating agents such as nitrogen mustards, ethyleneimine compounds, alkyl sulfonates, and other compounds with alkylating effects, such as nitrosoureas, cisplatin, and dacarbazine; antimetabolites such as folic acid, purine or pyrimidine antagonists; mitotic inhibitors such as vinca alkaloids and derivatives of podophyllotoxin; cytotoxic antibiotics and camptothecin derivatives. Chemotherapeutic agents may also include amifostine cisplatin, dacarbazine (DTIC), dactinomycin, streptomycin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin, liposomal doxorubicin, gemcitabine, erythromycin, daunorubicin liposomal procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil (5-FU), vinblastine, vincristine, bleomycin, paclitaxel, docetaxel aldesleukin, asparaginase, busulfan, carboplatin, cladribine, camptothecin, CPT-1 1. 10-Hydroxy-7-ethyl-camptothecin (SN38), floxuridine, fludarabine, hydroxyurea, ifosfamide, idarubicin, mesna, interferon alpha, interferon beta, irinotecan, mitoxantrone, topotecan, leuprorelin, megestrol acetate, melphalan, mercaptopurine, plicamycin, mitotane, pegaspargase, pegaspargase, pentostatin, pipobroman, plicamycin, streptozocin, tamoxifen, teniposide, testosterone, thioguanine, thiotepa, uracil mustard, vinorelbine, chlorambucil aromatase inhibitors and combinations thereof.

[0100] In this application, the term "cytotoxic agent" generally refers to an agent that inhibits a biological process in a cell or reduces the viability or proliferative potential of a cell. Cytotoxic agents can act in a variety of ways, for example, but not limited to, by inducing DNA damage, inducing cell cycle arrest, inhibiting DNA synthesis, inhibiting transcription, inhibiting translation or protein synthesis, inhibiting cell division, or inducing apoptosis.

[0101] In the present application, the term "substantially does not affect" generally means that the therapeutic effect of the combination of the drug described in the present application and the chemotherapy is equivalent to, or does not produce a significant disadvantage compared to, the therapeutic effect of the chemotherapy alone. For example, for any subject, the degree of reduction in tumor volume caused by the combination of the drug and the chemotherapy is the same as the therapeutic effect of the chemotherapy alone, or the degree of reduction is not less than about 5%, not less than about 4%, not less than about 3%, not less than about 2%, not less than about 1%, not less than about 0.5%, not less than about 0.1%, not less than about 0.01%, not less than about 0.001% or less.

[0102] In this application, the term "continuous administration" generally refers to repeated administration of the same drug every day. Repeated administration every day can be once a day, twice a day, three times a day or more. For example, continuous administration can be administration once a day, at least for more than 2 days. For example, continuous administration time is 2 days and can refer to administration once a day (2 times, 3 times or more), for 2 days of continuous administration. For example, continuous administration time is 3 days and can refer to administration once a day (2 times, 3 times or more), for 3 days of continuous administration. For example, continuous administration time is 5 days and can refer to administration once a day (2 times, 3 times or more), for 5 days of continuous administration. For example, continuous administration time is 7 days and can refer to administration once a day (2 times, 3 times or more), for 7 days of continuous administration. For example, continuous administration time is 10 days and can refer to administration once a day (2 times, 3 times or more), for 10 days of continuous administration. For example, continuous administration time is 14 days and can refer to administration once a day (2 times, 3 times or more), for 14 days of continuous administration. For example, continuous administration for 7 days or more may mean administration once (2 times, 3 times or more) a day for 7 days or more.

[0103] In this application, the term "discontinuous administration" generally refers to a mode of administration in which the same drug is not administered every day during a dosing cycle, and may also be referred to as intermittent administration and / or pulse administration. Discontinuous administration can be regular or irregular. In the case of discontinuous administration, if the dosing cycle is greater than 7 days, for any continuous period of time, if the drug is administered daily and continues for 7 days or more, it also falls under the situation of "continuous administration for 7 days or more".

[0104] In this application, the term "gastrointestinal adverse event" generally refers to a harmful, undesirable reaction, effect, action, result, result or influence related to the gastrointestinal tract or manifested in the gastrointestinal area due to a certain drug or other medical treatment such as chemotherapy or surgery. It can also be called gastrointestinal adverse effect, gastrointestinal adverse effect or gastrointestinal adverse consequence. Gastrointestinal adverse events include adverse events in various parts of the digestive system (such as the digestive tract and glands). For example, gastrointestinal adverse events may include, but are not limited to, abdominal distension, abdominal pain, anal fissure, anal fistula, anal bleeding, anal mucositis, anal necrosis, anal pain, anal stenosis, anal ulcer, ascites, hiccups, cecal bleeding, cheilitis, chylous ascites, colitis, colon fistula, colon bleeding, colon obstruction, colon perforation, colon stenosis, colon ulcer, constipation, dental caries, diarrhea, dry mouth, duodenal fistula, duodenal bleeding, duodenal obstruction, duodenal perforation , Duodenal stenosis, Duodenal ulcer, Indigestion, Dysphagia, Enterocolitis, Intestinal fistula, Esophageal fistula, Esophageal bleeding, Esophageal necrosis, Esophageal obstruction, Esophageal pain, Esophageal perforation, Esophageal stenosis, Esophageal ulcer, Esophageal variceal bleeding, Esophagitis, Fecal incontinence, Flatulence, Gastric fistula, Gastric bleeding, Gastric necrosis, Gastric perforation, Gastric stenosis, Gastric ulcer, Gastritis, Gastroesophageal reflux disease, Gastrointestinal disease - other, please specify, Gastrointestinal fistula, Gastrointestinal pain, gastroparesis, gum pain, hemorrhoidal bleeding, hemorrhoids, ileal fistula, ileal bleeding, ileal obstruction, ileal perforation, ileal stenosis, ileal ulcer, ileus, intra-abdominal bleeding, jejunal fistula, jejunal bleeding, jejunal obstruction, jejunal perforation, jejunal stenosis, jejunal ulcer, lip pain, lower gastrointestinal bleeding, malabsorption, oral mucositis, nausea, gastric obstruction, oral fistula, oral dysesthesia, oral bleeding, oral pain, pancreatic duct stenosis, pancreatic fistula, pancreatic bleeding, pancreas Necrosis, pancreatitis, periodontal disease, peritoneal necrosis, proctitis, rectal fissure, rectal fistula, rectal bleeding, rectal mucositis, rectal necrosis, rectal obstruction, rectal pain, rectal perforation, rectal stenosis, rectal ulcer, retroperitoneal bleeding, salivary duct inflammation, salivary gland fistula, small intestinal mucositis, small intestinal obstruction, small intestinal perforation, small intestinal stenosis, small intestinal ulcer, abdominal pain, tooth development disorder, tooth discoloration, toothache, appendicitis, upper gastrointestinal bleeding, visceral artery ischemia, vomiting.

[0105] In this application, the term "gastrointestinal side effects" generally refers to harmful and adverse effects related to the gastrointestinal tract or manifested in the gastrointestinal area caused by a prophylactic or therapeutic drug. Adverse effects are often undesirable, but undesirable effects are not necessarily adverse. The adverse effects of a prophylactic or therapeutic drug may be harmful, uncomfortable or dangerous. Gastrointestinal side effects include side effects of various parts of the digestive system (such as the digestive tract and glands). Gastrointestinal side effects associated with chemotherapy can refer to any abnormal clinical manifestations of the gastrointestinal tract that are temporally associated with the use of chemotherapeutic agents, and these abnormal manifestations may not have a causal relationship with the administration of chemotherapeutic agents.

[0106] In the present application, the term "gastric mucosal injury disease" generally refers to a disease or condition with symptoms of gastric mucosal injury, which may include abnormal gastric mucosal color, bleeding spots, congestion and erosion.

[0107] In this application, the term "intestinal mucosal injury disease" generally refers to a disease or condition with symptoms of intestinal mucosal injury, which may include abnormal intestinal mucosal color, bleeding spots, congestion and erosion.

