Novel CCNK-targeting molecular gel degradation agent, preparation method therefor and use thereof

Abstract

The present invention relates to a compound of general formula (I), a preparation method therefor and a use thereof. The compound, as a novel CCNK-targeting molecular gel degradation agent, can be used for treating CCNK-related diseases. Compared with the prior art, the present invention has a broader application prospect.

Description

A novel CCNK molecular glue degrader, a preparation method thereof and application thereof TECHNICAL FIELD

[0001] The present application belongs to the field of medicinal chemistry, and relates to a novel biphenyl molecular glue for triggering polyubiquitination and degrading CCNK (cyclin K), and the derivative structure of the present application is unique and novel in the field. BACKGROUND

[0002] The control of the cell cycle is generally maintained by three different types of proteins, known as CDKs (cyclin-dependent kinases), cyclins and CKIs (CDK inhibitors). Cyclins are a class of proteins that exhibit periodic changes in expression levels during cell cycle regulation, and cyclins were first discovered by Tom Evans in 1983 when studying the cell cycle of sea urchins. Cyclins are a family of proteins that mainly control the cell cycle process by activating CDK activity and other cell cycle-related enzymes. In vertebrates, cyclins include types A, B, D, E, F, G, H and K, and cyclin-dependent kinases (CDKs) can be divided into two categories: cell cycle-related CDKs (CDK1, CDK2, CDK4 and CDK6) and transcription-related CDKs (CDK7, CDK8, CDK9, CDK12 and CDK13). Among them, cyclin K (Cyclin K or CCNK) which is most similar to cyclins C and H is considered a new member of the transcriptional cyclin family. Initially, CCNK was proposed to play a dual role in controlling CDK and RNA polymerase II (RNAP II) activity. Existing studies have shown that CCNK forms a functional complex with CDK9, CDK12 and CDK13, indicating that the protein is involved in the regulation of gene transcription and DNA damage response, as well as maintaining embryonic stem cell pluripotency and genomic stability.

[0003] It has been reported that the mRNA of CCNK is increased in various types of cancer, including cholangiocarcinoma, esophageal cancer, glioblastoma, low-grade glioma, pancreatic cancer, gastric adenocarcinoma and thymoma, etc. In addition, the overexpression of CCNK in diseases has been verified in scientific literature in cancer cell lines and cancer patient samples: CCNK is overexpressed in various human cancer cell lines and invasive breast ductal carcinoma samples. CCNK levels in advanced breast cancer were also found to be elevated compared to early breast cancer. CCNK expression is significantly enhanced in patients with primary prostate cancer, and increased CCNK expression is associated with reduced biochemical recurrence-free survival. CCNK can be used as an independent biomarker to predict the biochemical recurrence-free survival of prostate cancer patients. Increased CCNK levels in lung cancer were observed from lung adenocarcinoma tissue arrays, and studies have also found that increased expression of CCNK is associated with a later stage of the disease. Therefore, the compounds in this study as CCNK degraders are expected to play an important role in the treatment of various cancers, and have broad prospects for research and drug development.

[0004] In addition, in addition to tumor cells, some normal cells in the human body are also in a state of rapid division, such as blood cells and immune cells. Because chemotherapy has strong killing effect on these rapidly dividing cells, one of the main side effects of chemotherapy is the killing of bone marrow and immune cells, which is also the main limiting factor of chemotherapy dose. CCNK is also essential for the growth and proliferation of hematopoietic stem and progenitor cells (HSPCs), which are the "reservoir" for the formation of all blood and immune system cells. Therefore, the use of CCNK degraders before chemotherapy, by suspending the cell cycle of immune cells and HSPCs, reduces their damage and death and enhances the immune response and reduces chemotherapy-induced myelosuppression, thereby treating non-CCNK-dependent tumors and improving the prognosis of chemotherapy patients, and therefore the present application also has the potential to improve chemotherapy regimens.

[0005] The existing CCNK molecular glue degrader (such as HQ461) has the defect of poor metabolic stability, and the inventors, aiming at its metabolic defect, have obtained a series of CCNK molecular glue degraders with excellent anti-tumor activity and good metabolic stability through skeleton transition research, which has a significant advantage and broader application prospect compared to the prior art. SUMMARY

[0006] The technical problem to be solved by the present application is to provide a new type of biphenyl CCNK molecular glue and a preparation method thereof, which provides the possibility of applying CCNK molecular glue to the prevention or / and treatment of cancer, inflammation, and improvement of the toxic side effects of chemotherapy, etc.

[0007] To achieve the above-mentioned purpose, the present application provides the following technical solutions:

[0008] In the first aspect, the present application provides a novel biphenyl CCNK molecule gel breaker, which is a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0009] wherein,

[0010] R is selected from hydrogen, alkyl, cycloalkyl, aryl, wherein the alkyl, cycloalkyl, aryl are optionally further substituted by one or more groups selected from hydrogen, halogen, alkyl, alkoxy, cycloalkyl;

[0011] R1and R2are each independently selected from hydrogen, alkyl, or R1and R2are joined into a carbocyclic ring;

[0012] R3is selected from hydrogen, halogen, alkyl, trifluoromethyl;

[0013] R4is selected from any one of the following structures:

[0014] wherein, R5is optionally selected from hydrogen, alkyl, cycloalkyl, trifluoromethyl, R6is optionally selected from alkyl, cycloalkyl, aryl, five- to six-membered aromatic heterocyclyl, W, X, Y and Z are each independently selected from N, CR7, and R7is optionally selected from hydrogen, halogen, alkyl, cycloalkyl, carboxyl, cyano, trifluoromethyl.

[0015] Preferred compounds of general formula (I) or a pharmaceutically acceptable salt thereof include, but are not limited to:

[0016] wherein,

[0017] R is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, wherein the alkyl, cycloalkyl, aryl are optionally further substituted by one or more groups selected from hydrogen, halogen, alkyl, alkoxy, cycloalkyl;

[0018] R1and R2are each independently selected from hydrogen, C1-C6 alkyl, or R1and R2are joined into a carbocyclic ring;

[0019] R3is selected from hydrogen, halogen, C1-C6 alkyl, trifluoromethyl;

[0020] R4is selected from any one of the following structures:

[0021] wherein, R5is optionally selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, trifluoromethyl, R6is optionally selected from alkyl, cycloalkyl, aryl, five- to six-membered aromatic heterocyclyl, W, X, Y and Z are each independently selected from N, CR7, and R7is optionally selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, carboxyl, cyano, trifluoromethyl.

[0022] More preferred compounds of general formula (I) or a pharmaceutically acceptable salt thereof include, but are not limited to:

[0023] 2-(4-(furan-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (1);

[0024] 2-(4-(furan-3-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (3);

[0025] 2-(4-(furan-3-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (3);

[0026] 5-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)furan-2-carboxylic acid (4);

[0027] 2-(4-(1 -methyl- 1 H-pyrazol-4-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (5);

[0028] 2-(4-(1 -methyl- 1 H-pyrazol-4-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (5);

[0029] 2-(4-(1 -methyl- 1 H-pyrazol-4-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (5);

[0030] N-(5-methylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide (10);

[0031] N-(5-methylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide (10);

[0032] N-(5-methylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide (10);

[0033] N-(5-methylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide (10);

[0034] 2-(4-(6-methylpyridin-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (12);

[0035] 2-(4-(6-methylpyridin-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (12);

[0036] 2-(4-(6-methylpyridin-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (12);

[0037] 2-(4-(3-methylpyridin-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (15);

[0038] 2-(4-(4-cyanopyridin-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (16);

[0039] N-(5-methylthiazol-2-yl)-2-(4-(pyrimidin-2-yl)phenyl)acetamide (17);

[0040] N-(5-methylthiazol-2-yl)-2-(4-(pyrazin-2-yl)phenyl)acetamide (18);

[0041] N-(5-methylthiazol-2-yl)-2-(4-(pyridazin-3-yl)phenyl)acetamide (19);

[0042] N-(5-phenylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide (20);

[0043] 2-(4-(pyridin-2-yl)phenyl)-N-(thiazol-2-yl)acetamide (21);

[0044] N-(5-isopropylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide (22);

[0045] N-(5-methylthiazol-2-yl)-2-(4-(oxazol-2-yl)phenyl)acetamide (24);

[0046] 2-(4-(oxazol-2-yl)phenyl)-N-(5-(trifluoromethyl)thiazol-2-yl)acetamide (25);

[0047] N-(5-isopropylthiazol-2-yl)-2-(4-(oxazol-2-yl)phenyl)acetamide (26);

[0048] 1-(4-(furan-2-yl)phenyl)-N-(5-methylthiazol-2-yl)cyclopropane-1-carboxamide (27);

[0049] 5-methyl-N-(4-(pyridin-2-yl)benzyl)thiazole-2-carboxamide (29);

[0050] 2-(4-acetamidophenyl)-N-(5-methylthiazol-2-yl)acetamide (31);

[0051] N-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-3-carboxamide (32);

[0052] N-(4-(2-(5-methylthiazol-2-ylamino)-2-oxoethyl)phenyl)-1 H-imidazole-2-carboxamide (33);

[0053] N-(4-(2-(5-methylthiazol-2-ylamino)-2-oxoethyl)phenyl)-1 H-imidazole-2-carboxamide (33);

[0054] N-(4-(2-(5-methylthiazol-2-ylamino)-2-oxoethyl)phenyl)-1 H-imidazole-2-carboxamide (33);

[0055] N-(4-(2-(5-methylthiazol-2-ylamino)-2-oxoethyl)phenyl)-1 H-imidazole-2-carboxamide (33);

[0056] N-(4-(2-(5-methylthiazol-2-ylamino)-2-oxoethyl)phenyl)-1 H-imidazole-2-carboxamide (33);

[0057] N-(4-(2-(5-methylthiazol-2-ylamino)-2-oxoethyl)phenyl)-1 H-imidazole-2-carboxamide (33);

[0058] N-(4-(2-(5-methylthiazol-2-ylamino)-2-oxoethyl)phenyl)-1 H-imidazole-2-carboxamide (33);

[0059] N-(4-(2-(5-methylthiazol-2-ylamino)-2-oxoethyl)phenyl)-1 H-imidazole-2-carboxamide (33);

[0060] N-(4-(2-(5-methylthiazol-2-ylamino)-2-oxoethyl)phenyl)-1 H-imidazole-2-carboxamide (33);

[0061] N-(4-(2-(5-methylthiazol-2-ylamino)-2-oxoethyl)phenyl)-1 H-imidazole-2-carboxamide (33);

[0062] N-(4-(2-(5-methylthiazol-2-ylamino)-2-oxoethyl)phenyl)-1 H-imidazole-2-carboxamide (33).

