Cyclin k degraders

Abstract

Provided are a compound of formula (I) and a pharmaceutical composition thereof. The compound of formula (I) can be used as a degradation agent for CyclinK protein, and can be used for preventing or treating diseases related to CyclinK protein.

Description

[0001] This application claims priority to Chinese Patent Application 202110994191.8, filed on August 27, 2021, entitled “Cell Cycle K Degradation Agents,” the contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0002] The present application relates to a compound that degrades cell cycle K, and methods of using the same to treat / prevent cell cycle K related disorders. BACKGROUND

[0003] Tumors are the second largest killer of human health, and about 100 million people die from tumors worldwide each year. Abnormal expression of cell proteins is considered an important factor leading to the occurrence and development of tumors, so most drugs target these abnormally expressed proteins. Compared with traditional inhibitor-based drug development, drug-induced protein degradation is a new strategy for these tumor-related proteins. According to the mechanism of action, protein degraders can be divided into three categories, namely, proteolysis targeting chimeras (PROTACs), monovalent degraders, and molecular glue degraders (Burslem, G. M. & Crews, C. M. Chem. Rev. 117, 11269-11301 (2017).) In recent years, protein degradation-based technology has been successfully applied to the development of anti-tumor drugs, and it is expected that at least 15 protein degradation drugs will enter clinical trials by the end of 2021.

[0004] PROTAC is the most widely used protein degradation technology at present, which is usually composed of a protein targeting binding region, an E3 ubiquitin ligase recruiting region and a linker. PROTAC molecules bind to target proteins and recruit E3 ligases, leading to ubiquitination of target proteins and ultimately degradation of target proteins. Due to the large molecular weight of PROTAC (usually between 700-1200), their membrane permeability and oral bioavailability are poor. The molecular weight of monovalent degraders and molecular glues is much smaller than that of PROTAC, which is more consistent with the Lipinski five principles (den Besten, W. et al. Nat Chem Biol 16, 1157-1158 (2020)). Monovalent degraders induce degradation by changing the conformation of the protein or other changes. Molecular glue induces the interaction between Culin-RING E3 ligase and target protein, ultimately leading to the degradation of target protein. Molecular glue-mediated degradation of target proteins can be independent of the ligand pocket of the target protein, such as the thalidomide analog (Simonetta, K. R. et al. Nat Commun 10, 1402 (2019)) and aryl sulfonamide analog (Baek, K. et al. Nat Chem Biol 16, 2-3 (2020)) that have been reported. Therefore, molecular glue can bring new hope for targets that were previously difficult to develop due to the lack of suitable ligand pockets.

[0005] CCNK, also known as Cyclin K, is the most important cell cycle protein of cell cycle protein-dependent kinase 12 / 13 (CDK12 / 13) eral.Int J Mol Sci.2021Mar;22(6):2935)。It can be involved in the regulation of transcription, post-transcriptional modification, cell cycle, cell proliferation and other biological processes by forming a complex with CDK12 / 13. Early studies have shown that CDK12 / 13 regulates the activity of RNA polymerase II by forming a complex with Cyclin K and phosphorylating the C-terminal domain of RNA polymerase II, thereby regulating the expression of DNA damage repair genes such as BRCA1, ATR, FANC1, etc. (Malgorzata Krajewska et al. Nat Commun. 2019 Apr 15; 10(1): 1757.). CDK12 / 13 is considered a potential tumor treatment target (Cells 2020, 9(6), 1483;), and by designing a degrader targeting Cyclin K to affect the formation of CDK12 / 13 and Cyclin K protein complex, a new idea is provided for inhibiting the function of CDK12 / 13. In 2020, Benjamin L. Ebert et al. reported (Nature 2020, 585, 293-297.) that CDK inhibitor CR8 is a molecular glue degrader that induces the degradation of Cyclin K protein. However, there are still few and unsatisfactory molecular glue degraders targeting Cyclin K, and there is an urgent need to find compounds with good degradation activity for Cyclin K. SUMMARY

[0006] The present application provides a class of compounds with good Cyclin K degradation activity, and the use of the compounds and their pharmaceutically acceptable salts, prodrugs, isotopic derivatives, isomers, solvates or metabolites thereof, and pharmaceutical compositions containing the compounds in the treatment or prevention of Cyclin K related disorders.

[0007] In one aspect of the present application, a compound having the structure of formula (I) or its pharmaceutically acceptable salt, prodrug, isotopic derivative, isomer, solvate or metabolite thereof is provided:

[0008]

[0009] wherein Cy 1 and Cy 2 each independently represents a 6-membered aromatic ring or a 6-membered heteroaromatic ring;

[0010] wherein R L and R L’ each independently represents hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl, R L and R L’ may form a 3-6 membered ring together with the carbon atom to which they are attached

[0011] wherein each W1is independently selected from CR 0 or N;

[0012] wherein R 0 represents hydrogen, halogen, nitro, cyano, -R a , -OR a , -SR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)2R a , -NR a C(O)R b , -S(O)2NR a , -S(O)R a , -P(O)R a R b ;

[0013] wherein each W2is independently selected from CR 1 or N;

[0014] wherein R 1 each independently represents hydrogen, halogen, nitro, cyano, -R a , -OR a , -SR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b , -P(O)R a R b , and C1-C6 alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl optionally substituted with 0, 1, 2, 3 substituents selected from OR a , SR a , NR a R b , NR a C(O)R b , C(O)R a , C(O)ORa , C(O)NR a R b , S(O)2R a , S(O)R a , S(O)2NR a R b , P(O)R a R b ;

[0015] wherein R 2 represents halogen, -R a , -OR a , -SR a , nitro, cyano, -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b , -P(O)R a R b ; (C2-C6)alkenyl, (C2-C6)alkynyl;

[0016] wherein R 3 represents C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C3-C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, -NR M R N , -NHR M , -OR M ;

[0017] when R 3 represents C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C3-C 10 cycloalkyl, 3-10 membered heterocycloalkyl, it is optionally substituted with 0, 1, 2, 3 substituents selected from the group consisting of oxo, nitro, halogen, cyano, -R a , -(C0-C6alkylene)OR a , -(C0-C6alkylene)SR a , -(C0-C6alkylene)NR a R b , -(C0-C6alkylene)NR aC(O)R b -(C0-C6alkylene)C(O)R a -(C0-C6alkylene)C(O)OR a -(C0-C6alkylene)C(O)NR a R b -(C0-C6alkylene)S(O)2R a -(C0-C6alkylene)S(O)R a -(C0-C6alkylene)S(O)2NR a R b -(C0-C6alkylene)P(O)R a R b ;

[0018] when R 3 represents C6-C 10 10 membered heteroaryl, it is optionally substituted with 0, 1, 2, 3 substituents selected from the group consisting of nitro, halogen, cyano, -R a -(C0-C6alkylene)OR a -(C0-C6alkylene)SR a -(C0-C6alkylene)NR a R b -(C0-C6alkylene)NR a C(O)R b -(C0-C6alkylene)C(O)R a -(C0-C6alkylene)C(O)OR a -(C0-C6alkylene)C(O)NR a R b -(C0-C6alkylene)S(O)2R a -(C0-C6alkylene)S(O)R a -(C0-C6alkylene)S(O)2NR a R b -(C0-C6alkylene)P(O)R a R b ;

[0019] when R 3 represents -NR M R N , -NHR M , -OR M , R M and R N each independently represent C1-C6alkyl, -(C0-C6alkylene)(C3-C 10C6alkyl), -(C0-C6alkylene)(3-10 membered cycloalkyl), -(C0-C6alkylene)(C6-C10aryl), -(C0-C6alkylene)(5-10 membered heteroaryl); 10 C6alkyl), -(C0-C6alkylene)(3-10 membered cycloalkyl), -(C0-C6alkylene)(C6-C10aryl), -(C0-C6alkylene)(5-10 membered heteroaryl);

[0020] wherein R M and R N are each independently hydrogen, C1-C6alkyl, or C3-C8cycloalkyl, which are optionally substituted with 0, 1, 2, 3 halogen atoms; a a a a b a b a a a b a a a b a b ;

[0021] wherein R a , R b are each independently hydrogen, C1-C6alkyl, or C3-C8cycloalkyl, which are optionally substituted with 0, 1, 2, 3 halogen atoms;

[0022] with the proviso that the compound of formula (I) does not include

[0023]

[0024] In another embodiment, R 2 is halogen, trifluoromethyl, or cyano.

[0025] In another embodiment, Cy1is selected from:

[0026] Preferably Cy1is selected from: ​​​​​​​​​​​​​​​​wherein the wavy line indicates the point of attachment of Cy1to the formula (I); wherein said Cy1is optionally substituted with 0, 1, 2, or 3 R0; preferably said Cy1is substituted with 0 R0.

[0027] In another embodiment, Cy2is selected from:

[0028] In another embodiment, Cy2is selected from: wherein the wavy line indicates the point of attachment of Cy2to the formula (I); wherein said Cy2is optionally substituted with 0, 1, 2, or 3 R1; preferably said Cy2is substituted with 0 R1; preferably said Cy2is substituted with 1 or 2 R1. 1 substituted.

[0029] In another embodiment, R 0 is hydrogen, halogen, -R a , -OR a , -SR a .

[0030] In another embodiment, R 1 each independently represents hydrogen, halogen, -R a , -OR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -S(O)2R a , -S(O)R a , -P(O)R a R b , -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6alkylene)OR a , -(C1-C6alkylene)NR a R b , -(C1-C6alkylene)NR a C(O)R b , -(C1-C6alkylene)C(O)R a , -(C1-C6alkylene)C(O)OR a , -(C1-C6alkylene)C(O)NR a R b , -(C1-C6alkylene)S(O)2R a , -(C1-C6alkylene)S(O)R a , -(C1-C6alkylene)P(O)Ra R b .

[0031] In yet another embodiment, R 3 is C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C3-C 10 cycloalkyl, 3-10 membered heterocycloalkyl, optionally substituted with 0, 1, 2, 3 of the following substituents: nitro, halo, cyano, -R a , -(C0-C6alkylene)OR a , -(C0-C6alkylene)SR a , -(C0-C6alkylene)NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b , -P(O)R a R b ; preferably, the R 3 is optionally substituted with 0, 1, 2, 3 of the following substituents: halo, -R a , -(C0-C6alkylene)OR a or -(C0-C6alkylene)SR a , -(C0-C6alkylene)NR a R b .

[0032] In another embodiment, R 3 is C6-C 10 aryl or 5-10 membered heteroaryl, optionally substituted with 0, 1, 2, 3 of the following substituents: nitro, halo, cyano, -R a , -(C0-C6alkylene)OR a , -(C0-C6alkylene)SR a , -(C0-C6alkylene)NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)2Ra -S(O)2R a -S(O)2NR a R b -P(O)R a R b ; preferably, the R 3 group is optionally substituted with 0, 1, 2, 3 substituents selected from the group consisting of halo, -R a , -(C0-C6alkylene)OR a , -(C0-C6alkylene)SR a , -(C0-C6alkylene)NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b , or -P(O)R a R b .

[0033] In yet another embodiment, R 3 is -NR M R N , -NHR M , -OR M , R M and R N each independently represent C1-C6alkyl, -(C0-C6alkylene)(C3-C 10 cycloalkyl), -(C0-C6alkylene)(3-10 membered heterocycloalkyl), -(C0-C6alkylene)(C6-C 10 aryl), -(C0-C6alkylene)(5-10 membered heteroaryl); wherein R M and R N are optionally substituted with 0, 1, 2, 3 substituents selected from the group consisting of oxo, nitro, halo, cyano, -R a , -OR a , -SR a , -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a Rb -S(O)2R a -S(O)R a -S(O)2NR a R b -P(O)R a R b ; more preferably, the R M and R N groups are optionally substituted with 0, 1, 2, 3 substituents selected from the group consisting of oxo, -R a , -OR a , -SR a , -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b or -P(O)R a R b .

[0034] In one embodiment, R a , R b each independently represent hydrogen, C1-C3 alkyl or C3-C6 cycloalkyl, which optionally can be substituted with 0, 1, 2, 3 halogen atoms.

[0035] In one embodiment, R a , R b each independently represent hydrogen, C1-C3 alkyl, which optionally can be substituted with 0, 1, 2, 3 halogen atoms. Preferably, the compounds according to any one of the above embodiments are selected from the following structures:

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[0059] Another embodiment of the present application provides a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, prodrug, isotopically enriched derivative, isomer, solvate, or metabolite thereof, and optionally a pharmaceutically acceptable carrier.

[0060] Another embodiment of the present application provides use of a compound as described herein, or a pharmaceutically acceptable salt, prodrug, isotopically enriched derivative, isomer, solvate, or metabolite thereof, or a pharmaceutical composition as described herein, in the manufacture of a medicament for preventing or treating a disease or disorder associated with Cyclin K protein. In particular, the disease or disorder is selected from the group consisting of a tumor, a cancer, a viral infection, an inflammation-related disease, and an autoimmune disease.

[0061] Another embodiment of the present application provides a method of treating a disease or disorder associated with Cyclin K protein, comprising administering to a mammal in need thereof a compound of the present application or a pharmaceutically acceptable salt, prodrug, isotopically enriched derivative, isomer, solvate, or metabolite thereof, or a pharmaceutical composition of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0062] Figure 1 : Inducing effect of Compound 1 of the present application on degradation of Cyclin K.

[0063] Figure 2 : Inducing effect of multiple compounds of the present application on degradation of Cyclin K. DETAILED DESCRIPTION

[0064] The compound of the present application or a prodrug thereof can have excellent Cyclin K degradation activity in an organism, and can be used as a preventive or therapeutic drug for cancer, a cancer proliferation inhibitor, or a cancer metastasis inhibitor. The compound of the present application exhibits Cyclin K degradation activity, and the compound of the present application is also expected to exhibit excellent performance in terms of efficacy expression, pharmacokinetics (e.g., absorption, distribution, metabolism, excretion), solubility (e.g., water solubility), and interaction with other pharmaceutical products (e.g., inhibition of drug-metabolizing enzymes), stability (e.g., chemical stability, stability to enzymes), and thus the compound can be used as a drug.

[0065] The compound of the present application can be expected to have low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, central nervous system toxicity), and can be used for administration to mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans).

[0066] The compound of the present application can be used as a preventive or therapeutic agent for a pathology or disease caused by Cyclin K. In addition, the compound of the present application can be superior in selectivity in degrading Cyclin K among the Cyclin protein subfamily, and is expected to have low toxicity.

[0067] The compounds of the present application are expected to be useful in the prevention or treatment of, for example, cancer [e.g., colorectal cancer (e.g., colon cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic ductal carcinoma, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), duodenal cancer, small intestinal cancer, breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low malignant potential tumor), testicular cancer, prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer, castration-resistant prostate cancer), liver cancer (e.g., hepatocellular carcinoma, primary liver cancer, extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid carcinoma), renal cancer (e.g., renal cell carcinoma (e.g., clear cell renal cell carcinoma), transitional cell carcinoma in the renal pelvis and ureter), uterine cancer (e.g., cervical cancer, uterine body cancer, uterine sarcoma), gestational choriocarcinoma, brain tumor (e.g., medulloblastoma, glioma, pineal astrocytoma, fibrous astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, pituitary adenoma), neuroblastoma, retinoblastoma, skin cancer (e.g., basal sarcoma, malignant melanoma (melanoma)), sarcoma (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cell sarcoma, osteosarcoma), malignant bone tumor, bladder cancer, hematological cancer (e.g., multiple myeloma, leukemia (e.g., acute myelocytic leukemia, acute lymphocytic leukemia), malignant lymphoma, Hodgkin's disease, chronic myeloproliferative disease), cancer of unknown primary origin], inhibition of cancer spread, inhibition of metastasis, promotion of apoptosis, or prevention or treatment of precancerous lesions (e.g., myelodysplastic syndrome). In addition, it is expected that the compounds of the present application can be used in the prevention or treatment of scleroderma, cirrhosis, idiopathic pulmonary fibrosis, inflammatory bowel disease, or muscular dystrophy.

[0068] The compounds of the present application can be administered to a mammal (preferably a human) as pharmaceuticals, alone or in combination with pharmaceutically acceptable carriers. Suitable routes of administration can include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, aural, nasal, and topical administration. By way of example only, parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary, intraventricular, intraperitoneal, intralymphatic, and intranasal administration. Pharmaceutical compositions comprising the compounds of the present application are described in detail below (sometimes referred to simply as "the pharmaceuticals of the present application"). Examples of dosage forms of the pharmaceuticals of the present application include oral preparations such as tablets (e.g., sugar-coated tablets, film-coated tablets, sublingual tablets, buccal tablets, oral rapidly dissolving tablets), pills, granules, powders, capsules (e.g., soft capsules, microcapsules), syrups, emulsions, suspensions, films (e.g., oral disintegrating films, oral mucosal patch films), and the like. In addition, examples of dosage forms of the pharmaceuticals of the present application include injections, drip infusions, transdermal preparations (e.g., iontophoresis transdermal preparations), suppositories, ointments, nasal preparations, pulmonary preparations, eye drops, and the like parenteral preparations.

[0069] The compounds of the present application can be used in combination with other drugs. In particular, the compounds of the present application can be used in combination with drugs such as hormone therapy agents, chemotherapeutic agents, immunotherapeutic agents, agents that inhibit the action of a cell growth factor or a cell growth factor receptor, and the like. Hereinafter, the drugs that can be used in combination with the compounds of the present application are referred to simply as combination drugs.

[0070] As "hormone therapeutic agents", for example, fosfestrol, stilbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, seprone acetate, danazol, allylestrenol, gestrinone, mepitiostane, raloxifene, ormeloxifene, levormeloxifene, antiestrogens (for example, tamoxifen citrate, toremifene citrate), pills, megestrol acetate, testrolactone, aminoglutethimide, LH-RH agonists (for example, goserelin acetate, buserelin, leuprolide acetate), droloxifene, epitiostanol, ethinyl estradiol sulfonate, aromatase inhibitors (for example, mefuxolone hydrochloride, anastrozole, Retrozole, exemestane, vorozole, formestane), antiandrogens (for example, flutamide, Bicartamide, nilutamide, enzalutamido), 5a-reductase inhibitors (for example, finasteride, epristeride, dutas teride), adrenocortical hormone drugs (for example, dexamethasone, predonisolone, betamethasone, fluocortolone), androgen synthesis inhibitors (for example, abiraterone), retinoids, and drugs that delay retinoid metabolism (for example, liarozole), thyroid hormones, and DDS (drug delivery system) preparations thereof.

[0071] As "chemotherapeutic agents", alkylating agents, antimetabolites, anticancer antibiotics, and plant-derived anticancer agents can be used.

[0072] As "alkylating agents", for example, mechlorethamine, mechlorethamine-N-oxide hydrochloride, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, pyrimidine hydrochloride, dibromomannitol, melphalan, dacarbazine, ranimustine, estramustine phosphate sodium, triaziquone, carmustine, lomustine, streptozocin, dibromopropyl piprazine, etoglucid, carboplatin, cisplatin, mepitiometine, oxaliplatin, hexamethylmelamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustin, temozolomide, treosulfan, chloroethyldiphosphamide, zinostatin stimalamer, adozelesin, cystemustine, bizelesin, and DDS preparations thereof can be used.

[0073] As "antimetabolites", for example, mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, Pemetrexed, enocitabine, cytarabine, cytarabine octadecyl sodium phosphate, ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, Gallocitabine, emitefur, capecitabine), aminopterin, nelzarabine, folvite, Tabloid, butocine, folvite, folvite calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxyurea, pentostatin, piritrexim, iododeoxyuridine, procarbazine, tiazofurin, aminoglutethimide, bendamustine, and DDS preparations thereof can be used.

[0074] As "antitumor antibiotics", for example, actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepleomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin, mithramycin, zinostatin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and DDS preparations thereof (e.g., PEG ribosome-encapsulated doxorubicin) can be used.

[0075] As "plant-derived antitumor agents", for example, etoposide, etoposide phosphate, vinblastine sulfate, vinleurosine sulfate, deacetylvinblastine amide sulfate, etoposide phosphate, pacilitaxel, docetaxel, cabazitaxel, vinorelbine, and DDS preparations thereof can be used.

[0076] As "immunotherapeutic agents", for example, picibanil, krestin, sizofiran, lentinan, ubenimex, interferon, interleukin, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphocyte toxin, BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, prochodazol, anti-CTLA4 antibodies (e.g., ipilimumab, tremelimumab), anti-PD-1 antibodies (e.g., nivolumab, pembrolizumab), and anti-PD-L1 antibodies can be used.

[0077] The "cell growth factor" in the "drug that inhibits the action of a cell growth factor and its receptor" can be any substance that promotes cell proliferation, which is usually a peptide with a molecular weight of not more than 20,000, and is capable of expressing activity at a low concentration by binding to a receptor, and specifically, the following can be used

[0078] (1) EGF (epidermal growth factor) or a substance having substantially the same activity as EGF (e.g., TGFa);

[0079] (2) insulin or a substance having substantially the same activity as insulin (e.g., insulin, IGF (insulin-like growth factor)-l, IGF-2);

[0080] (3) FGF (fibroblast growth factor) or a substance having substantially the same activity as FGF (e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10);

[0081] (4) other cell growth factors (e.g., CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGFβ (transforming growth factor β), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), modulin, angiogenin).

[0082] The "cell growth factor receptor" can be any receptor capable of binding to any of the above cell growth factors, and specifically, EGF receptor, heregulin receptor (e.g., HER3), insulin receptor, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, VEGF receptor, angiopoietin receptor (e.g., Tie2), PDGF receptor, etc. can be used.

