CDK inhibitor compound

Abstract

The invention relates to an aminopyrimidine compound as shown in a formula (I), a pharmaceutical composition containing the compound, and application of the compound as shown in the formula (I) to prevention and / or treatment of cancers, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a compound, in particular to a highly active CDK inhibitor and use thereof. Background Art

[0002] Cyclin-dependent kinases (CDKs) are a class of serine (Ser) / threonine (Thr) kinases that can be divided into two major categories: cell cycle-related (such as CDK1 / 2 / 4 / 6) and cell transcription-related (such as CDK7 / 9 / 12).

[0003] Currently, the most studied are CDK4 and CDK6, which play key regulatory roles in the cell division cycle. They can form a CDK-cyclin complex with cyclin D, participating in cell growth, proliferation, dormancy, and apoptosis. CDK4 / 6-cyclin D is a key pathway for the transition from G1 to S phase of the cell cycle. When overexpressed, it leads to uncontrolled cell division, which can cause cancer. Several CDK4 / 6 selective inhibitors have been approved for marketing, primarily for the treatment of HR+ / HER2- breast cancer, exemplified by Palbociclib, the world's first CDK4 / 6 selective inhibitor launched by Pfizer.

[0004] Despite the tremendous success of CDK4 / 6 inhibitors, significant side effects remain in clinical practice, particularly myelosuppression. Studies have demonstrated that CDK6 is a key factor in the activation of hematopoietic stem cells, while CDK4 has a relatively minor impact on the hematopoietic system. Further research indicates that CDK4 is highly expressed in tumors, while CDK6 is less expressed. This suggests that CDK4 may be a more important oncogenic factor in breast cancer. Therefore, maintaining CDK4 activity while reducing CDK6 inhibition would be beneficial for CDK inhibitors in reducing clinical toxicity.

[0005] CDK2 is another important cell cycle regulator that can bind to cyclin E or A, playing a role in the process of entering the S phase from the G1 phase and maintaining the S phase, respectively. When CDK4 / 6 are inhibited, CDK2-cyclin E is activated, compensating for the function of CDK4 / 6 and may be one of the main reasons for CDK4 / 6 inhibitor resistance.

[0006] In summary, optimizing selectivity to further improve the therapeutic efficacy and safety of existing CDK4 / 6 inhibitors has important social significance. Summary of the Invention

[0007] The present invention provides a new class of CDK inhibitors. This class of inhibitors differs from existing CDK4 / 6 dual-target inhibitors in that they have optimized activity and selectivity, thereby achieving the goal of improving anti-tumor efficacy and reducing toxic side effects.

[0008] In one aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof:

[0009]

[0010] in:

[0011] A represents N or CH;

[0012] R1 represents H, D, halogen, CN, C1-C3 alkyl, fluorinated C1-C2 alkyl, C3-C6 cycloalkyl, C1-C2 alkoxy;

[0013] U represents NR2 or CR3; R2 and R3 each independently represent H, D, C1-C6 alkyl, C3-C8 cycloalkyl or C3-C6 heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl or C3-C6 heterocycloalkyl can be arbitrarily replaced by R 20 replace;

[0014] When U represents NR2, V represents N or CR4, R4 represents H, D, C1-C6 alkyl, C3-C8 cycloalkyl or C3-C6 heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl or C3-C6 heterocycloalkyl can be substituted by R 21 replace;

[0015] When U represents CR3, V represents NR5, R5 represents H, D, C1-C6 alkyl, C3-C8 cycloalkyl or C3-C6 heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl or C3-C6 heterocycloalkyl can be arbitrarily replaced by R 22 replace;

[0016] X, Y, and Z each independently represent CR6 or N, wherein R6 represents H, D, F, Cl, CN, CH3, CH2F, CHF2, or CF3;

[0017] W each independently represents CR7R7', NR7, O or S;

[0018] R7 and R7' independently represent H, D, halogen, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C2 alkoxy, wherein the C1-C3 alkyl, C1-C2 alkoxy may be optionally replaced by R 23 replace;

[0019] T represents NR8, CR7NRaR8 or CR9R9', wherein R9, R9' and the C atom to which they are attached form a 4-6 membered heterocyclic ring containing NR8 ring atoms, and the heterocyclic ring may be optionally substituted by R7, wherein R8 represents -S(=O)2-Cy1 or -S(=O)(=NH)-Cy1, wherein Cy1 represents C6-C 12 Aryl, 5-10 membered heteroaryl, C4-C8 membered cycloalkyl or 4-8 membered heterocycloalkyl, which may be optionally replaced by 0, 1, 2, 3 or 4 R 10 Replacement, R 10 is selected from: deuterium, F, Cl, CN, C1-C3 alkyl and fluorinated C1-C3 alkyl, C3-C6 cycloalkyl or C1-C2 alkoxy, R a represents H, C1-C3 alkyl or halogenated C1-C3 alkyl;

[0020] R 20 、R 21 、R 22 、R 23 Each independently represents D, F, Cl, CN, OH, C1-C2 alkoxy, NR 24 R 25 、N(R 24 )COR 25 , C3-C8 cycloalkyl, 3-6 membered heterocycloalkyl, the C3-C8 cycloalkyl, 3-6 membered heterocycloalkyl may be optionally substituted by F, OH, C1-C2 alkyl, fluorinated C1-C2 alkyl, C1-C2 alkoxy, fluorinated C1-C2 alkoxy;

[0021] R 24 and R 25 Each independently represents H, D, C1-C3 alkyl;

[0022] p is 1, 2, 3, or 4;

[0023] q is 1, 2, 3, or 4.

[0024] In some embodiments, R1 represents H, D, halogen, CN, C1-C2 alkyl, fluorinated C1-C2 alkyl, cyclopropyl; preferably, R1 represents Cl, F, methyl, halomethyl; more preferably, R1 is preferably Cl.

[0025] For example, in some embodiments, R2 and R3 each independently represent a C1-C6 alkyl group, which may be substituted by R 20 replace.

[0026] In some embodiments, R4 represents a C1-C6 alkyl group, which may be optionally replaced by R 22 replace.

[0027] In some embodiments, R5 is preferably C1-C6 alkyl, which may be optionally replaced by R 22 replace.

[0028] In some embodiments, X represents CF.

[0029] In some embodiments, W represents CR7R7'.

[0030] In some embodiments, Cy1 is selected from the group consisting of: a benzene ring, pyridine, pyrimidine, pyrazine, pyridazine, pyrazole, thiazole, imidazole, isothiazole, morpholine, piperidine, and piperazine.

[0031] In some embodiments, R 10 Selected from F, Cl, CN, C1-C3 alkyl, fluorinated C1-C2 alkyl.

[0032] In some embodiments, R 20 、R 21 、R 22 、R 23 Each independently selected from F, Cl, OH, CN, NR 24 R 25 .

[0033] In some embodiments, X, Y, and Z are each independently CR6.

[0034] In some embodiments, U is NR2 and V is CR4.

[0035] In some embodiments, U is CR3 and V is NR5.

[0036] In some embodiments, the aforementioned compound or its pharmaceutically acceptable salt, isotopic derivative, or stereoisomer has a structure as shown in Formula II:

[0037]

[0038] wherein Ht represents O or NH, preferably O;

[0039] m is 0, 1, 2, 3, 4 or 5;

[0040] n represents 0, 1, 2, 3 or 4.

[0041] In one aspect, the present invention provides a compound having the following structure or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof:

[0042]

[0043]

[0044]

[0045]

[0046]

[0047] Furthermore, the present invention also provides a pharmaceutical composition comprising the compound of the present invention or its pharmaceutically acceptable salt, isotope derivative or stereoisomer.

[0048] Furthermore, the present invention also provides the use of the compound of the present invention or its pharmaceutically acceptable salt, isotopic derivative, stereoisomer, or pharmaceutical composition of the present invention in the preparation of a medicament for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases, or immune-mediated diseases. It is particularly noted that, herein, when a "compound" of a structural formula or general formula is referred to, stereoisomers, diastereomers, enantiomers, racemic mixtures, and isotopic derivatives thereof are generally also encompassed.

[0049] It is well known to those skilled in the art that salts, solvates and hydrates of a compound are alternative forms of existence of the compound, and they can all be converted into the compound under certain conditions. Therefore, it is particularly noted that when referring to a compound of a structural formula or general formula in this article, it generally also includes its pharmaceutically acceptable salts, and further includes its solvates and hydrates.

[0050] Similarly, reference herein to a compound generally also includes prodrugs, metabolites, and N-oxides thereof.

[0051] Pharmaceutically acceptable salts of the present invention may be formed using, for example, the following inorganic or organic acids: "pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, or the like, within the scope of sound medical judgment, and at a reasonable benefit / risk ratio. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid with a suitable reagent, as outlined below. For example, the free base function may be reacted with a suitable acid. Examples of pharmaceutically acceptable inorganic acid addition salts are salts formed of an amino group with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Representative alkali metal or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed with counterions, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0052] The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol and acetonitrile), adding an excess of an organic acid or an aqueous inorganic acid solution thereto to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and then isolating the precipitated salt.