[0063] In a second aspect, the present application relates to the use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof as described above for the manufacture of a medicament for the treatment of a CCNK mediated disease.

[0064] In a third aspect, the present application relates to the use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof as described above for the manufacture of a medicament for the prevention or / and treatment of cancer, inflammation, chemotherapy side effects.

[0065] In a fourth aspect, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof as described above and a pharmaceutically acceptable adjuvant.

[0066] Preferably, the pharmaceutical composition is prepared as a dosage form selected from oral dosage, injection dosage, external use dosage, inhalation dosage or mucosal dosage.

[0067] The following terms, as used in the specification and claims, have the meanings indicated below, unless otherwise apparent from context.

[0068] Any formula or structure, including the compounds of general formula (I), shown herein is also intended to represent unlabelled and isotopically-labeled forms of the compounds. Isotopically-labeled compounds have structures depicted by the formulas given above except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that are within the scope of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, among others. Unless otherwise stated, any atom within a compound of the present application can be an isotope of that atom, for example, any hydrogen can be ¾ or tritium ¾T. Therefore, illustrative isotopically-labeled compounds of the present application which can be prepared include those into which one or more atom has been replaced by an isotope of that atom. For example, compounds of the present application can include one or more deuterium atoms.

[0069] A "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein with other chemical components such that the combinations are useful for

[0070] A "dosage form" of a pharmaceutical composition refers to a particular form in which a drug is combined with an excipient, prepared by a specific process, and suitable for clinical use. According to the route of administration, the dosage forms can be divided into the following categories:

[0071] (1) Oral dosage forms: Oral dosage forms are one of the most important administration methods, and have better patient compliance through oral administration. Dosage forms suitable for oral administration include tablets, such as ordinary tablets (e.g., aspirin tablets), chewable tablets (e.g., calcium tablets), orally disintegrating tablets (e.g., olanzapine orally disintegrating tablets), sustained-release / controlled-release tablets (e.g., nifedipine controlled-release tablets), enteric-coated tablets (e.g., omeprazole enteric-coated tablets), and the like; capsules, such as hard capsules (e.g., cefalexin capsules), soft capsules (e.g., vitamin E soft capsules), enteric-coated capsules (e.g., pancreatin enteric-coated capsules), and the like; granules, such as ordinary granules (e.g., cold granules), sustained-release granules (e.g., ibuprofen sustained-release granules), and the like; oral liquids, such as solutions (e.g., cough syrup), suspensions (e.g., ibuprofen suspension), emulsions (e.g., fish oil oral emulsion), and the like; powders, such as children's fever-reducing powder (to be taken with water), and the like; and pills, such as traditional Chinese medicine pills (e.g., Liuwei Dihuang pills), and the like.

[0072] (2) Injection: Injection is another important dosage form, drugs are directly delivered to the body by injection, usually with the fastest onset time, the least drug loss, and the most direct drug effect. Dosage forms suitable for injection administration include: injection solutions, such as small volume injection solutions (such as water injection, such as vitamin C injection), large volume infusion solutions (such as normal saline infusion), etc.; powder injection, such as penicillin sodium for injection, etc.; suspension type injection, such as long-acting hormone injection, etc.; implant, such as slow-release contraceptive implant rod, etc.

[0073] (3) External dosage form: External dosage form refers to the drug preparation directly used on the skin, mucous membrane or specific site (such as eyes, nasal cavity, ear, rectum, vagina, etc.), mainly for local treatment, and also can play a systemic effect through transdermal absorption (such as nitroglycerin patch). Dosage forms suitable for external use include: ointment, such as erythromycin ointment, etc.; cream, such as bietamelt cream; gel, such as diclofenac sodium gel; patch, such as fentanyl transdermal patch; suppository, such as rectal suppository (such as acetaminophen suppository), vaginal suppository (such as clotrimazole suppository); drops, such as eye drops (such as levofloxacin eye drops), nasal drops (such as fumai nasal drops), ear drops (such as ofloxacin ear drops).

[0074] (4) Inhalation dosage form: Inhalation dosage form refers to a special dosage form for administration through the respiratory tract (nose, mouth, trachea, lung), the drug is delivered to the respiratory system in the form of aerosol, powder or vapor, for local treatment (such as asthma, COPD) or systemic absorption (such as insulin inhalation). Dosage forms suitable for inhalation administration include: aerosol, such as salbutamol aerosol; dry powder inhalation, such as budesonide formoterol powder inhalation; atomized solution, such as terbutaline sulfate atomized solution.

[0075] (5) Mucosal administration dosage form: Mucosal administration dosage form refers to the administration of drugs through oral, nasal, ocular conjunctiva, rectum, vagina and other mucosal surfaces, which has the characteristics of local treatment or systemic effect. Compared with traditional oral or injection administration, mucosal administration can avoid first-pass effect, improve bioavailability, and reduce side effects. Dosage forms suitable for mucosal administration include: sublingual tablets (such as nitroglycerin tablets), buccal film (such as oral ulcer film), nasal spray (such as calcitonin nasal spray), etc.

[0076] Pharmaceutically acceptable carriers, diluents, and excipients are indispensable inactive components in pharmaceutical formulations, used to stabilize the active pharmaceutical ingredient (API), improve drug delivery, regulate release rates, or enhance patient compliance (e.g., taste, appearance). The role of a carrier is to act as a medium for drug delivery, helping the active ingredient reach the target site or controlling release. Common carriers include, but are not limited to: liposomes (e.g., phosphatidylcholine), used to deliver hydrophobic drugs (e.g., liposomes of the antitumor drug doxorubicin); cyclodextrins (e.g., β-cyclodextrin), used to encapsulate poorly soluble drugs to improve solubility (e.g., itraconazole); polymer carriers (e.g., PLGA polylactic-co-glycolic acid copolymer), used for sustained-release injections or implants (e.g., long-acting contraceptives); and nanoparticles (e.g., albumin-bound paclitaxel, trade name...). Diluents increase the volume of a formulation, facilitating dispensing or compression into solid dosage forms (such as tablets or capsules). Common diluents include, but are not limited to, lactose and microcrystalline cellulose (e.g., lactose, microcrystalline cellulose). Mannitol, starch, dicalcium phosphate, etc. There are many types of excipients, which can be further classified according to their functions, such as (1) binders: hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP); (2) disintegrants: crosslinked sodium carboxymethyl cellulose (CCNa), sodium carboxymethyl starch (CMS-Na); (3) lubricants / flow aids: magnesium stearate, silica (colloidal); (4) preservatives: sodium benzoate, para-hydroxybenzoate esters; (5) solubilizers / surfactants: polysorbate 80 (Tween 80), poloxamer (such as Poloxamer 407); (6) flavoring agents / coloring agents: sweeteners, natural pigments; (7) sustained-release / controlled-release materials: ethyl cellulose, carbomer.

[0077] “Cancer” refers to any malignant tumor of any tissue or cell type. Examples of cancer can include cancers that can be caused by abnormally adhering cells or cancers that can be caused by abnormal blood cells (e.g., leukemia, lymphoma, multiple myeloma). Specifically, examples of cancers that can be caused by abnormally adhering cells can include lung cancer (e.g., squamous cell carcinoma, non-small cell lung cancer such as adenocarcinoma, large cell carcinoma, and small cell carcinoma), gastrointestinal cancers (e.g., stomach cancer, colorectal cancer, small bowel cancer, rectal cancer), pancreatic cancer, kidney cancer, liver cancer, thymic cancer, spleen cancer, thyroid cancer, adrenal cancer, prostate cancer, bladder cancer, ovarian cancer, uterine cancer (e.g., endometrial cancer, cervical cancer), bone cancer, skin cancer, brain tumors, sarcomas, melanoma, germ cell tumors (e.g., neurocytoma), adenocarcinoma, squamous cell carcinoma, solid carcinoma, epithelial carcinoma, and mesothelioma. In particular, cancer can be leukemia, especially acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL), chronic leukemia such as chronic myeloid leukemia; adenoid cystic carcinoma, osteosarcoma, ovarian cancer, Ewing tumor, lung adenocarcinoma and prostate cancer, lymphoma, neuroblastoma, gastrointestinal cancer, endometrial cancer, medulloblastoma, prostate cancer, esophageal cancer, breast cancer, thyroid cancer, meningioma, liver cancer, colorectal cancer, pancreatic cancer, chondrosarcoma, osteosarcoma, and kidney cancer.

[0078] Compared with the prior art, the beneficial effects of the present invention are: the present invention provides a novel CCNK molecular glue degrader that can be used to treat CCNK-related diseases, and has a wider range of application prospects compared with the prior art. Attached Figure Description

[0079] Figure 1: Degradation of intracellular CCNK by compound 24 (A) Degradation of intracellular CCNK in A549 cells; (B) CCNK degradation of DCs 50 Line graph.