[0083] As the "drug that inhibits the action of a cell growth factor and its receptor", for example, an EGF inhibitor, a TGFa inhibitor, a modulin inhibitor, an insulin inhibitor, an IGF inhibitor, an FGF inhibitor, a KGF inhibitor, a CSF inhibitor, an EPO inhibitor, an IL-2 inhibitor, an NGF inhibitor, a PDGF inhibitor, a TGFp inhibitor, an HGF inhibitor, a VEGF inhibitor, an angiogenin inhibitor, an EGF receptor inhibitor, a HER2 inhibitor, a HER4 inhibitor, an insulin receptor inhibitor, an IGF-1 receptor inhibitor, an IGF-2 receptor inhibitor, an FGF receptor-1 inhibitor, an FGF receptor-2 inhibitor, an FGF receptor-3 inhibitor, an FGF receptor-4 inhibitor, a VEGF receptor inhibitor, a Tie-2 inhibitor, a PDGF receptor inhibitor, an Abl inhibitor, a Raf inhibitor, an FLT3 inhibitor, a c-Kit inhibitor, a Src inhibitor, a PKC inhibitor, a Smo inhibitor, an ALK inhibitor, an ROR1 inhibitor, a Trk inhibitor, a Ret inhibitor, an mTOR inhibitor, an Aurora inhibitor, a PLK inhibitor, an MEK (MEK1 / 2) inhibitor, a MET inhibitor, a CDK inhibitor, an Akt inhibitor, an ERK inhibitor, a PI3K inhibitor, and the like can be used. More specifically, an anti-VEGF antibody (for example, Bevacizumab, Ramucirumab), an anti-HER2 antibody (for example, Trastuzumab, Pertuzumab), an anti-EGFR antibody (for example, Cetuximab, Panitumumab, Matuzumab, Nimotuzumab), an anti-HGF antibody, Imatinib, Erlotinib, Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib, Ibrutinib, Bosutinib, Cabozantinib, Crizotinib, Alectinib, Vismodegib, Axitinib, Motesanib, Nilotinib, 6-[4-(4-ethylpiperazin-1-ylmethyl)phenyl]-N-[1(R)-phenylethyl]-7H-pyrrolo[2,3-D]pyrimidine-4-amine (AEE-788), Vandetanib, Temsirolimus, Everolimus, Enzastaurin, Tozasertib, 2-[N-[3-[4-[5-[N-(3-fluorophenyl)carbamoylmethyl]-lH-pyrazol-3-ylamino]quinazolin-7- yloxy]propyl]-N-ethylamino]ethyl phosphate (AZD-1152), 4-[9-chloro-7-(2,6-difluorophenyl)- 5H-pyrimido[5,4-D][2]benzazepin-2-ylamino]benzoic acid, N-[2-methoxy-5-[(E)-2-(2,4,6- trimethoxyphenyl)ethenylsulfonylmethyl]phenyl]glycine sodium salt (ON-1910Na), Volasertib, Selumetinib, Trametinib, N-[2(R),3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4- iodophenylamino)benzamide (PD-0325901), Bosutinib, Regorafenib, Afatinib, Idelalisib, Ceritinib, Dabrafenib, etc.,

[0084] In addition to the above drugs, asparaginase, acetorphan, methylhydrazine hydrochloride, protoporphyrin-cobalt complex, mercury hemin-sodium, topoisomerase I inhibitors (e.g., irinotecan, topotecan, Indotecan, Indimitecan), topoisomerase II inhibitors (e.g., sobuzoxane), differentiation-inducing silver (e.g., retinoids, vitamin D), other angiogenesis inhibitors (e.g., fumagillin, shark extract, COX-2 inhibitors), alpha-blockers (e.g., tamsulosin hydrochloride), bisphosphonates (e.g., pamidronate, zoledronate), thalidomide, lenalidomide, pomalidomide, 5-azacytidine, decitabine, proteasome inhibitors (e.g., Bortezomib, carfilzomib, (ixazomib), NEDD8 inhibitors (e.g., pevonedistat), UAE inhibitors, PARP inhibitors (e.g., Olaparib, Niraparib, Veliparib, Rucaparib), anti-tumor antibodies, such as anti-CD20 antibodies (e.g., Rituximab, Obinutuzumab), anti-CCR4 antibodies (e.g., Mogamulizumab), and the like, antibody-drug conjugates (e.g., trastuzumab emtansine, (brentuximab vedotin), and the like can also be used as concomitant drugs.

[0085] Hereinafter, the compound of the present application and the concomitant drug used in combination are referred to as "the combination agent of the present application". As the administration method of the compound of the present application and the concomitant drug, the following methods can be mentioned: (1) the compound of the present application and the concomitant drug are formulated together to make a single preparation for administration. (2) the compound of the present application and the concomitant drug are formulated separately to make two preparations, and they are administered simultaneously by the same administration route. (3) the compound of the present application and the concomitant drug are formulated separately to make two preparations, and they are administered by the same administration route at staggered times. (4) the compound of the present application and the concomitant drug are formulated separately to make two preparations, and they are administered simultaneously by different administration routes. (5) the compound of the present application and the concomitant drug are formulated separately to make two preparations, and they are administered by different administration routes at staggered times (e.g., the compound of the present application and the concomitant drug are administered in this order or in the reverse order), and the like.

[0086] The compound of the present application or the combination agent of the present application can be further used in combination with non-drug therapy. Specifically, the compound of the present application or the combination agent of the present application can be used in combination with non-drug therapy, for example, (1) surgery, (2) hyperbaric chemotherapy, (3) gene therapy, (4) thermotherapy, (5) cryotherapy, (6) laser ablation, (7) radiotherapy.

[0087] For example, the compound of the present application or the combination agent of the present application can be used before or after the above-mentioned surgery or the like, or before or after the combination therapy of two or more drugs, to achieve effects such as prevention of drug resistance expression, prolongation of the disease or the like, prolongation of disease-free period (disease-free survival period), suppression of cancer metastasis or recurrence, prolongation of life span, and the like.

[0088] Further, the compound of the present application or the combination agent of the present application can be combined with the following supportive therapies: (i) administration of a combination of a plurality of antibiotics (for example, β-lactams such as cefotiam (Pansporin) and the like, macrolides such as clarithromycin and the like) to treat infectious diseases, (ii) intravenous administration of intravenous nutrition solution, amino acid preparation, general vitamin preparation for improvement of malnutrition, (iii) administration of morphine to alleviate pain, (iv) administration of a drug that can improve side effects such as nausea, vomiting, anorexia, diarrhea, leukopenia, thrombocytopenia, decrease in hemoglobin concentration, alopecia, liver disease, kidney disease, DIC, fever, and the like, (v) administration of a drug that suppresses drug resistance of cancer to a plurality of drugs.

[0089] Definitions of terms

[0090] The following definitions are used to better define the present application.

[0091] In the present text, when referring to a "compound" having a specific structural formula, generally also encompassed are stereoisomers, diastereomers, enantiomers, racemic mixtures and isotopic derivatives thereof, as well as pharmaceutically acceptable salts, solvates, hydrates and the like forms as alternative forms of existence thereof. It is well known to the person skilled in the art that a salt, a solvate, a hydrate of a compound are alternative forms of existence of the compound, which can be converted into the compound under certain conditions, and therefore, it is particularly noted that in the present text, when referring to a compound, generally also encompassed is a pharmaceutically acceptable salt thereof, and further encompassed are solvates and hydrates thereof.

[0092] Similarly, in the present text, when referring to a compound, generally also encompassed are prodrugs, metabolites and nitroso derivatives thereof.

[0093] The pharmaceutically acceptable salts or the pharmaceutically acceptable salts of the present application can be formed using inorganic or organic acids, and the "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" means a salt which, within the scope of sound medical judgment, is suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and is commensurate with a reasonable benefit / risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the present application, or by separately reacting the free base or free acid with a suitable reagent, as outlined below. For example, the free base can be reacted with a suitable acid. Also, where the compound of the present application carries an acidic moiety, suitable pharmaceutically acceptable salts thereof can include metal salts such as alkali metal salts (e.g., sodium salt or potassium salt), and alkaline earth metal salts (e.g., calcium salt or magnesium salt). Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as 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, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, bisulfate, bitartaric acid, borate, butyric acid, camphoric acid, camphorsulfonic acid, citric acid, cyclopentanepropionic acid, digluconic acid, dodecylsulfic acid, ethanesulfonic acid, formic acid, fumaric acid, glucoheptanoic acid, glycerophosphoric acid, glycolic acid, heptanoic acid, hexanoic acid, hydroiodic acid, 2-hydroxy-ethanesulfonic acid, lactobionic acid, lactic acid, lauric acid, lauryl sulfuric acid, malic acid, maleic acid, malonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pectinic acid, persulfate, 3-phenylpropionic acid, phosphoric acid, picric acid, pivalic acid, propionic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecanoic acid, valeric acid, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate, and aryl sulfonate.

[0094] The pharmaceutically acceptable salts of the present application can be prepared by conventional methods, for example, by dissolving the compound of the present application in an organic solvent which is miscible with water, such as acetone, methanol, ethanol, and acetonitrile, adding thereto an excess of an aqueous solution of an organic or inorganic acid, so that the salt is precipitated from the resulting mixture, removing the solvent and the remaining free acid therefrom, and isolating the precipitated salt.

[0095] The precursors or metabolites described in this invention can be precursors or metabolites known in the art, as long as they are metabolized and transformed in vivo to form compounds. For example, "prodrug" refers to those prodrugs of the compounds of this invention that, within a reasonable medical judgment, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and have a reasonable benefit / risk ratio and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to produce the parent compound of the above formula, for example, through in vivo metabolism, or through N-demethylation of the compounds of this invention.

[0096] The term "solvent" as used in this invention refers to the physical association of the compound of this invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvent" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0097] The "stereoisomerism" described in this invention is divided into conformational isomerism and configurational isomerism. Configurational isomerism can be further divided into cis-trans isomerism and optical isomerism. Conformational isomerism refers to the phenomenon where organic molecules with a certain configuration exhibit different spatial arrangements of atoms or groups of atoms due to the rotation or twisting of carbon atoms or carbon single bonds. Common examples include the structures of alkanes and cycloalkanes, such as the chair and boat conformations in cyclohexane. "Stereoisomers" refer to compounds of this invention containing one or more asymmetric centers, thus allowing them to exist as racemic mixtures and racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. Compounds of this invention can have asymmetric centers, each of which produces two optical isomers. The scope of this invention includes all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds. Compounds of this invention can exist as tautomers, having different hydrogen bonding sites through one or more double bond shifts. For example, ketones and their enol forms are ketone-enol tautomers. All tautomers and mixtures thereof are included in the compounds of this invention. All enantiomers, diastereomers, racemates, mesomates, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof of all compounds of formula (I) are included within the scope of this invention.

[0098] An "isotopically-labeled" compound of the application is a molecule of the application in which one or more atoms are replaced by an isotope of the atom. Typically, the isotopes of interest are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as: 2 H and 3 H; isotopes of carbon: 11 C, 13 C and 14 C; isotopes of chlorine: 35 Cl and 37 Cl; isotopes of fluorine: 18 F; isotopes of iodine: 123 I and 125 I; isotopes of nitrogen: 13 N and 15 N; isotopes of oxygen: 15 O, 17 O and 18 O and isotopes of sulfur 35 S. These isotopically-labeled compounds are useful in metabolic studies relating to the distribution of the compounds within organisms. In particular, deuterium 2 H and carbon 13 C are useful because of their ease of incorporation and relative non-toxicity of the isotopes. Certain heavier isotopes, such as hydrogen 2 H), can increase the metabolic stability of a compound increasing the half-life of the compound in vivo and thereby improve its efficacy.

[0099] Other features of the application will be apparent from consideration of the specification and the examples, given by way of illustration of the application and not intended to be limiting thereof, which follow.

[0100] The following terms are defined as follows if not otherwise indicated in the application (including the specification and claims). It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed in the application. In the application, the use of "or" or "and" means "and / or" unless stated otherwise.

[0101] In the specification and claims, the given chemical formula or name shall cover all stereo and optical isomers and racemic products containing such isomers. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of this invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc., may also be present in the compounds, and all such stable isomers are covered within this invention. This invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of this invention, which can be separated into mixtures of isomers or separate isomeric forms. The compounds of this invention can be separated in optically active or racemic forms. All methods used to prepare the compounds of this invention and the intermediates prepared therein are considered part of this invention. In the preparation of enantiomers or diastereomers, they can be separated by conventional methods (e.g., by chromatography or fractional crystallization). Depending on the method conditions, the end products of this invention are obtained in free (neutral) or salt form. Both the free form and salts of these end products are within the scope of this invention. If necessary, one form of the compound can be converted into another. A free base or acid can be converted into a salt; a salt can be converted into a free compound or another salt; a mixture of isomers of the present invention can be separated into individual isomers. The compounds of the present invention, their free forms, and salts can exist in a variety of tautomer forms, wherein hydrogen atoms are transposed to other parts of the molecule and thereby the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all possible tautomer forms are included within the scope of this invention.

[0102] Unless otherwise defined, the definitions of substituents in this invention are independent and not related to each other. For example, for R in a substituent... a (or R) b For R, the definitions of different substituents are independent. Specifically, for R a (or R) b Choosing a definition for a substituent does not mean that R a (or R) b The same definition applies to all other substituents. More specifically, for example (a non-exhaustive list only) for NR... a R b In the middle, when R a (or R) b When the definition of ) is taken from hydrogen, it does not mean that in -C(O)-NR a R b In the middle, R a (or R) b It must be hydrogen. On the other hand, when a substituent contains more than one R... a (or R) b When these R's a (or R)b ) are each independent. For example, in the substituent -(CR a R b ) m -O-(CR a R b ) n - in which the m+n R a ( or R b ) are each independent, they can have the same or different meanings.

[0103] Unless otherwise defined, when a substituent is labeled "optionally substituted," the substituent is selected from, for example, alkyl, cycloalkyl, aryl, heterocyclyl, halo, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine groups in which 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, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamido such as -SO2NH2, substituted sulfonamido, nitro, cyano, carboxy, carbamoyl such as -CONH2, substituted carbamoyl such as -CONHalkyl, -CONHaryl, -CONHarylalkyl, or where the nitrogen has two substituents selected from alkyl, aryl, or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclyl, such as indolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, and substituted heterocyclyl, for example.

[0104] The term "alkyl" or "alkylene" as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "Ci-C6alkyl" denotes alkyl groups with one to six carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl. Preferred alkyl groups of the present application include Ci-C6alkyl or Ci-C4alkyl.

[0105] The term "alkenyl" denotes straight-chain or branched-chain hydrocarbon groups containing one or more double bonds and typically having a length of from 2 to 20 carbon atoms. For example, "C2-C6alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Preferred alkenyl groups of the present application include C2-C6alkenyl.

[0106] The term "alkynyl" denotes straight-chain or branched hydrocarbon groups containing one or more triple bonds and typically having a length of from 2 to 20 carbon atoms. For example, "C2-C6alkynyl" contains from two to six carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like. Preferred alkynyl groups of the present application include C2-C6alkynyl. The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C1-C6alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, C6alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propyloxy (e.g., n- propyloxy and isopropyloxy), and t-butyloxy. Similarly, "alkylthio" or "thioalkoxy" denotes an alkyl group as defined above attached through a sulfur bridge; for example, methyl-S- and ethyl-S-. Preferred alkoxy groups of the present application include C1-C6alkoxy or C1-C4alkoxy.

[0107] The term "carbonyl" refers to an organic functional group (C=0) formed by the linkage of a carbon and oxygen atom by a double bond.

[0108] The term "aryl", alone or in combination with other terms, means a monocyclic, bicyclic or tricyclic ring system having from 5 to 12 ring members in which at least one ring is aromatic and wherein each ring in the system contains from 3 to 7 ring members. In certain embodiments of the application, "aryl" means 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" means an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, and the like. A fused aryl group can be attached to another group at a suitable position on either the cycloalkyl ring or the aromatic ring. Dashed lines drawn from the ring system indicate that the bond can be attached to any suitable ring atom.

[0109] The term "cycloalkyl" means a monocyclic or bicyclic cyclic alkyl group. Monocyclic cyclic alkyl groups refer to non-branched or branched cyclic alkyl groups including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, 1-methylcyclopropyl, and 2-methylcyclopropyl. Bicyclic cyclic alkyl groups include bridged, spiro, or fused ring cycloalkyl groups. Preferred cycloalkyl groups of the present application include C3-C6cycloalkyl.

[0110] The term "cycloalkenyl" means a monocyclic or bicyclic cyclic alkenyl group. Monocyclic cyclic alkenyl groups refer to non-branched or branched cyclic alkenyl groups including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornenyl, 1-methylcyclopropenyl, and 2-methylcyclopropenyl. Bicyclic cyclic alkenyl groups include bridged, spiro, or fused ring cyclic alkenyl groups. Preferred cycloalkenyl groups of the present application include C3-C6cycloalkenyl.

[0111] "Halo" or "halogen" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted by 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 heptafluoropropyl. Examples of haloalkyl also include "fluoroalkyl" intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted by one or more fluorine atoms.

[0112] "Haloalkoxy" or "haloalkyloxy" denotes an oxygen-bridged haloalkyl group as defined above having the specified number of carbon atoms. For example, "Ci-C6haloalkoxy" is intended to include Ci, C2, C3, C4, C5, C6haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" denotes a sulfur-bridged haloalkyl group as defined above having the specified number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0113] In the present disclosure, the expression C x1 -C x2 is used when referring to some substituent groups, which means that the number of carbon atoms in the substituent group can be from x1 to x2 For example, C 0- C8means that the group contains 0, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, Ci-C8means that the group contains 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, C2-C8means that the group contains 2, 3, 4, 5, 6, 7, or 8 carbon atoms, C3-C8means that the group contains 3, 4, 5, 6, 7, or 8 carbon atoms, C4-C8means that the group contains 4, 5, 6, 7, or 8 carbon atoms, C0-C6means that the group contains 0, 1, 2, 3, 4, 5, or 6 carbon atoms, Ci-C6means that the group contains 1, 2, 3, 4, 5, or 6 carbon atoms, C2-C6means that the group contains 2, 3, 4, 5, or 6 carbon atoms, C3-C6means that the group contains 3, 4, 5, or 6 carbon atoms.

[0114] In the present disclosure, when referring to cyclic groups (e.g., 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 from 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, which can have from 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; 3-6 membered ring means that the cyclic group can be a 3-, 4-, 5-, or 6-membered ring, which can have from 3, 4, 5, or 6 ring atoms; 3-8 membered ring means that the cyclic group can be a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, which can have from 3, 4, 5, 6, 7, or 8 ring atoms; 3-9 membered ring means that the cyclic group can be a 3-, 4-, 5-, 6-, 7-, 8-, or 9-membered ring, which can have from 3, 4, 5, 6, 7, 8, or 9 ring atoms; 4-7 membered ring means that the cyclic group can be a 4-, 5-, 6-, or 7-membered ring, which can have from 4, 5, 6, or 7 ring atoms; 5-8 membered ring means that the cyclic group can be a 5-, 6-, 7-, or 8-membered ring, which can have from 5, 6, 7, or 8 ring atoms; 5-12 membered ring means that the cyclic group can be a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which can have from 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; 6-12 membered ring means that the cyclic group can be a 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which can have from 6, 7, 8, 9, 10, 11, or 12 ring atoms. The ring atoms can be carbon atoms or heteroatoms, e.g., heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more ring heteroatoms, e.g., heteroatoms selected from N, O, and S.

[0115] In the SUMMARY, one or more halogens can each be independently selected from fluorine, chlorine, bromine, and iodine.

[0116] The term "heteroaryl" means a stable 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, 12-membered polyaromatic heterocyclic ring which is fully unsaturated, partially unsaturated, and which contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and includes any of the following polycyclic groups wherein any of the heterocyclic rings defined above are fused to a benzene ring. The nitrogen and sulfur heteroatoms can optionally be oxidized. The nitrogen atoms are substituted or unsubstituted (i.e., N or NR, where R is H or, if defined, another substituent). The heterocyclic rings can be attached to their side groups at any heteroatom or carbon atom that results in a stable structure. The heterocyclic groups described herein can be substituted on a carbon or a nitrogen atom if the resulting compound is stable. The nitrogens in the heterocyclic ring can optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocyclic ring exceeds 1, then these heteroatoms are not adjacent to one another. Preferably, the total number of S and O atoms in the heterocyclic ring is not more than 1. When the term "heterocycle" is used, it is intended to include heteroaryl.Examples of heteroaryl groups include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indoleninyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isochromanyl, isochromenyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthizidinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinyl, perimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 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" can also include biaryl structures formed from the above defined "aryl" groups with monocyclic "heteroaryl" groups, such as, but not limited to, "-phenylbipyridyl-", "-phenylbipyrimidyl-", "-pyridylbiphenyl-", "-pyridylbipyrimidyl-", "-pyrimidylbiphenyl-"; wherein the present application also includes fused ring and spiro compounds containing, for example, the above heterocycles.

[0117] The term "heterocycloalkyl" or "heterocycle" as used herein refers to a monocyclic heterocycloalkyl ring system, or to a bicyclic heterocycloalkyl ring system, and also includes spiro or bridged heterocycloalkyl groups. Monocyclic heterocycloalkyl refers to a saturated or unsaturated, but not aromatic, cyclic alkyl ring system containing at least one heteroatom selected from O, N, S, P. Bicyclic heterocycloalkyl ring systems refer to a bicyclic ring system in which a heterocycloalkyl group is fused to a phenyl group, or to a cycloalkyl group, or to a cycloalkenyl group, or to a heterocycloalkyl group, or to a heteroaryl group. Preferably, the "heterocycloalkyl" or "heterocycle" contains at least one or two heteroatoms selected from O, N, S.