[0053] As used herein, "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be capable of isolation. The solvent molecules in the solvate may exist in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0054] "Stereoisomerism" as used herein is divided into conformational isomerism and configurational isomerism. Configurational isomerism can be further divided into cis-trans isomerism and optical isomerism (i.e., optical isomerism). Conformational isomerism refers to the stereoisomerism phenomenon in which the atoms or atomic groups of an organic molecule with a certain configuration have different spatial arrangements due to the rotation or distortion of carbon-carbon single bonds. Common examples include the structures of alkanes and cycloalkanes, such as the chair and boat conformations that occur in the structure of cyclohexane. "Stereoisomers" refer to compounds of the present invention that contain one or more asymmetric centers and can therefore exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomers. The compounds of the present invention have asymmetric centers, and each asymmetric center can produce two optical isomers. The scope of the present invention includes all possible optical isomers and diastereomeric mixtures, as well as pure or partially purified compounds. The compounds of the present invention may exist as tautomers, which have different hydrogen attachment points due to the displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention. Enantiomers, diastereomers, racemates, mesomorphs, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof of all compounds of the structural formulae and general formulae disclosed herein are included within the scope of the present invention.

[0055] The "isotopic derivative" of the present invention refers to a molecule in which the compound is isotopically labeled. The isotopes commonly used as isotopic labels are: hydrogen isotopes, 2 H and 3 H; Carbon isotope: 11 C, 13 C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes:15 O, 17 O and 18 O and sulfur isotopes 35 These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. 3 H and carbon 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 H), substitution can enhance metabolic stability and prolong half-life, thereby achieving a reduction in dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques similar to those used for synthesizing non-isotope-labeled compounds.

[0056] The present invention also provides use of the compound of the present invention in preparing a medicament for preventing and / or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

[0057] In addition, the present invention provides a pharmaceutical composition for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases, or immune-mediated diseases, comprising a compound of the present invention as an active ingredient. The pharmaceutical composition may optionally contain a pharmaceutically acceptable carrier.

[0058] Furthermore, the present invention provides a method for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases or immune-mediated diseases, which comprises administering a compound of the present invention to a mammal in need thereof.

[0059] Representative examples of inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, atopic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic inflammatory lung disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjögren's syndrome, autoimmune thyroid disease, disease, urticaria (rubella), multiple sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.

[0060] Representative examples of cancer or tumors can include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis carcinoma, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral Neuroectodermal tumor, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchogenic carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, or plasmacytoma.

[0061] When the compound of the present invention or a pharmaceutically acceptable salt thereof is administered in combination with another anticancer agent or immune checkpoint inhibitor for treating cancer or tumors, the compound of the present invention or a pharmaceutically acceptable salt thereof may provide enhanced anticancer effects.

[0062] Representative examples of anticancer agents for treating cancer or tumors may include, but are not limited to, cell signaling inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixapram ... lon, tamoxifen, flutamide, gonadorelin analogs, megestrol acetate, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danuceritinib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib Tinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracutinib, saridegib, sorafenib, sunitinib, telatinib, tivantinib, Tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, berentuzumab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and / or A2B receptor antagonists, IDO inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies and anti-CTLA-4 antibodies, or any combination thereof.

[0063] When the compounds of the present invention, or pharmaceutically acceptable salts thereof, are administered in combination with another therapeutic agent for treating inflammatory diseases, autoimmune diseases, and immune-mediated diseases, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may provide enhanced therapeutic effects.

[0064] Representative examples of therapeutic agents for treating inflammatory diseases, autoimmune diseases and immune-mediated diseases may include, but are not limited to, steroidal drugs (e.g., prednisone, hydroprednisolone, methylhydroprednisolone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα agents (e.g., etanercept, infliximab, adalimumab, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.) and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one or more therapeutic agents selected therefrom may be contained in the pharmaceutical composition of the present invention.

[0065] In addition, the present invention also provides a method for preventing and / or treating tumors, cancers, viral infections, organ transplant rejection, neurodegenerative diseases, attention-related diseases or autoimmune diseases, which comprises administering the compound of the present invention or the pharmaceutical composition of the present invention to a mammal in need thereof.

[0066] The pharmaceutical composition of the present invention can be formulated into dosage forms for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes, intratumor injection) according to any of the conventional methods, such as tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions or suspensions.

[0067] The pharmaceutical composition of the present invention for oral administration can be prepared by mixing the active ingredient with carriers such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers and diluents.

[0068] Examples of carriers used in the pharmaceutical compositions for injection administration of the present invention may include water, saline solutions, glucose solutions, glucose-like solutions, alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, and emulsifying agents.

[0069] Other features of the present invention will become apparent as the present invention describes exemplary embodiments, which are given to illustrate the present invention and are not intended to be limiting thereof. The following examples were prepared, isolated, and characterized using the methods disclosed herein.

[0070] The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the following methods and synthetic methods known in the field of organic synthetic chemistry or variations thereof known to those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for the kit materials used and for the desired transformation. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule is consistent with the proposed transformation. This sometimes requires judgment to change the order of the synthesis steps or the raw materials to obtain the desired compounds of the present invention. DETAILED DESCRIPTION

[0071] the term

[0072] Unless otherwise indicated, the terms used in this application, including the specification and claims, are defined as follows. Unless otherwise indicated, conventional methods such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology will be used. Throughout this application, unless otherwise indicated, the use of "or" or "and" means "and / or."

[0073] In the specification and claims, a given chemical formula or name shall encompass all stereoisomers and optical isomers thereof and racemates thereof in which such isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereoisomers) and racemic forms are within the scope of the present invention. Multiple geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc. may also exist in the compounds, and all such stable isomers are encompassed by the present invention. The present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention, and they can be separated into mixtures of isomers or separate isomeric forms. The compounds of the present invention can be isolated in optically active or racemic form. All methods for preparing the compounds of the present invention and the intermediates prepared therein are considered part of the present invention. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods (e.g., by chromatography or fractional crystallization). Depending on the process conditions, the final products of the present invention are obtained in free (neutral) or salt form. Both the free forms and salts of these final products are within the scope of the present invention. If desired, one form of the compound can be converted into another form. A free base or acid can be converted into a salt; a salt can be converted into a free compound or another salt; and a mixture of isomeric compounds of the present invention can be separated into its individual isomers. The compounds of the present invention, their free forms, and salts can exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all tautomeric forms that may exist are included in the present invention.

[0074] In the present invention, when the linking group listed does not specify its connection direction, its connection direction is arbitrary, for example Where L is -C(O)NH-, in which case -C(O)NH- can be connected to form a phenyl group and a cyclohexyl group in the order of reading from left to right. It is also possible to connect phenyl and cyclohexyl groups in the reverse reading order from left to right to form Combinations of linking groups and linked groups are permitted only if they result in stable compounds. In some preferred embodiments of the present invention, the sequences are read from left to right.

[0075] Unless otherwise defined, the definitions of the substituents of the present invention are independent of each other and not interrelated. For example (listing but not exhaustive), in one aspect, for a substituent R a (or R a '), they are independent of each other in the definitions of different substituents. Specifically, for R a (or R a ') When a definition is selected in a substituent, it does not mean that the R a (or R a ') have the same definition in other substituents. More specifically, for example (listing only non-exhaustive) for NR a R a ', when R a (or R a ') is selected from hydrogen, it does not mean that in -C(O)-NR a R a 'In, R a (or R a ') must be hydrogen. In another aspect, when more than one R is present in a substituent a (or R a '), these R a (or R a ') are also independent of each other. For example, in the substituent -(CR a R a’ ) m -O-(CR a R a’ ) n -, when m+n is greater than or equal to 2, the m+n R a (or R a ') are independent of each other and can have the same or different meanings.

[0076] Unless otherwise defined, when a substituent is indicated as "optionally substituted" or "arbitrarily substituted", the substituent is selected, for example, from substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (wherein the two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthio carbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl such as -SO2NH2, substituted sulfonylamino, nitro, cyano, carboxyl, carbamoyl such as -CONH2, substituted carbamoyl such as -CONHalkyl, -CONHaryl, -CONHarylalkyl or in the case of having two substituents on nitrogen selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclic group such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl and the like and substituted heterocyclic group.

[0077] As used herein, the term "alkyl" or "alkylene" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). In this context, an alkyl group is preferably an alkyl group having 1 to 6, more preferably 1 to 4, carbon atoms.

[0078] As used herein, the term "alkyl" is intended to include side chains and straight chain saturated aliphatic hydrocarbon groups with a specified number of carbon atoms. For example, "C1-C6 alkyl" represents an alkyl group with 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl) and pentyl (such as n-pentyl, isopentyl, neopentyl). Alkyl can be unsubstituted or substituted, and when substituted, it can be substituted at any usable point of attachment, and the substituent is preferably one or more of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In this article, alkyl is preferably an alkyl group with 1 to 6, more preferably 1 to 4 carbon atoms.