[0108] In the present application, the term "diarrhea" generally refers to a disease or condition characterized by increased frequency of intestinal motility and / or loose or watery intestinal motility. In the present application, the diarrhea may occur or worsen after the administration of the chemotherapeutic agent. In some cases, reference may also be made to the rating of diarrhea in animal experiments: the severity of diarrhea may be scored using the Akinobu Kurita method (Cancer Chemother Pharmacol 2000; 46: 211-20.), wherein Grade 0: normal stool; Grade 1: mild diarrhea, with slightly soft stool; Grade 2: moderate diarrhea, with watery stool and mild perianal staining; Grade 3: severe diarrhea, with watery stool and severe perianal staining.

[0109] In the present application, the term "constipation" generally refers to a disease or condition characterized by irregular, infrequent or difficult bowel movements. In the present application, the constipation may occur or worsen after the administration of chemotherapy.

[0110] In the present application, the term "without prevention or treatment implementation" generally refers to the situation where prevention or treatment of gastrointestinal adverse events is not implemented, and no measures are taken to weaken or eliminate gastrointestinal adverse events. Measures to weaken or eliminate gastrointestinal adverse events can be, for example, the administration of drugs or other means to prevent or treat gastrointestinal adverse events, stopping the administration of drugs or other means that cause gastrointestinal adverse events, and the measures include the administration of CDK inhibitors or the drugs described in the present application. In the present application, after the administration of chemotherapy described in the present application, if no measures are taken to weaken or eliminate gastrointestinal adverse events, gastrointestinal adverse events will appear or worsen after the chemotherapy is administered 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 1 day, 2 days, 4 days, 7 days, 2 weeks, 3 weeks, 1 month, 2 months or more. If the CDK inhibitor or the drug described in the present application is administered, gastrointestinal adverse events can be weakened or disappear.

[0111] In this application, the term "NCI-CTCAE" generally refers to the standardized definition of adverse events issued by the National Cancer Institute (NCI) of the United States - the Common Terminology Criteria for Adverse Events (CTCAE), which is used to describe the severity of organ toxicity in patients treated for cancer. With the advancement of scientific evidence, this standard can be continuously updated. In this application, the evaluation of diarrhea can refer to the evaluation criteria of "NCI-CTCAE" in some cases. "NCI-CTCAE" can include any version of "NCI-CTCAE". In the 5th edition of CTCAE, constipation and diarrhea are defined as 5 grades, respectively, as shown in the table below.

[0112] Definition of constipation grade standards in CTCAE V5.0

[0113] Definition of diarrhea grade standards in CTCAE V5.0

[0114] As used herein, the term "cancer" generally refers to any medical condition mediated by the growth, proliferation, or metastasis of tumor or malignant cells, and giving rise to solid tumors and non-solid tumors (e.g., leukemias). Cancers herein may include, but are not limited to, epithelial malignancies (cancers of epithelial origin), lung cancer (e.g., non-small cell lung cancer), breast cancer, skin cancer, bladder cancer, colon cancer, intestinal (GI) cancer, prostate cancer, pancreatic cancer, uterine cancer, cervical cancer, ovarian cancer, esophageal cancer, head and neck cancer, stomach cancer, and laryngeal cancer.

[0115] Detailed Description of the Invention

[0116] Compound

[0117] In one aspect, the present application provides a compound of formula (I), and also provides a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer of the compound.

[0118] in,

[0119] n is 1, 2 or 3,

[0120] R1 is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,

[0121] R2, R3, R4, and R5 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted alkenyl;

[0122] Or any two groups among R2, R3, R4 and R5 are connected to form a ring.

[0123] In the present application, the compound is a CDK inhibitor. For example, the compound is a CDK4 / 6 inhibitor.

[0124] In the compounds of the present application, n is 1 to 3. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3.

[0125] In the compounds of the present application, R2, R3, R4, and R5 can be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted alkenyl.

[0126] In certain embodiments, R2 is hydrogen.

[0127] In certain embodiments, R3 is hydrogen.

[0128] In certain embodiments, the R4 is hydrogen. In certain embodiments, the R4 is unsubstituted alkyl. In certain embodiments, the R4 is optionally substituted alkyl.

[0129] In certain embodiments, the R5 is hydrogen. In certain embodiments, the R5 is unsubstituted alkyl. In certain embodiments, the R5 is optionally substituted alkyl.

[0130] In certain embodiments, R2, R3, R4, and R5 can each independently be C 1-10 Substituted or unsubstituted alkyl, C 1-10 Substituted or unsubstituted cycloalkyl, or C 1-10 When the R1 is a substituted group, it may be substituted by any other group.

[0131] In certain embodiments, the R1 may be cyclopentyl.

[0132] In the present application, R2, R3, R4, and R5 can each be independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted alkenyl. For example, R2, R3, R4, and R5 can each be hydrogen. For example, R2, R3, R4, and R5 can each be independently unsubstituted alkyl. For example, R2, R3, R4, and R5 can each be independently substituted alkyl. For example, R2, R3, R4, and R5 can each be independently unsubstituted cycloalkyl. For example, R2, R3, R4, and R5 can each be independently substituted cycloalkyl. For example, R2, R3, R4, and R5 can each be independently substituted alkenyl. For example, R2, R3, R4, and R5 can each be independently unsubstituted alkenyl. In the present application, when R2, R3, R4, and R5 are substituted groups, they may be substituted by any other groups. For example, the substituent group can be an alkyl, cycloalkyl, alkenyl, or heteroatom group. For example, the heteroatom can be selected from N, S, O, and P. In the present application, R1 can be a substituent group directly connected to the heteroatom and the carbon chain. For example, the maximum number of substituents can be full substitution.

[0133] In certain embodiments, R4 and R5 may each independently be an unsubstituted alkyl group. For example, R4 and R5 may be an unsubstituted methyl group.

[0134] In certain embodiments, each of the R4 can be the same. In certain embodiments, each of the R4 can be different.

[0135] In certain embodiments, each of the R5 groups may be the same.

[0136] In certain embodiments, each of the R5 groups may be different.

[0137] In certain embodiments, any two of the R2, R3, R4, and R5 groups may be linked to form a ring. For example, any two of the R2, R3, R4, and R5 groups may be linked to form an alkane ring.

[0138] In the present application, the compound may comprise a structure selected from the group consisting of:

[0139] as well as

[0140] In the present application, the compound may comprise a structure selected from the group consisting of:

[0141] as well as

[0142] In this application, when referring to the structure of a compound, this includes isotopic substitutions at any position in the compound structure. For example, hydrogen can include deuterated and tritiated isotopes. For example, carbon can include carbon-13. For example, nitrogen can include nitrogen-15.

[0143] In the present application, the compound may also include its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer.

[0144] chemotherapy

[0145] In the present application, the chemotherapeutic agent used in the chemotherapy can be selected from any compound or agent for cancer treatment in the categories known to those skilled in the art. In terms of mechanism of action, the chemotherapeutic agent may include DNA synthesis inhibitors, RNA synthesis inhibitors, protein synthesis inhibitors, cell division inhibitors, DNA base analogs, topoisomerase inhibitors and / or telomerase synthesis inhibitors.

[0146] In the present application, chemotherapeutics can be toxic to cells. In the present application, chemotherapeutics can inhibit cell growth. In the present application, the chemotherapeutics used can be chemotherapeutics of DNA damage. In the present application, chemotherapeutics are protein synthesis inhibitors, DNA-damaging chemotherapeutics, alkylating agents, topoisomerase inhibitors, RNA synthesis inhibitors, DNA complex binding agents, thiolate alkylating agents, guanine alkylating agents, tubulin binding agents, DNA polymerase inhibitors, anticancer enzymes, RAC1 inhibitors, thymidylate synthase inhibitors, oxazophosphorine compounds, integrin inhibitors such as cilengitide, camptothecin or homocamptothecin, antifolates, folic acid antimetabolites, telomerase inhibitors and / or telomeric DNA binding compounds.