[0118] The term "bridged cycloalkyl" as used herein refers to polycyclic compounds sharing two or more carbon atoms. It can be divided into bicyclic bridged cycloalkanes and polycyclic bridged cycloalkanes. The former consists of two aliphatic rings sharing two or more carbon atoms; the latter is a bridged cycloalkane consisting of three or more rings.

[0119] The term "spirocycloalkyl" as used herein refers to polycyclic hydrocarbons in which single rings share a carbon atom (called a spiro atom).

[0120] The term "bridged heterocyclyl" as used herein refers to polycyclic compounds sharing two or more carbon atoms, at least one of which is selected from O, N, S. It can be divided into bicyclic bridged heterocycles and polycyclic bridged heterocycles.

[0121] The term "spiroheterocyclyl" as used herein refers to polycyclic hydrocarbons in which single rings share a carbon atom (called a spiro atom), at least one of which is selected from O, N, S.

[0122] The term "substituted" as used herein means that at least one hydrogen atom has been replaced with a non-hydrogen group, provided that a stable compound results. Ring double bonds as used herein are double bonds between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0123] In cases wherein there are nitrogen atoms (e.g., amines) on the compounds of the present application, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to afford additional compounds of the present application. Thus, shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide to afford derivatives of the present application.

[0124] When any variable occurs more than one time in any constituent or formula, "each occurrence" is understood as referring to each independent occurrence of the variable. Thus, for example, if a group is shown to be substituted with 0-3 R groups, then said group can optionally be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0125] The term "patient" as used herein refers to an organism that is treated by the methods of the present application. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians / monkeys, equines, bovines, porcines, canines, felines, etc.) and most preferably refers to humans.

[0126] The term "effective amount" as used herein means that amount of a drug or pharmaceutical agent (i.e., a compound of the present application), which will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means an amount of a compound effective to achieve a therapeutic, healing, prophylactic, or palliative effect on a disease, condition, or adverse effect, or to decrease the rate of advancement of a disease or condition, as compared to the corresponding subject not receiving the amount. An effective amount can be given in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or route of administration. The term also includes within its scope an effective amount to enhance normal physiological function.

[0127] The term "treatment" as used herein includes its broadest meaning as a therapeutic and / or prophylactic treatment of a subject. In particular, the "treatment" includes any treatment which results in the alleviation, inhibition, elimination and amelioration and / or prevention of a condition, disease, disorder, etc., such as reducing, decreasing, modulating, ameliorating, eliminating, preventing, obviating or improving symptoms thereof. The therapeutic treatment includes alleviating, inhibiting or ameliorating symptoms or conditions of a disease; inhibiting the development of complications; ameliorating an underlying metabolic syndrome; inhibiting the development of a disease or symptoms, such as controlling the progression of a disease or condition; lessening a disease or symptoms; causing regression of a disease or symptoms; lessening complications resulting from a disease or symptoms, or treating an indication resulting from a disease or symptoms. The prophylactic treatment includes a prior treatment to prevent, block or delay, slow down the occurrence or development of a disease or condition or to attenuate the severity of a disease or condition.

[0128] Likewise, a "therapeutic agent" also includes an agent or reagent which has a therapeutic and / or prophylactic treatment of a subject.

[0129] The terms "pharmaceutical" or "pharmaceutically acceptable" are used herein to refer to those compounds, materials, compositions, and / or dosage forms which 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 problem or complication commensurate with a reasonable benefit / risk ratio.

[0130] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ or portion of the body to another organ or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which have been used to form pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium

[0131] The term "pharmaceutical composition" means a composition comprising a compound of the present application in combination with at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for the delivery of a biologically active agent to an animal, particularly a mammal, and includes, i.e., an adjuvant, excipient, or vehicle, such as a diluent, preservative, filler, flow regulator, disintegrating agent, wetting agent, emulsifying agent, suspending agent, sweetener, flavoring agent, perfuming agent, antibacterial agent, antifungal agent, lubricating agent, and dispersing agent, depending on the mode of administration and nature of the dosage form.

[0132] Specific Pharmaceutical and Medical Terms

[0133] The term "acceptable", as used herein, means no undue harmful influence on the health of the subject of treatment of the active ingredient of a prescription component.

[0134] The term "cancer", as used herein, refers to an abnormal growth of cells that is uncontrolled and, under some conditions, is able to metastasize (spread). This type of cancer includes, but is not limited to, solid tumors (e.g., bladder, bowel, brain, breast, uterus, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas, or other endocrine organ (e.g., thyroid), prostate, skin (melanoma), or blood (e.g., non-lymphocytic leukemia).

[0135] The term "co-administration" or its grammatical equivalents, as used herein, means the administration of two or more selected therapeutic agents to a single patient at the same time by the same or different routes of administration.

[0136] The term "enhance" or "enhancing" as used herein refers to the ability to increase or prolong either in potency or duration a desired result. Thus, in the context of enhancing the therapeutic effect of a drug, the term "enhancing" refers to the ability of a drug to increase or prolong, either in potency or duration, a desired result in a system. As used herein, "enhancing value" refers to the ability to maximize the enhancement of another therapeutic drug in an ideal system.

[0137] The term "immune disorder" refers to a disease or condition that results from an adverse or deleterious reaction to an endogenous or exogenous antigen. The result is usually a dysfunction of cells, or destruction and dysfunction as a result, or destruction of an organ or tissue that can result in an immune condition.

[0138] The terms "kit" and "product package" are synonymous.

[0139] The terms "subject," "recipient," or "patient" include mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and house cats; laboratory animals such as rats, mice, and guinea pigs; and the like. Non-mammals include, but are not limited to, birds, fish, and the like. In a preferred embodiment, the mammal is a human.

[0140] As used herein, a compound or pharmaceutical composition is "effective" to treat a disease, condition, or disorder if it has the ability to effect an improvement in the disease, condition, or disorder, especially an improvement in the severity of the disease, condition, or disorder, a delay in the onset of the disease, condition, or disorder, a slowing of the progression of the disease, condition, or disorder, or a reduction in the duration of the disease, condition, or disorder, whether fixed or temporally related, whether continuous or intermittent. The condition can be attributed to or associated with the administration. DETAILED DESCRIPTION

[0142] The application can be better understood with reference to the following examples, which are intended for the purpose of illustration only and are not intended to limit the application.

[0143] Starting materials

[0144] When no route of preparation is mentioned, the relevant intermediates are commercially available (e.g. from Sigma Aldrich, Alfa).

[0145] General procedure

[0146] Commercially available reagents were used without further purification. 1H-NMR spectra were recorded on a Bruker instrument at 500 MHz. Chemical shift values are expressed in parts per million, i.e. delta values. The following abbreviations are used for multiplicity in NMR signals: s = singlet, br s = broad singlet, d = doublet, t = triplet, m = multiplet. Coupling constants are listed as J values, measured in Hz. NMR and mass spectral results are corrected for background peaks. Chromatography refers to column chromatography performed using 100 mesh silica gel and completed under nitrogen pressure (flash chromatography). TLC for monitoring reactions refers to TLC performed using the specified mobile phase and silica gel F254 from Merck as stationary phase.

[0147] LC-MS experiments were measured under the following conditions:

[0148] Instrument: Thermo U3000, ALLtech ELSD, MSQ, UV detector combined with ELSD and MSD (flow ratio 4:1). Column: Waters X-Bridge C-18, 3.5 μm, 4.6 x 50 mm; column temperature: 30 °C. Gradient [time (min) / solvent B in A (%)] : 0.00 / 5.0, 1.40 / 95, 2.80 / 95, 2.82 / 5, 3.00 / 5. (Solvent A = 0.01% trifluoroacetic acid in water; solvent B = 0.01% trifluoroacetic acid in acetonitrile). UV detection: 214 / 254 / 280 / 300 nm; DAD detection: 210-350 nm; flow rate: 2 mL / min; MS: ESI, 100-1500 m / z

[0149] Preparative HPLC was generally performed using a basic method (gradient of acetonitrile and water with 10 mM ammonium bicarbonate in water); separation was performed with a Thermo U3000 AFC-3000; column: Globalsil C-18 12 nm, 250 x 20 mm, 10 μm, or equivalent; flow rate: 20 mL / min.

[0150] Example 1:

[0151]

[0152] 3-oxetine (1.26 g, 17.0 mmol) and 2,4-dichloro-5-trifluoromethylpyrimidine (3.50 g, 16.1 mmol) were dissolved in tetrahydrofuran (50 mL), and lithium bis(trimethylsilyl)amino (1 M in THF, 17.7 mL) was slowly added dropwise at 0 °C. After stirring the mixture at 0 °C for 3 hours, 50 mL of ammonium chloride solution was added to the reaction system, and the mixture was extracted twice with 100 mL of ethyl acetate. The combined organic phases were washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 1-a (1.10 g, 4.33 mmol), a white solid, in 26.9% yield.

[0153] 4-(2-pyridyl)benzaldehyde (10.0 g, 54.6 mmol) was dissolved in a mixture of ethanol (25 mL) and water (10 mL), and hydroxylamine hydrochloride (4.17 g, 60.0 mmol) and sodium acetate trihydrate (8.17 g, 60.0 mmol) were added. The mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, and the residue was washed twice with 2 mL of water and once with 2 mL of ethanol. The residue was filtered and dried to give compound 1-b (10.5 g, 53.0 mmol), a white solid, in 97.0% yield. MS (ESI): m / z 199.4 (M+H) + .

[0154] Compound 1-b (10.5 g, 53.0 mmol) was dissolved in ethanol (210 mL), and palladium / carbon (10% w / w, 1.05 g) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth and concentrated. The residue was purified by column chromatography to give 1-c (6.10 g, 33.1 mmol), a yellow oily liquid, in 62.5% yield. MS (ESI): m / z 185.5 (M+H) + .

[0155] Compound 1-c (30.0 mg, 163 μmol) and compound 1-a (41.5 mg, 163 μmol) were dissolved in N,N-dimethylformamide (2 mL), and diisopropylethylamine (63.1 mg, 488 μmol) was added. The mixture was stirred at 80 °C for 2 hours. After cooling the reaction solution to room temperature, it was purified by preparative liquid chromatography to give compound 1 (10.0 mg, 24.8 μmol), a white solid, in 15.3% yield. 1H NMR (500 MHz, DMSO-de) δ 8.71 - 8.38 (m, 3H), 8.09 - 8.01 (m, 2H), 7.93 (t, J = 7.0 Hz, 1H), 7.86 (td, J = 7.7, 1.9 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.36 - 7.31 (m, 1H), 5.67 - 5.52 (m, 1H), 4.92 - 4.70 (m, 2H), 4.62 - 4.41 (m, 4H); MS (ESI): m / z 403.4 (M+H) + .

[0156] Example 2:

[0157]

[0158] Compound 2-a (200 mg, 664 μmol) and 2,4,5-trichloropyrimidine (122 mg, 664 μmol) were dissolved in a mixture of acetonitrile (3 mL) and water (3 mL), sodium carbonate (141 mg, 1.33 mmol) and tetrakis triphenylphosphine palladium (38.2 mg, 33.1 μmol) were added. The mixture was stirred at 90 °C for 16 hours under nitrogen atmosphere. The reaction was cooled to room temperature, 30 mL of ethyl acetate was added, filtered with celite, the filtrate was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 2-b (150 mg, 371 μmol) as a white solid in 55.9% yield.

[0159] Compound 2-b (50.0 mg, 124 μmol) and compound 1-c (27.3 mg, 148 μmol) were dissolved in N,N-dimethylformamide (2 mL), sodium carbonate (32.8 mg, 309 μmol) was added. The mixture was stirred at 80 °C for 8 hours. The reaction was cooled to room temperature, 30 mL of ethyl acetate was added, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 2-c (50.0 mg, 90.6 μmol) as a light yellow solid in 73.2% yield.

[0160] Compound 2-c (50.0 mg, 90.6 μmol) was dissolved in 1,4-dioxane (2 mL), sodium hydroxide solution (1 N, 0.5 mL) was added. The mixture was stirred at 40 °C for 4 hours. The reaction was cooled to room temperature, concentrated to dryness after adjusting pH to 7 with 1 N hydrochloric acid. The residue was purified by preparative liquid chromatography to give compound 2 (6.0 mg, 14.6 μmol) as a white solid in 16.1% yield. 1H NMR (500 MHz, DMSO-de) δ 11.79 (s, 1H), 8.64 - 8.60 (m, 1H), 8.41 (s, 1H), 8.27 (s, 1H), 8.19 - 8.01 (m, 3H), 7.96 - 7.88 (m, 2H), 7.86 - 7.80 (m, 1H), 7.51 - 7.39 (m, 3H), 7.33 - 7.27 (m, 1H), 7.27 - 6.77 (m, 2H), 4.65 (s, 2H); MS (ESI): m / z 412.3 (M+H) + .

[0161] Example 3:

[0162]

[0163] Compound 3-a (50.0 mg, 226 μmol) and compound 1-c (41.7 mg, 226 μmol) were dissolved in 1,4-dioxane (3 mL), Pd(dba)2(20.7 mg, 22.6 μmol), Xantphos (13.1 mg, 22.6 μmol), cesium carbonate (147 mg, 452 μmol) were added. The mixture was stirred at 100 °C under nitrogen atmosphere for 16 hours. The reaction was cooled to room temperature and concentrated. The residue was purified by preparative liquid chromatography to give compound 3 (13.0 mg, 35.2 μmol), white solid, 15.6% yield.

[0164] Compound 3-a (50.0 mg, 226 μmol) and compound 1-c (41.7 mg, 226 μmol) were dissolved in 1,4-dioxane (3 mL), Pd(dba)2(20.7 mg, 22.6 μmol), Xantphos (13.1 mg, 22.6 μmol), cesium carbonate (147 mg, 452 μmol) were added. The mixture was stirred at 100 °C under nitrogen atmosphere for 16 hours. The reaction was cooled to room temperature and concentrated. The residue was purified by preparative liquid chromatography to give compound 3 (13.0 mg, 35.2 μmol), white solid, 15.6% yield. 1H NMR (500 MHz, Chloroform-d) δ 8.76 - 8.67 (m, 1H), 8.08 (s, 1H), 8.01 - 7.96 (m, 2H), 7.80 - 7.70 (m, 2H), 7.41 (d, J = 7.9 Hz, 2H), 7.30 - 7.28 (m, 1H), 7.26 - 7.23 (m, 1H), 5.61 - 5.51 (m, 1H), 4.96 - 4.82 (m, 2H), 4.79 - 4.70 (m, 2H), 4.66 - 4.56 (m, 2H); MS (ESI): m / z 369.4 (M+H) + .

[0165] Example 4:

[0166]

[0167] (6-cyanopyridin-3-yl)boronic acid (1.00 g, 6.76 mmol) and 2-bromopyridine (1.07 g, 6.76 mmol) were dissolved in a mixed solvent of dioxane (10 mL) and water (1 mL), and potassium carbonate (1.87 g, 13.5 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (495 mg, 676 μmol) were added. The mixture was stirred at 95 °C for 6 hours under nitrogen protection. The reaction solution was cooled to room temperature, 50 mL of ethyl acetate was added, and filtered through diatomite. The filtrate was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain compound 4-a (760 mg, 4.19 mmol) as a white solid with a yield of 62.0%.

[0168] Compound 4-a (760 mg, 4.19 mmol) was dissolved in ethanol (10 mL), and palladium on carbon (10% w / w, 76.0 mg) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomite, and concentrated. The residue was purified by column chromatography to obtain compound 4-b (300 mg, 1.62 mmol) as a yellow oily liquid with a yield of 38.6%.

[0169] Compound 4-b (36.4 mg, 196 μmol) and compound 1-a (50.0 mg, 196 μmol) were dissolved in N,N-dimethylformamide (2 mL), and diisopropylethylamine (76.2 mg, 589 μmol) was added. The mixture was stirred at 80 °C for 2 hours. After the reaction solution was cooled to room temperature, compound 4 (20.0 mg, 49.6 μmol) was obtained as a white solid with a yield of 25.2% by purification through preparative liquid chromatography. 1H NMR (500 MHz, DMSO-d6) δ 9.24 - 9.17 (m, 1H), 8.73 - 8.36 (m, 4H), 8.06 - 8.00 (m, 1H), 7.94 - 7.90 (m, 1H), 7.43 - 7.37 (m, 2H), 5.69 - 5.40 (m, 1H), 4.94 - 4.32 (m, 6H); MS (ESI): m / z 404.4 (M+H) + .

[0170] Example 5:

[0171]

[0172] Compound 5 was obtained from 4-(3-pyridyl)benzaldehyde following the synthesis of Reference Compound 1. 1 H NMR (500 MHz, DMSO-d6) δ 8.91 - 8.84 (m, 1H), 8.74 - 8.37 (m, 3H), 8.09 - 8.03 (m, 1H), 7.75 - 7.66 (m, 2H), 7.50 - 7.39 (m, 3H), 5.68 - 5.53 (m, 1H), 4.92 - 4.72 (m, 2H), 4.61 - 4.43 (m, 4H); MS (ESI): m / z 403.4 (M+H) + .

[0173] Example 6:

[0174]

[0175] Compound 6 was obtained from 4-(4-pyridyl)benzaldehyde following the synthesis of Reference Compound 1. 1 H NMR (500 MHz, DMSO-d6) δ 8.73 - 8.39 (m, 4H), 7.81 - 7.74 (m, 2H), 7.72 - 7.67 (m, 2H), 7.47 - 7.42 (m, 2H), 5.67 - 5.51 (m, 1H), 4.92 - 4.70 (m, 2H), 4.62 - 4.41 (m, 4H); MS (ESI): m / z 403.4 (M+H) + .

[0176] Example 7:

[0177]

[0178] Compound 7 was obtained from 4-biphenylcarboxaldehyde following the synthesis of Reference Compound 1. 1H NMR (500 MHz, DMSO-d6) δ 8.72 - 8.37 (m, 2H), 7.69 - 7.58 (m, 4H), 7.49 - 7.42 (m, 2H), 7.41 - 7.33 (m, 3H), 5.67 - 5.53 (m, 1H), 4.91 - 4.71 (m, 2H), 4.61 - 4.42 (m, 4H); MS (ESI): m / z 402.4 (M+H) + .

[0179] Example 8:

[0180]

[0181] Compound 8 was obtained from 3-oxetanamine following the synthesis of Reference Compound 1. 1 H NMR (500 MHz, Chloroform-d) δ 8.74 - 8.68 (m, 1H), 8.23 - 8.06 (m, 1H), 8.03 - 7.95 (m, 2H), 7.80 - 7.71 (m, 2H), 7.48 - 7.37 (m, 2H), 7.31 - 7.29 (m, 1H), 7.27 - 7.23 (m, 1H), 5.60 - 5.34 (m, 1H), 5.19 - 5.02 (m, 1H), 5.00 - 4.82 (m, 2H), 4.71 - 4.51 (m, 4H); MS (ESI): m / z 402.3 (M+H) + .

[0182] Example 9:

[0183]

[0184] Compound 9 was obtained from 2,4-dichloro-5-cyanopyrimidine following the synthesis of Reference Compound 1. 1 H NMR (500 MHz, Chloroform-d) δ 8.73 (d, J = 4.6 Hz, 1H), 8.48 - 8.29 (m, 1H), 8.02 (dd, J = 8.3, 2.1 Hz, 2H), 7.87 - 7.79 (m, 1H), 7.79 - 7.72 (m, 1H), 7.48 - 7.37 (m, 2H), 7.32 - 7.29 (m, 1H), 6.34 - 5.72 (m, 1H), 5.66 - 5.56 (m, 1H), 4.99 - 4.57 (m, 6H); MS (ESI): m / z 360.4 (M+H) + .

[0185] Example 10:

[0186]

[0187] Compound 10 was obtained from 2,5-dichloro-4-methoxy-pyrimidine following the synthesis of compound 2. 1 H NMR (500 MHz, DMSO-d6) δ 8.69 - 8.63 (m, 1H), 8.10 (s, 1H), 8.06 - 8.01 (m, 2H), 7.95 - 7.91 (m, 1H), 7.91 - 7.84 (m, 1H), 7.48 - 7.32 (m, 4H), 4.52 (d, J = 6.3 Hz, 2H), 3.90 (s, 3H); MS (ESI): m / z 327.3 (M+H) + .

[0188] Example 11:

[0189]

[0190] Compound 11-a (30 mg, 82.3 μmol) and (1-methyl-1H-pyrazol-3-yl)boronic acid (20.7 mg, 164 μmol) were dissolved in a mixture of 1,4-dioxane (3 mL) and water (0.3 mL), potassium carbonate (34.1 mg, 246 μmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (3.0 mg, 4.11 μmol) were added. The mixture was stirred at 95 °C under nitrogen atmosphere for 3 hours. The reaction was cooled to room temperature, 20 mL of ethyl acetate was added, filtered through celite, the filtrate was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give compound 11 (10.0 mg, 24.4 μmol), white solid, 29.6% yield.

[0191] Compound 11-a (30 mg, 82.3 μmol) and (1-methyl-1H-pyrazol-3-yl)boronic acid (20.7 mg, 164 μmol) were dissolved in a mixture of 1,4-dioxane (3 mL) and water (0.3 mL), potassium carbonate (34.1 mg, 246 μmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (3.0 mg, 4.11 μmol) were added. The mixture was stirred at 95 °C under nitrogen atmosphere for 3 hours. The reaction was cooled to room temperature, 20 mL of ethyl acetate was added, filtered through celite, the filtrate was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give compound 11 (10.0 mg, 24.4 μmol), white solid, 29.6% yield. 1H NMR (500 MHz, Chloroform-d) δ 8.81 - 8.52 (m, 2H), 8.06 - 7.89 (m, 2H), 7.81 - 7.69 (m, 2H), 7.52 - 7.44 (m, 2H), 7.41 (s, 1H), 7.25 - 7.23 (m, 1H), 6.78 (s, 1H), 6.16 - 5.75 (m, 1H), 4.78 (d, J = 5.4 Hz, 2H), 4.10 - 3.95 (m, 3H); MS (ESI): m / z 411.4 (M+H) + .