[0080] Figure 2: Compound 24 improves the histological characteristics of tumor-bearing mice: (A) Experimental procedure of tumor-bearing mouse model; (B) Photograph of tumor tissue; (C) Changes in tumor volume over time; (D) Tumor weight. One-way ANOVA and Tukey's multiple-comparison post hoc test were used for statistical analysis (n=6). *P<0.05, **P<0.01, ***P<0.001 indicate significant differences compared to the model group.

[0081] Figure 3: Effects of compound 24 on liver and kidney toxicity in tumor-bearing mice: (A) serum UA level; (B) serum ALP level, (C) serum BUN level; (D) serum CR level; (E) serum ALT level; (F) serum AST level; (G) serum TBIL level; (H) serum TBA level. Data statistical analysis was performed using one-way ANOVA and Tukey’s multiple-comparison post hoc test (n = 6), *P < 0.05, **P < 0.01, ***P < 0.001 represent significant difference compared with model group. DETAILED DESCRIPTION

[0082] The technical solutions of the present application will be described clearly and completely below in combination with specific examples. Obviously, the described examples are only some of the embodiments of the present application, but not all the embodiments. Based on the examples in the present application, all the other embodiments obtained by those skilled in the art without creative labor are within the protection scope of the present application.

[0083] Synthetic preparation route of the compound of the present application:

[0084] Synthetic route 1:

[0085] Reagents and conditions: (a) methanol, concentrated sulfuric acid, 70°C, 3 hours; (b) sodium carbonate, tetrakis(triphenylphosphine)palladium, 1,4-dioxane / water, under N2protection, 80°C, 16 hours; (c) lithium hydroxide monohydrate, tetrahydrofuran / methanol / water, room temperature, overnight; (d) HBTU, N,N-diisopropylethylamine, dichloromethane, room temperature, 6 hours.

[0086] To a stirred solution of 2b (1.0 equiv) in 1,4-dioxane / water (9:1, v / v) (15 mL) was added furan-2-boronic acid pinacol ester (1.0 equiv), sodium carbonate (3.0 equiv), and tetrakis(triphenylphosphine)palladium (0.05 equiv) sequentially. The reaction mixture was heated to 80 °C in an oil bath under N2for 18 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to give 4a. To a stirred solution of 4a (1 equiv) in tetrahydrofuran / methanol / water (3:3:1) (14 mL) was added lithium hydroxide monohydrate (1.5 equiv) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction was quenched by the dropwise addition of dilute hydrochloric acid to adjust the pH to 3-4. The white solid was collected by filtration and dried to give 5a. To a stirred solution of 5a (1.0 equiv) in dichloromethane was added HBTU (1.1 equiv), N,N-diisopropylethylamine (3 equiv), and 6a (1.1 equiv) sequentially at room temperature. The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate (3x). The combined organic layers were concentrated in vacuo and purified by column chromatography to give the title compound.

[0087] Synthesis Route 2:

[0088] Reagents and conditions: (a) sodium carbonate, tetrakis(triphenylphosphine)palladium, 1,4-dioxane / water, under N2, 80 °C, 16 h; (b) lithium hydroxide monohydrate, tetrahydrofuran / methanol / water, room temperature; (c) HBTU, N,N-diisopropylethylamine, dichloromethane, room temperature, 6 h.

[0089] Methyl 4-borono-2-methylphenylacetate (1 equiv) was dissolved in a mixture of 1,4-dioxane / water (9:1, v / v) (15 mL) and 2-bromothiophene (1.2 equiv), sodium carbonate (3.0 equiv), and tetrakis(triphenylphosphine)palladium (0.05 equiv) were added sequentially. The reaction mixture was heated to 80 °C under N2protection for 18 h. After the reaction was completed, the mixture was cooled to room temperature, extracted, and the organic phases were combined and purified by column chromatography to give 9a. 9a was dissolved in a mixture of tetrahydrofuran / methanol / water (3:3:1) (14 mL), and lithium hydroxide monohydrate (1.5 equiv) was added. The reaction mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation, and dilute hydrochloric acid was added dropwise to adjust the pH to 3-4 to precipitate a white solid. The solid was collected by suction filtration and dried to give 10a. 10a (1.0 equiv) was dissolved in dichloromethane, and HBTU (1.1 equiv), N,N-diisopropylethylamine (3 equiv), and 11b (1.1 equiv) were added sequentially. The reaction mixture was stirred at room temperature for 6 h. The solvent was removed by rotary evaporation, and the residue was extracted with ethyl acetate three times. The organic phases were combined and purified by column chromatography to give the target compound.

[0090] Synthetic Route 3:

[0091] Reagents and conditions: (a) sodium carbonate, tetrakis(triphenylphosphine)palladium, 1,4-dioxane / water, under N2protection, 80 °C, 16 h; (b) trifluoroacetic acid, dichloromethane, reaction for 4 h under ice bath; (c) HBTU, N,N-diisopropylethylamine, dichloromethane, room temperature, 6 h.

[0092] Methyl 3-amino-5-bromobenzoate (1 equiv) and 2-bromopyridine (1.2 equiv) were dissolved in sodium carbonate (3.0 equiv), tetrakis(triphenylphosphine)palladium (0.05 equiv), and the reaction mixture was heated to 80 °C under N2protection for 18 h. After the reaction was completed, the mixture was cooled to room temperature, filtered under reduced pressure, and the filtrate was dried by rotary evaporation. The residue was extracted and the organic phases were combined and purified by column chromatography to give 13a. 13a (1 equiv) was dissolved in dichloromethane, and trifluoroacetic acid (5 equiv) was added dropwise slowly under ice bath for 4 h. After the reaction was completed, the solvent was removed by rotary evaporation, and dichloromethane (10 mL) was added and dried by rotary evaporation three times. Saturated sodium bicarbonate solution was added dropwise under stirring to adjust the pH to 9-10 to precipitate a white solid, which was collected by suction filtration and dried to give 14a. 14a (1.0 equiv) was dissolved in dichloromethane, and HBTU (1.1 equiv), N,N-diisopropylethylamine (3 equiv), and 15a (1.1 equiv) were added sequentially. The reaction mixture was stirred at room temperature for 6 h. The solvent was removed by rotary evaporation, and water was added. The mixture was extracted with ethyl acetate three times. The organic phases were combined and purified by column chromatography to give the target compound.

[0093] Synthetic Route 4:

[0094] 4-Reagents and conditions: (a) HBTU, N,N-diisopropylethylamine, dichloromethane, room temperature, 6 hours; (b) Pd, dichloromethane:methanol (1 :1), H2, room temperature overnight reaction; (c) HBTU, N,N-diisopropylethylamine, dichloromethane, room temperature, 6 hours.

[0095] To a solution of 16a (1.0 equiv) in dichloromethane was added HBTU (1.1 equiv), N,N-diisopropylethylamine (3 equiv) and 6a (1.1 equiv) sequentially and the reaction was stirred at room temperature for 6 hours. The reaction mixture was concentrated and extracted with ethyl acetate (3x). The combined organic layers were purified by column chromatography to give 17a. 17a (1 equiv) was dissolved in a mixture of dichloromethane and methanol and a catalytic amount of Pd was added. The reaction was stirred at room temperature under a hydrogen atmosphere overnight. After the reaction was complete, the reaction mixture was filtered and concentrated to give 18a. 18a (1.0 equiv) was dissolved in dichloromethane and HBTU (1.1 equiv), N,N-diisopropylethylamine (3 equiv) and 19a (1.1 equiv) were added sequentially. The reaction was stirred at room temperature for 6 hours. The reaction mixture was concentrated and extracted with ethyl acetate (3x). The combined organic layers were purified by column chromatography to give the title compound.

[0096] Example 1

[0097] 2-(4-(Furan-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (1)

[0098] Dissolve p-bromophenylacetic acid (1.0 equiv) in methanol, then add concentrated sulfuric acid (3%) dropwise with stirring, and reflux at 70°C for 3 h. After the reaction is complete, cool to room temperature, quench the reaction with water, dry the solvent by rotary evaporation, extract with ethyl acetate, combine the organic phases, and purify by column chromatography to obtain 2b. Then dissolve 2b (1.2 equiv) in a mixture of 1,4-dioxane / water (9:1, v / v) (15 mL), and sequentially add furan-2-boronic acid pinacol ester (1.0 equiv), sodium carbonate (3.0 equiv), and tetrakis(triphenylphosphine)palladium (0.05 equiv), heat to 80°C in an oil bath under N2protection, and reflux for 18 h. After the reaction is complete, cool to room temperature, filter under reduced pressure, dry the filtrate by rotary evaporation, extract, combine the organic phases, and purify by column chromatography to obtain 4a. Dissolve 4a (1 equiv) in a mixture of tetrahydrofuran / methanol / water (3:3:1) (14 mL), add lithium hydroxide monohydrate (1.5 equiv), and react at room temperature overnight. Dry the solvent by rotary evaporation, add dilute hydrochloric acid dropwise to adjust the pH to 3-4, and filter to obtain a white solid. Dry the solid by oven drying to obtain 5a. Dissolve 5a (1.0 equiv) in dichloromethane, then sequentially add HBTU (1.1 equiv), N,N-diisopropylethylamine (3 equiv), and 6a (1.1 equiv), and react at room temperature for 6 h. Dry the solvent by rotary evaporation, extract with water three times, extract with ethyl acetate three times, combine the organic phases, and purify by column chromatography to obtain the target compound. Yield: 60.3%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 7.73 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.13 (s, 1H), 6.91 (d, J = 3.4 Hz, 1H), 6.60-6.56 (m, 1H), 3.74 (d, J = 10.3 Hz, 2H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 169.17, 156.60, 153.35, 143.27, 134.92, 134.73, 130.22, 129.44, 123.94, 120.51, 112.52, 106.14, 41.79, 11.53. TOF-MS m / z: calcd for: C 16 H 15 N2O2S + [M+H] + : 299.0849, found: 299.0844.