[0147] For example, the alkylating agent may include alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodizepa, carboquinone, meturedepa and uredepa; ethyleneimines and methylmelamines such as hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trishydroxymethylmelamine; nitrogen mustards such as chlorambucil, naphthyl nitrogen mustard, cyclophosphamide, estramustine, dichloromethyldiethylamine, methoxychlor hydrochloride, melphalan, novembichine, phenesterine, prednimustine, trofosamide and uracil mustard; and nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimustine. Other chemotherapeutic agents may include daunorubicin, doxorubicin, idarubicin, epirubicin, mitomycin and streptozotocin. Chemotherapeutic antimetabolites may include gemcitabine, mercaptopurine, thioguanine, cladribine, fludarabine phosphate, fluorouracil (5-FU), floxuridine, cytarabine, pentostatin, methotrexate, azathioprine, acyclovir, adenine beta-1-D-arabinoside, methotrexate, aminopterin, 2-aminopurine, aphidicolin, 8-azaguanine, azaserine, 6-azauracil, 2'-azido-2'-deoxynucleoside, 5-bromodeoxycytidine, cytosine beta-1-D-arabinoside, diazooxonoleucine, dideoxynucleosides, 5-fluorodeoxycytidine, 5-fluorodeoxyuridine, and hydroxyurea.

[0148] For example, protein synthesis inhibitors may include abrin, aurintricarboxylic acid, chloramphenicol, colicin E3, cycloheximide, diphtheria toxin, edemectin A, emetine, erythromycin, ethionine, fluoride, 5-fluorotryptophan, fusidic acid, guanylylmethylene diphosphonate and guanylylminodiphosphonate, kanamycin, kasugamycin, flavomycin, and O-methylthreonine. Other protein synthesis inhibitors include modeccin, neomycin, norvaline, pyromycin, paromomycine, puromycin, ricin, Shiga toxin, pyroxetine, sparse mycin, spectinomycin, streptomycin, tetracycline, thiostrepton, and trimethoprim.

[0149] For example, DNA synthesis inhibitors may include alkylating agents such as dimethyl sulfate, nitrogen mustards, and sulfur mustards; intercalating agents such as acridine dyes, actinomycins, anthracenes, benzopyrene, ethidium bromide, propidium diiodide-interlaced; topoisomerase inhibitors such as irinotecan, teniposide, coumermycin, nalidixic acid, novobiocin, and oxolinic acid; cell division inhibitors including colcemid, mitoxantrone, colchicine, vinblastine, and vincristine; and other agents such as distamycin and fusobacterin.

[0150] In the present application, the chemotherapeutic agent can be a DNA complex binding agent, such as camptothecin or etoposide; a thiolate alkylating agent, such as nitrosourea, BCNU, CCNU, ACNU or fotesmustine; a guanine alkylating agent, such as temozolomide, a tubulin binding agent such as vinblastine, vincristine, vinorelbine, vinflunine, monilidin 52, a halichondrin such as halichondrin B, a dolastatin such as dolastatin 10 and dolastatin 15, a hemiasterlin (such as hemiasterlin A and hemiasterlin B), a thiolate alkylating agent, such as nitrosourea, BCNU, CCNU, ACNU or fotesmustine, ... guanine alkylating agent, such as temozolomide, a guanine alkylating agent, such as temozolomide, a guanine alkylating agent, such as temozolomide, a guanine alkylating agent, such as temozolomide, a guanine alkylating agent, such as temozolomide, a guanine alkylating agent, such as temozolomide, a guanine alkylating agent, such B), colchicine, combrestatins, 2-methoxyestradiol, E7010, paclitaxel, docetaxel, epothilone, scutellariae; DNA polymerase inhibitors such as cytarabine; anticancer enzymes such as asparaginase; RAC1 inhibitors such as 6-thioguanine; thymidylate synthase inhibitors such as capecitabine or 5-FU; oxazophosphorine compounds such as oncostatin; integrin inhibitors such as cilengitide; antifolates such as pralatrexate; folic acid antimetabolites such as pemetrexed; or camptothecins or homocamptothecins such as diflutecan.

[0151] In the present application, the CDK inhibitor can be used to treat the gastrointestinal side effects associated with one or more of the above-mentioned chemotherapy. In the present application, the CDK inhibitor can be used to treat the gastrointestinal side effects associated with the administration of the following chemotherapeutic agents: fluorouracil, oxaliplatin, irinotecan (CPT-11), docetaxel (DTX), gemcitabine (GEM), paclitaxel, carboplatin, doxorubicin (DOX), methotrexate (MTX), cytarabine (Ara-C), vinorelbine (NVB), topotecan (TP), etoposide and cisplatin, and any combination thereof.

[0152] In the present application, the CDK inhibitors can be used to treat gastrointestinal side effects associated with the administration of the following chemotherapeutic agents: fluorouracil, oxaliplatin, topotecan, irinotecan, tetrahydrofolic acid, docetaxel, gemcitabine, carboplatin, cisplatin, etoposide, methotrexate, doxorubicin, cytarabine, vinorelbine and capecitabine, as well as any combination thereof.

[0153] In the present application, the CDK inhibitors can be used to treat gastrointestinal side effects associated with the administration of the following chemotherapeutic agents: fluorouracil, oxaliplatin, irinotecan, docetaxel, gemcitabine, carboplatin, methotrexate, doxorubicin, cytarabine, vinorelbine and capecitabine, as well as any combination thereof.

[0154] In the present application, the chemotherapy can be administered continuously. For example, the chemotherapy can be administered continuously for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or more days. In certain embodiments, the chemotherapy is administered continuously for no more than 7 days, for example, the chemotherapy can be administered continuously for 2 days, 3 days, 4 days, 5 days or 6 days. In the present application, the frequency of administration of the chemotherapy can be once a day, twice a day, 3 times a day or other.

[0155] In the present application, the chemotherapy can be administered discontinuously. In the present application, the administration frequency of the chemotherapy can be once every two days, once every three days, twice every three days or other.

[0156] In the present application, the chemotherapeutic agent may be administered once a day, and the administration time may be not more than 7 days and / or not more than 7 days.

[0157] In the present application, the administration cycle of the chemotherapeutic agent can be 3 days, 5 days, 7 days, 2 weeks, 20 days, 1 month, 2 months or longer.

[0158] In the present application, one or more different chemotherapeutic agents can be used. In the present application, two or more different chemotherapeutic agents can be used in combination. In some embodiments, the CDK inhibitor can be used in combination with one or more other cancer treatments. The other cancer treatments can be methods conventionally used to treat cancer in the art, such as cytotoxic anticancer agents, immunotherapy anticancer agents, or hormone therapy anticancer agents. According to the present application, drugs for cancer treatment can also be used in combination with radiotherapy or surgery. In some embodiments, when CDK inhibitors and other anticancer agents are used in combination, they can be administered to the subject simultaneously, or administered separately at certain intervals.

[0159] Gastrointestinal side effects

[0160] In the present application, the CDK inhibitor can prevent, alleviate and / or treat the gastrointestinal side effects related to the administration of chemotherapy in a subject. In the present application, the gastrointestinal side effects related to chemotherapy can refer to that the gastrointestinal side effects are caused by the administration of the chemotherapy, and the gastrointestinal side effects are produced or increased after the administration of the chemotherapeutics. In the absence of prevention or treatment implementation, the gastrointestinal side effects can occur or increase after the chemotherapeutics are administered for 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 1 day, 2 days, 4 days, 7 days, 2 weeks, 3 weeks, 1 month, 2 months or more.

[0161] In certain embodiments, the subject does not experience the gastrointestinal side effects before the chemotherapeutic agent is administered to the subject; and the subject experiences the gastrointestinal side effects after the chemotherapeutic agent is administered to the subject.

[0162] In certain embodiments, the subject has already developed the gastrointestinal side effect before the chemotherapeutic agent is administered to the subject; and the extent of the gastrointestinal side effect in the subject is aggravated after the chemotherapeutic agent is administered to the subject.

[0163] In the present application, after administration of the chemotherapeutic agent, the subject's gastrointestinal side effect symptoms can be aggravated by at least about 10%, for example, by about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% or more.

[0164] For example, according to the NCI-CTCAE criteria, after the subject is administered the chemotherapeutic agent, the subject's gastrointestinal side effect (e.g., diarrhea or constipation) severity increases from grade 1 to grade 2, from grade 1 to grade 3, from grade 1 to grade 4, from grade 1 to grade 5, from grade 2 to grade 3, from grade 2 to grade 4, from grade 2 to grade 5, from grade 3 to grade 4, from grade 3 to grade 5, or from grade 4 to grade 5. For example, according to the Akinobu Kurita method, after the subject is administered the chemotherapeutic agent, the subject's constipation score increases from grade 0 to grade 1, from grade 0 to grade 2, from grade 0 to grade 3, from grade 1 to grade 2, from grade 1 to grade 3, or from grade 2 to grade 3.