[0192] Example 12:

[0193]

[0194] N-BOC-4-bromobenzylamine (3.00 g, 10.5 mmol) and bis(pinacolato)diboron (2.93 g, 11.5 mmol) were dissolved in 1,4-dioxane (45 mL), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (383 mg, 524 μmol) and potassium acetate (3.09 g, 31.5 mmol) were added. The mixture was stirred at 95 °C under nitrogen atmosphere for 16 hours. The reaction was cooled to room temperature, 50 mL of ethyl acetate was added, filtered with celite, and the filtrate was concentrated. The residue was purified by column chromatography to give compound 12-a (3.30 g, 9.90 mmol) as a colorless oily liquid with a yield of 94.5%.

[0195] Compound 12-a (100 mg, 300 μmol) and 2-bromoanisole (56.1 mg, 300 μmol) were dissolved in a mixture of 1,4-dioxane (3 mL) and water (0.3 mL), and potassium carbonate (124 mg, 900 μmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (11.0 mg, 15.0 μmol) were added. The mixture was stirred at 95 °C under nitrogen atmosphere for 3 hours. The reaction was cooled to room temperature, 20 mL of ethyl acetate was added, filtered with celite, and the filtrate was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 12-b (80.0 mg, 255 μmol) as a colorless oily liquid with a yield of 85.1%.

[0196] Compound 12-b (80 mg, 255 μmol) was dissolved in dichloromethane (2 mL), and hydrogen chloride dioxane solution (4 N, 1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was directly concentrated to give compound 12-c (63.8 mg, 255 μmol) as a hydrochloride salt, a white solid with a yield of 100%.

[0197] Compound 12-c (29.4 mg, 118 μmol) and compound 1-a (30 mg, 118 μmol) were dissolved in N,N-dimethylformamide (2 mL), and diisopropylethylamine (45.7 mg, 354 μmol) was added. The mixture was stirred at 80 °C for 2 h. The reaction was cooled to room temperature and purified by preparative liquid chromatography to give compound 12 (15.0 mg, 34.8 μmol) as a white solid in 29.5% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.70 - 8.38 (m, 2H), 7.44 - 7.30 (m, 5H), 7.29 - 7.20 (m, 1H), 7.15 - 6.94 (m, 2H), 5.66 - 5.56 (m, 1H), 4.91 - 4.73 (m, 2H), 4.67 - 4.35 (m, 4H), 3.88 - 3.61 (m, 3H); MS (ESI): m / z 432.4 (M+H) + .

[0198] Example 13:

[0199]

[0200] Compound 13-a was obtained from 3-bromo-5-(methylsulfonyl)pyridine following the synthesis of compound 12-a. Compound 13 was obtained from 13-a following the synthesis of compound 11. 1 H NMR (500 MHz, DMSO-d6) δ 9.27 - 9.18 (m, 1H), 9.05 - 8.88 (m, 2H), 8.82 - 8.72 (m, 1H), 8.68 - 8.61 (m, 1H), 8.53 - 8.39 (m, 1H), 8.07 - 8.00 (m, 2H), 7.98 - 7.82 (m, 2H), 7.50 - 7.41 (m, 2H), 7.39 - 7.28 (m, 1H), 4.72 - 4.56 (m, 2H), 3.40 - 3.37 (m, 3H); MS (ESI): m / z 486.3 (M+H) + .

[0201] Example 14:

[0202]

[0203] Compound 14 was obtained from phenol following the synthesis of compound 9. 1H NMR (400 MHz, DMSO-d6) δ 9.05 - 8.72 (m, 1H), 8.72 - 8.61 (m, 2H), 8.05 - 7.85 (m, 4H), 7.55 - 7.44 (m, 2H), 7.41 - 7.27 (m, 4H), 7.26 - 7.21 (m, 1H), 6.99 - 6.95 (m, 1H), 4.63 - 4.06 (m, 2H); MS (ESI): m / z 380.4 (M+H) + .

[0204] Example 15:

[0205]

[0206] Compound 15 was obtained from 2-bromo-6-methylpyridine following the synthesis of Reference Compound 12. 1 H NMR (400 MHz, DMSO-d6) δ 8.74 - 8.39 (m, 2H), 8.09 - 7.98 (m, 2H), 7.78 - 7.69 (m, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.20 (dd, J = 6.8, 1.5 Hz, 1H), 5.68 - 5.50 (m, 1H), 4.93 - 4.68 (m, 2H), 4.61 - 4.39 (m, 4H), 2.53 (s, 3H); MS (ESI): m / z 417.4 (M+H) + .

[0207] Example 16:

[0208]

[0209] Compound 16 was obtained from 2-bromo-6-trifluoromethylpyridine following the synthesis of Reference Compound 12. 1 H NMR (400 MHz, DMSO-d6) δ 8.76 - 8.45 (m, 1H), 8.44 - 8.39 (m, 1H), 8.30 - 8.23 (m, 1H), 8.20 - 8.14 (m, 1H), 8.13 - 8.06 (m, 2H), 7.85 (d, J = 7.6 Hz, 1H), 7.50 - 7.43 (m, 2H), 5.69 - 5.49 (m, 1H), 4.93 - 4.68 (m, 2H), 4.64 - 4.40 (m, 4H).; MS (ESI): m / z 471.1 (M+H) + .

[0210] Example 17:

[0211]

[0212] Compound 17 was obtained from 2-bromo-6-methoxypyridine, referring to the synthesis of compound 12. 1 H NMR (400 MHz, DMSO-d6) δ 8.75 - 8.37 (m, 2H), 8.11 - 8.00 (m, 2H), 7.81 - 7.73 (m, 1H), 7.57 - 7.50 (m, 1H), 7.44 - 7.37 (m, 2H), 6.80 - 6.73 (m, 1H), 5.68 - 5.50 (m, 1H), 4.92 - 4.68 (m, 2H), 4.61 - 4.40 (m, 4H), 3.99 - 3.92 (m, 3H); MS (ESI): m / z 433.4 (M+H) + .

[0213] Example 18:

[0214]

[0215] Compound 18 was obtained from 2-bromo-6-hydroxymethylpyridine, referring to the synthesis of compound 12. 1 H NMR (400 MHz, DMSO-d6) δ 8.74 - 8.39 (m, 2H), 8.08 - 8.00 (m, 2H), 7.90 - 7.84 (m, 1H), 7.81 - 7.76 (m, 1H), 7.44 - 7.38 (m, 3H), 5.68 - 5.50 (m, 1H), 5.49 - 5.43 (m, 1H), 4.91 - 4.69 (m, 2H), 4.65 - 4.61 (m, 2H), 4.61 - 4.41 (m, 4H); MS (ESI): m / z 433.4 (M+H) + .

[0216] Example 19:

[0217]

[0218] Compound 19 was obtained from 2-bromopyrimidine, referring to the synthesis of compound 12. 1 H NMR (400 MHz, DMSO-d6) δ 8.92 - 8.87 (m, 2H), 8.75 - 8.44 (m, 1H), 8.44 - 8.40 (m, 1H), 8.39 - 8.32 (m, 2H), 7.47 - 7.42 (m, 3H), 5.68 - 5.49 (m, 1H), 4.92 - 4.66 (m, 2H), 4.64 - 4.39 (m, 4H); MS (ESI): m / z 403.9 (M+H) + .

[0219] Example 20:

[0220]

[0221] Compound 20-a (1.00 g, 3.56 mmol) and (2-pyridyl)tributylstannane (1.44 g, 3.91 mmol) were dissolved in N,N-dimethylformamide (20 mL), and lithium chloride (196 mg, 4.62 mmol) and tetrakis triphenylphosphine palladium (411 mg, 356 μmol) were added. The mixture was stirred at 95 °C under nitrogen atmosphere for 5 hours. The reaction was cooled to room temperature, and 50 mL of ethyl acetate and 100 mL of IN potassium fluoride solution were added, and stirred for 1 hour. The mixture was filtered through celite, and the organic phase was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 20-b (450 mg, 2.14 mmol) as a white solid in 60.2% yield.

[0222] Compound 20-a (1.00 g, 3.56 mmol) and (2-pyridyl)tributylstannane (1.44 g, 3.91 mmol) were dissolved in N,N-dimethylformamide (20 mL), and lithium chloride (196 mg, 4.62 mmol) and tetrakis triphenylphosphine palladium (411 mg, 356 μmol) were added. The mixture was stirred at 95 °C under nitrogen atmosphere for 5 hours. The reaction was cooled to room temperature, and 50 mL of ethyl acetate and 100 mL of IN potassium fluoride solution were added, and stirred for 1 hour. The mixture was filtered through celite, and the organic phase was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 20-b (450 mg, 2.14 mmol) as a white solid in 60.2% yield.

[0223] Compound 20-a (1.00 g, 3.56 mmol) and (2-pyridyl)tributylstannane (1.44 g, 3.91 mmol) were dissolved in N,N-dimethylformamide (20 mL), and lithium chloride (196 mg, 4.62 mmol) and tetrakis triphenylphosphine palladium (411 mg, 356 μmol) were added. The mixture was stirred at 95 °C under nitrogen atmosphere for 5 hours. The reaction was cooled to room temperature, and 50 mL of ethyl acetate and 100 mL of IN potassium fluoride solution were added, and stirred for 1 hour. The mixture was filtered through celite, and the organic phase was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 20-b (450 mg, 2.14 mmol) as a white solid in 60.2% yield.

[0224] Compound 20-c (25.2 mg, 118 μmol) and compound 1-a (30.0 mg, 118 μmol) were dissolved in N,N-dimethylformamide (2 mL), and diisopropylethylamine (45.7 mg, 354 μmol) was added. The mixture was stirred at 80 °C for 2 hours. After the reaction solution was cooled to room temperature, compound 20 (8.5 mg, 19.7 μmol) was obtained by purification through preparative liquid chromatography as a white solid with a yield of 16.7%. 1 H NMR (400 MHz, DMSO-d6) δ 8.73 - 8.39 (m, 3H), 7.87 - 7.75 (m, 2H), 7.74 - 7.65 (m, 1H), 7.35 - 7.26 (m, 1H), 7.12 (s, 1H), 7.03 - 6.95 (m, 1H), 5.69 - 5.54 (m, 1H), 4.93 - 4.74 (m, 2H), 4.62 - 4.42 (m, 4H), 3.90 - 3.77 (m, 3H); MS (ESI): m / z 433.4 (M+H) + .

[0225] Example 21:

[0226]

[0227] Compound 21 was obtained by referring to the synthesis of compound 12 from 2-bromopyrazine. 1 H NMR (500 MHz, DMSO-d6) δ 9.28 - 9.21 (m, 1H), 8.75 - 8.38 (m, 4H), 8.16 - 8.07 (m, 2H), 7.51 - 7.44 (m, 2H), 5.71 - 5.49 (m, 1H), 4.95 - 4.42 (m, 6H); MS (ESI): m / z 404.2 (M+H) + .

[0228] Example 22:

[0229]

[0230] Compound 22 was obtained by referring to the synthesis of compound 3 from 2,4-dichloro-5-fluoropyrimidine. 1H NMR (500 MHz, DMSO-d6) δ 8.70 - 8.62 (m, 1H), 8.17 (d, J = 3.2 Hz, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.93 (dd, J = 8.0, 1.2 Hz, 1H), 7.87 (td, J = 7.7, 1.9 Hz, 1H), 7.81 (s, 2H), 7.41 (d, J = 8.2 Hz, 2H), 5.65 - 5.45 (m, 1H), 4.91 - 4.66 (m, 2H), 4.64 - 4.34 (m, 4H); MS (ESI): m / z 353.3 (M+H) + .

[0231] Example 23:

[0232]

[0233] Compound 23 was obtained by referring to the synthesis of compound 11 from 2,4-dichloro-5-cyanopyrimidine and imidazo[l,2-a]pyridine-6-boronic acid. 1 H NMR (500 MHz, DMSO-d6) δ 9.23 (s, 1H), 9.10 - 8.99 (m, 1H), 8.90 - 8.79 (m, 1H), 8.65 (t, J = 5.2 Hz, 1H), 8.22 - 8.14 (m, 1H), 8.06 (dd, J = 8.2, 4.2 Hz, 2H), 7.98 - 7.84 (m, 2H), 7.83 - 7.59 (m, 3H), 7.58 - 7.40 (m, 2H), 7.40 - 7.29 (m, 1H), 4.79 - 4.66 (m, 2H); MS (ESI): m / z 404.2 (M+H) + .

[0234] Example 24:

[0235]

[0236] Compound 11-a (30.0 mg, 82.2 μmol) and morpholine (14.3 mg, 164 μmol) were dissolved in N,N-dimethylformamide (2 mL), and diisopropylethylamine (45.7 mg, 353 μmol) was added. The mixture was stirred at 80 °C for 2 hours. After the reaction solution was cooled to room temperature, compound 24 (10 mg, 24.07 μmol) was obtained by purification through preparative liquid chromatography as a white solid in a yield of 29.27%. 1H NMR (500 MHz, DMSO-de) δ 8.68 - 8.60 (m, 1H), 8.32 - 8.23 (m, 1H), 8.23 - 8.00 (m, 3H), 7.95 - 7.90 (m, 1H), 7.89 - 7.84 (m, 1H), 7.46 - 7.37 (m, 2H), 7.36 - 7.30 (m, 1H), 4.62 - 4.45 (m, 2H), 3.70 - 3.53 (m, 4H), 3.52 - 3.41 (m, 4H); MS (ESI): m / z 416.4 (M+H) + .

[0237] Example 25:

[0238]

[0239] Compound 25 was obtained by referring to the synthesis of compound 24 from (R)-2-aminobutanol. 1 H NMR (500 MHz, DMSO-de) δ 8.68 - 8.62 (m, 1H), 8.08 - 7.76 (m, 6H), 7.45 - 7.37 (m, 2H), 7.37 - 7.30 (m, 1H), 5.94 - 5.81 (m, 1H), 4.82 - 4.71 (m, 1H), 4.61 - 4.41 (m, 2H), 4.27 - 4.04 (m, 1H), 3.54 - 3.35 (m, 2H), 1.68 - 1.40 (m, 2H), 0.91 - 0.65 (m, 3H); MS (ESI): m / z 418.4 (M+H) + .

[0240] Example 26:

[0241]

[0242] Compound 11-a (30.0 mg, 82.3 μmol) and oxetan-3-ylmethanol (10.9 mg, 123 μmol) were dissolved in tetrahydrofuran (4 mL), and potassium tert-butoxide (18.5 mg, 164 μmol) was added. The mixture was stirred at 80 °C for 16 hours. After the reaction solution was cooled to room temperature, 10 mL of ammonium chloride was added, and extracted with 20 mL of ethyl acetate. The organic phase was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to obtain compound 26 (15.0 mg, 36.0 μmol) as a white solid, with a yield of 43.8%. 1H NMR (500 MHz, DMSO-d6) δ 8.70 - 8.45 (m, 2H), 8.39 - 8.32 (m, 1H), 8.08 - 8.01 (m, 2H), 7.95 - 7.90 (m, 1H), 7.90 - 7.84 (m, 1H), 7.48 - 7.39 (m, 2H), 7.36 - 7.31 (m, 1H), 4.70 - 4.64 (m, 1H), 4.61 - 4.32 (m, 7H), 3.30 - 3.23 (m, 1H); MS (ESI): m / z 417.3 (M+H) + .

[0243] Example 27:

[0244]

[0245] Compound 27 was obtained by the synthesis of Reference Compound 4 from 3-bromopyridine. 1 H NMR (500 MHz, DMSO-d6) δ 8.99 - 8.86 (m, 2H), 8.72 - 8.38 (m, 3H), 8.19 - 8.07 (m, 2H), 7.59 - 7.48 (m, 1H), 7.47 - 7.37 (m, 1H), 5.73 - 5.39 (m, 1H), 4.95 - 4.54 (m, 5H), 4.41 - 4.35 (m, 1H); MS (ESI): m / z 404.3 (M+H) + .

[0246] Example 28:

[0247]

[0248] Compound 28 was obtained by the synthesis of Reference Compound 26 from benzyl alcohol. 1 H NMR (500 MHz, DMSO-d6) δ 8.68 - 8.48 (m, 2H), 8.42 - 8.34 (m, 1H), 8.06 - 8.01 (m, 2H), 7.95 - 7.89 (m, 1H), 7.90 - 7.84 (m, 1H), 7.49 - 7.25 (m, 8H), 5.52 - 5.43 (m, 2H), 4.66 - 4.55 (m, 2H); MS (ESI): m / z 437.5 (M+H) + .

[0249] Example 29:

[0250]

[0251] Compound 29 was obtained by the synthesis of Reference Compound 11 from phenylboronic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.86 - 8.78 (m, 1H), 8.78 - 8.57 (m, 4H), 8.08 - 8.02 (m, 2H), 7.96 - 7.84 (m, 3H), 7.58 - 7.51 (m, 1H), 7.49 - 7.40 (m, 2H), 7.37 - 7.30 (m, 1H), 4.69 - 4.60 (m, 2H); MS (ESI): m / z 408.4 (M+H) + .

[0252] Example 30:

[0253]

[0254] Compound 30 was obtained by the synthesis of Reference Compound 11 from pyridin-3-ylboronic acid. 1 H NMR (500 MHz, DMSO-d6) δ 8.86 - 8.78 (m, 1H), 8.78 - 8.57 (m, 4H), 8.08 - 8.02 (m, 2H), 7.96 - 7.84 (m, 3H), 7.58 - 7.51 (m, 1H), 7.49 - 7.40 (m, 2H), 7.37 - 7.30 (m, 1H), 4.69 - 4.60 (m, 2H); MS (ESI): m / z 408.4 (M+H) + .

[0255] Example 31:

[0256]

[0257] Compound 31 was obtained by the synthesis of Reference Compound 11 from pyridin-4-ylboronic acid. 1 H NMR (500 MHz, DMSO-d6) δ 8.86 - 8.78 (m, 1H), 8.78 - 8.57 (m, 4H), 8.08 - 8.02 (m, 2H), 7.96 - 7.84 (m, 3H), 7.58 - 7.51 (m, 1H), 7.49 - 7.40 (m, 2H), 7.37 - 7.30 (m, 1H), 4.69 - 4.60 (m, 2H); MS (ESI): m / z 408.4 (M+H) + .

[0258] Example 32:

[0259]

[0260] Compound 32 was obtained by the synthesis of Reference Compound 11 from (5-fluoro-2-methoxyphenyl)boronic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.78 - 8.57 (m, 3H), 8.11 - 7.98 (m, 2H), 7.98 - 7.91 (m, 1H), 7.91 - 7.82 (m, 1H), 7.51 - 7.37 (m, 2H), 7.37 - 7.22 (m, 2H), 7.21 - 7.01 (m, 2H), 4.76 - 4.46 (m, 2H), 3.74 - 3.61 (m, 3H); MS (ESI): m / z 455.3 (M+H) + .

[0261] Example 33:

[0262]

[0263] Compound 33 was obtained from 2-bromo-6-(methoxymethyl)pyridine following the synthesis of Reference Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.72 - 8.38 (m, 2H), 8.09 - 7.81 (m, 4H), 7.46 - 7.34 (m, 3H), 5.70 - 5.52 (m, 1H), 4.92 - 4.71 (m, 2H), 4.61 - 4.42 (m, 6H), 3.41 (s, 3H); MS (ESI): m / z 447.3 (M+H) + .

[0264] Example 34:

[0265]

[0266] Compound 34 was obtained from tetrahydropyran-4-ol following the synthesis of Reference Compound 26. 1 H NMR (500 MHz, DMSO-d6) δ 8.68 - 8.63 (m, 1H), 8.63 - 8.40 (m, 1H), 8.39 - 8.32 (m, 1H), 8.08 - 8.00 (m, 2H), 7.95 - 7.90 (m, 1H), 7.90 - 7.83 (m, 1H), 7.46 - 7.38 (m, 2H), 7.37 - 7.29 (m, 1H), 5.45 - 5.17 (m, 1H), 4.65 - 4.46 (m, 2H), 3.85 - 3.64 (m, 2H), 3.59 - 3.39 (m, 2H), 2.05 - 1.73 (m, 2H), 1.71 - 1.43 (m, 2H); MS (ESI): m / z 431.3 (M+H) + .

[0267] Example 35:

[0268]

[0269] Compound 35 was obtained from N-methyl-4-piperidinol by the synthesis of Reference Compound 26. 1 H NMR (500 MHz, DMSO-d6) δ 8.68 - 8.63 (m, 1H), 8.62 - 8.36 (m, 1H), 8.37 - 8.30 (m, 1H), 8.06 - 8.00 (m, 2H), 7.95 - 7.89 (m, 1H), 7.90 - 7.83 (m, 1H), 7.47 - 7.38 (m, 2H), 7.37 - 7.30 (m, 1H), 5.25 - 4.99 (m, 1H), 4.62 - 4.47 (m, 2H), 2.46 - 2.21 (m, 2H), 2.19 - 2.10 (m, 4H), 1.97 - 1.51 (m, 4H); MS (ESI): m / z 444.4 (M+H) + .