[0099] Example 2

[0100] 2-(4-(Furan-2-yl)-3-methylphenyl)-N-(5-methylthiazol-2-yl)acetamide (2)

[0101] Synthesis method same as compound 1. Yield: 68.6%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 7.79 - 7.74 (m, 1H), 7.63 - 7.57 (m, 1H), 7.25 - 7.20 (m, 2H), 7.15 - 7.10 (m, 1H), 6.69 (d, J = 3.4 Hz, 1H), 6.61 (dd, J = 3.4, 1.8 Hz, 1H), 3.72 (s, 2H), 2.43 (s, 3H), 2.31 (s, 4H). 13 C NMR (101 MHz, DMSO-d6) δ 168.72, 156.17, 152.39, 142.49, 134.78, 134.32, 133.93, 132.08, 128.82, 128.29, 126.25, 111.80, 108.90, 41.26, 21.54, 11.10. TOF-MS m / z: calcd for: C 17 H 17 N2O2S + [M+H] + : 313.1005, found: 313.0996.

[0102] Example 3

[0103] (3) 2-(4-(Furan-3-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (3)

[0104] Synthesis method same as compound 1. Yield: 69.4%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.15 (s, 1H), 7.72 (s, 1H), 7.56 (d, J = 7.7 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 7.12 (s, 1H), 6.93 (s, 1H), 3.73 (s, 2H), 2.31 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.85, 156.19, 144.29, 139.21, 134.77, 133.71, 130.56, 129.70, 126.23, 125.60, 120.14, 108.72, 41.35, 11.10. TOF-MS m / z: calcd for: C 16 H 15 N2O2S + [M+H] + : 299.0849, found: 299.0843.

[0105] Example 4

[0106] 5-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)furan-2-carboxylic acid (4)

[0107] Synthesis method same as compound 1. Yield: 72.7%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 7.77 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 3.6 Hz, 1H), 7.13 (s, 1H), 7.11 (d, J = 3.6 Hz, 1H), 3.78 (s, 2H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.55, 159.30, 156.22, 156.14, 144.06, 135.98, 134.78, 130.01, 127.80, 126.28, 124.49, 119.94, 107.79, 41.39, 11.10. TOF-MS m / z: calcd for: C 17 H 15 N2O4S + [M+H] + : 343.0747, found: 343.0734.

[0108] Example 5

[0109] 2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (5)

[0110] Synthesis method same as compound 1. Yield: 68.1%, white powder. 1HNMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.09 (s, 1H), 7.82 (s, 1H), 7.50 (d, J = 7.8 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H), 7.12 (s, 1H), 3.85 (s, 3H), 3.71 (s, 2H), 2.31 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.94, 156.21, 135.98, 134.77, 132.66, 131.24, 129.69, 127.71, 126.22, 124.99, 121.67, 41.33, 38.67, 11.10. TOF-MS m / z: calcd for: C 16 H 17 N4OS + [M+H] + : 313.1118, found: 313.1100.

[0111] Example 6

[0112] 2-(4-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (6)

[0113] Synthesis method is the same as compound 1. Yield: 63.3%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.19 (s, 1H), 7.82 (s, 1H), 7.52 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 7.9 Hz, 2H), 7.12 (s, 1H), 3.71 (s, 2H), 2.54 - 2.47 (m, 1H), 2.31 (s, 3H), 1.10 - 1.04 (m, 2H), 1.01 - 0.93 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 168.93, 156.20, 136.02, 134.77, 132.69, 131.14, 129.65, 126.84, 126.22, 125.03, 121.41, 41.33, 32.79, 11.10, 6.30. TOF-MS m / z: calcd for: C 18 H 19 N4OS + [M+H] + : 339.1274, found: 339.1262.

[0114] Example 7

[0115] 2-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (7)

[0116] Synthesis method is the same with compound 1. Yield: 65.8%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 7.53 - 7.39 (m, 5H), 7.13 (d, J = 1.5 Hz, 1H), 6.37 (d, J = 1.9 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 2H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.66, 156.15, 142.48, 137.92, 135.31, 134.80, 129.68, 128.77, 128.47, 126.30, 105.82, 41.34, 37.54, 11.11. TOF-MS m / z: calcd for: C 16 H 17 N4OS + [M+H] + : 313.1118, found: 313.1102.

[0117] Example 8

[0118] N-(5-methylthiazol-2-yl)-2-(4-(thiophen-2-yl)phenyl)acetamide (8)

[0119] The synthetic method is the same as compound 1. The commercially available methyl 4-boronic acid pinacol ester phenylacetate (1 equiv) was dissolved in a mixed solvent of 1,4-dioxane / water (9:1, v / v) (15 mL), 2-bromothiophene (1.2 equiv), sodium carbonate (3.0 equiv), and tetrakis(triphenylphosphine)palladium (0.05 equiv) were added successively. The reaction was heated to 80 °C in an oil bath under N2protection for 18 h. After the reaction was completed, the reaction was cooled to room temperature, filtered under reduced pressure, and the filtrate was rotary evaporated. The organic phase was extracted and combined, and then purified by column chromatography to obtain 9a. 9a was dissolved in a mixed solvent of tetrahydrofuran / methanol / water (3:3:1) (14 mL), and lithium hydroxide monohydrate (1.5 equiv) was added. The reaction was stirred at room temperature overnight, the solvent was rotary evaporated, diluted hydrochloric acid was added dropwise, and the pH was adjusted to 3-4 to precipitate a white solid. The white solid was filtered and dried to obtain 10a. 10a (1.0 equiv) was dissolved in dichloromethane, and then HBTU (1.1 equiv), N,N-diisopropylethylamine (3 equiv), and 11b (1.1 equiv) were added successively. The reaction was stirred at room temperature for 6 h, the solvent was rotary evaporated, water was added, and the organic phase was extracted with ethyl acetate three times. The combined organic phase was purified by column chromatography to obtain the target compound. Yield: 66.7%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 7.61 (d, J = 7.9 Hz, 2H), 7.55 - 7.45 (m, 2H), 7.35 (d, J = 7.8 Hz, 2H), 7.18 - 7.08 (m, 2H), 3.75 (s, 2H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.72, 156.17, 143.15, 134.79, 134.48, 132.41, 130.00, 128.52, 126.26, 125.58, 125.50, 123.61, 41.28, 11.11. TOF-MS m / z: calcd for: C 16 H 15 N2OS2 + [M+H] + : 315.0620, found: 315.0612.

[0120] Example 9

[0121] 2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (9)

[0122] The synthetic method is the same as compound 8. Yield: 73.5%, white powder.1 HNMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.13 (s, 1H), 3.85 (s, 2H), 2.57 (s, 3H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.27, 163.91, 163.87, 156.07, 138.98, 134.81, 130.33, 126.43, 126.34, 122.13, 41.43, 11.09, 10.67. TOF-MS m / z: calcd for: C 15 H 15 N4O2S + [M+H] + : 315.0910, found: 315.0902.

[0123] Example 10

[0124] N-(5-methylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide (10)

[0125] Synthesis method is the same with compound 8. Yield: 73.5%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.68 - 8.63 (m, 1H), 8.07 - 8.01 (m, 2H), 7.96 - 7.91 (m, 1H), 7.90 - 7.83 (m, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.36 - 7.31 (m, 1H), 7.15 - 7.11 (m, 1H), 3.80 (s, 2H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.71, 156.17, 155.80, 149.54, 137.32, 137.25, 136.04, 134.78, 129.66, 126.59, 126.26, 122.56, 120.14, 41.39, 11.10. TOF-MS m / z: calcd for: C 17 H 16 N3OS + [M+H] + : 310.1009, found: 310.1000.

[0126] Example 11

[0127] N-(5-methylthiazol-2-yl)-2-(4-(pyridin-3-yl)phenyl)acetamide (11)

[0128] Synthesis method same as compound 8. Yield: 77.8%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.88 (d, J = 2.4 Hz, 1H), 8.59 - 8.51 (m, 1H), 8.07 - 8.02 (m, 1H), 7.69 (d, J = 7.9 Hz, 2H), 7.51 - 7.40 (m, 3H), 7.13 (s, 1H), 3.80 (s, 2H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.74, 156.17, 148.31, 147.47, 135.59, 135.41, 135.20, 134.79, 134.22, 130.05, 126.99, 126.28, 123.98, 41.30, 11.11. TOF-MS m / z: calcd for: C 17 H 16 N3OS + [M+H] + : 310.1009, found: 310.1001.

[0129] Example 12

[0130] 2-(4-(6-methylpyridin-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (12)

[0131] Synthesis method same as compound 8. Yield: 68.3%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.88 (d, J = 2.4 Hz, 1H), 8.59 - 8.51 (m, 1H), 8.07 - 8.02 (m, 1H), 7.69 (d, J = 7.9 Hz, 2H), 7.51 - 7.40 (m, 3H), 7.13 (s, 1H), 3.80 (s, 2H), 2.32 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.73, 157.73, 156.18, 155.13, 137.46, 137.44, 135.83, 134.78, 129.58, 126.58, 126.25, 121.83, 117.17, 41.40, 24.37, 11.10. TOF-MS m / z: calcd for: C 18 H 18 N3OS + [M+H] + : 324.1165, found: 324.1155.