[0079] As used herein, the term "alkylene" is intended to include saturated aliphatic hydrocarbon groups, branched, straight-chain, with or without cyclic alkyl groups, having the specified number of carbon atoms, which are residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. For example, "C0-C6 alkylene" means an alkylene group having 0 (i.e., a bond), 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (—CH—), ethylene (—CH—CH—), propylene (e.g., —(CH)—, —(CHCH)—, —(CHCH—), butylene (e.g., —(CH)—, —CH—CH(CH—CH)—, —CH—(CHCH—CH)—, etc.), pentylene (e.g., —(CH)—, —CH—CH(CH—), —CH—(CHCH—CH)—, etc.), hexylene (e.g., —(CH)—, —CH—CH—CH(CH—), —CH—(CHCH—(CH)—)—, etc.). Herein, the alkylene group is preferably an alkylene group having 0-6, 0-4, 0-3, 1-6, 1-4, or 1-3 carbon atoms. Herein, the alkylene group is preferably an alkylene group that does not include a cyclic alkyl group.

[0080] The term "cycloalkyl" refers to a monocyclic, polycyclic or branched cyclic alkyl group. For example, C3-C 12 Cyclic alkyl includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl. Branched cycloalkyls such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Polycyclic, for example bicyclic and tricyclic cycloalkyls include cycloalkyls of bridged rings, spiro rings or condensed rings. Cyclic alkyl can be unsubstituted or substituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In the invention, cycloalkyl is preferably C3-C 12 Cycloalkyl, more preferably C3-C8 cycloalkyl.

[0081] Similarly, the term "heterocycloalkyl" refers to a ring structure in which at least one carbon atom of a cycloalkyl ring structure is replaced by a heteroatom selected from N, O, S and P. The N atom may be optionally quaternized, and the N and S atoms may be optionally oxidized (i.e., NO, SO and SO2). It includes monocyclic heterocycles, bicyclic heterocycles and tricyclic heterocycle systems, wherein the bicyclic heterocycles and tricyclic heterocycle systems include spirocyclic heterocycles, cyclic heterocycles and bridged heterocycles. Heterocycloalkyl may be unsubstituted or substituted, and when substituted, it may be substituted at any available point of attachment, the substituent being preferably selected from one or more of halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In the present invention, heterocycloalkyl is preferably a 4-12 membered heterocycloalkyl, more preferably a 4-8 membered heterocycloalkyl.

[0082] In the present invention, the term "paracyclic" refers to a polycyclic group formed by two or more cyclic structures sharing two adjacent atoms.

[0083] In the present invention, the term "bridged ring" refers to a polycyclic group in which two rings in the system share two or more ring atoms.

[0084] In the present invention, the term "spirocycle" refers to a polycyclic group in which single rings share a carbon atom (called a spiro atom).

[0085] The term "alkenyl" refers to a straight or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl includes, but is not limited to, vinyl, propenyl, butenyl, 1-methyl-2-butene-1-yl, etc. In this article, alkenyl is preferably C2-C6 alkenyl.

[0086] The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl. Monocyclic cyclic alkenyl refers to a C3-C8 cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornyl. Branched cycloalkenyls such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cyclic alkenyls include cyclic alkenyls of bridged rings, spirocycles or condensed rings.

[0087] The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkynyl" contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, etc. In this article, alkynyl is preferably C2-C6 alkynyl.

[0088] The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C1-C6 alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, C6 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) and tert-butoxy. In this article, alkoxy is preferably an alkoxy having 1 to 6, more preferably 1 to 4 carbon atoms. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as defined above connected by a sulfur bridge having a specified number of carbon atoms; for example, methyl-S- and ethyl-S-. Alkoxy can be unsubstituted or substituted, and when substituted, it can be substituted at any usable point of attachment, the substituent preferably being one or more selected from deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0089] The term "carbonyl" refers to an organic functional group composed of carbon and oxygen atoms connected by a double bond (C=O).

[0090] The term "aryl", alone or as part of a larger moiety such as "aralkyl", "arylalkoxy" or "aryloxyalkyl", refers to a monocyclic, bicyclic or tricyclic ring system having a total of 5 to 12 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, which includes but is not limited to phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring, non-limiting examples of which include benzyl, phenethyl and the like. The fused aryl group may be attached to another group at a suitable position on the cycloalkyl ring or the aromatic ring. The dotted line drawn from the ring system indicates that the bond may be attached to any suitable ring atom. The aryl group may be unsubstituted or substituted, and when substituted, it may be substituted at any available point of attachment, preferably one or more of deuterium, halogen, hydroxy, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0091] The term "heteroaryl" means a stable 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic polycyclic heterocyclic ring that is fully unsaturated or partially unsaturated and contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; it includes a structure in which a cycloalkane or heterocycloalkane is fused to an aromatic ring such as a benzene ring or a heteroaromatic ring such as pyridine, and the site of the substituent can be located on the cycloalkane, heterocycloalkane, aromatic ring, or heteroaromatic ring. The nitrogen and sulfur heteroatoms may be optionally oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, wherein R is H or, if defined, another substituent). The heterocycle may be attached to its side group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclic group described herein may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle may be optionally quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1. Heteroaryl groups may be unsubstituted or substituted. When substituted, they may be substituted at any available point of attachment, preferably one or more of halogen, hydroxy, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. When the term "heterocycle" is used, it is intended to include heteroaryl groups.Examples of aromatic hetero groups include, but are not limited to, acridinyl, azetidinyl, azcinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolenyl, dihydroindole , indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolidinyl, oxazolopyridinyl, oxazolidinyl, perylene, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiol, phenoxazinyl , phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl.The term "heteroaryl" may also include biaryl structures formed by the above-defined "aryl" and a monocyclic "heteroaryl", such as but not limited to "-phenylbipyridyl-", "-phenylbipyrimidyl-", "-pyridylbiphenyl-", "-pyridylbipyrimidyl-", "-pyrimidylbiphenyl-"; the present invention also includes fused ring and spiro compounds containing, for example, the above-mentioned heterocycles.

[0092] As used herein, the term "substituted" means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valence is maintained and the substitution results in a stable compound. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0093] "Halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "Haloalkyl" / "haloalkylene" is intended to include branched and straight-chain saturated alkyl / alkylene groups having a specified number of carbon atoms substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" which is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms substituted with one or more fluorine atoms. "Halocycloalkyl" / "haloheterocycloalkyl" is intended to include cycloalkyl / heterocycloalkyl groups having a specified number of carbon atoms substituted with one or more halogens. In the present invention, the halogen atom is preferably fluorine or chlorine.

[0094] "Haloalkoxy" or "haloalkyloxy" means a haloalkyl group as defined above having the specified number of carbon atoms attached via an oxygen bridge. For example, "halo C1-C6 alkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" means a haloalkyl group as defined above having the specified number of carbon atoms attached via a sulfur bridge; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0095] In this disclosure, C is used when referring to certain substituent groups. x1 -C x2, which means that the number of carbon atoms in the substituent group can be x1 to x2. For example, C0-C8 means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C1-C8 means that the group contains 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C2-C8 means that the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C3-C8 means that the group contains 3, 4, 5, 6, 7 or 8 carbon atoms, C4-C8 means that the group contains 4, 5, 6, 7 or 8 carbon atoms, C0-C6 means that the group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C1-C6 means that the group contains 1, 2, 3, 4, 5 or 6 carbon atoms, C2-C6 means that the group contains 2, 3, 4, 5 or 6 carbon atoms, and C3-C6 means that the group contains 3, 4, 5 or 6 carbon atoms.

[0096] In the present disclosure, when referring to a cyclic group (such as an aryl, heteroaryl, cycloalkyl and heterocycloalkyl), the expression "x1-x2 membered ring" is used, which means that the number of ring atoms of the group can be x1 to x2. For example, the 3-12 membered cyclic group can be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; the 3-6 membered ring means that the cyclic group can be a 3-, 4-, 5- or 6-membered ring, and the number of its ring atoms can be 3, 4, 5 or 6; the 3-8 membered ring means that the cyclic group can be a 3-, 4, 5, 6, 7- or 8-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7 or 8; the 3-9 membered ring means that the cyclic group can be a 3-, 4, 5, 6, 7, 8 or 9-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7, The term "4-7 membered ring" refers to a 4-, 5-, 6-, or 7-membered ring having 4, 5, 6, or 7 ring atoms; a 5-, 8-, or 5-membered ring refers to a 5-, 6-, 7-, or 8-membered ring having 5, 6, 7, or 8 ring atoms; a 5-, 12-, or 5-membered ring refers to a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; and a 6-, 12-, or 6-membered ring refers to a 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring having 6, 7, 8, 9, 10, 11, or 12 ring atoms. The ring atoms may be carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, such as heteroatoms selected from N, O and S.

[0097] Where nitrogen atoms (e.g., amines) are present on the compounds of the invention, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to obtain other compounds of the invention. Thus, the shown and claimed nitrogen atoms are considered to encompass both the shown nitrogen and its N-oxide to obtain the derivatives of the invention.