[0270] Example 36:

[0271]

[0272] Compound 36 was obtained from 2,4-dichloro-5-methylpyrimidine by the synthesis of Reference Compound 3. 1 H NMR (500 MHz, DMSO-d6) δ 8.68 - 8.63 (m, 1H), 8.62 - 8.36 (m, 1H), 8.37 - 8.30 (m, 1H), 8.06 - 8.00 (m, 2H), 7.95 - 7.89 (m, 1H), 7.90 - 7.83 (m, 1H), 7.47 - 7.38 (m, 2H), 7.37 - 7.30 (m, 1H), 5.25 - 4.99 (m, 1H), 4.62 - 4.47 (m, 2H), 2.46 - 2.21 (m, 2H), 2.19 - 2.10 (m, 4H), 1.97 - 1.51 (m, 4H); MS (ESI): m / z 444.4 (M+H) + .

[0273] Example 37:

[0274]

[0275] Compound 37 was obtained from 2,4-dichloro-5-bromopyrimidine by the synthesis of Reference Compound 1. 1H NMR (500 MHz, DMSO-d6) δ 8.73 - 8.58 (m, 1H), 8.22 (s, 1H), 8.19 - 7.81 (m, 5H), 7.39 (d, J = 8.0 Hz, 2H), 7.37 - 7.29 (m, 1H), 5.65 - 5.37 (m, 1H), 4.98 - 4.65 (m, 2H), 4.64 - 4.35 (m, 4H); MS (ESI): m / z 413.2 (M+H) + .

[0276] Example 38:

[0277]

[0278] Compound 38 was obtained by the synthesis of Reference Compound 1 from 2,4-dichloro-5-iodopyrimidine. 1 H NMR (500 MHz, DMSO-d6) δ 8.73 - 8.58 (m, 1H), 8.22 (s, 1H), 8.19 - 7.81 (m, 5H), 7.39 (d, J = 8.0 Hz, 2H), 7.37 - 7.29 (m, 1H), 5.65 - 5.37 (m, 1H), 4.98 - 4.65 (m, 2H), 4.64 - 4.35 (m, 4H); MS (ESI): m / z 413.2 (M+H) + .

[0279] Example 39:

[0280]

[0281] Compound 39 was obtained by the synthesis of Reference Compound 12 from 2-bromo-3-methylpyridine. 1 H NMR (500 MHz, DMSO-d6) δ 8.73 - 8.58 (m, 1H), 8.22 (s, 1H), 8.19 - 7.81 (m, 5H), 7.39 (d, J = 8.0 Hz, 2H), 7.37 - 7.29 (m, 1H), 5.65 - 5.37 (m, 1H), 4.98 - 4.65 (m, 2H), 4.64 - 4.35 (m, 4H); MS (ESI): m / z 413.2 (M+H) + .

[0282] Example 40:

[0283]

[0284] Compound 40 was obtained by the synthesis of Reference Compound 12 from 2-bromo-4-methylpyridine.1 H NMR (500 MHz, DMSO-d6) δ 8.73 - 8.36 (m, 3H), 8.13 - 7.73 (m, 3H), 7.47 - 7.14 (m, 3H), 5.69 - 5.51 (m, 1H), 4.93 - 4.69 (m, 2H), 4.62 - 4.40 (m, 4H), 2.38 (s, 3H); MS (ESI): m / z 417.4 (M+H) + .

[0285] Example 41:

[0286]

[0287] Compound 41 was obtained from 2-bromo-5-methylpyridine following the synthesis of Reference Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.69 - 8.37 (m, 3H), 8.06 - 7.81 (m, 3H), 7.74 - 7.38 (m, 3H), 5.70 - 5.52 (m, 1H), 4.92 - 4.71 (m, 2H), 4.62 - 4.49 (m, 3H), 4.46 - 4.43 (m, 1H), 2.33 (s, 3H); MS (ESI): m / z 417.6 (M+H) + .

[0288] Example 42:

[0289]

[0290] Compound 42 was obtained from 2-chloro-3-pyridinmethanol following the synthesis of Reference Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.72 - 8.34 (m, 3H), 7.98 - 7.93 (m, 1H), 7.57 - 7.52 (m, 2H), 7.43 - 7.37 (m, 3H), 5.71 - 5.53 (m, 1H), 5.44 - 5.32 (m, 1H), 4.94 - 4.70 (m, 2H), 4.67 - 4.42 (m, 6H); MS (ESI): m / z 433.4 (M+H) + .

[0291] Example 43:

[0292]

[0293] Compound 43 was obtained from (2-chloro-4-pyridinyl)methanol following the synthesis of Reference Compound 12. 1H NMR (500 MHz, DMSO-d6) δ 8.74 - 8.35 (m, 3H), 8.11 - 7.83 (m, 3H), 7.48 - 7.26 (m, 3H), 5.71 - 5.52 (m, 1H), 5.49 - 5.43 (m, 1H), 4.95 - 4.70 (m, 2H), 4.63 - 4.42 (m, 6H); MS (ESI): m / z 433.4 (M+H) + .

[0294] Example 44:

[0295]

[0296] Compound 44 was obtained from tert-butyl (l-(4-bromophenyl)ethyl)carbamate following the synthesis of Reference Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.75 - 8.35 (m, 3H), 8.12 - 8.00 (m, 2H), 7.98 - 7.83 (m, 2H), 7.57 - 7.28 (m, 3H), 5.77 - 5.46 (m, 1H), 5.30 - 4.18 (m, 5H), 1.55 - 1.44 (m, 3H); MS (ESI): m / z 417.4 (M+H) + .

[0297] Example 45:

[0298]

[0299] Compound 45 was obtained from 2-(6-chloropyridin-2-yl)propan-2-ol following the synthesis of Reference Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.72 - 8.39 (m, 2H), 8.11 - 8.01 (m, 2H), 7.87 - 7.72 (m, 2H), 7.62 - 7.39 (m, 3H), 5.68 - 5.52 (m, 1H), 5.24 (s, 1H), 4.92 - 4.72 (m, 2H), 4.61 - 4.44 (m, 4H), 1.51 (s, 6H); MS (ESI): m / z 461.4 (M+H) + .

[0300] Example 46:

[0301]

[0302] Compound 46 was obtained from l-(6-chloropyridin-2-yl)-N,N-dimethylmethanamine following the synthesis of Reference Compound 12. 1H NMR (500 MHz, DMSO-d6) δ 8.73 - 8.37 (m, 2H), 8.11 - 7.75 (m, 4H), 7.46 - 7.34 (m, 3H), 5.72 - 5.51 (m, 1H), 4.98 - 4.67 (m, 2H), 4.63 - 4.38 (m, 4H), 3.58 (s, 2H), 2.23 (s, 6H); MS (ESI): m / z 460.4 (M+H) + .

[0303] Example 47:

[0304]

[0305] Compound 47 was obtained from 1-(difluoromethyl)-1H-pyrazole-3-boronic acid pinacol ester following the synthesis of Reference Compound 11. 1 H NMR (500 MHz, DMSO-d6) δ 8.84 - 8.68 (m, 2H), 8.68 - 8.62 (m, 1H), 8.42 - 8.33 (m, 1H), 8.05 (d, J = 8.0 Hz, 2H), 8.03 - 7.76 (m, 3H), 7.52 - 7.42 (m, 2H), 7.38 - 7.29 (m, 1H), 6.96 - 6.88 (m, 1H), 4.70 - 4.64 (m, 2H); MS (ESI): m / z 447.4 (M+H) + .

[0306] Example 48:

[0307]

[0308] Compound 48 was obtained from tert-butyl ((6-chloropyridin-3-yl)methyl)carbamate following the synthesis of Reference Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 9.27 - 9.22 (m, 1H), 8.72 - 8.37 (m, 5H), 8.06 - 7.99 (m, 1H), 7.86 - 7.80 (m, 1H), 7.55 - 7.48 (m, 1H), 5.70 - 5.53 (m, 1H), 4.93 - 4.74 (m, 2H), 4.63 - 4.45 (m, 4H); MS (ESI): m / z 404.3 (M+H) + .

[0309] Example 49:

[0310]

[0311] Compound 49 was obtained from 2-methoxyethylamine following the synthesis of Reference Compound 24.1 H NMR (500 MHz, DMSO-d6) δ 8.71 - 8.56 (m, 1H), 8.07 - 7.79 (m, 6H), 7.46 - 7.26 (m, 3H), 6.81 - 6.51 (m, 1H), 4.63 - 4.43 (m, 2H), 3.62 - 3.38 (m, 3H), 3.29 - 3.24 (m, 2H), 3.17 - 3.07 (m, 2H); MS (ESI): m / z 404.3 (M+H) + .

[0312] Example 50:

[0313]

[0314] Compound 50 was obtained by the synthesis of Reference Compound 24 from N,N,N'-trimethylethylenediamine. 1 H NMR (500 MHz, DMSO-d6) δ 8.71 - 8.56 (m, 1H), 8.07 - 7.79 (m, 6H), 7.46 - 7.26 (m, 3H), 6.81 - 6.51 (m, 1H), 4.63 - 4.43 (m, 2H), 3.62 - 3.38 (m, 3H), 3.29 - 3.24 (m, 2H), 3.17 - 3.07 (m, 2H); MS (ESI): m / z 404.3 (M+H) + .

[0315] Example 51:

[0316]

[0317] Compound 51 was obtained by the synthesis of Reference Compound 24 from (S)-2-aminobutanol. 1 H NMR (500 MHz, DMSO-d6) δ 8.71 - 8.56 (m, 1H), 8.07 - 7.79 (m, 6H), 7.46 - 7.26 (m, 3H), 6.81 - 6.51 (m, 1H), 4.63 - 4.43 (m, 2H), 3.62 - 3.38 (m, 3H), 3.29 - 3.24 (m, 2H), 3.17 - 3.07 (m, 2H); MS (ESI): m / z 404.3 (M+H) + .

[0318] Example 52:

[0319]

[0320] Compound 52 was obtained from glycine hydrochloride salt by the synthesis of compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.74 - 8.57 (m, 1H), 8.12 - 7.94 (m, 4H), 7.94 - 7.82 (m, 2H), 7.51 - 7.29 (m, 4H), 7.17 - 7.04 (m, 1H), 6.93 - 6.63 (m, 1H), 4.59 - 4.45 (m, 2H), 3.98 - 3.86 (m, 2H); MS (ESI): m / z 403.2 (M+H) + .

[0321] Example 53:

[0322]

[0323] Compound 53-a was obtained from methyl 6-chloropyridine-2-carboxylate by the synthesis of compound 12.

[0324] Compound 53-a (30.0 mg, 65.2 μmol) was dissolved in a mixture solvent of tetrahydrofuran (2 mL) and methanol (1 mL), and 1 N sodium hydroxide solution (1 mL) was added. The mixture was stirred at room temperature for 6 hours. 1 N hydrochloric acid solution was added to the reaction solution to pH = 7, and concentrated to dryness. The residue was purified by preparative liquid chromatography to obtain compound 53 (10.1 mg, 22.4 μmol) as a white solid, with a yield of 34.4%. 1 H NMR (500 MHz, DMSO-d6) δ 8.74 - 8.57 (m, 1H), 8.12 - 7.94 (m, 4H), 7.94 - 7.82 (m, 2H), 7.51 - 7.29 (m, 4H), 7.17 - 7.04 (m, 1H), 6.93 - 6.63 (m, 1H), 4.59 - 4.45 (m, 2H), 3.98 - 3.86 (m, 2H); MS (ESI): m / z 403.2 (M+H) + .

[0325] Example 54:

[0326]

[0327] Compound 54 was obtained from (R)-2-piperidinemethanol by the synthesis of compound 24. 1H NMR (500 MHz, DMSO-d6) δ 8.73 - 8.57 (m, 1H), 8.26 - 8.14 (m, 1H), 8.12 - 7.98 (m, 3H), 7.98 - 7.80 (m, 2H), 7.49 - 7.28 (m, 3H), 4.68 - 4.60 (m, 1H), 4.60 - 4.46 (m, 2H), 4.36 - 4.24 (m, 1H), 3.73 - 3.43 (m, 3H), 3.12 - 2.99 (m, 1H), 1.87 - 1.74 (m, 1H), 1.64 - 1.35 (m, 5H); MS (ESI): m / z 444.5 (M+H) + .

[0328] Example 55:

[0329]

[0330] Compound 55 was obtained by the synthesis of Reference Compound 26 from N,N- dimethylethanolamine. 1 H NMR (500 MHz, DMSO-d6) δ 8.66 - 8.62 (m, 1H), 8.61 - 8.37 (m, 1H), 8.36 - 8.29 (m, 1H), 8.08 - 7.99 (m, 2H), 7.96 - 7.83 (m, 2H), 7.46 - 7.29 (m, 3H), 4.66 - 4.51 (m, 2H), 4.51 - 4.36 (m, 2H), 2.65 - 2.51 (m, 2H), 2.24 - 2.06 (m, 6H); MS (ESI): m / z 418.5 (M+H) + .

[0331] Example 56:

[0332]

[0333] Compound 56 was obtained by the synthesis of Reference Compound 12 from 1-(6- bromopyridin-2-yl)ethan-1-ol. 1 H NMR (500 MHz, DMSO-d6) δ 8.72 - 8.33 (m, 2H), 8.16 - 7.95 (m, 2H), 7.89 - 7.68 (m, 2H), 7.49 - 7.37 (m, 3H), 5.65 - 5.52 (m, 1H), 5.39 - 5.31 (m, 1H), 4.96 - 4.80 (m, 1H), 4.79 - 4.69 (m, 2H), 4.61 - 4.41 (m, 4H), 1.48 - 1.36 (m, 3H); MS (ESI): m / z 447.5 (M+H) + .

[0334] Example 57:

[0335]

[0336] Compound 57 was obtained from ethanolamine by the synthesis of reference compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.67 - 8.60 (m, 1H), 8.05 - 7.76 (m, 6H), 7.50 - 7.28 (m, 3H), 6.67 - 6.43 (m, 1H), 4.77 - 4.60 (m, 1H), 4.59 - 4.45 (m, 2H), 3.49 - 3.37 (m, 4H); MS (ESI): m / z 390.4 (M+H) + .

[0337] Example 58:

[0338]

[0339] Compound 58 was obtained from 2-(methylamino)ethanol by the synthesis of reference compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.72 - 8.59 (m, 1H), 8.27 - 8.12 (m, 1H), 8.10 - 7.95 (m, 3H), 7.95 - 7.81 (m, 2H), 7.45 - 7.36 (m, 2H), 7.36 - 7.27 (m, 1H), 4.65 - 4.44 (m, 2H), 3.66 - 3.47 (m, 2H), 3.03 - 2.98 (m, 2H), 2.35 - 2.09 (m, 3H); MS (ESI): m / z 404.2 (M+H) + .

[0340] Example 59:

[0341]

[0342] Compound 59 was obtained from N,N-dimethylethylenediamine by the synthesis of reference compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.65 - 8.59 (m, 1H), 8.27 - 7.96 (m, 5H), 7.93 - 7.80 (m, 2H), 7.42 - 7.30 (m, 3H), 4.82 - 4.35 (m, 4H), 3.72 - 3.55 (m, 2H), 3.55 - 3.49 (m, 3H), 3.07 - 3.04 (m, 3H); MS (ESI): m / z 417.7 (M+H) + .

[0343] Example 60:

[0344]

[0345] Compound 60 was obtained from D-prolinol, referring to the synthesis of compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.66-8.62 (m, 1H), 8.21-8.13 (m, 1H), 8.04-7.99 (m, 2H), 7.97-7.80 (m, 3H), 7.46-7.28 (m, 3H), 4.64-4.58 (m, 1H), 4.57-4.41 (m, 3H), 3.62-3.32 (m, 4H), 1.98-1.73 (m, 4H); MS (ESI): m / z 430.5 (M+H) + .

[0346] Example 61:

[0347]

[0348] Compound 61 was obtained from ethylene glycol, referring to the synthesis of compound 26. 1 H NMR (500 MHz, DMSO-d6) δ 8.70-8.26 (m, 3H), 8.07-7.99 (m, 2H), 7.95-7.82 (m, 2H), 7.48-7.37 (m, 2H), 7.36-7.29 (m, 1H), 4.87-4.73 (m, 1H), 4.65-4.50 (m, 2H), 4.45-4.32 (m, 2H), 3.79-3.58 (m, 2H); MS (ESI): m / z 391.5 (M+H) + .

[0349] Example 62:

[0350]

[0351] Compound 62-a was obtained from glycine methyl ester hydrochloride, referring to the synthesis of compound 24.

[0352] Compound 62 was obtained from compound 62-a, referring to the synthesis of compound 53. 1 H NMR (500 MHz, DMSO-d6) δ 8.66-8.60 (m, 1H), 8.17-7.74 (m, 6H), 7.46-7.29 (m, 3H), 7.16-6.78 (m, 1H), 4.55-4.44 (m, 2H), 4.03-3.78 (m, 2H); MS (ESI): m / z 404.2 (M+H) + .

[0353] Example 63:

[0354]

[0355] Compound 63 was obtained from 1-(4-bromophenyl)cyclopropanamine by following the synthesis of Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 9.01 - 8.67 (m, 2H), 8.65 - 8.37 (m, 2H), 8.06 - 7.98 (m, 1H), 7.73 - 7.53 (m, 2H), 7.52 - 7.20 (m, 3H), 5.69 - 5.27 (m, 1H), 4.70 - 4.27 (m, 4H), 1.40 - 1.22 (m, 4H); MS (ESI): m / z 429.5 (M+H) + .

[0356] Example 64:

[0357]

[0358] Compound 64 was obtained from (2-chloro-6-methylpyridin-4-yl)methanol by following the synthesis of Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.67 - 8.36 (m, 2H), 8.08 - 7.92 (m, 2H), 7.68 - 7.60 (m, 1H), 7.46 - 7.35 (m, 2H), 7.13 (s, 1H), 5.71 - 5.49 (m, 1H), 5.47 - 5.34 (m, 1H), 4.90 - 4.70 (m, 2H), 4.62 - 4.40 (m, 6H), 2.51 - 2.50 (m, 3H); MS (ESI): m / z 447.5 (M+H) + .

[0359] Example 65:

[0360]

[0361] Compound 65 was obtained from (1S,2S)-2-aminocyclopentanol hydrochloride by following the synthesis of Compound 24. 1H NMR (500 MHz, DMSO-d6) δ 8.67 - 8.61 (m, 1H), 8.05 - 7.73 (m, 6H), 7.47 - 7.14 (m, 3H), 6.92 - 6.62 (m, 1H), 4.61 - 4.45 (m, 3H), 3.49 - 3.36 (m, 4H), 1.72 - 1.55 (m, 2H); MS (ESI): m / z 404.2 (M+H) + .

[0362] Example 66:

[0363]

[0364] Compound 66 was obtained by the synthesis of Reference Compound 24 from 3-aminopropanol. 1 H NMR (500 MHz, DMSO-d6) δ 8.67 - 8.61 (m, 1H), 8.05 - 7.73 (m, 6H), 7.47 - 7.14 (m, 3H), 6.92 - 6.62 (m, 1H), 4.61 - 4.45 (m, 3H), 3.49 - 3.36 (m, 4H), 1.72 - 1.55 (m, 2H); MS (ESI): m / z 404.2 (M+H) + .

[0365] Example 67:

[0366]

[0367] Compound 67 was obtained by the synthesis of Reference Compound 12 from 2-(6-chloropyridin-2-yl)ethan-1-ol. 1 H NMR (500 MHz, DMSO-d6) δ 8.67 - 8.61 (m, 1H), 8.05 - 7.73 (m, 6H), 7.47 - 7.14 (m, 3H), 6.92 - 6.62 (m, 1H), 4.61 - 4.45 (m, 3H), 3.49 - 3.36 (m, 4H), 1.72 - 1.55 (m, 2H); MS (ESI): m / z 404.2 (M+H) + .

[0368] Example 68:

[0369]

[0370] From 6-chloronicotinamide, compound 68 was obtained by the synthesis of reference compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.71 - 8.38 (m, 2H), 8.29 - 8.10 (m, 4H), 8.07 - 7.90 (m, 2H), 7.69 (s, 1H), 7.45 - 7.38 (m, 2H), 5.69 - 5.49 (m, 1H), 4.91 - 4.70 (m, 2H), 4.61 - 4.42 (m, 4H); MS (ESI): m / z 446.3 (M+H) + .

[0371] Example 69:

[0372]

[0373] From (6-chloro-4-methylpyridin-2-yl)methanol, compound 69 was obtained by the synthesis of reference compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.71 - 8.36 (m, 2H), 8.11 - 7.94 (m, 2H), 7.72 - 7.55 (m, 1H), 7.51 - 7.33 (m, 2H), 7.31 - 7.17 (m, 1H), 5.68 - 5.49 (m, 1H), 5.43 - 5.28 (m, 1H), 4.93 - 4.66 (m, 2H), 4.61 - 4.40 (m, 6H), 2.41 - 2.36 (m, 3H); MS (ESI): m / z 447.4 (M+H) + .

[0374] Example 70:

[0375]

[0376] From (1R,2R)-2-aminocyclopentanol hydrochloride, compound 70 was obtained by the synthesis of reference compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.70 - 8.61 (m, 1H), 8.09 - 8.00 (m, 3H), 7.99 - 7.75 (m, 3H), 7.54 - 7.27 (m, 3H), 6.24 - 6.12 (m, 1H), 4.78 - 4.65 (m, 1H), 4.62 - 4.40 (m, 2H), 4.28 - 3.96 (m, 2H), 1.94 - 1.25 (m, 6H); MS (ESI): m / z 430.5 (M+H) + .