[0132] Example 13

[0133] 2-(4-(5-methylpyridin-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (13)

[0134] Synthesis method same as compound 8. Yield: 71.6%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.48 (s, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.13 (s, 1H), 3.79 (s, 2H), 2.32 (s, 6H). 13 CNMR (101 MHz, DMSO-d6) δ 168.74, 156.18, 153.17, 149.78, 137.54, 137.32, 135.63, 134.77, 131.76, 129.60, 126.30, 126.25, 119.55, 41.39, 17.64, 11.09. TOF-MS m / z: calcd for: C 18 H 18 N3OS + [M+H] + : 324.1165, found: 324.1153.

[0135] Example 14

[0136] 2-(4-(4-methylpyridin-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (14)

[0137] Synthesis method same as compound 8. Yield: 84.5%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.03 (d, J = 8.1 Hz, 2H), 7.78 (s, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 4.9 Hz, 1H), 7.13 (s, 1H), 3.79 (s, 2H), 2.38 (s, 3H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.75, 156.18, 155.66, 149.24, 147.92, 137.39, 135.92, 134.80, 129.61, 126.60, 126.29, 123.42, 120.92, 41.40, 20.70, 11.11. TOF-MS m / z: calcd for: C 18 H 18 N3OS + [M+H] + : 324.1165, found: 324.1157.

[0138] Example 15

[0139] 2-(4-(3-methylpyridin-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (15)

[0140] Synthesis method same as compound 8. Yield: 77.6%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 8.50 - 8.44 (m, 1H), 7.73 - 7.67 (m, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.32 - 7.24 (m, 1H), 7.14 (d, 1H), 3.80 (s, 2H), 2.32 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 169.22, 157.89, 156.62, 147.29, 139.35, 139.10, 135.24, 135.17, 130.94, 129.53, 129.29, 126.68, 122.74, 41.84, 20.25, 11.56. TOF-MS m / z: calcd for: C 18 H 18 N3OS+ [M+H] + : 324.1165, found: 324.1152.

[0141] Example 16

[0142] 2-(4-(4-cyanopyridin-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (16)

[0143] Synthesis method same as compound 8. Yield: 69.8%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.90 - 8.87 (m, 1H), 8.45 (s, 1H), 8.14 - 8.09 (m, 2H), 7.81 - 7.76 (m, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.13 (s, 1H), 3.82 (s, 2H), 2.31 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.57, 156.98, 156.15, 150.74, 137.22, 135.59, 134.79, 129.89, 126.92, 126.29, 123.95, 122.11, 120.59, 117.04, 41.39, 11.10. TOF-MS m / z: calcd for: C 18 H 15 N4OS + [M+H] + : 335.0961, found: 335.0953.

[0144] Example 17

[0145] N-(5-methylthiazol-2-yl)-2-(4-(pyrimidin-2-yl)phenyl)acetamide (17)

[0146] Synthesis method same as compound 8. Yield: 73.1%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.89 (d, J = 4.2 Hz, 2H), 8.35 (d, J = 7.6 Hz, 2H), 7.47 (d, J = 7.6 Hz, 2H), 7.43 (t, J = 4.2 Hz, 1H), 7.13 (s, 1H), 3.83 (s, 2H), 2.32 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.55, 163.16, 157.73, 156.15, 137.98, 135.88, 134.78, 129.66, 127.77, 126.29, 119.88, 41.49, 11.10. TOF-MS m / z: calcd for: C 16 H 15 N4OS + [M+H] + : 311.0961, found: 311.0943.

[0147] Example 18

[0148] N-(5-methylthiazol-2-yl)-2-(4-(pyrazin-2-yl)phenyl)acetamide (18)

[0149] Synthesis method same as compound 8. Yield: 75.6%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 9.24 - 9.13 (m, 1H), 8.72 - 8.64 (m, 1H), 8.60 - 8.55 (m, 1H), 8.09 (d, J = 7.9 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H), 7.12 (s, 1H), 3.83 (s, 2H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.33, 155.97, 151.22, 144.03, 143.07, 141.72, 136.85, 134.53, 134.39, 129.68, 126.59, 126.10, 41.26, 10.78. TOF-MS m / z: calcd for: C 16 H 15 N4OS + [M+H] + : 311.0961, found: 311.0947.

[0150] Example 19

[0151] N-(5-methylthiazol-2-yl)-2-(4-(pyridazin-3-yl)phenyl)acetamide (19)

[0152] Synthesis method same as compound 8. Yield: 69.4%, off-white powder. 1HNMR (400 MHz, DMSO-d6) δ 12.22 - 11.90 (m, 1H), 9.23 - 9.14 (m, 1H), 8.16 (dd, J = 8.7, 1.6 Hz, 1H), 8.10 (d, J = 7.9 Hz, 2H), 7.74 (dd, J = 8.6, 4.9 Hz, 1H), 7.51 (d, J = 7.9 Hz, 2H), 7.12 (s, 1H), 3.85 (s, 2H), 2.33 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.33, 158.14, 155.96, 150.17, 136.93, 134.64, 134.53, 129.66, 127.20, 126.71, 126.08, 123.77, 41.25, 10.77. TOF-MS m / z: calcd for: C 16 H 15 N4OS + [M+H] + : 311.0961, found: 311.0945.

[0153] Example 20

[0154] N-(5-phenylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide (20)

[0155] Synthesis method same as compound 8. Yield: 67.7%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.67 (dd, J = 4.9, 1.7 Hz, 1H), 8.07 - 8.03 (m, 2H), 8.00 - 7.93 (m, 2H), 7.92 - 7.88 (m, 2H), 7.61 (s, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.43 (t, 2H), 7.40 - 7.36 (m, 1H), 7.32 (t, J = 7.4 Hz, 1H), 3.87 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 169.36, 157.92, 155.57, 149.18, 148.91, 137.81, 136.97, 136.10, 134.30, 129.79, 128.81, 127.87, 126.74, 125.71, 122.76, 120.49, 108.18, 41.49. TOF-MS m / z: calcd for: C 22 H 18 N3OS+ [M+H] + : 372.1165, found: 372.1154.

[0156] Example 21

[0157] 2-(4-(Pyridin-2-yl)phenyl)-N-(thiazol-2-yl)acetamide (21)

[0158] Synthesis method same as compound 8. Yield: 70.1%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.68 - 8.62 (m, 1H), 8.09 - 8.00 (m, 2H), 7.96 - 7.90 (m, 1H), 7.90 - 7.82 (m, 1H), 7.51 - 7.42 (m, 3H), 7.37 - 7.30 (m, 1H), 7.20 (d, J = 3.6 Hz, 1H), 3.84 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 169.01, 158.00, 155.80, 149.54, 137.69, 137.36, 137.24, 135.95, 129.69, 126.60, 122.55, 120.14, 113.55, 41.41. TOF-MS m / z: calcd for: C 16 H 14 N3OS + [M+H] + : 296.0852, found: 296.0845.

[0159] Example 22

[0160] N-(5-Isopropylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide (22)

[0161] Synthesis method same as compound 8. Yield: 58.5%, white powder. 1HNMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.68 - 8.61 (m, 1H), 8.07 - 8.00 (m, 2H), 7.93 (d, J = 8.1 Hz, 1H), 7.89 - 7.80 (m, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.37 - 7.29 (m, 1H), 7.18 - 7.12 (m, 1H), 3.80 (s, 2H), 3.14 - 3.03 (m, 1H), 1.24 (s, 3H), 1.23 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 169.17, 156.26, 156.24, 149.99, 139.83, 137.76, 137.69, 136.51, 132.47, 130.04, 127.03, 123.00, 120.58, 41.88, 27.16, 24.84. TOF-MS m / z: calcd for: C 19 H 20 N3OS + [M+H] + : 338.1322, found: 338.1309.

[0162] Example 23

[0163] N-(lH-benzimidazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide (23)

[0164] Synthesis method same as compound 8. Yield: 66.5%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 11.86 (s, 1H), 8.69 - 8.62 (m, 1H), 8.10 - 8.03 (m, 2H), 7.94 (d, J = 8.0 Hz, 1H), 7.89 - 7.82 (m, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.46 - 7.41 (m, 2H), 7.33 (dd, J = 7.4, 4.8 Hz, 1H), 7.08 (dd, J = 5.9, 3.2 Hz, 2H), 3.85 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 170.26, 155.79, 149.54, 146.54, 137.30, 137.24, 136.16, 129.67, 126.56, 122.55, 121.06, 120.13, 42.08. TOF-MS m / z: calcd for: C 20H 17 N4OS + [M+H] + :329.1397, found:329.1386.

[0165] Example 24

[0166] N-(5-methylthiazol-2-yl)-2-(4-(oxazol-2-yl)phenyl)acetamide (24)

[0167] Synthesis method same as compound 8. Yield: 37.9%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.20 (s, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.37 (s, 1H), 7.16 - 7.10 (m, 1H), 3.82 (s, 2H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.41, 160.74, 156.12, 140.04, 137.67, 134.78, 130.06, 128.51, 126.30, 126.01, 125.62, 41.43, 11.09. TOF-MS m / z: calcd for: C 15 H 14 N3O2S + [M+H] + :300.0801, found:300.0796.

[0168] Example 25

[0169] 2-(4-(oxazol-2-yl)phenyl)-N-(5-(trifluoromethyl)thiazol-2-yl)acetamide (25)

[0170] Synthesis method same as compound 8. Yield: 59.2%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.37 (s, 2H), 3.93 (s, 2H). 13C NMR (101 MHz, DMSO-d6) δ 169.99, 160.88, 160.70, 140.81, 140.10, 136.94, 130.21, 128.54, 128.47, 126.06, 125.79, 124.20, 41.25. TOF-MS m / z: calcd for: C 15 H 11 N3F3O2S + [M+H] + : 354.0519, found: 354.0508.