[0165] In certain embodiments, the gastrointestinal side effects include gastric mucosal damage disease and / or intestinal mucosal damage disease.

[0166] In certain embodiments, the gastrointestinal side effects include diarrhea, abdominal pain, nausea, vomiting, mucositis, loss of appetite, gastric ulcer, gastritis, constipation, enteritis, intestinal perforation, intestinal bleeding, ulcer and / or intestinal necrosis. In certain embodiments, the gastrointestinal side effects include abnormal excretion. In certain embodiments, the gastrointestinal side effects include diarrhea and / or constipation.

[0167] In certain embodiments, the chemotherapy-related gastrointestinal side effects include chemotherapy-related gastric mucosal damage disease and / or chemotherapy-related intestinal mucosal damage disease.

[0168] In certain embodiments, the gastrointestinal side effects associated with chemotherapy include diarrhea associated with chemotherapy, abdominal pain associated with chemotherapy, nausea associated with chemotherapy, vomiting associated with chemotherapy, mucositis associated with chemotherapy, anorexia associated with chemotherapy, gastric ulcer associated with chemotherapy, gastritis associated with chemotherapy, constipation associated with chemotherapy, enteritis associated with chemotherapy, intestinal perforation associated with chemotherapy, intestinal bleeding associated with chemotherapy, ulcer associated with chemotherapy and / or intestinal necrosis associated with chemotherapy. In certain embodiments, the gastrointestinal side effects associated with chemotherapy include abnormal excretion associated with chemotherapy. In certain embodiments, the gastrointestinal side effects associated with chemotherapy include diarrhea associated with chemotherapy and / or constipation associated with chemotherapy.

[0169] In the present application, after administration of the CDK inhibitor of the present application, the severity of the subject's gastrointestinal side effects associated with chemotherapy is alleviated. In the present application, the alleviation can generally refer to that the onset or development of the subject's gastrointestinal side effects is delayed. In the present application, after administration of the CDK inhibitor, the subject's gastrointestinal side effect symptoms can be alleviated. In the present application, after administration of the CDK inhibitor, the subject's gastrointestinal side effect symptoms can be alleviated by at least about 10%, for example, by about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% or more.

[0170] For example, according to the NCI-CTCAE criteria, after administration of the CDK inhibitor, the subject's gastrointestinal side effects (e.g., diarrhea and / or constipation) symptoms can be reduced from grade 5 to grade 4, from grade 5 to grade 3, from grade 5 to grade 2, from grade 5 to grade 1, from grade 4 to grade 3, from grade 4 to grade 2, from grade 4 to grade 1, from grade 3 to grade 2, from grade 3 to grade 1, or from grade 2 to grade 1.

[0171] Alternatively, according to the Akinobu Kurita method, after administration of the CDK inhibitor, the subject's diarrhea score can be reduced from grade 3 to grade 2, from grade 3 to grade 1, from grade 3 to grade 0, from grade 2 to grade 1, from grade 2 to grade 0, or from grade 1 to grade 0.

[0172] In the present application, the subject's gastrointestinal side effects can be eliminated after administration of the CDK inhibitor, but this does not rule out the possibility that the gastrointestinal side effects may recur or worsen after discontinuation of the CDK inhibitor.

[0173] Preparation method and composition

[0174] In another aspect, the present application provides a method for preparing the above-mentioned compound of the present application, its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer.

[0175] In another aspect, the present application provides a composition comprising a compound of the present application, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof.

[0176] In the present application, the composition may comprise a compound provided herein, such as a compound of formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

[0177] In certain embodiments, the compositions of the present application are pharmaceutical compositions. For example, they may comprise one or more pharmaceutically acceptable carriers. For example, the pharmaceutically acceptable carriers may be selected from the group consisting of fillers, binders, disintegrants, buffers, preservatives, lubricants, flavoring agents, thickeners, colorants, and emulsifiers.

[0178] In this application, many carriers and excipients can serve multiple functions, even within the same formulation.

[0179] The compositions provided herein can be formulated into a variety of dosage forms, including but not limited to dosage forms for oral administration. The compositions can also be formulated into modified-release formulations, including delayed, extended, sustained, controlled, accelerated, rapid, targeted, programmed release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al., Eds.; Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008.

[0180] The compositions provided herein can be provided in unit dosage form or multiple dosage form. As used herein, a unit dosage form refers to a physically discrete unit suitable for supplying a patient, i.e., each unit contains a predetermined amount of calculated active agent, to produce the desired therapeutic effect alone or in combination with one or more additional units. For example, the unit dosage form can be a capsule, a tablet, a pill, and the like, or a unit package suitable for parenteral administration. The unit dosage form can be administered in divided or multiple doses. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container, administered in separate unit dosage forms. Examples of multiple dosage forms include, but are not limited to, sample bottles, tablets, or capsule bottles.

[0181] The compositions provided herein can be administered once or multiple times at intervals. It should be understood that the precise dosage and duration of treatment can vary with the age, weight, and condition of the subject being treated, and can be determined using known experimental protocols or by empirical inference from in vivo or in vitro tests or diagnostic data. It should also be understood that for any particular individual, the specific dosage regimen should be adjusted at any time based on the needs of the subject and the professional judgment of the administrator / supervisor.

[0182] Methods, uses, and kits

[0183] On the other hand, the present application provides the compound, its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer, or the use of the composition in the preparation of a medicament for preventing, alleviating and / or treating chemotherapy-related gastrointestinal side effects in a subject.

[0184] On the other hand, the present application also provides a method for preventing, alleviating and / or treating gastrointestinal side effects associated with chemotherapy in a subject, comprising administering the compound, its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer, or the composition to a subject in need.

[0185] On the other hand, the present application also provides the compound, its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer, or the composition, which is used to prevent, alleviate and / or treat chemotherapy-related gastrointestinal side effects in a subject.

[0186] The term "prevention" as used in this application generally refers to preventing the onset, recurrence or spread of a disease or one or more of its symptoms. In this application, "prevention" can be used interchangeably with "prophylactic treatment". In certain embodiments, "prevention" generally refers to providing the treatment of the medicine described herein to a patient suffering from a disease or condition described herein, with or without other drugs described herein, before the onset of symptoms. In certain embodiments, patients with a family history of a specific disease can be candidates for a preventive regimen. In certain embodiments, patients with a history of recurrent symptoms are also potential preventive targets.

[0187] The term "treat" as used herein generally refers to eliminating or ameliorating a disease, or one or more symptoms associated with a disease. In some embodiments, treatment generally refers to eliminating or ameliorating a disease by administering one or more therapeutic agents to a patient suffering from the disease. In some embodiments, "treatment" can be the administration of a drug after the onset of symptoms of a particular disease, with or without the presence of other therapeutic agents.

[0188] The term "subject" as used in this application generally refers to a human or non-human animal (including mammals) in need of diagnosis, prognosis, improvement, prevention, alleviation and / or treatment of a disease, particularly those subjects in need of treatment or prevention of the compound or the composition. In some embodiments, the subject may include a cancer patient. For example, the cancer patient may have been, is currently, and / or will be administered chemotherapy.

[0189] In some embodiments, the subject can be a human or a non-human mammal. Non-human mammals can include any mammalian species other than humans, such as livestock animals (e.g., cattle, pigs, sheep, chickens, rabbits, or horses), or rodents (e.g., rats and mice), or primates (e.g., gorillas and monkeys), or domestic animals (e.g., dogs and cats). "Subjects" can be male or female, and can also be of different ages.

[0190] As used herein, the term "effective amount" generally refers to an amount of a drug that can alleviate or eliminate a disease or symptom in a subject, or that can prophylactically inhibit or prevent the occurrence of a disease or symptom. An effective amount can be an amount of the drug that alleviates one or more diseases or symptoms in a subject to a certain degree; an amount of the drug that partially or completely restores one or more physiological or biochemical parameters associated with the cause of the disease or symptom to normal; and / or an amount of the drug that reduces the likelihood of the disease or symptom occurring.