[0377] Example 71:

[0378]

[0379] Compound 71 was obtained from (1R,2S)-2-aminocyclopentanol hydrochloride by referring to the synthesis of Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.67 - 8.62 (m, 1H), 8.12 - 7.99 (m, 4H), 7.97 - 7.81 (m, 2H), 7.44 - 7.37 (m, 2H), 7.36 - 7.29 (m, 1H), 6.01 - 5.91 (m, 1H), 5.26 - 5.12 (m, 1H), 4.62 - 4.39 (m, 2H), 4.23 - 3.91 (m, 2H), 1.90 - 1.32 (m, 6H); MS (ESI): m / z 430.5 (M+H) + .

[0380] Example 72:

[0381]

[0382] Compound 72 was obtained from (1S,2R)-2-aminocyclopentanol hydrochloride by referring to the synthesis of Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.67 - 8.62 (m, 1H), 8.12 - 7.99 (m, 4H), 7.97 - 7.81 (m, 2H), 7.44 - 7.37 (m, 2H), 7.36 - 7.29 (m, 1H), 6.01 - 5.91 (m, 1H), 5.26 - 5.12 (m, 1H), 4.62 - 4.39 (m, 2H), 4.23 - 3.91 (m, 2H), 1.90 - 1.32 (m, 6H); MS (ESI): m / z 430.5 (M+H) + .

[0383] Example 73:

[0384]

[0385] Compound 38 (30.0 mg, 65.2 μmol) and vinylboronic acid pinacol ester (50.2 mg, 326 μmol) were dissolved in a mixture of 1,4-dioxane (3 mL) and water (0.3 mL), potassium carbonate (18.0 mg, 130 μmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (4.8 mg, 6.52 μmol) were added. The mixture was stirred at 95 °C under nitrogen atmosphere for 3 hours. The reaction was cooled to room temperature, 20 mL of ethyl acetate was added, filtered with celite, the filtrate was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give compound 73 (10.0 mg, 27.8 μmol), white solid, yield 42.6%. 1 H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 4.8 Hz, 1H), 8.26 (s, 1H), 8.15 - 7.95 (m, 3H), 7.91 (d, J = 8.0 Hz, 1H), 7.88 - 7.82 (m, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.32 (dd, J = 7.4, 4.9 Hz, 1H), 6.60 - 6.49 (m, 1H), 5.78 - 5.66 (m, 1H), 5.65 - 5.37 (m, 1H), 5.10 (d, J = 11.5 Hz, 1H), 4.91 - 4.65 (m, 2H), 4.63 - 4.38 (m, 4H); MS (ESI): m / z 361.1 (M+H) + .

[0386] Example 74:

[0387]

[0388] Compound 74 was obtained from (6-(methylsulfonyl)pyridin-3-yl)boronic acid, referring to the synthesis of compound 11. 1 H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 4.8 Hz, 1H), 8.26 (s, 1H), 8.15 - 7.95 (m, 3H), 7.91 (d, J = 8.0 Hz, 1H), 7.88 - 7.82 (m, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.32 (dd, J = 7.4, 4.9 Hz, 1H), 6.60 - 6.49 (m, 1H), 5.78 - 5.66 (m, 1H), 5.65 - 5.37 (m, 1H), 5.10 (d, J = 11.5 Hz, 1H), 4.91 - 4.65 (m, 2H), 4.63 - 4.38 (m, 4H); MS (ESI): m / z 361.1 (M+H) + .

[0389] Example 75:

[0390]

[0391] Compound 75 was obtained by the synthesis of compound 73 from cyclopropylboronic acid. 1 H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 4.5 Hz, 1H), 8.01 (d, J = 7.9 Hz, 2H), 7.91 (d, J = 7.9 Hz, 1H), 7.88 - 7.82 (m, 1H), 7.76 (s, 1H), 7.61 - 7.35 (m, 3H), 7.31 (dd, J = 7.4, 4.8 Hz, 1H), 5.61 - 5.35 (m, 1H), 4.89 - 4.62 (m, 2H), 4.57 - 4.37 (m, 4H), 1.73 - 1.66 (m, 1H), 0.79 - 0.73 (m, 2H), 0.60 - 0.55 (m, 2H); MS (ESI): m / z 375.4 (M+H) + .

[0392] Example 76:

[0393]

[0394] Compound 76 was obtained by the synthesis of compound 4 from 2-methyl-4- cyanophenylboronic acid. 1 H NMR (500 MHz, DMSO-d6) δ 8.69 - 8.35 (m, 3H), 7.90 - 7.82 (m, 1H), 7.51 - 7.45 (m, 1H), 7.38 - 7.30 (m, 2H), 7.26 - 7.18 (m, 2H), 5.68 - 5.55 (m, 1H), 4.91 - 4.74 (m, 2H), 4.59 - 4.44 (m, 4H), 2.33 - 2.27 (m, 3H); MS (ESI): m / z 417.4 (M+H) + .

[0395] Example 77:

[0396]

[0397] Compound 38 (25.0 mg, 54.3 μmol) and trimethylsilylethynyl (16.0 mg, 163 μmol) were dissolved in tetrahydrofuran (3 mL), triethylamine (27.5 mg, 271 μmol), copper iodide (1.0 mg, 5.43 μmol) and dichlorobis(triphenylphosphine)palladium (3.8 mg, 5.43 μmol) were added. The mixture was stirred at 50 °C under nitrogen atmosphere for 3 hours. The reaction was cooled to room temperature, 3 mL of 1 M tetra-n-butylammonium fluoride in tetrahydrofuran was added and stirred for 1 hour. To the mixture was added 20 mL of ethyl acetate, filtered with celite, the filtrate was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative liquid chromatography to give compound 77 (5.0 mg, 14.0 μmol) as a white solid in 25.7 % yield. 1 H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J = 4.8 Hz, 1H), 8.38 - 8.27 (m, 1H), 8.26 - 8.21 (m, 1H), 8.06 - 8.01 (m, 2H), 7.94 - 7.90 (m, 1H), 7.88 - 7.83 (m, 1H), 7.42 - 7.36 (m, 2H), 7.35 - 7.29 (m, 1H), 5.60 - 5.41 (m, 1H), 4.91 - 4.68 (m, 2H), 4.62 - 4.40 (m, 4H), 4.36 - 4.29 (m, 1H); MS (ESI): m / z 359.4 (M+H) + .

[0398] Example 78:

[0399]

[0400] Compound 38 (30.0 mg, 65.2 μmol) and dimethyl phosphine oxide (6.4 mg, 81.5 μmol) were dissolved in 1,4-dioxane (3 mL), cesium carbonate (42.5 mg, 130 μmol), Pd2(dba)3(6.0 mg, 6.52 μmol) and Xantphos (7.5 mg, 13.0 μmol) were added. The mixture was stirred at 95 °C under nitrogen atmosphere for 3 hours. The reaction was cooled to room temperature, 20 mL of ethyl acetate was added, filtered with celite, the filtrate was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative liquid chromatography to give compound 78 (8.0 mg, 19.5 μmol) as a white solid in 29.9 % yield. 1H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J = 4.9 Hz, 1H), 8.49 - 8.15 (m, 2H), 8.10 - 8.00 (m, 2H), 7.99 - 7.82 (m, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.32 (dd, J = 7.4, 4.8 Hz, 1H), 5.66 - 5.49 (m, 1H), 4.90 - 4.68 (m, 2H), 4.62 - 4.43 (m, 4H), 1.67 - 1.58 (m, 6H); MS (ESI): m / z 411.3 (M+H) + .

[0401] Example 79:

[0402]

[0403] Compound 79 was obtained from 5-(hydroxymethyl)pyridine-3-boronic acid following the synthesis of Reference Compound 11. 1 H NMR (500 MHz, DMSO-d6) δ 8.84 - 8.78 (m, 1H), 8.77 - 8.71 (m, 1H), 8.70 - 8.60 (m, 2H), 8.58 - 8.49 (m, 1H), 8.09 - 8.01 (m, 2H), 7.96 - 7.91 (m, 1H), 7.90 - 7.79 (m, 2H), 7.50 - 7.41 (m, 2H), 7.37 - 7.31 (m, 1H), 5.50 - 5.41 (m, 1H), 4.71 - 4.57 (m, 4H); MS (ESI): m / z 437.7 (M+H) + .

[0404] Example 80:

[0405]

[0406] Compound 80 was obtained from 6-(hydroxymethyl)pyridine-3-boronic acid following the synthesis of Reference Compound 11. 1 H NMR (500 MHz, DMSO-d6) δ 8.81 - 8.76 (m, 1H), 8.75 - 8.69 (m, 1H), 8.69 - 8.62 (m, 1H), 8.60 - 8.52 (m, 1H), 8.06 - 8.02 (m, 2H), 7.99 - 7.83 (m, 3H), 7.62 - 7.56 (m, 1H), 7.49 - 7.40 (m, 2H), 7.36 - 7.30 (m, 1H), 5.55 - 5.47 (m, 1H), 4.67 - 4.60 (m, 4H); MS (ESI): m / z 437.7 (M+H) + .

[0407] Example 81:

[0408]

[0409] Compound 81 was obtained by the synthesis of Reference Compound 11 from 5- carbamoylpyridine-3-boronic acid pinacol ester. 1 H NMR (500 MHz, DMSO-d6) δ 9.19 - 9.11 (m, 1H), 8.92 - 8.72 (m, 3H), 8.68 - 8.61 (m, 1H), 8.38 - 8.30 (m, 1H), 8.29 - 8.19 (m, 1H), 8.07 - 8.01 (m, 2H), 7.95 - 7.89 (m, 1H), 7.87 (d, J = 7.0 Hz, 1H), 7.78 - 7.66 (m, 1H), 7.49 - 7.40 (m, 2H), 7.37 - 7.29 (m, 1H), 4.70 - 4.59 (m, 2H); MS (ESI): m / z 451.4 (M+H) + .

[0410] Example 82:

[0411]

[0412] Compound 38 (30.0 mg, 65.2 μmol) and N,N'-dimethylethylenediamine (1.92 mg, 21.7 μmol) were dissolved in 1,4-dioxane (3 mL), sodium methanesulfinate (6.4 mg, 81.5 μmol) and copper trifluoromethanesulfonate (3.9 mg, 10.8 μmol) were added. The mixture was stirred at 115 °C under nitrogen atmosphere for 3 hours. The reaction was cooled to room temperature, 20 mL of ethyl acetate was added, filtered with celite, the filtrate was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give compound 82 (15.0 mg, 36.4 μmol) as a white solid in 33.5% yield. 1 H NMR (500 MHz, DMSO-d6) δ 9.19 - 9.11 (m, 1H), 8.92 - 8.72 (m, 3H), 8.68 - 8.61 (m, 1H), 8.38 - 8.30 (m, 1H), 8.29 - 8.19 (m, 1H), 8.07 - 8.01 (m, 2H), 7.95 - 7.89 (m, 1H), 7.87 (d, J = 7.0 Hz, 1H), 7.78 - 7.66 (m, 1H), 7.49 - 7.40 (m, 2H), 7.37 - 7.29 (m, 1H), 4.70 - 4.59 (m, 2H); MS (ESI): m / z 451.4 (M+H) + .

[0413] Example 83:

[0414]

[0415] Compound 83 was obtained from 4-cyano-3-methylphenylboronic acid following the synthesis of Reference Compound 4. 1 H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J = 4.5 Hz, 1H), 8.60 - 8.31 (m, 2H), 7.98 - 7.89 (m, 2H), 7.89 - 7.82 (m, 2H), 7.36 - 7.20 (m, 2H), 5.68 - 5.49 (m, 1H), 4.93 - 4.34 (m, 6H), 2.44 - 2.37 (m, 3H); MS (ESI): m / z 417.4 (M+H) + .

[0416] Example 84:

[0417]

[0418] Compound 84 was obtained from D-valinol following the synthesis of Reference Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.67 - 8.61 (m, 1H), 8.12 - 7.72 (m, 6H), 7.45 - 7.36 (m, 2H), 7.35 - 7.27 (m, 1H), 5.81 - 5.66 (m, 1H), 4.76 - 4.62 (m, 1H), 4.60 - 4.38 (m, 2H), 4.17 - 3.95 (m, 1H), 3.64 - 3.36 (m, 2H), 2.01 - 1.80 (m, 1H), 0.95 - 0.67 (m, 6H); MS (ESI): m / z 432.5 (M+H) + .

[0419] Example 85:

[0420]

[0421] Compound 85 was obtained from D-tert-leucinol following the synthesis of Reference Compound 24. 1H NMR (500 MHz, DMSO-d6) δ 8.69 - 8.62 (m, 1H), 8.13 - 7.77 (m, 6H), 7.40 (d, J = 7.8 Hz, 2H), 7.34 - 7.30 (m, 1H), 5.65 - 5.53 (m, 1H), 4.72 - 4.60 (m, 1H), 4.60 - 4.36 (m, 2H), 4.32 - 4.10 (m, 1H), 3.70 - 3.44 (m, 2H), 0.96 - 0.70 (m, 9H); MS (ESI): m / z 446.5 (M+H) + .

[0422] Example 86:

[0423]

[0424] Compound 86 was obtained from tert-butyl (5-bromopyrimidin-2-yl)methylcarbamate following the synthesis of Reference Compound 48. 1 H NMR (500 MHz, DMSO-d6) δ 9.33 - 9.22 (m, 2H), 8.74 - 8.39 (m, 5H), 7.58 - 7.53 (m, 1H), 5.68 - 5.43 (m, 1H), 4.91 - 4.57 (m, 5H), 4.40 - 4.38 (m, 1H); MS (ESI): m / z 405.4 (M+H) + .

[0425] Example 87:

[0426]

[0427] Compound 87 was obtained from 2-bromo-5-cyanopyrazine following the synthesis of Reference Compound 48. 1 H NMR (500 MHz, DMSO-d6) δ 9.33 - 9.22 (m, 2H), 8.74 - 8.39 (m, 5H), 7.58 - 7.53 (m, 1H), 5.68 - 5.43 (m, 1H), 4.91 - 4.57 (m, 5H), 4.40 - 4.38 (m, 1H); MS (ESI): m / z 405.4 (M+H) + .

[0428] Example 88:

[0429]

[0430] From (E)-3-(tert-butyldimethylsilyloxy)prop-1-en-1-yl-boronic acid pinacol ester, compound 88-a was obtained by referring to the synthesis of compound 11.

[0431] Compound 88-a (55.0 mg, 110 μmol) was dissolved in tetrahydrofuran (3 mL), and tetrabutylammonium fluoride (1 M, 0.33 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was added to 20 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to obtain compound 88 (15.0 mg, 38.8 μmol) as a white solid, with a yield of 35.3%. 1 H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 4.8 Hz, 1H), 8.57 - 8.50 (m, 1H), 8.49 - 8.41 (m, 1H), 8.02 (d, J = 7.9 Hz, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.87 - 7.83 (m, 1H), 7.47 - 7.39 (m, 2H), 7.36 - 7.29 (m, 2H), 6.76 - 6.67 (m, 1H), 4.67 - 4.57 (m, 2H), 4.28 - 4.17 (m, 2H); MS (ESI): m / z 387.3 (M+H) + .

[0432] Example 89:

[0433]

[0434] Compound 89 was obtained by referring to the synthesis of compound 1 from 2,4-dichloro-5-nitropyrimidine and (R)-2-aminobutanol. 1 H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 4.8 Hz, 1H), 8.57 - 8.50 (m, 1H), 8.49 - 8.41 (m, 1H), 8.02 (d, J = 7.9 Hz, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.87 - 7.83 (m, 1H), 7.47 - 7.39 (m, 2H), 7.36 - 7.29 (m, 2H), 6.76 - 6.67 (m, 1H), 4.67 - 4.57 (m, 2H), 4.28 - 4.17 (m, 2H); MS (ESI): m / z 387.3 (M+H) + .

[0435] Example 90:

[0436]

[0437] Compound 89 (50 mg, 127 μmol) was dissolved in ethanol (5 mL), and palladium on carbon (10% w / w, 10 mg) was added. The mixture was stirred at room temperature under hydrogen atmosphere for 12 hours. The reaction was filtered through celite, and concentrated. The residue was purified by preparative liquid chromatography to give compound 90 (12.0 mg, 32.9 μmol) as a white solid in 26.0% yield. 1 H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 4.8 Hz, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.0 Hz, 1H), 7.84 (td, J = 7.7, 1.8 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.31 (dd, J = 7.3, 4.9 Hz, 1H), 7.24 (s, 1H), 6.30 (t, J = 6.4 Hz, 1H), 5.71 (d, J = 8.1 Hz, 1H), 4.71 - 4.52 (m, 1H), 4.45 - 4.35 (m, 2H), 3.96 (td, J = 7.9, 3.6 Hz, 1H), 3.74 (s, 2H), 3.46 (dd, J = 10.7, 4.7 Hz, 1H), 3.40 - 3.36 (m, 1H), 1.67 - 1.58 (m, 1H), 1.48 - 1.39 (m, 1H), 0.83 (t, J = 7.4 Hz, 3H); MS (ESI): m / z 365.5 (M+H) + .

[0438] Example 91:

[0439]

[0440] Compound 91 was obtained from cis-2-aminocyclobutan-1-ol hydrochloride, following the synthesis of compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 4.8 Hz, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.0 Hz, 1H), 7.84 (td, J = 7.7, 1.8 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.31 (dd, J = 7.3, 4.9 Hz, 1H), 7.24 (s, 1H), 6.30 (t, J = 6.4 Hz, 1H), 5.71 (d, J = 8.1 Hz, 1H), 4.71 - 4.52 (m, 1H), 4.45 - 4.35 (m, 2H), 3.96 (td, J = 7.9, 3.6 Hz, 1H), 3.74 (s, 2H), 3.46 (dd, J = 10.7, 4.7 Hz, 1H), 3.40 - 3.36 (m, 1H), 1.67 - 1.58 (m, 1H), 1.48 - 1.39 (m, 1H), 0.83 (t, J = 7.4 Hz, 3H); MS (ESI): m / z 365.5 (M+H) + .

[0441] Example 91:

[0442]

[0443] From cis-3-aminocyclopentanol hydrochloride, compound 92 was obtained by referring to the synthesis of compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.67-8.62 (m, 1H), 8.07-7.99 (m, 3H), 7.98-7.78 (m, 3H), 7.49-7.37 (m, 2H), 7.36-7.30 (m, 1H), 6.29-6.21 (m, 1H), 4.84-4.62 (m, 1H), 4.57-4.44 (m, 3H), 4.24-4.13 (m, 1H), 1.99-1.77 (m, 3H), 1.77-1.67 (m, 1H), 1.52-1.38 (m, 2H); MS (ESI): m / z 430.4 (M+H) + .

[0444] Example 93:

[0445]

[0446] From D-phenylalaninol, compound 93 was obtained by referring to the synthesis of compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.69-8.63 (m, 1H), 8.10-7.99 (m, 3H), 7.99-7.75 (m, 3H), 7.47-7.35 (m, 2H), 7.34-7.04 (m, 6H), 6.04-5.93 (m, 1H), 4.98-4.89 (m, 1H), 4.62-4.31 (m, 3H), 3.48-3.35 (m, 2H), 2.91-2.77 (m, 2H); MS (ESI): m / z 480.4 (M+H) + .

[0447] Example 94:

[0448]

[0449] From 3-trimethylsiloxyl-1-propyne, compound 94 was obtained by referring to the synthesis of compound 77. 1H NMR (500 MHz, DMSO-de) δ 8.64 (d, J = 4.8 Hz, 1H), 8.27 - 7.97 (m, 4H), 7.92 (d, J = 8.1 Hz, 1H), 7.85 (td, J = 7.6, 1.7 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.32 (dd, J = 7.3, 4.9 Hz, 1H), 5.54 - 5.45 (m, 1H), 5.25 (s, 1H), 4.87 - 4.70 (m, 2H), 4.58 - 4.43 (m, 4H), 4.28 (d, J = 4.5 Hz, 2H); MS (ESI): m / z 389.5 (M+H) + .

[0450] Example 95:

[0451]

[0452] Compound 88-a (55.0 mg, 110 μmol) was dissolved in ethanol (5 mL), and palladium on carbon (10% w / w, 10.0 mg) was added. The mixture was stirred at room temperature under hydrogen atmosphere for 12 hours. The reaction was filtered through celite, and concentrated to give compound 95-a (50.0 mg, 99.4 μmol) as a white solid in 90.5% yield.

[0453] Compound 95 was prepared from 95-a according to the procedure described for the synthesis of compound 88. 1 H NMR (500 MHz, DMSO-de) δ 8.64 (d, J = 4.8 Hz, 1H), 8.27 - 7.97 (m, 4H), 7.92 (d, J = 8.1 Hz, 1H), 7.85 (td, J = 7.6, 1.7 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.32 (dd, J = 7.3, 4.9 Hz, 1H), 5.54 - 5.45 (m, 1H), 5.25 (s, 1H), 4.87 - 4.70 (m, 2H), 4.58 - 4.43 (m, 4H), 4.28 (d, J = 4.5 Hz, 2H); MS (ESI): m / z 389.5 (M+H) + .

[0454] Example 96:

[0455]

[0456] Compound 96 was prepared from 3-bromopyridine-5-methanol according to the procedure described for the synthesis of compound 12. 1H NMR (500 MHz, DMSO-d6) δ 8.78 - 8.72 (m, 1H), 8.72 - 8.35 (m, 3H), 7.95 (d, J = 7.4 Hz, 1H), 7.70 - 7.65 (m, 2H), 7.42 (d, J = 7.9 Hz, 2H), 5.64 - 5.55 (m, 1H), 5.41 - 5.30 (m, 1H), 4.89 - 4.72 (m, 2H), 4.61 - 4.42 (m, 6H); MS (ESI): m / z 433.4 (M+H) + .