[0098] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R groups, then said group may be optionally substituted with up to three R groups, and at each occurrence R is independently selected from the definition of R. Furthermore, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0099] The term "patient" as used herein refers to an organism to be treated by the method of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., mice, apes, monkeys, horses, cows, pigs, dogs, cats, etc.) and most preferably refer to humans.

[0100] As used herein, the term "effective amount" means an amount of a drug or pharmaceutical agent (i.e., a compound of the present invention) that will cause a biological or medical response in a tissue, system, animal, or human being, such as that sought by a researcher or clinician. In addition, the term "therapeutically effective amount" means an amount that results in improved treatment, cure, prevention, or alleviation of a disease, condition, or side effect, or reduces the rate of progression of a disease or condition, compared to a corresponding subject that has not received the above amount. An effective amount can be given in one or more administrations, applications, or dosages and is not intended to be limited by a specific formulation or route of administration. The term also includes within its scope an effective amount that enhances normal physiological function.

[0101] As used herein, the term "treating" includes any effect that results in improvement of a condition, disease, disorder, etc., such as alleviation, reduction, modulation, improvement, or elimination, or amelioration of the symptoms thereof.

[0102] The term "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response and / or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0103] As used herein, the phrase "pharmaceutically acceptable carrier" or "pharmaceutically acceptable carrier" means a pharmaceutical substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate, zinc stearate, or stearic acid), or solvent encapsulating substance, which is involved in carrying or transporting the subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0104] The term "pharmaceutical composition" means a composition comprising a compound of the present invention and at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals (particularly mammals), including (i.e.) adjuvants, excipients or vehicles such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the mode of administration and the nature of the dosage form.

[0105] Specific pharmaceutical and medical terms

[0106] The term "acceptable," as used herein, means that a prescribed ingredient or active ingredient has no undue adverse effect on health and well-being for the general purpose of treatment.

[0107] The term "cancer," as used herein, refers to an abnormal, uncontrolled growth of cells that can metastasize (spread) under certain conditions. This type of cancer includes, but is not limited to, solid tumors (such as those of the bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (such as the thyroid), prostate, skin (melanoma), or blood tumors (such as non-leukemic leukemias).

[0108] The term "combination administration" or its like, as used herein, refers to the administration of several selected therapeutic agents to a single patient, using the same or different administration routes at the same or different times.

[0109] The terms "enhance" or "capable of enhancing," as used herein, refer to the ability to increase or prolong the potency or duration of a desired outcome. Thus, in the context of enhancing the therapeutic effect of a drug, the term "capable of enhancing" refers to the ability of the drug to increase or prolong the potency or duration of the drug in a system. "Potentiation," as used herein, refers to the ability of another therapeutic agent to maximize its effectiveness in an ideal system.

[0110] The term "immune disease" refers to a disease or condition that results from an adverse or deleterious response to an endogenous or exogenous antigen. The result is usually cellular dysfunction, or the resulting damage and malfunction of, or destruction of, organs or tissues that may be responsible for the immune condition.

[0111] The terms "kit" and "product packaging" are synonymous.

[0112] The term "subject" or "patient" includes both mammals and non-mammals. Mammals include, but are not limited to, mammals such as humans, non-human primates such as gorillas, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, and pigs; livestock such as rabbits and dogs; and laboratory animals including rodents such as rats, mice, and guinea pigs. Non-mammals include, but are not limited to, birds and fish. In a preferred aspect, the selected mammal is a human.

[0113] The terms "treat," "treatment," or "therapy" as used herein include alleviating, inhibiting, or ameliorating the symptoms of a disease or condition; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing a regression of a disease or symptom; alleviating complications caused by a disease or symptom, or preventing and / or treating signs caused by a disease or symptom.

[0114] As used herein, a compound or pharmaceutical composition, when administered, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration, regardless of whether the administration is fixed or temporary, continuous or intermittent, and can be attributed to or related to the administration.

[0115] Pharmaceutical composition and dosage

[0116] The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the present invention formulated with one or more pharmaceutical carriers (additives) and / or diluents, and optionally one or more of the above-mentioned other therapeutic agents. The compounds of the present invention can be administered in any suitable manner for any of the above-mentioned uses, for example, orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion technology (e.g., in the form of a sterile injectable aqueous or non-aqueous solution or suspension); nasally, including administration to the nasal membrane, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository; or by intratumoral injection. They can be administered alone, but are typically administered using a pharmaceutical carrier selected based on the selected route of administration and standard pharmaceutical practice.

[0117] Pharmaceutical carriers include aqueous and non-aqueous liquid media and various solid and semi-solid pharmaceutical carriers. The above-mentioned carriers may include many different ingredients and additives in addition to the active agent. The above-mentioned other ingredients are included in the formulation for various reasons well known to those skilled in the art, such as stabilizers, adhesives, etc. Descriptions of suitable pharmaceutical carriers and factors involved in carrier selection can be found in a number of readily available sources, such as Allen LV Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0118] Of course, the dosage regimen of the compounds of the present invention will vary depending on known factors, such as the pharmacodynamic properties of the specific agent and its mode and route of administration; the species, age, sex, health condition, medical condition, and weight of the recipient; the nature and extent of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and hepatic function, and the desired effect. As a general guide, when used for the specified effect, the daily oral dose of each active ingredient should be from about 0.001 mg / day to about 10-5000 mg / day, preferably from about 0.01 mg / day to about 1000 mg / day, and most preferably from about 0.1 mg / day to about 250 mg / day. The most preferred intravenous dose during a constant rate infusion should be from about 0.01 mg / kg / minute to about 10 mg / kg / minute. The compounds of the present invention can be administered in a single daily dose, or the total daily dose can be administered in divided doses twice, three times, or four times daily.

[0119] The compounds are usually administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) appropriately selected according to the intended administration form (e.g., oral tablets, capsules, elixirs and syrups) and in accordance with conventional pharmaceutical practice.

[0120] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1-95% by weight based on the total weight of the composition.

[0121] The present invention includes within its scope pharmaceutical compositions comprising (alone or in combination with a pharmaceutical carrier) a therapeutically effective amount of at least one compound of the present invention as an active ingredient. Optionally, the compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (e.g., anticancer agents or other pharmaceutically active substances).

[0122] Regardless of the route of administration selected, the compound of the present invention (which may be used in a suitable hydrated form) and / or the pharmaceutical composition of the present invention are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art.

[0123] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0124] The selected dosage level will depend upon a variety of factors, including the activity of the specific compound of the present invention being employed, or its ester, salt or amide; the route of administration; the time of administration; the rate of excretion of the specific compound being employed; the rate and extent of absorption; the duration of the treatment; other drugs, compounds and / or substances used in combination with the specific compound being employed; and factors well known in the medical arts such as the age, sex, weight, condition, general health and prior medical history of the patient being treated.

[0125] A doctor or veterinarian with ordinary skill in the art can determine and prescribe an effective amount of the desired pharmaceutical composition. Typically, a suitable daily dose of the compounds of the present invention will be the amount of the compound that effectively produces the lowest dose of the therapeutic effect. Such an effective dose generally depends on the above-mentioned factors. Typically, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of the present invention for patients range from about 0.01 to about 50 mg / kg body weight / day. If necessary, the effective daily dose of the active compound can be administered separately in two, three, four, five, six or more subdoses at appropriate intervals throughout the day, optionally in unit dosage form. In certain aspects of the present invention, medication is administered once a day.

[0126] While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).

[0127] The features described above, or in the embodiments, may be combined in any combination. All features disclosed in this specification may be used in any combination, and each feature disclosed in this specification may be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the features disclosed are merely general examples of equivalent or similar features.

[0128] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight.

[0129] The units used in the present invention for weight-volume percentages are well known to those skilled in the art, for example, referring to the weight (g) of solute in 100 ml of solution. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0130] Example

[0131] General Process

[0132] When the preparation route is not included, the raw materials and reagents used in the present invention are all known products, which can be synthesized according to methods known in the art, or can be obtained by purchasing commercial products. No further purification is required for the commercially available reagents used.

[0133] Room temperature refers to 20-30℃.

[0134] Unless otherwise specified in the reaction examples, all reactions were carried out under a nitrogen atmosphere, which means that the reaction flask was connected to a nitrogen balloon of approximately 1 L.

[0135] The hydrogenation reaction is usually carried out by evacuating the flask and filling it with hydrogen, and this operation is repeated three times. The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1L.

[0136] Microwave reaction use Initiator + microwave reactor.

[0137] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker Ascend TM The NMR spectra were obtained using a 500 nm NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard. The following abbreviations are used for NMR signal multiplicities: s = singlet, brs = broad, d = doublet, t = triplet, and m = multiplet. Coupling constants are listed as J values and are measured in Hz.

[0138] Reverse phase preparative chromatography was performed using a Thermo (UltiMate 3000) reverse phase preparative chromatograph. Flash column chromatography was performed using an Aeger (FS-9200T) automatic column machine, and silica gel prepacked columns were performed using a Santai Pre-packed columns. Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for thin layer chromatography separation and purification products are 0.4mm to 0.5mm.