[0171] Example 26

[0172] N-(5-isopropylthiazol-2-yl)-2-(4-(oxazol-2-yl)phenyl)acetamide (26)

[0173] Synthesis method same as compound 8. Yield: 45.9%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 8.19 (s, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.36 (s, 1H), 7.16 (s, 1H), 3.81 (s, 2H), 3.13 - 3.04 (m, 1H), 1.24 (s, 3H), 1.23 (s, 3H). 13 CNMR (101 MHz, DMSO-d6) δ 168.50, 160.78, 155.78, 140.10, 139.53, 137.75, 132.08, 130.06, 128.55, 126.06, 125.65, 41.51, 26.75, 24.43. TOF-MS m / z: calcd for: C 17 H 18 N3O2S + [M+H] + : 328.1114, found: 328.1104.

[0174] Example 27

[0175] 1-(4-(furan-2-yl)phenyl)-N-(5-methylthiazol-2-yl)cyclopropane-1-carboxamide (27)

[0176] Synthesis method same as compound 8. Yield: 60.2%, white powder. 1HNMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.75 (s, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 1.6 Hz, 1H), 6.94 (d, J = 1.6 Hz, 1H), 6.64 - 6.56 (m, 1H), 2.31 (d, J = 1.5 Hz, 3H), 1.63 - 1.45 (m, 2H), 1.28 - 1.12 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 175.07, 161.14, 153.32, 143.44, 138.89, 132.34, 131.78, 130.47, 129.79, 124.02, 112.57, 106.39, 31.06, 15.77, 15.70, 11.54. TOF-MS m / z: calcd for: C 18 H 17 N2O2S + [M+H] + : 325.1005, found: 325.0997.

[0177] Example 28

[0178] 1-(3-(Furan-2-yl)phenyl)-N-(5-methylthiazol-2-yl)cyclopropane-1-carboxamide (28)

[0179] Synthesis method is same with compound 8. Yield: 56.2%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.75 (s, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 1.6 Hz, 1H), 6.94 (d, J = 1.6 Hz, 1H), 6.64 - 6.56 (m, 1H), 2.31 (d, J = 1.5 Hz, 3H), 1.63 - 1.45 (m, 2H), 1.28 - 1.12 (m, 2H). 13CNMR (101 MHz, DMSO-d6) δ 175.47, 152.85, 142.97, 132.28, 130.53, 130.15, 129.10, 128.83, 128.80, 124.65, 122.44, 121.61, 112.09, 106.14, 30.87, 15.18, 15.10, 11.07. TOF-MS m / z: calcd for: C 18 H 17 N2O2S + [M+H] + : 325.1005, found: 325.0999.

[0180] Example 29

[0181] 5-methyl-N-(4-(pyridin-2-yl)benzyl)thiazole-2-carboxamide (29)

[0182] Methyl 3-amino-5-bromobenzoate (1 equiv) was dissolved in sodium carbonate (3.0 equiv), tetrakis(triphenylphosphine)palladium (0.05 equiv) and 2-bromopyridine (1.2 equiv) under N2protection, heated to 80 °C in an oil bath for 18 h. After the reaction was completed, it was cooled to room temperature, filtered under reduced pressure, and the filtrate was rotary evaporated. The organic phase was extracted and combined and purified by column chromatography to obtain 13a. 13a (1 equiv) was dissolved in dichloromethane, and trifluoroacetic acid (5 equiv) was slowly added dropwise under ice bath for 4 h. After the reaction was completed, the solvent was rotary evaporated, 10 mL of dichloromethane was added, rotary evaporated, repeated three times, and a saturated sodium bicarbonate solution was added dropwise under stirring to adjust the pH to 9-10. White solid was precipitated and filtered under suction to obtain 14a. 14a (1.0 equiv) was dissolved in dichloromethane, and then HBTU (1.1 equiv), N,N-diisopropylethylamine (3 equiv), and 15a (1.1 equiv) were sequentially added. The reaction was performed at room temperature for 6 h, rotary evaporated, and extracted with ethyl acetate three times. The organic phase was combined and purified by column chromatography to obtain the target compound. Yield: 50.2%, yellow powder. 1 H NMR (400 MHz, DMSO-d6) δ 9.36 (t, J = 6.4 Hz, 1H), 8.65 (d, J = 3.9 Hz, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.92 (d, J = 8.1 Hz, 1H), 7.89 - 7.84 (m, 1H), 7.72 (s, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.37 - 7.29 (m, 1H), 4.51 (d, J = 6.4 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 161.74, 159.42, 155.85, 149.52, 141.98, 140.13, 139.96, 137.41, 137.21, 127.76, 126.52, 122.50, 120.12, 42.24, 11.88. TOF-MS m / z: calcd for: C 17 H 16 N3OS + [M+H] + : 310.1009, found: 310.1002.

[0183] Example 30

[0184] 5-isopropyl-N-(4-(pyridin-2-yl)benzyl)-lH-pyrazole-3-carboxamide (30)

[0185] Synthesis method is the same as compound 29. Yield: 55.2%, yellow powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.88 - 7.80 (m, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.35 - 7.28 (m, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.42 (s, 1H), 4.47 (d, J = 6.3 Hz, 2H), 3.04 - 2.91 (m, 1H), 1.22 (d, J = 6.7 Hz, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 162.22, 155.95, 150.90, 149.54, 141.06, 137.25, 128.66, 127.62, 126.45, 122.50, 101.54, 41.69, 25.14, 22.33. TOF-MS m / z: calcd for: C 19 H 21 N4OS + [M+H] + : 321.1710, found: 321.1693.

[0186] Example 31

[0187] 2-(4-acetamidophenyl)-N-(5-methylthiazol-2-yl)acetamide (31)

[0188] To a solution of 16a (1.0 equiv) in dichloromethane was added HBTU (1.1 equiv), N,N-diisopropyl ethylamine (3 equiv) and 6a (1.1 equiv) sequentially. The mixture was stirred at room temperature for 6 hours. The mixture was concentrated and water was added. The mixture was extracted with ethyl acetate three times. The organic phase was combined and purified by column chromatography to give 17a. 17a (1 equiv) was dissolved in a mixture of dichloromethane and methanol. A catalytic amount of Pd was added. The mixture was stirred at room temperature overnight under hydrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated to give 18a. 18a (1.0 equiv) was dissolved in dichloromethane. HBTU (1.1 equiv), N,N-diisopropyl ethylamine (3 equiv) and 19a (1.1 equiv) were added sequentially. The mixture was stirred at room temperature for 6 hours. The mixture was concentrated and water was added. The mixture was extracted with ethyl acetate three times. The organic phase was combined and purified by column chromatography to give the target compound. Yield: 67%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 9.90 (s, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 7.11 (s, 1H), 3.66 (s, 2H), 2.31 (s, 3H), 2.02 (s, 3H). 13 CNMR (101 MHz, DMSO-d6) δ 169.00, 168.24, 156.20, 138.08, 134.75, 129.55, 129.45, 126.18, 119.06, 41.06, 23.97, 11.09. TOF-MS m / z: calcd for: C 14 H 15 N3NaO2S + [M+H] + : 312.0777, found: 312.0772.

[0189] Example 32

[0190] N-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-3-carboxamide (32)

[0191] Synthesis method is the same as compound 31. Yield: 62%, white powder. 1HNMR (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 12.13 (s, 1H), 10.02 (s, 1H), 7.94 - 7.84 (m, 1H), 7.75 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 7.17 - 7.08 (m, 1H), 6.84 - 6.72 (m, 1H), 3.69 (s, 2H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 169.00, 160.42, 156.22, 146.72, 134.75, 130.40, 129.35, 126.17, 120.29, 105.66, 41.11, 11.10. TOF-MS m / z: calcd for: C 16 H 16 N5O2S + [M+H] + : 342.1019, found: 342.1012.

[0192] Example 33

[0193] N-(4-(2-(5-methylthiazol-2-ylamino)-2-oxoethyl)phenyl)-1H-imidazole-2-carboxamide (33)

[0194] Synthesis method is same with compound 31. Yield: 64%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 10.34 (s, 1H), 7.81 - 7.73 (m, 2H), 7.31 - 7.21 (m, 4H), 7.15 - 7.08 (m, 1H), 3.69 (s, 2H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 169.04, 156.86, 156.36, 140.99, 137.23, 134.73, 130.33, 129.39, 126.09, 120.32, 41.16, 11.12. TOF-MS m / z: calcd for: C 16 H 16 N5O2S + [M+H] + : 342.1019, found: 342.1012.

[0195] Example 34

[0196] N-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)benzamide (35)

[0197] Synthesis method same as compound 31. Yield: 63%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 10.62 (s, 1H), 8.76 - 8.69 (m, 1H), 8.19 - 8.11 (m, 1H), 8.10 - 8.01 (m, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.71 - 7.62 (m, 1H), 7.30 (d, J = 8.5 Hz, 2H), 7.15 - 7.08 (m, 1H), 3.72 (s, 2H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.94, 162.40, 156.20, 149.89, 148.44, 138.16, 137.09, 134.75, 130.58, 129.47, 126.93, 126.17, 122.38, 120.35, 41.12, 11.10. TOF-MS m / z: calcd for: C 18 H 17 N4O2S + [M+H] + : 353.1067, found: 353.1058.

[0198] Example 35

[0199] N-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)benzamide (35)

[0200] Synthesis method same as compound 31. Yield: 67%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 10.62 (s, 1H), 8.76 - 8.69 (m, 1H), 8.19 - 8.11 (m, 1H), 8.10 - 8.01 (m, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.71 - 7.62 (m, 1H), 7.30 (d, J = 8.5 Hz, 2H), 7.15 - 7.08 (m, 1H), 3.72 (s, 2H), 2.32 (s, 3H). 13CNMR (101 MHz, DMSO-d6) δ 169.00, 165.51, 156.23, 137.93, 134.94, 134.76, 131.59, 130.31, 129.41, 128.42, 127.67, 126.21, 120.47, 41.13, 11.11. TOF-MS m / z: calcd for: C 19 H 18 N3O2S + [M+H] + : 352.1114, found: 352.1109.