[0457] Example 97:

[0458]

[0459] Compound 97 was obtained by the synthesis of Reference Compound 12 from 3-bromo-5- (methylsulfonyl)pyridine. 1 H NMR (500 MHz, DMSO-d6) δ 9.25 - 9.19 (m, 1H), 9.08 - 9.00 (m, 1H), 8.75 - 8.37 (m, 3H), 7.89 - 7.78 (m, 2H), 7.52 - 7.44 (m, 2H), 5.68 - 5.51 (m, 1H), 4.91 - 4.72 (m, 2H), 4.63 - 4.42 (m, 4H), 3.39 (s, 3H); MS (ESI): m / z 481.3 (M+H) + .

[0460] Example 98:

[0461]

[0462] Compound 98 was obtained by the synthesis of Reference Compound 24 from trans-2- aminocyclobutanol hydrochloride. 1 H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 4.8 Hz, 1H), 8.02 (d, J = 7.8 Hz, 3H), 7.98 - 7.77 (m, 3H), 7.51 - 7.36 (m, 2H), 7.36 - 7.29 (m, 1H), 6.79 - 6.69 (m, 1H), 5.22 - 5.12 (m, 1H), 4.60 - 4.31 (m, 3H), 4.22 - 4.11 (m, 1H), 2.03 - 1.87 (m, 2H), 1.49 - 1.30 (m, 2H); MS (ESI): m / z 416.5 (M+H) + .

[0463] Example 99:

[0464]

[0465] Compound 99 was obtained from 2,4-dichloro-5-methoxypyrimidine according to the synthesis of Compound 3. 1 H NMR (500 MHz, DMSO-d6) δ 8.66 - 8.62 (m, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.97 - 7.82 (m, 3H), 7.45 - 7.28 (m, 4H), 5.54 - 5.41 (m, 1H), 4.75 (s, 2H), 4.49 (t, J = 6.4 Hz, 2H), 4.42 (d, J = 6.3 Hz, 2H), 3.70 (s, 3H); MS (ESI): m / z 365.4 (M+H) + .

[0466] Example 100:

[0467]

[0468] Compound 100 was obtained from (1R,2R)-2-aminocyclohexanol hydrochloride according to the synthesis of Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 4.8 Hz, 1H), 8.08 - 7.93 (m, 4H), 7.92 - 7.89 (m, 1H), 7.87 - 7.83 (m, 1H), 7.43 - 7.37 (m, 2H), 7.34 - 7.30 (m, 1H), 5.88 (d, J = 6.3 Hz, 1H), 4.65 - 4.59 (m, 1H), 4.57 - 4.38 (m, 2H), 3.91 - 3.59 (m, 1H), 3.50 - 3.36 (m, 1H), 2.07 - 1.95 (m, 1H), 1.95 - 1.77 (m, 2H), 1.64 - 1.57 (m, 1H), 1.50 - 1.42 (m, 1H), 1.19 - 1.11 (m, 2H), 1.08 - 0.95 (m, 1H).; MS (ESI): m / z 444.5 (M+H) + .

[0469] Example 101:

[0470]

[0471] Compound 101-a was obtained from ((3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1- carboxylate tert-butyl ester according to the synthesis of Compound 24.

[0472] Compound 101-a (50.0 mg, 89.5 μmol) was dissolved in dichloromethane (3 mL), hydrochloric acid dioxane (4 M, 0.50 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated, the residue was purified by preparative liquid chromatography to give compound 101 (15.0 mg, 32.7 μmol), white solid, yield 36.5%. 1 H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 4.9 Hz, 1H), 8.05 - 7.89 (m, 5H), 7.88 - 7.83 (m, 1H), 7.47 - 7.36 (m, 2H), 7.35 - 7.29 (m, 1H), 7.01 - 6.83 (m, 1H), 5.23 - 5.01 (m, 1H), 4.56 - 4.49 (m, 2H), 3.64 - 3.36 (m, 3H), 2.99 - 2.92 (m, 1H), 2.90 - 2.71 (m, 1H), 2.38 - 2.18 (m, 2H), 1.59 - 1.40 (m, 2H), 1.12 - 0.95 (m, 1H); MS (ESI): m / z 459.4 (M+H) + .

[0473] Example 102:

[0474]

[0475] Compound 102 was obtained from 2,4-dichloro-5-methylsulfanylpyrimidine, referring to the synthesis of compound 3. 1 H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 4.9 Hz, 1H), 8.05 - 7.89 (m, 5H), 7.88 - 7.83 (m, 1H), 7.47 - 7.36 (m, 2H), 7.35 - 7.29 (m, 1H), 7.01 - 6.83 (m, 1H), 5.23 - 5.01 (m, 1H), 4.56 - 4.49 (m, 2H), 3.64 - 3.36 (m, 3H), 2.99 - 2.92 (m, 1H), 2.90 - 2.71 (m, 1H), 2.38 - 2.18 (m, 2H), 1.59 - 1.40 (m, 2H), 1.12 - 0.95 (m, 1H); MS (ESI): m / z 459.4 (M+H) + .

[0476] Example 103:

[0477]

[0478] Compound 102 (30.0 mg, 78.8 μmol) was dissolved in dichloromethane (5 mL), and m-chloroperoxybenzoic acid (13.6 mg, 78.8 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was added to 20 mL of ethyl acetate, washed once with saturated sodium bicarbonate, once with water, once with saturated brine, dried, and concentrated. The residue was purified by preparative liquid chromatography to give compound 103 (12 mg, 30.2 μmol) as a white solid in 38.4% yield. 1 H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J = 4.8 Hz, 1H), 8.53 - 8.19 (m, 2H), 8.07 - 8.00 (m, 2H), 7.95 - 7.90 (m, 1H), 7.89 - 7.83 (m, 1H), 7.44 - 7.39 (m, 2H), 7.35 - 7.30 (m, 1H), 5.66 - 5.49 (m, 1H), 4.88 - 4.69 (m, 2H), 4.62 - 4.44 (m, 4H), 2.84 - 2.79 (m, 3H); MS (ESI): m / z 397.3 (M+H) + .

[0479] Example 104:

[0480]

[0481] Compound 104 was obtained by referring to the synthesis of compound 24 from serinol. 1 H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J = 4.8 Hz, 1H), 8.53 - 8.19 (m, 2H), 8.07 - 8.00 (m, 2H), 7.95 - 7.90 (m, 1H), 7.89 - 7.83 (m, 1H), 7.44 - 7.39 (m, 2H), 7.35 - 7.30 (m, 1H), 5.66 - 5.49 (m, 1H), 4.88 - 4.69 (m, 2H), 4.62 - 4.44 (m, 4H), 2.84 - 2.79 (m, 3H); MS (ESI): m / z 397.3 (M+H) + .

[0482] Example 105:

[0483]

[0484] Compound 105 was obtained by referring to the synthesis of compound 24 from (R)-1- amino-2-propanol. 1H NMR (500 MHz, DMSO-de) δ 8.69 - 8.57 (m, 1H), 8.10 - 7.76 (m, 6H), 7.49 - 7.23 (m, 3H), 6.00 - 5.89 (m, 1H), 4.88 - 4.76 (m, 1H), 4.60 - 4.43 (m, 2H), 4.31 - 4.16 (m, 1H), 3.50 - 3.35 (m, 2H), 1.18 - 1.00 (m, 3H); MS (ESI): m / z 404.2 (M+H) + .

[0485] Example 106:

[0486]

[0487] Compound 106 was obtained by the synthesis of Reference Compound 26 from (R)-1 -methyl-3-pyrrolidinol. 1 H NMR (500 MHz, DMSO-de) δ 8.67 - 8.61 (m, 1H), 8.61 - 8.30 (m, 2H), 8.07 - 8.00 (m, 2H), 7.94 - 7.81 (m, 2H), 7.47 - 7.27 (m, 3H), 5.50 - 5.24 (m, 1H), 4.70 - 4.46 (m, 2H), 2.68 - 2.54 (m, 2H), 2.44 - 2.10 (m, 6H), 1.86 - 1.64 (m, 1H); MS (ESI): m / z 430.4 (M+H) + .

[0488] Example 107:

[0489]

[0490] Compound 107 was obtained by the synthesis of Reference Compound 26 from (S)-1 -methyl-3-pyrrolidinol. 1 H NMR (500 MHz, DMSO-de) δ 8.67 - 8.61 (m, 1H), 8.61 - 8.30 (m, 2H), 8.07 - 8.00 (m, 2H), 7.94 - 7.81 (m, 2H), 7.47 - 7.27 (m, 3H), 5.50 - 5.24 (m, 1H), 4.70 - 4.46 (m, 2H), 2.68 - 2.54 (m, 2H), 2.44 - 2.10 (m, 6H), 1.86 - 1.64 (m, 1H); MS (ESI): m / z 430.4 (M+H) + .

[0491] Example 108:

[0492]

[0493] Compound 108 was obtained by the synthesis of Reference Compound 12 from 3-bromobenzene methanol. 1 H NMR (500 MHz, DMSO-d6) δ 8.72-8.33 (m, 2H), 7.65-7.56 (m, 3H), 7.52-7.47 (m, 1H), 7.42-7.36 (m, 3H), 7.32-7.28 (m, 1H), 5.66-5.55 (m, 1H), 5.26-5.19 (m, 1H), 4.91-4.72 (m, 2H), 4.59-4.43 (m, 6H); MS (ESI): m / z 432.3 (M+H) + .

[0494] Example 109:

[0495]

[0496] Compound 109 was obtained by the synthesis of Reference Compound 12 from 1-(4-bromophenyl)-1-methylethylamine. 1 H NMR (500 MHz, DMSO-d6) δ 8.79-8.35 (m, 3H), 8.12-7.83 (m, 4H), 7.57-7.23 (m, 3H), 5.04-4.02 (m, 5H), 1.77-1.60 (m, 6H); MS (ESI): m / z 431.4 (M+H) + .

[0497] Example 110:

[0498]

[0499] Compound 110 was obtained by the synthesis of Reference Compound 12 from [(S)-1-(4-bromophenyl)ethyl] tert-butyl carbamate. 1 H NMR (500 MHz, DMSO-d6) δ 8.72-8.32 (m, 3H), 8.12-7.80 (m, 4H), 7.60-7.24 (m, 3H), 5.71-5.43 (m, 1H), 5.06-4.87 (m, 2H), 4.64-4.18 (m, 3H), 1.48 (d, J = 6.9 Hz, 3H); MS (ESI): m / z 417.4 (M+H) + .

[0500] Example 111:

[0501]

[0502] Compound 111 was obtained from trans-1,2-cyclohexanediol following the synthesis of Reference Compound 26. 1 H NMR (500 MHz, DMSO-d6) δ 8.67 - 8.61 (m, 1H), 8.57 - 8.27 (m, 2H), 8.06 - 7.99 (m, 2H), 7.94 - 7.89 (m, 1H), 7.89 - 7.82 (m, 1H), 7.47 - 7.38 (m, 2H), 7.36 - 7.29 (m, 1H), 5.13 - 4.91 (m, 1H), 4.83 - 4.72 (m, 1H), 4.63 - 4.42 (m, 2H), 3.57 - 3.50 (m, 1H), 2.05 - 1.92 (m, 1H), 1.88 - 1.54 (m, 3H), 1.49 - 1.24 (m, 4H); MS (ESI): m / z 445.4 (M+H) + .

[0503] Example 112:

[0504]

[0505] Compound 112 was obtained from 4-cyano-3-methoxyphenylboronic acid following the synthesis of Reference Compound 4. 1 H NMR (500 MHz, DMSO-d6) δ 8.67 - 8.61 (m, 1H), 8.57 - 8.27 (m, 2H), 8.06 - 7.99 (m, 2H), 7.94 - 7.89 (m, 1H), 7.89 - 7.82 (m, 1H), 7.47 - 7.38 (m, 2H), 7.36 - 7.29 (m, 1H), 5.13 - 4.91 (m, 1H), 4.83 - 4.72 (m, 1H), 4.63 - 4.42 (m, 2H), 3.57 - 3.50 (m, 1H), 2.05 - 1.92 (m, 1H), 1.88 - 1.54 (m, 3H), 1.49 - 1.24 (m, 4H); MS (ESI): m / z 445.4 (M+H) + .

[0506] Example 113:

[0507]

[0508] Compound 113 was obtained from 2,4-dichloropyrimidine-5-carboxamide following the synthesis of Reference Compound 89. 1H NMR (500 MHz, DMSO-de) δ 9.08 - 8.87 (m, 1H), 8.64 (d, J = 4.9 Hz, 1H), 8.36 (s, 1H), 8.01 (d, J = 7.9 Hz, 2H), 7.92 (d, J = 7.9 Hz, 1H), 7.89 - 7.83 (m, 1H), 7.79 - 7.63 (m, 1H), 7.61 - 7.47 (m, 1H), 7.47 - 7.36 (m, 2H), 7.36 - 7.29 (m, 1H), 4.79 - 4.65 (m, 1H), 4.60 - 4.41 (m, 2H), 4.07 - 3.93 (m, 1H), 3.53 - 3.43 (m, 1H), 3.42 - 3.35 (m, 1H), 3.30 - 3.29 (m, 1H), 2.05 - 1.95 (m, 1H), 1.68 - 1.51 (m, 1H), 1.50 - 1.25 (m, 3H); MS (ESI): m / z 393.5 (M+H) + .

[0509] Example 114:

[0510]

[0511] Compound 114 was obtained by the synthesis of compound 12 from 2-bromo-4- methoxypyridine. 1 H NMR (500 MHz, DMSO-de) δ 9.08 - 8.87 (m, 1H), 8.64 (d, J = 4.9 Hz, 1H), 8.36 (s, 1H), 8.01 (d, J = 7.9 Hz, 2H), 7.92 (d, J = 7.9 Hz, 1H), 7.89 - 7.83 (m, 1H), 7.79 - 7.63 (m, 1H), 7.61 - 7.47 (m, 1H), 7.47 - 7.36 (m, 2H), 7.36 - 7.29 (m, 1H), 4.79 - 4.65 (m, 1H), 4.60 - 4.41 (m, 2H), 4.07 - 3.93 (m, 1H), 3.53 - 3.43 (m, 1H), 3.42 - 3.35 (m, 1H), 3.30 - 3.29 (m, 1H), 2.05 - 1.95 (m, 1H), 1.68 - 1.51 (m, 1H), 1.50 - 1.25 (m, 3H); MS (ESI): m / z 393.5 (M+H) + .

[0512] Example 115:

[0513]

[0514] Compound 115 was obtained by the synthesis of compound 26 from trans-1,2- cyclopentanediol. 1H NMR (500 MHz, DMSO-d6) δ 8.69 - 8.61 (m, 1H), 8.61 - 8.36 (m, 1H), 8.36 - 8.28 (m, 1H), 8.08 - 7.98 (m, 2H), 7.97 - 7.82 (m, 2H), 7.50 - 7.38 (m, 2H), 7.38 - 7.28 (m, 1H), 5.24 - 5.12 (m, 1H), 4.99 - 4.88 (m, 1H), 4.65 - 4.47 (m, 2H), 4.11 - 3.99 (m, 1H), 2.13 - 1.92 (m, 1H), 1.91 - 1.75 (m, 1H), 1.75 - 1.41 (m, 4H); MS (ESI): m / z 431.3 (M+H) + .

[0515] Example 116:

[0516]

[0517] Compound 116 was obtained from trans-1,2-cyclopentanediol following the synthesis of Reference Compound 101. 1 H NMR (500 MHz, DMSO-d6) δ 8.67 - 8.61 (m, 1H), 8.13 - 7.77 (m, 6H), 7.50 - 7.35 (m, 2H), 7.35 - 7.29 (m, 1H), 6.52 - 6.24 (m, 1H), 5.32 - 4.79 (m, 1H), 4.65 - 4.43 (m, 2H), 4.31 - 4.02 (m, 2H), 3.20 - 2.94 (m, 3H), 2.59 - 2.52 (m, 1H); MS (ESI): m / z 431.4 (M+H) + .

[0518] Example 117:

[0519]

[0520] Compound 117 was obtained from 2-bromo-4-chloropyridine following the synthesis of Reference Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.73 - 8.37 (m, 3H), 8.13 - 8.04 (m, 3H), 7.49 - 7.46 (m, 1H), 7.43 - 7.38 (m, 2H), 5.67 - 5.50 (m, 1H), 4.93 - 4.69 (m, 2H), 4.65 - 4.38 (m, 4H); MS (ESI): m / z 437.1 (M+H) + .

[0521] Example 118:

[0522]

[0523] Compound 118 was obtained from 4-cyano-3-trifluoromethylphenylboronic acid following the synthesis of Compound 4. 1 H NMR (500 MHz, DMSO-d6) δ 8.79 - 8.39 (m, 4H), 8.39 - 8.27 (m, 1H), 8.11 - 8.02 (m, 1H), 7.99 - 7.90 (m, 1H), 7.61 - 7.50 (m, 1H), 7.46 - 7.37 (m, 1H), 5.73 - 5.37 (m, 1H), 4.97 - 4.28 (m, 6H); MS (ESI): m / z 471.1 (M+H) + .

[0524] Example 119:

[0525]

[0526] Compound 119 was obtained from [(R)-1-(4-bromophenyl)ethyl] tert-butyl carbamate following the synthesis of Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.79 - 8.27 (m, 3H), 8.14 - 7.80 (m, 4H), 7.57 - 7.29 (m, 3H), 5.73 - 5.39 (m, 1H), 5.10 - 4.84 (m, 2H), 4.65 - 4.47 (m, 2H), 4.33 - 4.15 (m, 1H), 1.53 - 1.43 (m, 3H); MS (ESI): m / z 417.4 (M+H) + .

[0527] Example 120:

[0528]

[0529] Compound 120 was obtained from Compound 4-b following the synthesis of Compound 70. 1H NMR (500 MHz, DMSO-d6) δ 9.20 - 9.15 (m, 1H), 8.72 - 8.67 (m, 1H), 8.41 - 8.35 (m, 1H), 8.03 (s, 1H), 8.02 - 7.99 (m, 1H), 7.98 - 7.81 (m, 2H), 7.43 - 7.37 (m, 2H), 6.25 - 6.15 (m, 1H), 4.75 - 4.69 (m, 1H), 4.67 - 4.53 (m, 2H), 4.24 - 3.88 (m, 2H), 2.11 - 1.95 (m, 1H), 1.77 - 1.61 (m, 2H), 1.51 - 1.43 (m, 2H), 1.39 - 1.29 (m, 1H); MS (ESI): m / z 431.4 (M+H) + .

[0530] Example 121:

[0531]

[0532] Compound 121 was obtained by referring to the synthesis of compound 120, starting from (R)-2-aminobutanol. 1 H NMR (500 MHz, DMSO-d6) δ 9.20 - 9.15 (m, 1H), 8.72 - 8.67 (m, 1H), 8.41 - 8.35 (m, 1H), 8.03 (s, 1H), 8.02 - 7.99 (m, 1H), 7.98 - 7.81 (m, 2H), 7.43 - 7.37 (m, 2H), 6.25 - 6.15 (m, 1H), 4.75 - 4.69 (m, 1H), 4.67 - 4.53 (m, 2H), 4.24 - 3.88 (m, 2H), 2.11 - 1.95 (m, 1H), 1.77 - 1.61 (m, 2H), 1.51 - 1.43 (m, 2H), 1.39 - 1.29 (m, 1H); MS (ESI): m / z 431.4 (M+H) + .

[0533] Example 122:

[0534]

[0535] Compound 122 was obtained by referring to the synthesis of compound 12, starting from 2-chloro-4,6-dimethylpyridine. 1H NMR (500 MHz, DMSO-d6) δ 8.69 - 8.37 (m, 2H), 8.06 - 7.97 (m, 2H), 7.60 - 7.53 (m, 1H), 7.43 - 7.35 (m, 2H), 7.02 (s, 1H), 5.67 - 5.51 (m, 1H), 4.90 - 4.69 (m, 2H), 4.61 - 4.40 (m, 4H), 2.47 (s, 3H), 2.32 (s, 3H).; MS (ESI): m / z 431.5 (M+H) + .

[0536] Example 123:

[0537]

[0538] Compound 123 was obtained by the synthesis of compound 24 with reference to the compound from 2-amino-2-methyl-1-propanol. 1 H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 4.8 Hz, 1H), 8.12 - 7.96 (m, 4H), 7.93 - 7.89 (m, 1H), 7.87 - 7.83 (m, 1H), 7.42 - 7.36 (m, 2H), 7.35 - 7.29 (m, 1H), 5.74 - 5.56 (m, 1H), 5.33 - 5.24 (m, 1H), 4.54 (d, J = 6.3 Hz, 2H), 3.30 - 3.25 (m, 2H), 1.28 - 1.13 (m, 6H); MS (ESI): m / z 418.5 (M+H) + .

[0539] Example 124:

[0540]

[0541] Compound 124 was obtained by the synthesis of compound 24 with reference to the compound from (R)-3-amino-2-pyrrolidinone. 1 H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 4.8 Hz, 1H), 8.11 - 8.09 (m, 1H), 8.01 (d, J = 7.9 Hz, 2H), 7.99 - 7.74 (m, 4H), 7.39 (d, J = 7.8 Hz, 2H), 7.35 - 7.27 (m, 1H), 6.83 - 6.62 (m, 1H), 4.83 - 4.36 (m, 3H), 3.11 - 2.93 (m, 2H), 2.11 - 1.95 (m, 2H); MS (ESI): m / z 429.4 (M+H) + .