[0191] In the present application, before administering chemotherapy, for example, administering chemotherapy about 0.5 hour, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours or more, the compound or the composition can be administered to prevent, alleviate and / or treat the generation or weight of gastrointestinal side effects. For example, 0.5-12 hours before administering chemotherapy, administering the compound or the composition can prevent, alleviate and / or treat the generation or weight of gastrointestinal side effects.

[0192] In the present application, after administering chemotherapy, for example, administering chemotherapy about 0.5 hour, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours or more, the compound or the composition can be administered to prevent, alleviate and / or treat the generation or weight of gastrointestinal side effects. For example, 0.5-12 hours after administering chemotherapy, administering the compound or the composition can prevent, alleviate and / or treat the generation or weight of gastrointestinal side effects.

[0193] In the present application, the administration site of the compound may or may not be the site of cancer occurrence or the potential metastasis site of cancer.

[0194] The compounds described herein can be administered by modes of administration known in the art, such as injection (e.g., subcutaneous, intraperitoneal, intraarticular, intraarterial, intrathecal, intrasternal, intrathecal, intralesional, intracranial, intramuscular, intradermal, and intravenous push or infusion) or non-injection (e.g., oral, nasal, sublingual, vaginal, rectal, or topical). The compounds described herein can be administered in the form of a drug combination or a kit. In some embodiments, the compounds described herein can be administered with the same route of administration as chemotherapy or with a different route of administration.

[0195] In the present application, the medicine and / or the compound can be prepared as and be applicable to oral administration.In the present application, the compound can act preferentially in the intestinal cavity, or can preferentially arrive in the intestinal cavity, without being exposed in the systemic circulation.The compound can be prepared as a dosage form suitable for being delivered to the intestinal cavity or playing an effect (for example, the effect of preventing, alleviating and / or treating gastrointestinal side effects) in the intestinal cavity, can adopt the route of administration or the mode that is suitable for compound delivery to the intestinal cavity or playing an effect in the intestinal cavity, can also use auxiliary means such as apparatus so that the compound is delivered to the intestinal cavity or plays an effect in the intestinal cavity.In the present application, the systemic drug concentration of the compound is lower than the onset concentration (IC50).

[0196] In the present application, the drug and / or the compound can be prepared as a dosage form suitable for administration through the gastrointestinal tract, for example, a powder, tablet, granule, capsule, solution, emulsion and / or suspension. In the present application, the drug and / or the compound can be prepared as a dosage form suitable for lumen administration, for example, a suppository and / or a drop pill. In the present application, the drug and / or the compound can be prepared as a dosage form suitable for delivery to the gastrointestinal tract by artificial auxiliary means, for example, by intubation.

[0197] In the present application, the drug and / or the compound is prepared into a dosage form suitable for gastrointestinal exposure. The dosage form suitable for gastrointestinal exposure can be a dosage form suitable for delivery to the gastrointestinal tract, a dosage form suitable for administration through the gastrointestinal tract, a dosage form suitable for intracavitary administration, a dosage form suitable for oral administration, and / or a dosage form suitable for delivery to the gastrointestinal tract via artificial assisted means.

[0198] In the present application, the compound may be administered at a dosage of about 0.01-1000 mg / kg, for example, about 10-1000 mg / kg, about 20-1000 mg / kg, about 30-1000 mg / kg, or about 50-1000 mg / kg.

[0199] For example, the compound can be administered orally at a dosage of about 0.01-1000 mg / kg, for example, about 10-1000 mg / kg, about 20-1000 mg / kg, about 30-1000 mg / kg, or about 50-1000 mg / kg.

[0200] For example, the compound can be administered orally at a dosage of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 50 mg / kg, about 75 mg / kg, about 100 mg / kg, or about 200 mg / kg.

[0201] A particular dose can be divided into multiple interval administrations, such as once a day, twice a day or more, once a week, once every two weeks, once every three weeks, once a month, or once every two months or more. In some embodiments, the dosage may vary with the course of treatment. For example, in some embodiments, the initial dosage may be higher than the subsequent dosage. In some embodiments, the dosage is adjusted according to the response of the subject during the course of treatment. When the subject's condition is improved, the CDK inhibitor of the present application can be administered at a maintenance dose as needed. Subsequently, the dosage or frequency of administration or both can be reduced to a level that maintains the improved state when the symptoms are alleviated to the desired level. In some embodiments, administration can be spaced according to the subject's disease condition.

[0202] The compounds provided herein may also be used in combination with other therapeutic agents / combinations of therapeutic agents useful in treating and / or preventing the diseases or conditions described herein.

[0203] In the present application, term " combination " includes the use of more than one therapy (for example, one or more preventives and / or therapeutic agents). However, the use of term " combination " does not limit the order in which therapy (for example, preventive and / or therapeutic agents) is applied to the subject suffering from disease or illness. The first therapy (for example, preventive or therapeutic agents, such as compound provided by the invention) can be before (for example, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 6 weeks, 8 weeks or 12 weeks), simultaneously or afterwards to subject, apply the second therapy (for example, preventive or therapeutic agents). The application can also use triple therapy.

[0204] The route of administration of the compound provided herein is independent of the route of administration of the second therapy. In certain embodiments, the compound provided by the present invention is orally administered. Therefore, according to an embodiment, the compound provided by the present invention is orally administered, and the second therapy can be by oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, subcutaneous, sublingual, intramuscular, rectal, buccal, intranasal, liposome, suction, vaginal, intraocular, by catheter or stent local delivery, fat, intraarticular, intrathecal administration. In some embodiments, the compound provided by the present invention and the second therapy are orally administered by identical mode of administration. In certain embodiments, the compound provided by the present application is by a mode of administration such as oral administration, and the second medicament (anticancer agent) is by another mode of administration such as parenteral administration.

[0205] On the other hand, the present application provides a method for inhibiting cyclin-dependent kinase (CDK) activity, comprising reacting CDK with an effective amount of a compound of formula (I), a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof.

[0206] On the other hand, the application provides a kit that, when used by a medical practitioner, can simplify administering an appropriate amount of a compound provided by the invention as an active ingredient to a subject. In certain embodiments, the application provides a kit that includes a container and a dosage form of the compound provided by the invention. The application's kit may also include instructions for use.

[0207] The kits provided herein may also include a pharmaceutically acceptable carrier that can be used to administer one or more active ingredients. For example, if the active ingredient is provided in solid form and must be reconstituted for parenteral administration, the kit may include a sealed container with a suitable carrier in which the active ingredient can be dissolved to form a sterile, particle-free solution suitable for parenteral administration.

[0208] Without intending to be bound by any theory, the following examples are merely for illustrating the compounds, preparation methods and uses of the present application, and are not intended to limit the scope of the present invention.

[0209] Example

[0210] Example 1 Synthesis and structural characterization of compound 1 described in this application

[0211] Step 1: Synthesis of (tert-butyl (2)-(chlorosulfonyl)aminoethyl)carbamate

[0212] To a solution of sulfonyl chloride (69.86 g) in dichloromethane (800 mL) was added DMAP (63.24 g) and a solution of N-tert-butoxycarbonyl-1,2-ethylenediamine (91.22 g) in dichloromethane (200 mL) at -70°C. The reaction mixture was warmed to 15°C and stirred for 2 hours to obtain a dichloromethane solution of (tert-butyl (2)-(chlorosulfonyl)aminoethyl)carbamate. This was used directly in the next step.

[0213] Step 2: Synthesis of Intermediate 3

[0214] To a solution of palbociclib (50 g) and DMAP (75.89 g) in dichloromethane (400 mL) was added dropwise the dichloromethane solution of (tert-butyl (2)-(chlorosulfonyl)aminoethyl)carbamate obtained in the first step. The reaction mixture was allowed to react at 40°C for 16 hours. Diluted with dichloromethane (500 mL), washed twice with water (200 mL), separated and dried, and the solvent was removed by vacuum distillation to yield a yellow solid. The mixture was slurried with a dichloromethane / ethyl acetate mixture (10 / 1, 1 L). Filtered and dried by vacuum distillation to yield Intermediate 3 (61 g, 87.97% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ: 10.21 (s, 1H), 8.97 (s, 1H), 8.09 (d, J = 2.9Hz, 1H), 7.8 9(d,J=9.0Hz,1H),7.53(dd,J=2.9,9.1Hz,1H),7.40(t,J=5.7Hz,1H),6.85(br t,J=5.4Hz,1H),5.91-5.76(m,1H),3.22(br dd,J=5.4,15.6Hz,8H),3.08-2.99(m,2H),2.99-2.91(m,2H),2.43(s,3H),2.31(s,3H),2.28-2. 19(m,2H),1.96-1.84(m,2H),1.83-1.70(m,2H),1.65-1.52(m,2H),1.37(s,9H).MS=670.4(M+1).