[0201] Example 36

[0202] N-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)isoxazole-5-carboxamide (36)

[0203] Synthesis method same as compound 31. Yield: 59%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 10.75 (s, 1H), 8.81 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 7.29 - 7.20 (m, 1H), 7.16 - 7.06 (m, 1H), 3.72 (s, 2H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.85, 162.62, 156.18, 154.01, 151.90, 136.49, 134.77, 131.36, 129.61, 126.21, 120.81, 106.80, 41.09, 11.10. TOF-MS m / z: calcd for: C 16 H 15 N4O3S + [M+H] + : 343.0859, found: 343.0852.

[0204] Example 37

[0205] N-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)oxazole-5-carboxamide (37)

[0206] Synthesis method same as compound 31. Yield: 57%, white powder.1 HNMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 10.43 (s, 1H), 8.65 (s, 1H), 7.98 (s, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.18 - 7.07 (m, 1H), 3.71 (s, 2H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.90, 156.20, 154.90, 153.84, 145.22, 136.81, 134.76, 130.90, 130.06, 129.56, 126.20, 120.59, 41.08, 11.10. TOF-MS m / z: calcd for: C 16 H 15 N4O3S + [M+H] + : 343.0859, found: 343.0848.

[0207] Example 38

[0208] N-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)oxazole-2-carboxamide (38)

[0209] Synthesis method same as compound 31. Yield: 53%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 10.43 (s, 1H), 8.65 (s, 1H), 7.98 (s, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.18 - 7.07 (m, 1H), 3.71 (s, 2H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.90, 156.20, 154.90, 153.84, 145.22, 136.81, 134.76, 130.90, 130.06, 129.56, 126.20, 120.59, 41.08, 11.10. TOF-MS m / z: calcd for: C 16 H 15 N4O3S + [M+H] + : 343.0859, found: 343.0851.

[0210] Example 39

[0211] N-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)isoxazole-3-carboxamide (39)

[0212] Synthesis method same as compound 31. Yield: 58%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 10.71 (s, 1H), 9.17 - 9.13 (m, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.15 - 7.09 (m, 1H), 7.04 - 7.00 (m, 1H), 3.71 (s, 2H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.87, 161.69, 158.30, 157.12, 156.18, 136.75, 134.76, 131.12, 129.54, 126.19, 120.69, 104.59, 41.08, 11.10. TOF-MS m / z: calcd for: C 16 H 15 N4O3S + [M+H] + : 343.0859, found: 343.0846.

[0213] Example 40

[0214] N-(5-methylthiazol-2-yl)-2-(4-(thiazol-2-yl)phenyl)acetamide (40).

[0215] Synthesis method same as compound 8. Yield: 44%, yellowish powder, m.p. 212-213 °C. 1 HNMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 10.71 (s, 1H), 9.17 - 9.13 (m, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.15 - 7.09 (m, 1H), 7.04 - 7.00 (m, 1H), 3.71 (s, 2H), 2.32 (s, 3H). 13C NMR (101 MHz, DMSO) δ 168.46, 166.92, 156.13, 143.83, 137.25, 134.77, 131.77, 130.14, 126.27, 120.37, 41.37, 11.09. TOF-MS m / z: calcd for: C 15 H 14 N3OS2 + [M+H] + : 316.0573, found: 316.0565.

[0216] Example 41

[0217] N-(5-methylthiazol-2-yl)-2-(4-(4-methylthiazol-2-yl)phenyl)acetamide (41).

[0218] Synthesis as for compound 8. Yield: 47%, white powder, m.p. 215-216 °C. 1 HNMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.32 - 7.27 (m, 1H), 7.15 - 7.11 (m, 1H), 3.80 (s, 2H), 2.41 (s, 3H), 2.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.47, 166.06, 156.13, 153.27, 137.08, 134.79, 131.87, 130.08, 126.27, 126.04, 114.56, 41.37, 16.96, 11.10. TOF-MS m / z: calcd for: C 16 H 16 N3OS2 + [M+H] + : 330.0729, found: 330.0721.

[0219] Example 42

[0220] N-(5-methylthiazol-2-yl)-2-(4-(5-methylthiazol-2-yl)phenyl)acetamide (42).

[0221] Synthesis as for compound 8. Yield: 49%, white powder, m.p. 228-229 °C. 1HNMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.62 - 7.56 (m, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.17 - 7.11 (m, 1H), 3.79 (s, 2H), 2.48 (s, 3H), 2.32 (s, 3H). 13 CNMR (101 MHz, DMSO-d6) δ 168.49, 165.13, 156.12, 141.69, 136.90, 134.77, 134.10, 132.02, 130.07, 126.25, 125.85, 41.35, 11.66, 11.09. TOF-MS m / z: calcd for: C 16 H 16 N3OS2 + [M+H] + : 330.0729, found: 330.0719.

[0222] Example 43

[0223] 2-(4-(5-cyanothiazol-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (43).

[0224] Synthesis as for compound 8. Yield: 52%, white powder, m.p. 285-286 °C. 1 HNMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.62 - 7.56 (m, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.17 - 7.11 (m, 1H), 3.79 (s, 2H), 2.48 (s, 3H), 2.32 (s, 3H). 13 CNMR (101 MHz, DMSO-d6) δ 168.49, 165.13, 156.12, 141.69, 136.90, 134.77, 134.10, 132.02, 130.07, 126.25, 125.85, 41.35, 11.66, 11.09. TOF-MS m / z: calcd for: C 16 H 13 N4OS2 + [M+H] + : 341.0525, found: 341.0517.

[0225] Example 44 In vitro biological activity test

[0226] 1) 7000 A549 cells (or MDA-MB-231 cells, HepG2 cells) per well were cultured in 96-well flat-bottom plates. After overnight culture, the medium in the wells was removed, 100 μL of different concentrations of compounds prepared with complete medium was added, mixed well, and cultured for 4 days; the cell survival rate was measured by cell counting kit-8 (CCK-8), 10 μL of CCK-8 was added to each well, mixed well, and incubated in the incubator for 1 hour, and then the fluorescence intensity of the system was measured using a Thermo multifunctional enzyme labeler. IC 50 The results are shown in Table 1, and the results show that the compounds of the present application have good broad-spectrum anti-tumor cell proliferation activity.

[0227] 2) Western blotting detection

[0228] The protein level was determined by standard Western blotting. After A549 cells were cultured with different concentrations of compounds for 24 hours, the cells were collected with trypsin, and total protein was extracted with 1x RIPA lysis buffer (NCM Biotech, China). Then, an equal amount of protein (4-40 μg / lane) in the total cell lysate was separated by sodium dodecyl sulfate (8%, 10%, or 12%) polyacrylamide gel electrophoresis, wet-transferred to a PVDF membrane (Merck Millipore, Germany), and incubated with a primary antibody for CCNK overnight, and then incubated with a secondary antibody specific for the same species for 1 hour at 37°C. The ChemiDOC XRS system (BioRad Laboratories, Hercules, CA) was used to detect the bound immune complexes. The experimental results are shown in Table 1 and Figure 1, and the results show that the compounds of the present application have the ability to degrade CCNK protein (Table 1), and compound 24 can degrade CCNK protein in a dose-dependent manner (Figure 1), with a degradation IC 50 41.5 nM, which is much better than the positive control HQ461.

[0229] Table 1: Tumor cell anti-proliferation activity and CCNK protein degradation activity

[0230] Note: a The inhibition rate is the average of three independent experiments, and the IC 50 value is the average ± standard deviation of three independent experiments.

[0231] b Indicates the degradation rate of CCNK protein in A549 cells (average of three independent repeated experiments, incubated for 24 h).

[0232] Example 45 In vitro liver microsomal stability study

[0233] The test compound concentration 1 μM and liver microsomes (concentration 0.5 mg / mL) were incubated at 37°C for 5 min, and the metabolic reaction was started by adding reduced coenzyme (NADPH, 5 mM). The incubation system solution was PBS buffer (pH 7.4), and the content of DMSO was less than 1% of the total volume, ensuring that the microsomal enzyme activity was not affected. The experimental group, positive control group (testosterone) and negative control group (without reduced coenzyme) were set. The incubation samples were immediately taken out at 0, 15 min after the start of the incubation system and added to 150 μL of ice methanol containing an internal standard to terminate the reaction, vortexed for 1 min, centrifuged at 10,000 rpm for 5 min, and 100 μL of supernatant was mixed with 300 μL of methanol-water solution (1:1, v / v) to filter with a filter membrane. 20 μL was taken for LC-MS / MS determination of the response peak area of the test compound and the internal standard, and the percentage of the remaining original drug after 15 min of liver microsomal incubation was calculated. The experimental results are shown in Table 2. The results show that the liver microsomal stability of HQ461 is poor in each animal species, and the liver microsomal stability of the compounds of the present application is significantly better than that of HQ461, and has better metabolic stability.

[0234] Table 2: In vitro liver microsomal stability of preferred compounds (percentage of remaining original drug after 15 min of incubation)

[0235] a All the values are expressed as mean±SD (n=3).

[0236] b ND means not detected.