[0139] The LC-MS analysis method is as follows:

[0140] 1) Mass spectrometry: Thermo Fisher MSQ PLUS mass spectrometer, ESI source, positive ion mode. Ion source parameters: drying gas temperature, 350°C; drying gas flow rate, 10 L / min; MS range: 120–1000.

[0141] 2) Liquid phase conditions: Chromatographic column: Waters XBridge (3.5 μm, 50 mm × 4.6 mm); mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, linear gradient elution according to Table 1 below; flow rate: 2 mL / min; column temperature: 30°C; UV detection wavelengths: 214 nm, 254 nm, 280 nm; injection volume: 2 μL.

[0142] Table 1. Gradient elution conditions

[0143]

[0144] The HPLC analysis method is as follows:

[0145] Chromatographic column: Waters XBridge phenyl (3.5 μm, 150 mm × 4.6 mm); mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, linear gradient elution according to Table 2; flow rate: 1 mL / min; column temperature: 30°C; UV detection wavelengths: 214 nm, 254 nm, 280 nm; injection volume: 2 μL.

[0146] Table 2. Gradient elution conditions

[0147]

[0148]

[0149] The synthetic methods of some intermediates in the invention are as follows:

[0150] Intermediate 1

[0151]

[0152] Intermediate 1 was prepared by the following steps:

[0153]

[0154] Step 1: Dissolve 5-bromo-1,3-difluoro-2-nitrobenzene INT-1a (4 g, 16.81 mmol) in 40 mL of tetrahydrofuran, add cesium carbonate (5.48 g, 16.81 mol), and stir for 10 minutes. Isopropylamine (0.99 g, 16.81 mmol) is added dropwise at room temperature. After the addition is complete, stirring is continued for 16 hours. After the reaction is complete, the reaction solution is poured into 50 mL of water, and the suspension is extracted with ethyl acetate (50 mL x 3). The organic phase is washed three times with water and concentrated under reduced pressure to obtain INT-1b as a yellow oil (4.6 g, 98% yield). ESI-MS (m / z): 277.2 [M+H] + .

[0155] Step 2: INT-1b (4.6 g, 16.60 mmol) was added to 30 mL of ethanol and 3 mL of water, followed by iron powder (3.71 g, 66.40 mmol) and ammonium chloride (1.78 g, 33.20 mmol). The mixture was stirred at 90°C for 16 hours. After the reaction was complete, the mixture was filtered, concentrated, and the filtrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford INT-1c (3.7 g, 90% yield) as a yellow oil. ESI-MS (m / z): 247.2 [M+H] + .

[0156] Step 3: INT-1c (3.2 g, 12.95 mmol) and INT-1d (2.33 g, 25.90 mol, 1.93 mL) were stirred at 90°C for 16 hours. After the reaction was complete, 100 mL of dichloromethane and saturated aqueous sodium bicarbonate were added. The layers were separated, and the aqueous phase was extracted with dichloromethane (50 mL x 2). The organic phases were combined, dried, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to afford INT-1e (3.5 g, 89% yield) as a yellow oil. ESI-MS (m / z): 300.9 [M+H] + .

[0157] Step 4: Dissolve INT-1e (3.2 g, 10.63 mmol) in 40 mL of dichloromethane. Add Dess-Martin periodinane (5.86 g, 13.81 mmol) at 0°C, slowly warm to room temperature, and continue stirring for 16 hours. After the reaction is complete, add saturated aqueous sodium bicarbonate solution and extract with dichloromethane (50 mL x 3). The organic phases are combined, dried, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain INT-1f (1.8 g, 56% yield) as a white solid. ESI-MS (m / z): 299.1 [M+H] + .

[0158] Step 5: Dissolve INT-1f (1.6 g, 5.35 mmol) in 20 mL of tetrahydrofuran under nitrogen. Add methylmagnesium bromide (3 M, 5.35 mmol, 1.78 mL) at 0°C and stir for 3 hours. Quench the mixture by adding it to a saturated aqueous ammonium chloride solution. Extract with ethyl acetate (50 mL x 3). The combined organic phases are dried and concentrated under reduced pressure. Purify by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a yellow solid INT-1g (1.5 g, 88% yield). ESI-MS (m / z): 315.0 [M+H] + .

[0159] Step 6: INT-1g (1 g, 3.17 mmol) was dissolved in 100 mL of tetrahydrofuran under nitrogen. n-Butyl lithium (2.5 mol / L in hexanes, 6.98 mmol, 2.79 mL) was added dropwise at -78°C. After complete addition, the mixture was stirred at -78°C for 30 minutes. INT-1h (885.47 mg, 4.76 mmol, 0.97 mL) was then added dropwise and stirred at -78°C for another 2 hours. After the reaction was complete, the mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried, and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) afforded INT-1i (1 g, 60% purity, 52% yield) as a yellow solid. ESI-MS (m / z): 363.2 [M+H] + .

[0160] Step 7: Compound INT-1i (1 g, 1.66 mmol), INT-1j (455.72 mg, 2.48 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (121.19 mg, 0.17 mmol), and sodium carbonate (526.66 mg, 4.97 mmol) were dissolved in 1,4-dioxane (10 mL) / water (1 mL) under nitrogen protection and stirred at 90°C overnight. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain a yellow solid INT-1 (630 mg, purity 53%, yield 52%). ESI-MS (m / z): 383.0 [M+H] + .

[0161] Intermediate 2

[0162]

[0163] Intermediate 2 was prepared by the following steps:

[0164]

[0165] Step 1: Dissolve INT-2a (1 g, 4.27 mmol) and N,N-diisopropylethylamine (1.1 g, 8.54 mmol) in 10 mL of tetrahydrofuran. Add p-toluenesulfonyl chloride (0.98 g, 5.12 mol) and stir at room temperature for 16 hours. After the reaction is complete, filter the reaction mixture and dry the filter cake to obtain INT-2b (1.5 g, 90% yield) as a white solid. ESI-MS (m / z): 389.0 [M+H] + .

[0166] Step 2: Dissolve INT-2b (0.8 g, 2.06 mmol) in 5 mL of methanol and 5 mL of dichloromethane, add palladium on carbon (80 mg, 10% wt), and stir at room temperature under a hydrogen atmosphere for 16 hours. After the reaction is complete, filter, concentrate the filtrate, and purify it by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain INT-2 (400 mg, 76% yield) as a white solid. ESI-MS (m / z): 255.2 [M+H] + .

[0167] Intermediate 3

[0168]

[0169] Intermediate 3 was prepared by the following steps:

[0170]

[0171] Step 1: Dissolve INT-2a (1 g, 4.27 mmol) and N,N-diisopropylethylamine (1.1 g, 8.54 mmol) in 10 mL of tetrahydrofuran. Add p-chlorobenzenesulfonyl chloride INT-3a (1.1 g, 5.12 mol) and stir at room temperature for 16 hours. After the reaction is complete, filter the reaction mixture and dry the filter cake to obtain INT-3b (1.6 g, 91% yield) as a white solid. ESI-MS (m / z): 408.9 [M+H] + .

[0172] Step 2: INT-3b (0.8 g, 1.96 mmol) was dissolved in 4 mL of trifluoroacetic acid and stirred at 80°C for 16 hours. After the reaction was complete, the reaction solution was concentrated and slurried with petroleum ether / ethyl acetate (10 / 1). The mixture was filtered and the filter cake dried to afford INT-3 as a white solid (600 mg, 79% yield). ESI-MS (m / z): 275.2 [M+H] + .

[0173] Intermediate 4

[0174]

[0175] Intermediate 4 was prepared by the following steps

[0176]

[0177] Step 1: Dissolve INT-3b (0.8 g, 1.96 mmol) in 5 mL of methanol and 5 mL of dichloromethane, add palladium on carbon (80 mg, 10% wt), and stir at room temperature under a hydrogen atmosphere for 16 hours. After the reaction is complete, filter, concentrate the filtrate, and purify it by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain INT-4 (350 mg, 74% yield) as a white solid. ESI-MS (m / z): 241.2 [M+H] + .

[0178] Intermediate 5

[0179]

[0180] Intermediate 5 was prepared by the following steps:

[0181]

[0182] Step 1: Dissolve INT-1c (1.4 g, 5.67 mmol) and INT-5a (2.12 g, 11.33 mol) in dimethyl sulfoxide (15 mL) and ethanol (4 mL). Add sodium dithionite (2.47 g, 14.16 mmol) at room temperature and stir at 80°C for 16 hours. After the reaction is complete, add ethyl acetate (100 mL), filter, and wash the filtrate with saturated brine (50 mL x 3). The organic phase is dried, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain INT-5b (690 mg, 29% yield) as a white solid. ESI-MS (m / z): 413.9 [M+H] + .

[0183] Step 2: Compound INT-5b (360 mg, 0.87 mmol), bis-pinacol boronate (330.98 mg, 1.3 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (73.55 mg, 87 umol), and potassium acetate (255.83 mg, 2.61 mmol) were dissolved in 1,4-dioxane (5 mL) under nitrogen protection and stirred at 90°C overnight. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain a white solid INT-5c (330 mg, purity 82%, yield 52%). ESI-MS (m / z): 462.1 [M+H] + .