[0215] Step 3: Synthesis of Compound 1

[0216] Intermediate 3 (61 g) was dissolved in dichloromethane (1 L), and a trifluoroacetic acid / methanol solution (v:v = 1:1) (150 g, 4.1 mL) was added. The mixture was allowed to react at 40°C for 28 hours. The solvent was then removed under reduced pressure to yield compound 1 (43 g). 1 H NMR(400MHz,DMSO-d6)δ:11.61(br s,1H),9.05(s,1H),8.30(br,2H),8.16(dd,J=9.60,2.32Hz,1H),8.06(d,J=2.72Hz,1H),7.88(t,J=5.76Hz,1H),7.82(d,J=9.28Hz,2H),5.84(quin ,J=8.80Hz,1H),3.34(m,4H),3.27(m,4H),3.22(m,2H),2.93(m,2H),2.44 (s,3H),2.35(s,3H),2.22(m,2H),1.97(m,2H),1.81(m,2H),1.60(m,2H).

[0217] MS test results: [M+H + ]The molecular ion peak is 572.27.

[0218] Example 2 Synthesis of Compound 2-6 of the present application

[0219] The synthetic route of compound 2-6 is consistent with that of compound 1, and the mass spectrometry detection results are shown in Table 1.

[0220] Table 1. Mass spectrometry results of compounds 2-6

[0221] Example 3 In vitro enzyme inhibitory activity of the compounds described in this application

[0222] KinaseProfile radiometric protein kinase assay was used to detect the inhibitory activity of compounds against CDK2 / cyclin E, CDK4 / cyclin D, CDK6 / cyclin D, CDK7 / cyclin H, and CDK9 / cyclin T.

[0223] Compounds were prepared in 100% DMSO to a 50X stock solution at the final concentration. A working stock of this compound was added to the reaction wells as the first component of the experimental reaction, and then CDK2 / cyclin E, CDK4 / cyclin D, CDK6 / cyclin D, CDK7 / cyclin H, and CDK9 / cyclin T were mixed with kinase buffer (CDK4: 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.03% BSA, 0.03% Tween 20, 20 mM DTT, and 0.2 mg / ml Rb fragment, 10 mM Magnesium acetate; CDK2, CDK6: 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.1 mg / mL histone H1, 10 mM Magnesium acetate; CDK7: 8 mM MOPS pH 7.0, 0.2 mM EDTA, 500 μM peptide, 10 mM Magnesium acetate; CDK9: 8 mM MOPS pH 7.0, 0.2 mM EDTA, 100 μM KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC, 10mM Magnesium acetate) and [γ- 33The reaction was initiated by adding a Mg / ATP mixture. After incubation at room temperature for 40 minutes, the reaction was terminated by adding 0.5% phosphoric acid. 10 μL of the reaction solution was then spotted onto a P30 filter pad and washed four times with 0.425% phosphoric acid for 4 minutes, followed by a single wash in methanol, before drying and counting. The data were recorded and converted into inhibition percentages, and the corresponding IC50 values ​​were calculated and analyzed. Table 2 summarizes the in vitro enzymology results for the compounds of this application.

[0224] Table 2 In vitro enzyme inhibitory activity of the compounds of the present invention

[0225] Example 4 Cellular activity assay of the compounds of the present application

[0226] 4.1 Cell viability assay

[0227] CELLTITER-GLO cell viability was assessed using MCF-7 human breast cancer cells under normal culture conditions. MCF-7 cells were seeded at 3,000 cells / well in a 96-well plate. The cells were incubated overnight in an incubator. The next day, a series of dilutions of Compound 1 were added to the plate, and the plate was incubated for another 7 days. After 7 days, the plate was removed and allowed to equilibrate at room temperature for half an hour. 100 μL of CELLTITER-GLO assay solution was added, and the plate was shaken on a shaker for 5 minutes. After an additional 10-minute incubation, the plate was measured using the Envision instrument, and the data was processed and analyzed to determine the corresponding IC50 values. The experimental results are shown in Table 3.

[0228] Table 3 Cell viability assay of the compounds of the present invention

[0229] The results showed that the compound of the present application had a significant inhibitory effect on the activity of MCF-7 cells.

[0230] 4.2 Cell apoptosis assay

[0231] Experiment 3 / 7 was used to evaluate the protective effect of the compounds of the present invention on 5-FU-induced cell apoptosis. COLO205 human colon cancer cells were cultured in RPMI 1640 medium (Invitrogen) in an incubator at 37°C and 5% CO2.

[0232] COLO205 cells were seeded at 4,000 cells / well in a 96-well plate. The cells were placed in an incubator and incubated overnight. The next day, a gradient dilution of compound 1 at different concentrations was added to the plate, and the plate was incubated in an incubator for 16 hours. 5-FU was then added and cultured for another 48 hours. Caspase 3 / 7 reagent (100 μL) was then added, and the cells were shaken on a shaker for 10 minutes and then incubated for another 2 hours. After another 10 minutes of incubation, the plate was measured using an Envision instrument and the data was processed. Remission rate (%) = (5-FU group - CDK group) / 5-FU group * 100%. The experimental results are shown in Table 4.

[0233] Table 4 Protective effect of the compounds of the present invention on 5-FU-induced cell apoptosis

[0234] The results in Table 4 show that the compounds described in the present application have a significant protective effect on 5-FU-induced COLO205 cell damage.

[0235] Example 5 In vivo pharmacodynamic activity of the compounds of the present application

[0236] 5.1. 5-FU-induced diarrhea model

[0237] The 5-FU-induced diarrhea model was used as an experimental model of the present invention to study the activity of the compounds in vivo.

[0238] 5-FU 1-day model

[0239] After one week of acclimatization, Balb / c mice (20-25 g, 7-8 weeks old, Jihui) were divided into three groups: a control group, a 5-FU group, and a CDK inhibitor group, with 10 mice in each group. The dosing schedule and dosage are shown in Table 5. The control group received the same solvent as the CDK inhibitor group orally, followed by an injection of the same solvent as the 5-FU group; the 5-FU group received the same solvent as the CDK inhibitor group orally, followed by an injection of 5-FU; and the CDK inhibitor group received the CDK inhibitor orally, followed by an injection of 5-FU. From day 1 to day 7, the diarrhea grade of each mouse was assessed based on the diarrhea score.

[0240] 5-FU 3-day model

[0241] After one week of adaptive feeding, Balb / c mice (20-25g, 7-8 weeks old, Jihui) were grouped and divided into 3 groups: control group, 5-FU group and CDK inhibitor group, with 10 mice in each group. As shown in Table 6, the control group: oral administration of the same solvent as the CDK inhibitor group, followed by injection of the same solvent as the 5-FU group, for 3 consecutive days; the 5-FU group: oral administration of the same solvent as the CDK inhibitor group, followed by injection of 5-FU, for 3 consecutive days; the CDK inhibitor group: oral administration of CDK inhibitors, followed by injection of 5-FU, for 3 consecutive days. The dosing time and frequency are shown in Table 6. From day 1 to day 7, the diarrhea grade of each mouse was evaluated according to the diarrhea score.

[0242] Diarrhea scoring was based on the Akinobu-Kurita method (Cancer Chemother Pharmacol 2000; 46: 211-20). Grade 0: normal stool; Grade 1: mild diarrhea with slightly soft stool; Grade 2: moderate diarrhea with loose stools and mild perianal staining; Grade 3: severe diarrhea with loose watery stools and severe perianal staining.

[0243] The diarrhea relief rate of compound treatment was calculated: Diarrhea relief rate (%) = (5-FU group diarrhea score - CDK inhibitor group diarrhea score) / 5-FU group diarrhea score * 100%.