[0237] Example 46 Pharmacokinetic study

[0238] To prepare the preparation required for oral administration, the compound was dissolved in a mixture of 5% DMSO and 0.5% CMC-Na. After a single oral dose (3 mg / kg) in SD rats, blood samples were collected at predetermined time points, and each sample had a volume of 200 μL. The blood samples were placed in test tubes containing sodium heparin and stored on ice. Then they were centrifuged at 12,000 g for 10 minutes at a temperature of 2 to 8 degrees Celsius, and the collected samples were placed for 1 hour. When analyzed, 50 μL aliquots of the plasma samples were precipitated with 200 μL of methanol, the mixture was vortexed for 3 minutes, centrifuged at 12,000 rpm for 10 minutes, and the supernatant was added to the internal standard for LC-MS / MS analysis. The results of the pharmacokinetic experiment are shown in Table 3. The results show that compared with HQ461, compound 24 has more excellent in vivo pharmacokinetic properties and is suitable for oral administration.

[0239] Table 3: Pharmacokinetic parameters

[0240] a T 1 / 2 half-life.

[0241] b Cl,intrinsic clearance rate.

[0242] Example 47 Study of Anti-tumor Activity in vivo

[0243] Six-week-old female Balb / c nude mice were purchased from Guangdong Medical Laboratory Animal Center (License No. SCXK(Y)2022-0002) and were raised in a SPF barrier environment. During the entire experiment, the temperature and relative humidity of the animal room were controlled at 23±2℃, 50±10%, and the light / dark cycle was constant at 12 hours. Before starting the animal experiment, all mice were adaptively raised for one week. The mice were raised under specific pathogen-free conditions and could freely obtain feed and water. A549 cells in the logarithmic growth phase and with a confluence of 80% were collected, resuspended into a cell suspension with a density of 6×10 6 The right abdominal skin of the mice was sterilized with 75% ethanol, 100 μL of the cell suspension was injected subcutaneously into the right abdomen of the mice using a 1 mL syringe, the needle was slowly withdrawn, and the injection site was gently pressed for 30 s with a cotton swab to prevent the cell suspension from exuding. The size of the tumor was measured every other day using a digital vernier caliper. When the tumor volume reached a mean of about 100 mm 3After (tumor volume = (length x width2) / 2), the mice were randomly divided into 4 groups, 6 in each group. Then daily gavage administration, the model group was given 0.5% carboxymethylcellulose sodium (CMC-Na), 24 low-dose group (10 mg / kg), 24 middle-dose group (20 mg / kg) and 24 high-dose group (40 mg / kg), for 17 days. During the administration, the mouse body weight and tumor volume were recorded every other day. Before sampling, the mice were fasted for 8 h (free water), given 2% sodium pentobarbital (50 mg / kg) for intraperitoneal injection anesthesia, then blood was collected by orbital blood collection, the mice were killed by cervical dislocation, fixed on the mouse table, after the blood collection was completed, the complete tumor tissue was stripped, weighed and photographed. The tumor tissue was placed in a 1.5 mL cryogenic tube, frozen in liquid nitrogen, and then stored at -80℃ for later use. The total protein of the tumor tissue was extracted for Western blotting experiment to detect the expression of the target protein. The experimental results are shown in Figures 2 and 3, and the results show that the tumor volume of the mice in the low, middle and high dose groups of compound 24 is significantly smaller than that of the control group, and the tumor weight of the mice is also significantly lower than that of the control group, indicating that compound 24 can inhibit the growth of transplanted tumors in vivo (Figure 2). In addition, compared with the model group, each dose of compound 24 did not significantly affect the content of ALT, AST, ALP, TBA and TBIL in the serum of the mice, indicating that compound 24 has no obvious hepatotoxicity at the pharmacological dose (Figure 3); in addition, the CR, BUN and UA of the administration group decreased significantly, indicating that compound 24 may have a good protective effect on kidney function under the condition of tumor-bearing.

[0244] The details of the present application not described are well known to those skilled in the art.

[0245] Finally, it should be pointed out that the above specific embodiments are only used to illustrate the technical solutions of the present application and are not limiting. Although the present application has been described in detail with reference to the examples, those skilled in the art should understand that the technical solutions of the present application can be modified and replaced by equivalents without departing from the spirit and scope of the technical solutions of the present application, which should be covered in the scope of the claims of the present application.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: wherein, R is selected from hydrogen, alkyl, cycloalkyl, aryl, wherein said alkyl, cycloalkyl, aryl are optionally further substituted by one or more groups selected from hydrogen, halogen, alkyl, alkoxy, cycloalkyl; R1and R2are each independently selected from hydrogen, alkyl, or R1and R2are joined into a carbocyclic ring; R3is selected from hydrogen, halogen, alkyl, trifluoromethyl; R4is selected from any one of the following structures: wherein, R5is optionally selected from hydrogen, alkyl, cycloalkyl, trifluoromethyl, R6is optionally selected from alkyl, cycloalkyl, aryl, five- to six-membered aromatic heterocyclyl, W, X, Y and Z are each independently selected from N, CR7, said R7is optionally selected from hydrogen, halogen, alkyl, cycloalkyl, carboxyl, cyano, trifluoromethyl.

2. A compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof: wherein, wherein, R is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, wherein said alkyl, cycloalkyl, aryl are optionally further substituted by one or more groups selected from hydrogen, halogen, alkyl, alkoxy, cycloalkyl; R1and R2are each independently selected from hydrogen, C1-C6 alkyl, or R1and R2are joined into a carbocyclic ring; R3is selected from hydrogen, halogen, C1-C6 alkyl, trifluoromethyl; R4is selected from any one of the following structures: wherein, R5is optionally selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, trifluoromethyl, R6is optionally selected from alkyl, cycloalkyl, aryl, five- to six-membered aromatic heterocyclyl, W, X, Y and Z are each independently selected from N, CR7, said R7is optionally selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, carboxyl, cyano, trifluoromethyl.

3. A compound of general formula (I) according to claim 1 or 2, including but not limited to: 2-(4-(furan-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (1); 2-(4-(furan-2-yl)-3-methylphenyl)-N-(5-methylthiazol-2-yl)acetamide (2); 2-(4-(furan-3-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (3); 5-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)furan-2-carboxylic acid (4); 2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (5); 2-(4-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (6); 2-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (7); N-(5-methylthiazol-2-yl)-2-(4-(thiophen-2-yl)phenyl)acetamide (8); 2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (9); N-(5-methylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide (10); N-(5-methylthiazol-2-yl)-2-(4-(pyridin-3-yl)phenyl)acetamide (11); or a pharmaceutically acceptable salt thereof. 2-(4-(furan-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (1); 2-(4-(furan-2-yl)-3-methylphenyl)-N-(5-methylthiazol-2-yl)acetamide (2); 2-(4-(furan-3-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (3); 5-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)furan-2-carboxylic acid (4); 2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (5); 2-(4-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (6); 2-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (7); N-(5-methylthiazol-2-yl)-2-(4-(thiophen-2-yl)phenyl)acetamide (8); 2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (9); N-(5-methylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide (10); N-(5-methylthiazol-2-yl)-2-(4-(pyridin-3-yl)phenyl)acetamide (11); ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 2-(4-(6-methylpyridin-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (12); 2-(4-(5-methylpyridin-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (13); 2-(4-(4-methylpyridin-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (14); 2-(4-(3-methylpyridin-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (15); 2-(4-(4-cyanopyridin-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (16); N-(5-methylthiazol-2-yl)-2-(4-(pyrimidin-2-yl)phenyl)acetamide (17); N-(5-methylthiazol-2-yl)-2-(4-(pyrazin-2-yl)phenyl)acetamide (18); N-(5-methylthiazol-2-yl)-2-(4-(pyridazin-3-yl)phenyl)acetamide (19); N-(5-phenylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide (20); 2-(4-(pyridin-2-yl)phenyl)-N-(thiazol-2-yl)acetamide (21); N-(5-isopropylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide (22); N-(5-methylthiazol-2-yl)-2-(4-(oxazol-2-yl)phenyl)acetamide (24); 2-(4-(oxazol-2-yl)phenyl)-N-(5-(trifluoromethyl)thiazol-2-yl)acetamide (25); N-(5-isopropylthiazol-2-yl)-2-(4-(oxazol-2-yl)phenyl)acetamide (26); 1-(4-(furan-2-yl)phenyl)-N-(5-methylthiazol-2-yl)cyclopropane-1-carboxamide (27); 5-methyl-N-(4-(pyridin-2-yl)benzyl)thiazole-2-carboxamide (29); 2-(4-acetamidophenyl)-N-(5-methylthiazol-2-yl)acetamide (31); N-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-3-carboxamide (32); N-(4-(2-(5-methylthiazol-2-ylamino)-2-oxoethyl)phenyl)-1H-imidazole-2-carboxamide (33); N-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)picolinamide (34); N-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)benzamide (35); N-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)isoxazole-5-carboxamide (36); N-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)oxazole-5-carboxamide (37); N-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)oxazole-2-carboxamide (38); N-(4-(2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)oxazole-2-carboxamide (38); N-(5-methylthiazol-2-yl)-2-(4-(5-methylthiazol-2-yl)phenyl)acetamide (42); N-(5-methylthiazol-2-yl)-2-(4-(5-methylthiazol-2-yl)phenyl)acetamide (42); N-(5-methylthiazol-2-yl)-2-(4-(5-methylthiazol-2-yl)phenyl)acetamide (42); 2-(4-(5-cyanothiazol-2-yl)phenyl)-N-(5-methylthiazol-2-yl)acetamide (43).

4. Use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of CCNK-mediated diseases.

5. Use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 for the manufacture of a medicament for the prevention or / and treatment of cancer, inflammation, chemotherapy side effects.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and a pharmaceutically acceptable adjuvant.

7. The pharmaceutical composition according to claim 6, which is prepared in a dosage form selected from the group consisting of oral, injectable, topical, inhalable or mucosal dosage forms.

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