[0184] Step 3: Dissolve compound INT-5c (300 mg, 650.23 μmol), INT-5d (190.26 mg, 975.34 μmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (47.58 mg, 65.02 μmol), and sodium carbonate (206.75 mg, 1.95 mmol) in 1,4-dioxane (5 mL) / water (0.5 mL) under nitrogen atmosphere and stir overnight at 90°C. After the reaction is complete, the reaction solution is filtered through celite, and the filtrate is concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain INT-5e (270 mg, 84% yield) as a yellow solid. ESI-MS (m / z): 494.2 [M+H] + .

[0185] Step 4: INT-5e (100 mg, 202.42 μmol) was dissolved in dichloromethane (2 mL), and m-chloroperbenzoic acid (69.86 mg, 404.84 μmol) was added to the reaction solution at 0°C. The reaction mixture was stirred at 0°C for 4 hours. After the reaction was complete, saturated aqueous sodium bicarbonate solution (5 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound INT-5 (90 mg, yield 84%). ESI-MS (m / z): 526.1 [M+H] + .

[0186] Intermediate 6

[0187]

[0188] Intermediate 6 was prepared by the following steps:

[0189]

[0190] Step 1: Dissolve INT-1g (3g, 9.52mmol) in acetic anhydride (10mL), add 4-dimethylaminopyridine (116.28mg, 0.952mol), and heat to 80°C with stirring for 16 hours. After the reaction is complete, cool to room temperature and dilute the reaction mixture with dichloromethane (200mL). Wash with saturated sodium bicarbonate solution (50mL x 3). The organic phase is dried and concentrated under reduced pressure to obtain INT-6a (3.3g, 97% yield) as a yellow solid. ESI-MS (m / z): 357.3 [M+H] + .

[0191] Step 2: Compound INT-6a (1 g, 2.80 mmol), bis-pinacol boronate (1.07 g, 4.20 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (236.96 mg, 279.94 umol), and potassium acetate (824.2 mg, 8.40 mmol) were dissolved in 1,4-dioxane (10 mL) under nitrogen protection and stirred at 90°C overnight. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound INT-6b (1.1 g, yield 97%). ESI-MS (m / z): 405.6 [M+H] + .

[0192] Step 3: Compound INT-6b (1.1 g, 2.72 mmol), INT-1j (748.61 mg, 4.08 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (199.09 mg, 272.09 umol), and sodium carbonate (865.15 mg, 8.16 mmol) were dissolved in 1,4-dioxane (10 mL) / water (0.1 mL) under nitrogen protection and stirred at 90°C overnight. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain a yellow solid INT-6 (1 g, yield 86%). ESI-MS (m / z): 425.3 [M+H] + .

[0193] The synthesis method of the embodiment compounds of the present invention is as follows:

[0194] Example 1

[0195] 2-(6-(5-chloro-2-((1-tosylpiperidin-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-

[0196] isopropyl-1H-benzo[d]imidazol-2-yl)propan-2-ol

[0197]

[0198] Example 1 was prepared by the following steps:

[0199]

[0200] Step 1: Compound INT-1 (100 mg, 0.14 mmol), INT-2 (52.76 mg, 0.21 mmol), methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (12.54 mg, 0.014 mmol), and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (14.58 mg, 0.028 mmol) were dissolved in 1,4-dioxane (3 mL), and cesium carbonate (135.17 mg, 0.42 mmol) was added. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction solution was filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 5) to obtain a yellow oil. The oil was then purified by preparative liquid chromatography to obtain a white solid compound 1 (4.28 mg, yield 5%). ESI-MS (m / z): 600.9 [M+H] + .

[0201] 1 H NMR (500MHz, DMSO-d6) δ8.40(s,1H),7.98–7.82(m,1H),7.66–7.57(m,3H),7.46(d,J=8.0Hz,2H),7.43–7.25(m,1H),5.83(s,1 H),5.78–5.70(m,1H),3.74–3.64(m,1H),3.57–3.49(m,2H),2.41(s,3H),2.02–1.91(m,2H),1.66(s,6H),1.63–1.44(m,10H).

[0202] Example 2

[0203] 2-(6-(5-chloro-2-((1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)propan-2-ol

[0204]

[0205] Example 2 was prepared by the following steps:

[0206]

[0207] Step 1: Compounds INT-1 (100 mg, 0.14 mmol), INT-3 (80.44 mg, 0.21 mmol), methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (12.54 mg, 0.014 mmol), and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (14.58 mg, 0.028 mmol) were dissolved in 1,4-dioxane (3 mL), and cesium carbonate (135.17 mg, 0.42 mmol) was added. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction solution was filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 5) to obtain a yellow oil. The oil was then purified by preparative liquid chromatography to obtain a white solid compound 1 (1.9 mg, yield 2%). ESI-MS (m / z): 621.0 [M+H] + .

[0208] 1 H NMR(500MHz,DMSO-d6)δ8.41(s,1H),7.97–7.87(m,1H),7.81–7.72(m,4H),7.61(s,1H),7.48–7.25(m,1H),5.84(s ,1H),5.80–5.71(m,1H),3.80–3.72(m,1H),3.59–3.53(m,2H),2.01–1.92(m,2H),1.67(s,6H),1.64–1.45(m,10H).

[0209] Example 3

[0210] 2-(6-(5-chloro-2-((1-(phenylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-4-

[0211] fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)propan-2-ol

[0212]

[0213] Example 3 was prepared by the following steps:

[0214]

[0215] Step 1: Compounds INT-1 (80 mg, 0.11 mmol), INT-4 (39.88 mg, 0.17 mmol), methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (10.03 mg, 0.011 mmol), and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (11.88 mg, 0.022 mmol) were dissolved in 1,4-dioxane (3 mL), and cesium carbonate (108.14 mg, 0.33 mmol) was added. The reaction mixture was stirred at 120°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction solution was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 5) to obtain a yellow oil. The oil was then purified by preparative liquid chromatography to obtain a white solid compound 1 (3.03 mg, yield 4%). ESI-MS (m / z): 586.9 [M+H] + .

[0216] 1 H NMR(500MHz,DMSO-d6)δ8.41(s,1H),7.98–7.87(m,1H),7.78–7.72(m,3H),7.69–7.64(m,2H),7.63–7.57(m,1H),7.48–7.24(m, 1H),5.83(s,1H),5.78–5.69(m,1H),3.74–3.67(m,1H),3.62–3.53(m,2H),2.03–1.93(m,2H),1.67(s,6H),1.64–1.48(m,10H).

[0217] Example 4

[0218] 4-(2-(2-aminopropan-2-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-chloro-N-(1-tosylpiperidin-4-yl)pyrimidin-2-amine

[0219]

[0220] Example 4 was prepared by the following steps:

[0221]

[0222] Step 1: INT-5 (90 mg, 171.1 μmol), N,N-diisopropylethylamine (66.34 mg, 513.29 μmol), and INT-2 (43.52 mg, 171.1 μmol) were placed in a microwave tube, n-butanol (2 mL) was added, and the mixture was heated to 150°C in a microwave reactor for 1.5 hours. After the reaction was complete, the mixture was dried and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 4a (20 mg, yield 16%). ESI-MS (m / z): 700.1 [M+H] + .

[0223] Step 2: Dissolve compound 4a (20 mg, 28.56 μmol) in dichloromethane (1 mL) and add hydrochloric acid (28.56 μL, 114.24 μmol, 4 M, 1,4-dioxane solution). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated and purified by preparative liquid chromatography to obtain compound 4 as a white solid (4.59 mg, 26% yield). ESI-MS (m / z): 600.7 [M+H] + .

[0224] 1 H NMR(500MHz,DMSO-d6)δ8.40(s,1H),7.99–7.82(m,1H),7.63(d,J=7.8Hz,3H),7.46(d,J=7.8Hz,3H),6.2 4–6.09(m,1H),3.72–3.66(m,1H),3.55–3.51(m,2H),2.42(s,3H),2.02–1.91(m,2H),1.69–1.46(m,16H).

[0225] Example 5

[0226] 2-(6-(5-chloro-2-((1-tosylpyrrolidin-3-yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)propan-2-ol

[0227]

[0228] Example 5 was prepared by the following steps:

[0229]

[0230] Step 1: Dissolve 5a (320 mg, 1.45 mmol), triethylamine (441.02 mg, 4.36 mmol), and p-toluenesulfonyl chloride (304.67 mg, 1.60 mmol) in dichloromethane (8 mL). The reaction mixture was stirred at room temperature under nitrogen for 12 hours. After completion of the reaction, the reaction mixture was concentrated to dryness to obtain a crude product. Column chromatography (petroleum ether / ethyl acetate = 3 / 1) afforded the desired product 5b (480 mg, 88.24% yield). ESI-MS (m / z): 374.7 [M+H] + .

[0231] Step 2: Dissolve 5b (450 mg, 1.20 mmol) and palladium on carbon (50 mg) in a mixture of dichloromethane (8 mL) and methanol (8 mL). Stir the reaction mixture at room temperature under a hydrogen atmosphere for 12 hours. After completion of the reaction, filter the reaction mixture, and concentrate the filtrate to obtain crude compound 5c (250 mg, 86.56% yield).