[0244] Table 5 Pharmacodynamic activity of the compounds of the present invention in the 5-FU 1-day model

[0245] Table 6 Pharmacodynamic activity of the compounds of the present invention in the 5-FU 3-day model

[0246] The results in Table 5 and Table 6 show that compared with the 5-FU group, the diarrhea scores of animals treated with the compounds of the present application were significantly reduced, indicating that the compounds of the present application can effectively alleviate diarrhea caused by 5-FU.

[0247] 5.2. Irinotecan-induced diarrhea and / or constipation model

[0248] Irinotecan-induced diarrhea and / or constipation models were used as two other experimental models to study the in vivo activities of the compounds of the present invention.

[0249] Irinotecan-induced diarrhea model

[0250] After one week of acclimatization, Balb / c mice (20-25g, 7-8 weeks old, Jihui) were divided into three groups: a control group, an irinotecan group, and a CDK inhibitor group, with 10 mice in each group. The dosing schedule and dosage are shown in Table 7. The control group received an oral administration of the same solvent as the CDK inhibitor group, followed by an injection of the same solvent as the irinotecan group; the irinotecan group received an oral administration of the same solvent as the CDK inhibitor group, followed by an injection of irinotecan; and the CDK inhibitor group received an oral administration of the CDK inhibitor, followed by an injection of irinotecan.

[0251] In the irinotecan group, diarrhea occurred in approximately 6 to 9 mice out of 10. Diarrhea was assessed in each mouse on days 1 to 7 according to the following score:

[0252] Diarrhea scoring was based on the Akinobu-Kurita method (Cancer Chemother Pharmacol 2000;46:211-20). Grade 0: normal stool; Grade 1: mild diarrhea, slightly soft stool; Grade 2: moderate diarrhea, loose stool with mild perianal staining; Grade 3: severe diarrhea, loose watery stool with severe perianal staining. The diarrhea remission rate for compound treatment was calculated: Remission rate (%) = (diarrhea score in the irinotecan group - diarrhea score in the CDK inhibitor group) / diarrhea score in the irinotecan group * 100%.

[0253] The results are shown in Table 7. The results show that compared with the irinotecan group, the diarrhea score of the compound of the present invention group was significantly reduced, indicating that the compound of the present invention has a good protective effect on diarrhea caused by irinotecan.

[0254] Table 7 Pharmacodynamics of the compounds of the present invention in irinotecan-induced diarrhea model

[0255] Irinotecan-induced constipation model

[0256] SD rats (180-200 g, 7-8 weeks old, Jihui) were acclimated for 7 days and then divided into three groups: a control group, an irinotecan group, and a CDK inhibitor group, with 10 rats in each group. The administration schedule and dosage are shown in Table 8. The control group received the same solvent as the CDK inhibitor group orally, followed by an injection of the same solvent as the irinotecan group; the irinotecan group received the same solvent as the CDK inhibitor group orally, followed by an injection of irinotecan; and the CDK inhibitor group received the CDK inhibitor orally, followed by an injection of irinotecan.

[0257] In the irinotecan group, approximately 5 to 7 out of 10 rats began to experience constipation symptoms starting on day 2. From day 2 to day 7, the constipation status of each rat was evaluated according to the following score:

[0258] Constipation observation: Feces were collected within 3 hours, their shape was observed, and they were weighed using an electronic balance. The defecation rate was calculated according to the Ji Eun Kim method (Lab Anim Res. 2016 Dec; 32(4): 231-240). Stool reduction rate (%) = (control group - irinotecan or CDK inhibitor group) / control group * 100%

[0259] The constipation relief rate of CDK inhibitor treatment was calculated: Relief rate (%) = (stool reduction rate in the CDK inhibitor group - stool reduction rate in the irinotecan group) / stool reduction rate in the irinotecan group * 100%. The results are shown in Table 8.

[0260] Table 8 Pharmacodynamics of the compounds of the present invention in irinotecan-induced constipation model

[0261] From the results in Table 8, it can be seen that the compound of the present invention has a significant alleviating effect on irinotecan-induced constipation.

[0262] Example 6 PK study of single intravenous injection and oral administration in mice

[0263] Twenty-seven male Balb / c mice were randomly divided into three groups, each with nine mice. Group 1: Compound 1 was administered intravenously at 5 mg / kg in a 5 ml / kg volume, with blood samples collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose. Group 2: Compound 1 was administered orally at 50 mg / kg in a 10 ml / kg volume, with blood samples collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose. Group 3: Palbociclib was administered orally at 50 mg / kg in a 10 ml / kg volume, with blood samples collected at 1, 3, 4, 6, 8, 10, 12, and 24 hours post-dose. Three samples were collected from each group at each time point. Plasma samples were prepared by centrifugation and stored at -70°C. The concentrations of Compound 1 or palbociclib in the plasma samples were determined by LC-MS / MS. The results are shown in Table 9.

[0264] Table 9 Main pharmacokinetics of single intravenous injection and oral administration in male Balb / c mice

[0265] From the results in Table 9, it can be seen that the blood concentration of compound 1 after oral administration is much lower than that of palbociclib after oral administration; that is, the in vivo exposure of the compound involved in this application is much lower than the in vivo exposure of existing CDK inhibitors.

[0266] Example 7 PK study of single intravenous injection and oral administration in rats

[0267] Six male SD rats were randomly divided into two groups of three. Compound 1 was administered intravenously at 2 mg / kg or orally at 10 mg / kg in 5 ml / kg and 10 ml / kg volumes, respectively, with purified water as the vehicle. Blood samples were collected serially from the intravenous group at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration, while those from the orally administered group were collected serially at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. Plasma samples were prepared by centrifugation and stored at -70°C. LC-MS / MS was used to determine the concentration of compound 1 in plasma samples. The results showed that the plasma concentrations of compound 1 after orally administered were all below the limit of quantification of 1 ng / mL. The main pharmacokinetic parameters are shown in Table 10.

[0268] Table 10 Main pharmacokinetics of single intravenous injection and oral administration in male SD rats

[0269] Note: The plasma sample concentrations in the PO group were all below the limit of quantification of 1 ng / mL, so the relevant PK parameters could not be calculated.

[0270] Example 8 Intestinal tissue distribution test of single oral administration in rats

[0271] Nine male Sprague Dawley rats were gavaged with 25 mg / kg of compound 1 in a volume of 10 ml / kg using purified water as the solvent. Three rats were euthanized 0.25, 2, and 6 hours after administration, and 200 μL of whole blood was collected by cardiac puncture and centrifuged to prepare plasma.

[0272] Duodenum, jejunum, ileum, and colon tissues were collected, their contents removed, and the tissues washed with ice water. The tissues were then dried with filter paper and weighed. For every 1 g of tissue, 5 mL of methanol-water (1:3, v / v) was added for homogenization. Drug concentrations in plasma and homogenates of each intestinal segment were determined by LC-MS / MS. The AUC ratios for concentrations in each intestinal segment to plasma are shown in Table 11.

[0273] Table 11 Ratio of intestinal tissue to plasma concentrations in male rats after single oral administration

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, in, n is 1, 2 or 3, R1 is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl; R2, R3, R4, and R5 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted alkenyl; Or any two groups among R2, R3, R4 and R5 are connected to form a ring.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, wherein the substitution comprises heteroatom substitution.

3. The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, wherein the substitution comprises alkyl, cycloalkyl or alkenyl substitution.

4. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer, wherein R2, R3, R4, R5 are each independently selected from: C 1-10 Substituted or unsubstituted alkyl, C 1-10 Substituted or unsubstituted cycloalkyl, C 1-10 Substituted or unsubstituted alkenyl.

5. The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer, wherein R2, R3, R4, R5 are each independently selected from C 1-5 a substituted or unsubstituted alkyl group.

6. The compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, wherein each R4 is the same or different.

7. The compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, wherein each R5 is the same or different.

8. The compound according to claim 1, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, wherein any two of the groups R2, R3, R4 and R5 are linked to form an alkane ring.

9. A compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, comprising a structure selected from the group consisting of: as well as 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, wherein said R1 is selected from: C 1-10 Substituted or unsubstituted alkyl, C 1-10 Substituted or unsubstituted cycloalkyl, C 1-10 Substituted or unsubstituted alkenyl.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, wherein R1 is a substituted or unsubstituted cycloalkyl group.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, wherein R1 is cyclopentyl.