[0232] NBK0268-007

[0233] Step 3: Compound 5c (67.81 mg, 0.28 mmol), INT-6 (100.00 mg, 0.24 mmol), methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (21.32 mg, 0.02 mmol), and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (25.24 mg, 0.05 mmol) were dissolved in 1,4-dioxane (5 mL), and cesium carbonate (153.22 mg, 0.50 mmol) was added. The reaction mixture was stirred at 120°C under nitrogen for 16 hours. After the reaction was complete, the reaction solution was filtered through celite, and the filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 5d (40 mg, yield 27.04%). ESI-MS (m / z): 629.2 [M+H] + .

[0234] Step 4: Dissolve 5d (40 mg, 0.06 mmol) and lithium hydroxide monohydrate (8.00 mg, 0.19 mmol) in a mixture of tetrahydrofuran (2 mL) and water (1 mL). The reaction mixture was stirred at room temperature under air for 4 hours. After the reaction was complete, the reaction mixture was concentrated to dryness to obtain a crude product. The crude product was purified by reverse-phase column chromatography to obtain the target compound 5 (15 mg, 40.18% yield). ESI-MS (m / z): 587.6 [M+H] + .

[0235] 1 HNMR(500MHz,DMSO-d6)δ8.44-8.43(m,1H),7.96(s,1H),7.64(d,J=7.8Hz,3H),7.36(s,2H),5.85(s,1H),5.81–5.73(m,1H),4.15(q,J=5.7Hz,1 H),3.45(s,1H),3.40–3.36(m,1H),3.25-3.20(m,2H),2.39-2.33(m,4H ),2.06-2.00(m,1H),1.89-1.82(m,1H),1.67(s,6H),1.62–1.58(m,6H).

[0236] Example 6

[0237] 2-(6-(5-chloro-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-

[0238] yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-

[0239] yl)propan-2-ol

[0240]

[0241] Example 6 was prepared by the following steps:

[0242]

[0243] Step 1: Compound 6a (300 mg, 1.66 mmol) and compound 6b (333 mg, 1.66 mmol) were dissolved in dichloromethane (3 mL) and triethylamine (504 mg, 4.98 mmol) was added. The reaction mixture was stirred at room temperature for 6 hours. After the reaction was complete, the reaction solution was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 6c (523 mg, 92% yield). ESI-MS (m / z): 345.5 [M+H] + .

[0244] (NBK0266-59)

[0245] Step 2: Compound 6c (523 mg, 1.52 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (865 mg, 7.59 mmol) was added. The reaction mixture was stirred at 0°C for 2 hours. After the reaction was complete, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (20 mL), extracted with dichloromethane (20 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative chromatography to obtain a colorless oily liquid compound 6d (250 mg, yield 67%). ESI-MS (m / z): 245.5 [M+H] + (NBK0266-61)

[0246] Step 3: Compound 6d (69 mg, 282 umol) and compound INT-6 (100 mg, 235 umol) were dissolved in 1,4-dioxane (2 mL), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (22 mg, 24 umol), cesium carbonate (153 mg, 470 umol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (25 mg, 47 umol) were added in sequence. The reaction mixture was stirred at 100 ° C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to give compound 6e (25 mg, yield 17%). ESI-MS (m / z): 633.2 [M+H] + (NBK0266-98)

[0247] Step 4: Compound 6e (25 mg, 40 μmol) was dissolved in a mixed solvent of tetrahydrofuran (1 mL) and water (0.5 mL). Lithium hydroxide (3 mg, 120 μmol) was added, and the reaction mixture was stirred at 0°C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative chromatography to obtain compound 6 (12 mg, 52% yield) as a white solid. ESI-MS (m / z): 591.1 [M+H] + (NBK0266-100)

[0248] 1H NMR(500MHz,DMSO-d6)δ8.41(s,1H),8.33(s,1H),7.99–7.87(m,1H),7.77(s,1H),7.68–7.57(m,1H),7.45–7.28(m,1H),5.84(s,1H),5.7 9–5.72(m,1H),3.90(s,3H),3.76–3.69(m,1H),3.49–3.44(m,2H),2.47–2.35(m,2H),2.05–1.92(m,2H),1.66(s,6H),1.63–1.52(m,8H).

[0249] Example 7

[0250] 2-(6-(5-chloro-2-((1-((4-(piperazin-1-yl)phenyl)sulfonyl)piperidin-4-

[0251] yl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-

[0252] yl)propan-2-ol

[0253]

[0254] Example 7 was prepared by the following steps:

[0255]

[0256] Step 1: Compound 7a (500 mg, 1.96 mmol) and compound 6b (458 mg, 1.96 mmol) were dissolved in dichloromethane (3 mL) and triethylamine (594 mg, 5.87 mmol) was added. The reaction mixture was stirred at room temperature for 6 hours. After the reaction was complete, the reaction solution was quenched with saturated aqueous ammonium chloride (10 mL), extracted with dichloromethane (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 7c (880 mg, yield 99%). ESI-MS (m / z): 453.8 [M+H] + (NBK0266-45)

[0257] Step 2: Compound 7c (500 mg, 1.10 mmol) and N-tert-butyloxycarbonylpiperazine (247 mg, 1.32 mmol) were dissolved in 1,4-dioxane (2 mL). Palladium acetate (25 mg, 110 umol), sodium tert-butoxide (212 mg, 2.21 mmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (137 mg, 221 umol) were added sequentially. The reaction mixture was stirred at 90°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 7d (582 mg, 95% yield) as a white solid. ESI-MS (m / z): 559.0 [M+H] + .

[0258] (NBK0266-51)

[0259] Step 3: Compound 7d (582 mg, 1.04 mmol) was dissolved in dichloromethane (5 mL) and methanol (5 mL), followed by the addition of palladium on carbon (120 mg, 50%-60% water-wet paste). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was complete, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 7e (229 mg, 52% yield) as a white solid. ESI-MS (m / z): 425.0 [M+H] + .

[0260] Step 4: Compound 7e (120 mg, 282 umol) and compound INT-6 (100 mg, 235 umol) were dissolved in 1,4-dioxane (2 mL), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (22 mg, 24 umol), cesium carbonate (153 mg, 470 umol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (25 mg, 47 umol) were added in sequence. The reaction mixture was stirred at 100 ° C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to give compound 7f (122 mg, yield 64%). ESI-MS (m / z): 813.8 [M+H] + (NBK0266-92)

[0261] Step 5: Compound 7f (122 mg, 150 μmol) was dissolved in a mixture of tetrahydrofuran (1 mL) and water (0.5 mL). Lithium hydroxide (11 mg, 450 μmol) was added, and the reaction mixture was stirred at 0°C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain crude compound 7g (115 mg, 99% yield). ESI-MS (m / z): 771.4 [M+H] + (NBK0266-95)

[0262] Step 6: Dissolve compound 7g (115 mg, 149 umol) in dichloromethane (1 mL) and add a 1,4-dioxane solution of hydrochloric acid (2 mL, 4 M). The reaction mixture was stirred at 0°C for 2 hours. After the reaction was complete, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (5 mL), extracted with dichloromethane (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative chromatography to obtain a white solid compound 7 (7 mg, yield 5%). ESI-MS (m / z): 671.6 [M+H] + .

[0263] (NBK0266-99)

[0264] 1 H NMR(500MHz,DMSO-d6)δ8.39(s,1H),7.99–7.86(m,1H),7.66–7.42(m,4H),7.10–7.01(m,2H),5.93–5.79(m,1H),5.77–5.70(m,1H) ),3.70–3.65(m,1H),3.54–3.46(m,4H),3.27–3.21(m,4H),2.88–2.79(m,4H),2.01–1.91(m,2H),1.65(s,6H),1.62–1.45(m,9H).

[0265] Other structures disclosed in the present invention can be prepared by referring to the above synthesis method.

[0266] Experimental Example 1

[0267] CDK2 / Cyclin E1 kinase activity inhibition assay

[0268] The purpose of this study was to evaluate the inhibitory ability of small molecule compounds on CDK2 / Cyclin E1 kinase activity (% inhibition and IC 50First, the enzyme, ATP, substrate, and compound were diluted to the desired concentration using kinase buffer, which consists of 40mM Tris-HCl, pH 7.5; 20mM MgCl2; 0.01% Triton X-100; and 1mM DTT. The experiment was performed in a 384-well plate. First, 2μL of CDK2 / Cyclin E1 and 1μL of the test compound (generally, the compound starting concentration was 10μM, and 3-fold dilutions were used to create an 8-point concentration gradient) were added to the plate. After centrifugation, the plate was incubated at room temperature for 10 minutes. Then, 2μL of a mixture of substrate Histone H1 and ATP was added, followed by centrifugation and incubation at room temperature in the dark for 60 minutes. Then, 5μL of ADP-Glo was added. TM Reagent (Promega, V9102) was incubated at room temperature for 120 minutes to terminate the reaction and consume the remaining ATP. Then 10 μL Kinase Detection Reagent (Promega, V9102) was added and incubated at room temperature for 30 minutes to convert ADP into ATP. The ATP was detected using a multifunctional microplate reader ( i3x, Molecular devices) was used to read the fluorescence signal value, which was then normalized and a four-parameter regression equation was used for curve fitting to calculate the half-maximal inhibitory concentration (IC) of the compound on the cell line. 50 ).

[0269] CDK4 / Cyclin D3 kinase activity inhibition assay

[0270] The purpose of this study was to evaluate the inhibitory ability of small molecule compounds on CDK4 / Cyclin D3 kinase activity (% inhibition and IC 50 First, the enzyme, ATP, substrate, and compound were diluted to the desired concentration using kinase buffer, which consists of 40mM Tris-HCl, pH 7.5; 20mM MgCl2; 0.01% Triton X-100; and 1mM DTT. The experiment was performed in a 384-well plate. First, 2μL of CDK4 / Cyclin D3 and 1μL of the test compound (generally, the starting concentration of the compound was 10μM, and 3-fold dilutions provided 8 concentration gradients) were added to the 384-well plate. After centrifugation, the plate was incubated at room temperature for 5 minutes. 2μL of a mixture of substrate DYRKtide (RRRFRPASPLRGPPK) and ATP was added, and after centrifugation, the plate was incubated at room temperature in the dark for 60 minutes. 5μL of ADP-Glo was added. TMReagent (Promega, V9102) was incubated at room temperature for 40 minutes to terminate the reaction and consume the remaining ATP. Then 10 μL Kinase Detection Reagent (Promega, V9102) was added and incubated at room temperature for 30 minutes to convert ADP into ATP. The ATP was detected using a multifunctional microplate reader ( i3x, Molecular devices) was used to read the fluorescence signal value, which was then normalized and a four-parameter regression equation was used for curve fitting to calculate the half maximal inhibitory concentration (IC) of the compound on the cell line. 50 ).

[0271] CDK6 / Cyclin D3 kinase activity inhibition assay

[0272] The purpose of this experiment is to evaluate the inhibitory ability of small molecule compounds on CDK6 / Cyclin D3 kinase activity (% inhibition and IC50). First, the enzyme, ATP, substrate, and compound are diluted to the required concentration using kinase buffer. The kinase buffer composition is 40mM Tris-HCl, pH 7.5; 20mM MgCl2; 0.01% Triton X-100; 1mM DTT. The experiment is performed in a 384-well plate. First, 2μL CDK6 / Cyclin D1 and 1μL of the test compound (generally, the starting concentration of the compound is 10μM, and 3-fold dilutions are 8 concentration gradients) are added to the 384-well plate. After centrifugation, incubate at room temperature for 5 minutes; then add 2μL of a mixture of substrate DYRKtide (RRRFRPASPLRGPPK) and ATP, centrifuge, and incubate at room temperature in the dark for 60 minutes; then add 5μL ADP-Glo TM Reagent (Promega, V9102) was incubated at room temperature for 40 minutes to terminate the reaction and consume the remaining ATP. Then 10 μL Kinase Detection Reagent (Promega, V9102) was added and incubated at room temperature for 30 minutes to convert ADP into ATP. The ATP was detected using a multifunctional microplate reader ( i3x, Molecular devices) was used to read the fluorescence signal value, which was then normalized and a four-parameter regression equation was used for curve fitting to calculate the half maximal inhibitory concentration (IC) of the compound on the cell line. 50 ).

[0273] The inhibitory activities of the compounds of the present invention on CDK2, CDK4 and CDK6 are shown in Table 3:

[0274] Table 3

[0275] CDK2 / E1 (nM) CDK4 / D3 (nM) CDK6 / D3 (nM) Example 1 76.19 388.5 1121.64 Example 2 67.14 376.1 Example 3 248.57 Example 4 42.23 74.63 995.6 Example 6 47.36 98.77 311.91 Example 7 80.39

[0276] The compounds of the present invention have strong inhibition on CDK2 and CDK4.

Claims

1. The compound represented by Formula I or its pharmaceutically acceptable salt, isotopic derivative, or stereoisomer: in: A represents N or CH; R1 represents H, D, halogen, CN, C1-C3 alkyl, fluorinated C1-C2 alkyl, C3-C6 cycloalkyl, C1-C2 alkoxy; U represents NR2 or CR3; R2 and R3 each independently represent H, D, C1-C6 alkyl, C3-C8 cycloalkyl or C3-C6 heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl or C3-C6 heterocycloalkyl can be arbitrarily replaced by R 20 replace; When U represents NR2, V represents N or CR4, R4 represents H, D, C1-C6 alkyl, C3-C8 cycloalkyl or C3-C6 heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl or C3-C6 heterocycloalkyl can be substituted by R 21 replace; When U represents CR3, V represents NR5, R5 represents H, D, C1-C6 alkyl, C3-C8 cycloalkyl or C3-C6 heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl or C3-C6 heterocycloalkyl can be arbitrarily replaced by R 22 replace; X, Y, and Z each independently represent CR6 or N, wherein R6 represents H, D, F, Cl, CN, CH3, CH2F, CHF2, or CF3; W each independently represents CR7R7', NR7, O or S; R7 and R7' independently represent H, D, halogen, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C2 alkoxy, wherein the C1-C3 alkyl, C1-C2 alkoxy may be optionally replaced by R 23 replace; T represents NR8, CR7NRaR8 or CR9R9', wherein R9, R9' and the C atom to which they are attached form a 4-6 membered heterocyclic ring containing NR8 ring atoms, and the heterocyclic ring may be optionally substituted by R7, wherein, R8 represents -S(=O)2-Cy1 or -S(=O)(=NH)-Cy1, wherein Cy1 represents C6-C 12 Aryl, 5-10 membered heteroaryl, which may be optionally replaced by 0, 1, 2, 3 or 4 R 10 Replacement, R 10 is selected from: deuterium, F, Cl, CN, C1-C3 alkyl and fluorinated C1-C3 alkyl, C3-C6 cycloalkyl or C1-C2 alkoxy, R a represents H, C1-C3 alkyl or halogenated C1-C3 alkyl; R 20 、R 21 、R 22 、R 23 Each independently represents D, F, Cl, CN, OH, C1-C2 alkoxy, NR 24 R 25 、N(R 24 )COR 25 , C3-C8 cycloalkyl, 3-6 membered heterocycloalkyl, the C3-C8 cycloalkyl, 3-6 membered heterocycloalkyl may be optionally substituted by F, OH, C1-C2 alkyl, fluorinated C1-C2 alkyl, C1-C2 alkoxy, fluorinated C1-C2 alkoxy; R 24 and R 25 Each independently represents H, D, C1-C3 alkyl; p is 1, 2, 3, or 4; q is 1, 2, 3 or 4.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, isotopic derivative, or stereoisomer, wherein: R1 represents H, D, halogen, CN, C1-C2 alkyl, fluorinated C1-C2 alkyl, cyclopropyl; preferably, R1 represents Cl, F, methyl, halomethyl; more preferably, R1 is preferably Cl.

3. A compound according to any preceding claim, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein: R2 and R3 each independently represent a C1-C6 alkyl group, and the C1-C6 alkyl group may be optionally replaced by R 20 replace.

4. A compound according to any preceding claim, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein: R4 represents a C1-C6 alkyl group, which may be optionally replaced by R 22 replace.

5. A compound according to any preceding claim, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein: R5 is preferably a C1-C6 alkyl group, which may be optionally replaced by R 22 replace.

6. A compound according to any preceding claim, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein: X represents CF.

7. A compound according to any preceding claim, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein: W stands for CR7R7'.

8. A compound according to any preceding claim, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein: Cy1 is selected from the group consisting of: benzene ring, pyridine, pyrimidine, pyrazine, pyridazine, pyrazole, thiazole, imidazole, isothiazole, morpholine, piperidine, and piperazine.

9. A compound according to any preceding claim, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein: R 10 Selected from F, Cl, CN, C1-C3 alkyl, fluorinated C1-C2 alkyl.

10. A compound according to any preceding claim, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein: R 20 、R 21 、R 22 、R 23 Each independently selected from F, Cl, OH, CN, NR 24 R 25 .

11. A compound according to any preceding claim, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein: X, Y and Z are each independently CR6.

12. A compound according to any preceding claim, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein: U is NR2 and V is CR4.

13. A compound according to any preceding claim, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein: U is CR3 and V is NR5.

14. The compound according to any preceding claim, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, having the structure shown in Formula II: in, Ht represents O or NH, preferably O; m is 0, 1, 2, 3, 4 or 5; n represents 0, 1, 2, 3 or 4.

15. A compound having the following structure or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof:

16. A pharmaceutical composition comprising the compound according to any one of the preceding claims or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof.

17. Use of the compound according to any one of claims 1 to 15 or its pharmaceutically acceptable salt, isotopic derivative, stereoisomer, and the pharmaceutical composition according to claim 16 in the preparation of a medicament for preventing and / or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

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