13. The compound according to any one of claims 1 to 12, wherein n is 1, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof.

14. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, wherein n is 2.

15. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, wherein n is 3.

16. A compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, comprising a structure selected from the group consisting of: as well as 17. A compound according to any one of claims 1 to 16, a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, which is a cyclin-dependent kinase (CDK) inhibitor.

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, wherein the CDK inhibitor is a CDK4 / 6 inhibitor.

19. A process for preparing a compound according to any one of claims 1 to 18, a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof.

20. A composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof.

21. The composition of claim 20, further comprising, optionally, a pharmaceutically acceptable carrier.

22. The composition of claim 21 further comprising one or more other active ingredients.

23. The composition according to any one of claims 20 to 22, which is an oral preparation.

24. Use of a compound according to any one of claims 1 to 18, a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, or a composition according to any one of claims 20 to 23 in the preparation of a medicament for preventing, alleviating and / or treating a disease and / or condition.

25. Use according to claim 24, wherein the disease and / or condition comprises gastrointestinal side effects associated with chemotherapy.

26. The use according to claim 25, wherein the chemotherapy comprises administering a chemotherapeutic agent.

27. The use according to claim 26, wherein the chemotherapeutic agent is a cytotoxic agent.

28. The use according to any one of claims 26-27, wherein the chemotherapeutic agent is selected from one or more of the following groups: DNA synthesis inhibitors, RNA synthesis inhibitors, protein synthesis inhibitors, cell division inhibitors, DNA base analogs, topoisomerase inhibitors and / or telomerase synthesis inhibitors.

29. The method of any one of claims 26 to 28, wherein the chemotherapeutic agent is selected from the group consisting of fluorouracil, oxaliplatin, topotecan, irinotecan, tetrahydrofolic acid, docetaxel, gemcitabine, carboplatin, cisplatin, etoposide, methotrexate, doxorubicin, cytarabine, vinorelbine, and capecitabine, and combinations thereof.

30. The use according to any one of claims 26 to 29, wherein the chemotherapeutic agent is administered continuously and / or discontinuously.

31. The use according to any one of claims 25 to 30, wherein the chemotherapy is used in combination with one or more other therapies.

32. The use according to any one of claims 25 to 31, wherein the gastrointestinal side effects associated with chemotherapy include gastrointestinal side effects caused by chemotherapy.

33. The use according to any one of claims 25 to 32, wherein the chemotherapy-related gastrointestinal side effects include gastrointestinal adverse events that occur or worsen after administration of a chemotherapeutic agent.

34. The use of claim 33, wherein the gastrointestinal adverse event, in the absence of prophylaxis or treatment, occurs or worsens after about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 1 day, about 2 days, about 4 days, about 7 days, about 2 weeks, about 3 weeks, about 1 month, about 2 months, or more after administration of the chemotherapeutic agent.

35. The use according to any one of claims 25 to 34, wherein the gastrointestinal side effects include gastric mucosal damage diseases and / or intestinal mucosal damage diseases.

36. The method of any one of claims 25 to 35, wherein the gastrointestinal side effects include diarrhea, abdominal pain, nausea, vomiting, mucositis, anorexia, gastric ulcer, gastritis, constipation, enteritis, intestinal perforation, intestinal bleeding, ulcer and / or intestinal necrosis.

37. The use according to any one of claims 25-36, wherein the gastrointestinal side effects include diarrhea and / or constipation.

38. The use according to any one of claims 25 to 37, wherein the severity of the gastrointestinal side effect is grade 1 or higher, grade 2 or higher, grade 3 or higher, grade 4 or higher, or grade 5 according to NCI-CTCAE.

39. The use according to any one of claims 25 to 38, wherein the drug does not substantially affect the therapeutic effect of the chemotherapy.

40. The method of any one of claims 25-39, wherein the drug is administered about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours or more before the chemotherapy is administered.

41. The method of any one of claims 25-40, wherein the drug is administered about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours or more after the chemotherapy is administered.

42. The use according to any one of claims 25-41, wherein the medicament is administered concurrently with the chemotherapy.

43. The use according to any one of claims 24 to 42, wherein the medicament is administered one or more times.

44. The use according to any one of claims 24 to 43, wherein the medicament is prepared for oral administration, intravenous injection, subcutaneous injection, intraperitoneal injection and / or intramuscular injection.

45. The use according to any one of claims 24 to 44, wherein the medicament is prepared as a tablet and / or a capsule.

46. ​​A method for preventing, alleviating and / or treating a disease and / or condition in a subject, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 18, a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, or a composition according to any one of claims 20 to 23.

47. The method of claim 46, wherein the disease and / or condition comprises gastrointestinal side effects associated with chemotherapy.

48. The method of claim 47, wherein the chemotherapy comprises administering a chemotherapeutic agent.

49. The method of claim 48, wherein the chemotherapeutic agent is a cytotoxic agent.

50. The method of any one of claims 48-49, wherein the chemotherapeutic agent is selected from one or more of the following groups: DNA synthesis inhibitors, RNA synthesis inhibitors, protein synthesis inhibitors, cell division inhibitors, DNA base analogs, topoisomerase inhibitors and / or telomerase synthesis inhibitors.

51. The method of any one of claims 48-50, wherein the chemotherapeutic agent is selected from fluorouracil, oxaliplatin, topotecan, irinotecan, folinic acid, docetaxel, gemcitabine, carboplatin, cisplatin, etoposide, methotrexate, doxorubicin, cytarabine, vinorelbine, and capecitabine, and combinations thereof.

52. The method of any one of claims 48-51, wherein the chemotherapeutic agent is administered continuously and / or discontinuously.

53. The method of any one of claims 47-52, wherein the chemotherapy is used in combination with one or more other therapies.

54. The method of any one of claims 47-53, wherein the chemotherapy-related gastrointestinal side effects comprise chemotherapy-induced gastrointestinal side effects.

55. The method of any one of claims 47-54, wherein the chemotherapy-related gastrointestinal side effects comprise gastrointestinal adverse events that occur or worsen after administration of a chemotherapeutic agent.

56. The method of claim 55, wherein the gastrointestinal adverse event, in the absence of prophylaxis or treatment, occurs or worsens after about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 1 day, about 2 days, about 4 days, about 7 days, about 2 weeks, about 3 weeks, about 1 month, about 2 months, or more after administration of the chemotherapeutic agent.

57. The method according to any one of claims 47 to 56, wherein the gastrointestinal side effects include gastric mucosal damage disease and / or intestinal mucosal damage disease.

58. The method of any one of claims 47-57, wherein the gastrointestinal side effects comprise diarrhea, abdominal pain, nausea, vomiting, mucositis, anorexia, gastric ulcer, gastritis, constipation, enteritis, intestinal perforation, intestinal bleeding, ulcers, and / or intestinal necrosis.

59. The method of any one of claims 47-58, wherein the gastrointestinal side effects include diarrhea and / or constipation.

60. The method of any one of claims 47-59, wherein the severity of the gastrointestinal side effect is Grade 1 or higher, Grade 2 or higher, Grade 3 or higher, Grade 4 or higher, or Grade 5 according to NCI-CTCAE.

61. The method of any one of claims 47-60, wherein the compound, its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer, or the composition does not substantially affect the therapeutic effect of the chemotherapy.

62. The method of any one of claims 47-61, wherein the compound, a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, or the composition is administered about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours or more prior to administration of the chemotherapy.

63. The method of any one of claims 47-62, wherein the compound, a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, or the composition is administered about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours or more after administration of the chemotherapy.

64. The method of any one of claims 47-63, wherein the compound, a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, or the composition is administered concurrently with the chemotherapy.

65. The method of any one of claims 46-64, wherein the compound, a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, or the composition is administered one or more times.

66. The method of any one of claims 46-65, wherein the compound, pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof, or the composition is administered at a dose of about 10-1000 mg / kg.

67. The method of any one of claims 46-66, wherein the subject is a cancer patient.

68. A kit comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer thereof.

69. The kit of claim 68, further comprising instructions for use of the compound, its pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, racemate, enantiomer or stereoisomer.

70. The kit of any one of claims 68-69, further comprising one or more pharmaceutically acceptable carriers.