[0542] Example 125:

[0543]

[0544] Compound 125 was obtained from 2-chloro-4,6-dihydroxymethylpyridine, referring to the synthesis of Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.70 - 8.36 (m, 2H), 8.04 - 7.97 (m, 2H), 7.70 - 7.66 (m, 1H), 7.41 - 7.37 (m, 3H), 5.68 - 5.50 (m, 1H), 5.46 - 5.43 (m, 1H), 5.43 - 5.38 (m, 1H), 4.93 - 4.66 (m, 2H), 4.64 - 4.54 (m, 6H), 4.53 - 4.39 (m, 3H); MS (ESI): m / z 463.6 (M+H) + .

[0545] Example 126:

[0546]

[0547] Compound 126 was obtained from L-threoninol, referring to the synthesis of Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.75 - 8.54 (m, 1H), 8.20 - 7.72 (m, 6H), 7.55 - 7.28 (m, 3H), 5.81 - 5.63 (m, 1H), 5.13 - 4.44 (m, 4H), 4.17 - 3.95 (m, 2H), 3.55 - 3.43 (m, 2H), 1.09 - 0.92 (m, 3H); MS (ESI): m / z 434.4 (M+H) + .

[0548] Example 127:

[0549]

[0550] Compound 127 was obtained from D-serinamide hydrochloride, referring to the synthesis of Compound 24. 1H NMR (500 MHz, DMSO-d6) δ 8.67 - 8.63 (m, 1H), 8.10 - 7.99 (m, 4H), 7.94 - 7.90 (m, 1H), 7.89 - 7.84 (m, 1H), 7.56 - 7.41 (m, 3H), 7.35 - 7.31 (m, 1H), 7.28 - 7.20 (m, 1H), 6.41 - 6.09 (m, 1H), 5.04 - 4.97 (m, 1H), 4.59 - 4.47 (m, 3H), 3.83 - 3.61 (m, 2H); MS (ESI): m / z 433.3 (M+H) + .

[0551] Example 128:

[0552]

[0553] Compound 128 was obtained by the synthesis of Reference Compound 12 from 2-chloro-4-cyclopropylpyridine. 1 H NMR (500 MHz, DMSO-d6) δ 8.75 - 8.36 (m, 3H), 8.09 - 7.97 (m, 2H), 7.64 - 7.57 (m, 1H), 7.42 - 7.34 (m, 2H), 7.03 - 6.97 (m, 1H), 5.68 - 5.48 (m, 1H), 4.93 - 4.37 (m, 6H), 2.04 - 1.95 (m, 1H), 1.10 - 1.02 (m, 2H), 0.92 - 0.86 (m, 2H); MS (ESI): m / z 443.5 (M+H) + .

[0554] Example 129:

[0555]

[0556] Compound 129 was obtained by the synthesis of Reference Compound 12 from 2-chloro-4-vinylpyridine. 1 H NMR (500 MHz, DMSO-d6) δ 8.75 - 8.36 (m, 3H), 8.16 - 8.04 (m, 2H), 8.04 - 7.93 (m, 1H), 7.48 - 7.37 (m, 3H), 6.90 - 6.73 (m, 1H), 6.32 - 6.18 (m, 1H), 5.67 - 5.50 (m, 2H), 4.94 - 4.67 (m, 2H), 4.62 - 4.41 (m, 4H); MS (ESI): m / z 429.4 (M+H) + .

[0557] Example 130:

[0558]

[0559] Compound 130 was obtained from D-threoninol by the synthesis of Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 9.01 - 8.67 (m, 2H), 8.10 - 7.99 (m, 4H), 7.65 - 7.41 (m, 3H), 6.88 - 6.56 (m, 1H), 4.72 - 4.60 (m, 2H), 4.18 - 3.96 (m, 2H), 3.57 - 3.47 (m, 2H), 1.08 - 0.93 (m, 3H); MS (ESI): m / z 434.4 (M+H) + .

[0560] Example 131:

[0561]

[0562] Compound 131 was obtained from (R,R)-2,3-butanediol by the synthesis of Compound 26. 1 H NMR (500 MHz, DMSO-d6) δ 8.72 - 8.66 (m, 1H), 8.59 - 8.35 (m, 1H), 8.35 - 8.29 (m, 1H), 8.08 - 7.97 (m, 4H), 7.54 - 7.41 (m, 3H), 5.27 - 5.12 (m, 1H), 4.62 - 4.48 (m, 2H), 3.79 - 3.74 (m, 2H), 1.23 - 1.20 (m, 1H), 1.12 - 1.04 (m, 3H), 1.03 - 0.95 (m, 2H); MS (ESI): m / z 419.4 (M+H) + .

[0563] Example 132:

[0564]

[0565] Compound 132 was obtained from L-serinamide hydrochloride by the synthesis of Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.82 - 8.68 (m, 2H), 8.40 - 8.30 (m, 1H), 8.10 - 7.98 (m, 4H), 7.66 - 7.49 (m, 3H), 7.46 - 7.35 (m, 2H), 4.69 - 4.58 (m, 3H), 3.82 - 3.78 (m, 2H), 3.74 - 3.70 (m, 2H); MS (ESI): m / z 433.4 (M+H) + .

[0566] Example 133:

[0567]

[0568] Compound 133 was obtained from 4-cyano-3-chlorophenylboronic acid, following the synthesis of Reference Compound 4. 1 H NMR (500 MHz, DMSO-d6) δ 8.68 - 8.66 (m, 1H), 8.45 - 8.39 (m, 1H), 8.22 - 8.14 (m, 1H), 8.06 - 7.97 (m, 2H), 7.95 - 7.87 (m, 1H), 7.43 - 7.35 (m, 2H), 5.74 - 5.44 (m, 1H), 4.96 - 4.80 (m, 1H), 4.72 - 4.32 (m, 6H); MS (ESI): m / z 437.5 (M+H) + .

[0569] Example 134:

[0570]

[0571] Compound 134 was obtained from R-2-aminobutyramide hydrochloride, following the synthesis of Reference Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.67 - 8.63 (m, 1H), 8.13 - 7.84 (m, 6H), 7.82 - 7.50 (m, 1H), 7.49 - 7.24 (m, 4H), 6.59 - 6.12 (m, 1H), 4.67 - 4.16 (m, 3H), 2.02 - 1.60 (m, 2H), 0.87 - 0.67 (m, 3H); MS (ESI): m / z 431.4 (M+H) + .

[0572] Example 135:

[0573]

[0574] Compound 135 was obtained from 2-chloro-4-ethylpyridine, following the synthesis of Reference Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.75 - 8.36 (m, 3H), 8.09 - 7.97 (m, 2H), 7.64 - 7.57 (m, 1H), 7.42 - 7.34 (m, 2H), 7.03 - 6.97 (m, 1H), 5.68 - 5.48 (m, 1H), 4.93 - 4.37 (m, 6H), 2.04 - 1.95 (m, 1H), 1.10 - 1.02 (m, 2H), 0.92 - 0.86 (m, 2H); MS (ESI): m / z 431.5 (M+H)+ .

[0575] Example 136:

[0576]

[0577] Compound 136 was obtained from [(R)-1-(4-bromophenyl)-2-methylpropyl] tert- butyl carbamate following the synthesis of Reference Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.72 - 8.66 (m, 1H), 8.66 - 8.62 (m, 1H), 8.37 - 8.33 (m, 1H), 8.07 - 7.99 (m, 2H), 7.96 - 7.90 (m, 1H), 7.89 - 7.83 (m, 1H), 7.54 - 7.45 (m, 2H), 7.36 - 7.29 (m, 1H), 5.69 - 5.58 (m, 1H), 5.05 - 4.33 (m, 5H), 2.17 - 2.07 (m, 1H), 1.04 - 0.96 (m, 3H), 0.79 - 0.71 (m, 3H); MS (ESI): m / z 445.4 (M+H) + .

[0578] Example 137:

[0579]

[0580] Compound 137 was obtained from [(R)-(4-bromophenyl)-cyclopropylmethyl] tert-butyl carbamate following the synthesis of Reference Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.88 - 8.56 (m, 2H), 8.39 - 8.29 (m, 1H), 8.09 - 7.98 (m, 2H), 7.92 (t, J = 7.8 Hz, 1H), 7.86 (td, J = 7.7, 1.9 Hz, 1H), 7.59 - 7.50 (m, 2H), 7.38 - 7.29 (m, 1H), 5.70 - 5.45 (m, 1H), 5.35 - 4.16 (m, 5H), 2.04 - 1.92 (m, 1H), 0.61 - 0.33 (m, 4H); MS (ESI): m / z 443.4 (M+H) + .

[0581] Example 138:

[0582]

[0583] Compound 138 was obtained from 2-chloro-4-cyanopyridine following the synthesis of Reference Compound 12. 1H NMR (500 MHz, DMSO-d6) δ 8.88 (d, J = 5.0 Hz, 1H), 8.72 - 8.36 (m, 3H), 8.18 - 8.07 (m, 2H), 7.78 (dd, J = 5.0, 1.4 Hz, 1H), 7.43 (dd, J = 8.5, 2.4 Hz, 2H), 5.69 - 5.47 (m, 1H), 4.90 - 4.38 (m, 6H); MS (ESI): m / z 428.5 (M+H) + .

[0584] Example 139:

[0585]

[0586] Compound 139 was obtained by the synthesis of compound 12 from 2-chloro-4- dimethoxyphosphinylpyridine. 1 H NMR (500 MHz, DMSO-d6) δ 8.80 (t, J = 4.4 Hz, 1H), 8.71 - 8.38 (m, 2H), 8.25 - 8.16 (m, 1H), 8.16 - 8.06 (m, 2H), 7.72 - 7.65 (m, 1H), 7.43 (d, J = 8.1 Hz, 2H), 5.68 - 5.51 (m, 1H), 4.91 - 4.39 (m, 6H), 1.74 (d, J = 13.6 Hz, 6H); MS (ESI): m / z 479.4 (M+H) + .

[0587] Example 140:

[0588]

[0589] Compound 140 was obtained by the synthesis of compound 12 from [(S)-l-(4- bromophenyl)-2-methylpropyl] carbamic acid tert-butyl ester. 1 H NMR (500 MHz, DMSO-d6) δ 8.73 - 8.66 (m, 1H), 8.66 - 8.62 (m, 1H), 8.37 - 8.33 (m, 1H), 8.07 - 7.98 (m, 2H), 7.96 - 7.90 (m, 1H), 7.89 - 7.83 (m, 1H), 7.54 - 7.44 (m, 2H), 7.36 - 7.29 (m, 1H), 5.69 - 5.58 (m, 1H), 5.05 - 4.33 (m, 5H), 2.17 - 2.07 (m, 1H), 1.04 - 0.96 (m, 3H), 0.79 - 0.71 (m, 3H); MS (ESI): m / z 445.4 (M+H) + .

[0590] Example 141:

[0591]

[0592] Compound 141 was obtained from 6-chloro-2-cyanopyridine following the synthesis of Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.72 - 8.39 (m, 2H), 8.34 - 8.25 (m, 1H), 8.17 - 8.04 (m, 3H), 7.98 (d, J = 7.7 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 5.70 - 5.51 (m, 1H), 4.95 - 4.40 (m, 6H); MS (ESI): m / z 428.4 (M+H) + .

[0593] Example 142:

[0594]

[0595] Compound 142 was obtained from [(R)-1-(4-bromophenyl)propyl] tert- butyl carbamate following the synthesis of Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.73 - 8.30 (m, 3H), 8.12 - 8.00 (m, 2H), 7.97 - 7.91 (m, 1H), 7.91 - 7.82 (m, 1H), 7.56 - 7.45 (m, 2H), 7.40 - 7.29 (m, 1H), 5.75 - 5.52 (m, 1H), 5.04 - 4.25 (m, 5H), 1.93 - 1.74 (m, 2H), 0.98 - 0.89 (m, 3H); MS (ESI): m / z 431.4 (M+H) + .

[0596] Example 143:

[0597]

[0598] Compound 143 was obtained from 2-chloro-4-trifluoromethylpyridine following the synthesis of Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.93 (d, J = 5.1 Hz, 1H), 8.74 - 8.37 (m, 2H), 8.31 - 8.23 (m, 1H), 8.22 - 8.13 (m, 2H), 7.71 (d, J = 5.1 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 5.72 - 5.50 (m, 1H), 4.96 - 4.40 (m, 6H); MS (ESI): m / z 471.4 (M+H)+ .

[0599] Example 144:

[0600]

[0601] Compound 144 was obtained from 6-chloro-4-methoxypyridin-2-methanol following the synthesis of Reference Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.74 - 8.38 (m, 2H), 8.09 - 7.98 (m, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.35 - 7.29 (m, 1H), 6.99 (s, 1H), 5.69 - 5.52 (m, 1H), 5.43 (t, J = 5.9 Hz, 1H), 4.97 - 4.40 (m, 8H), 3.91 (s, 3H); MS (ESI): m / z 463.4 (M+H) + .

[0602] Example 145:

[0603]

[0604] Compound 145 was obtained from 6-chloro-4-methoxypyridin-2-methanol following the synthesis of Reference Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.76 - 8.38 (m, 3H), 8.11 - 8.01 (m, 2H), 7.87 - 7.82 (m, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 4.8 Hz, 1H), 5.74 - 5.53 (m, 1H), 4.91 - 4.40 (m, 8H), 3.38 (s, 3H); MS (ESI): m / z 447.4 (M+H) + .

[0605] Example 146:

[0606]

[0607] Compound 146 was obtained from 3-bromophenyl methyl sulfone following the synthesis of Reference Compound 13. 1H NMR (500 MHz, DMSO-d6) δ 8.89 - 8.83 (m, 1H), 8.77 - 8.75 (m, 1H), 8.66 (d, J = 4.8 Hz, 1H), 8.10 - 8.05 (m, 4H), 7.98 - 7.77 (m, 4H), 7.46 (dd, J = 8.4, 2.5 Hz, 2H), 7.34 (t, J = 6.1 Hz, 1H), 4.69 - 4.61 (m, 2H), 3.28 (d, J = 5.0 Hz, 3H); MS (ESI): m / z 485.4 (M+H) + .

[0608] Example 147:

[0609]

[0610] Compound 147 was obtained by the synthesis of Reference Compound 13 from 5-bromo pyridine-3-sulfonamide. 1 H NMR (500 MHz, DMSO-d6) δ 9.12 (t, J = 2.2 Hz, 1H), 8.98 - 8.77 (m, 3H), 8.66 (s, 1H), 8.36 - 8.29 (m, 1H), 8.05 (dd, J = 8.1, 4.9 Hz, 2H), 8.00 - 7.69 (m, 4H), 7.46 (t, J = 8.4 Hz, 2H), 7.35 (t, J = 5.9 Hz, 1H), 4.70 - 4.62 (m, 2H); MS (ESI): m / z 487.4 (M+H) + .

[0611] Example 148:

[0612]

[0613] Compound 148 was obtained by the synthesis of Reference Compound 12 from 4-chloro-6-methoxy pyrimidine. 1 H NMR (500 MHz, DMSO-d6) δ 8.93 - 8.38 (m, 3H), 8.17 - 8.12 (m, 2H), 7.53 - 7.41 (m, 3H), 5.67 - 5.53 (m, 1H), 4.92 - 4.68 (m, 2H), 4.64 - 4.40 (m, 4H), 3.98 (s, 3H); MS (ESI): m / z 434.4 (M+H) + .

[0614] Example 149:

[0615]

[0616] Compound 149 was obtained from R-l-tert-butyldimethylsilyloxy-2-butanol following the synthesis of compound 26, and compound 149-a from 149-a following the synthesis of compound 88. 1 H NMR (500 MHz, DMSO-d6) δ 8.68 - 8.62 (m, 1H), 8.62 - 8.38 (m, 1H), 8.37 - 8.28 (m, 1H), 8.08 - 8.00 (m, 2H), 7.95 - 7.89 (m, 1H), 7.91 - 7.82 (m, 1H), 7.48 - 7.38 (m, 2H), 7.36 - 7.30 (m, 1H), 5.29 - 3.44 (m, 6H), 1.80 - 1.29 (m, 2H), 0.96 - 0.72 (m, 3H); MS (ESI): m / z 419.4 (M+H) + .

[0617] Example 150:

[0618]

[0619] Compound 150 was obtained from cis-l,2-cyclohexanediol following the synthesis of compound 26. 1 H NMR (500 MHz, DMSO-d6) δ 8.71 - 8.62 (m, 1H), 8.54 - 8.29 (m, 2H), 8.07 - 8.01 (m, 2H), 7.96 - 7.89 (m, 1H), 7.89 - 7.83 (m, 1H), 7.50 - 7.37 (m, 2H), 7.37 - 7.29 (m, 1H), 5.48 - 5.21 (m, 1H), 4.71 - 4.39 (m, 3H), 3.77 - 3.65 (m, 1H), 1.94 - 1.21 (m, 8H); MS (ESI): m / z 445.5 (M+H) + .

[0620] Example 151:

[0621]

[0622] Compound 151 was obtained from cis-tetrahydrofuran-3,4-diol following the synthesis of compound 26. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (d, J = 4.9 Hz, 1H), 8.62 - 8.33 (m, 2H), 8.09 - 8.01 (m, 2H), 8.00 - 7.90 (m, 2H), 7.52 - 7.42 (m, 2H), 7.42 - 7.35 (m, 1H), 5.54 - 5.32 (m, 1H), 4.69 - 4.28 (m, 3H), 4.13 - 3.94 (m, 1H), 3.93 - 3.84 (m, 1H), 3.75 - 3.63 (m, 1H), 3.57 - 3.50 (m, 2H); MS (ESI): m / z 433.4 (M+H) + .

[0623] Example 152:

[0624]

[0625] Compound 152 was obtained from (1R,2R)-2-aminocyclopentan-1-ol hydrochloride following the synthesis of Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.65 (d, J = 4.8 Hz, 1H), 8.10 - 8.02 (m, 3H), 8.00 - 7.81 (m, 3H), 7.50 - 7.39 (m, 2H), 7.38 - 7.32 (m, 1H), 6.18 (d, J = 7.0 Hz, 1H), 4.75 - 4.70 (m, 1H), 4.61 - 4.46 (m, 2H), 4.22 - 4.02 (m, 2H), 2.02 - 1.82 (m, 2H), 1.69 - 1.40 (m, 4H); MS (ESI): m / z 430.5 (M+H) + .

[0626] Example 153:

[0627]

[0628] Compound 153 was obtained from (1S,2R)-2-aminocyclopentan-1-ol hydrochloride following the synthesis of Compound 24. 1H NMR (500 MHz, DMSO-de) δ 8.65 (d, J = 4.8 Hz, 1H), 8.15 - 7.98 (m, 4H), 7.93 (d, J = 7.9 Hz, 1H), 7.89 - 7.85 (m, 1H), 7.42 (d, J = 7.8 Hz, 2H), 7.37 - 7.31 (m, 1H), 6.02 - 5.93 (m, 1H), 5.27 - 5.15 (m, 1H), 4.60 - 4.44 (m, 2H), 4.21 - 3.94 (m, 2H), 1.88 - 1.76 (m, 2H), 1.73 - 1.52 (m, 2H), 1.47 - 1.31 (m, 2H); MS (ESI): m / z 430.5 (M+H) + .

[0629] Example 154:

[0630]

[0631] Compound 154 was obtained from 3-hydroxypyridine following the synthesis of Reference Compound 24. 1 H NMR (500 MHz, DMSO-de) δ 8.84 - 8.51 (m, 5H), 8.04 - 7.89 (m, 4H), 7.86 - 7.68 (m, 1H), 7.62 - 7.53 (m, 1H), 7.49 - 7.37 (m, 2H), 7.00 (d, J = 8.0 Hz, 1H), 4.59 - 4.13 (m, 2H); MS (ESI): m / z 424.4 (M+H) + .

[0632] Example 155:

[0633]

[0634] Compound 155 was obtained from 5-hydroxypyridine-3-sulfone following the synthesis of Reference Compound 24. 1 H NMR (500 MHz, DMSO-de) δ 9.09 - 9.03 (m, 1H), 9.00 - 8.61 (m, 3H), 8.57 (d, J = 6.7 Hz, 1H), 8.42 - 8.35 (m, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.94 - 7.86 (m, 3H), 7.45 - 7.32 (m, 2H), 6.98 (d, J = 7.9 Hz, 1H), 4.58 - 4.16 (m, 2H), 3.42 - 3.38 (m, 3H); MS (ESI): m / z 502.4 (M+H) + .

[0635] Example 156:

[0636]

[0637] Compound 156 was obtained by the synthesis of compound 24 from (1S,2R)-2- aminocyclohexan-1-ol hydrochloride. 1 HNMR (500 MHz, DMSO-d6) δ 8.65 (d, J = 4.8 Hz, 1H), 8.13 - 7.99 (m, 4H), 7.92 (d, J = 7.9 Hz, 1H), 7.87 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 7.9 Hz, 2H), 7.35 - 7.31 (m, 1H), 5.68 (d, J = 7.6 Hz, 1H), 5.08 - 4.91 (m, 1H), 4.55 - 4.40 (m, 2H), 4.08 - 3.68 (m, 2H), 1.79 - 1.58 (m, 2H), 1.51 - 1.46 (m, 4H), 1.38 - 1.30 (m, 2H); MS (ESI): m / z 444.6 (M+H) + .

[0638] Example 157:

[0639]

[0640] Compound 157 was obtained by the synthesis of compound 24 from cis-2,6- dimethylpiperazine. 1 HNMR (500 MHz, DMSO-d6) δ 8.69 - 8.60 (m, 1H), 8.33 - 7.72 (m, 6H), 7.51 - 7.17 (m, 3H), 4.65 - 4.41 (m, 2H), 3.96 - 3.72 (m, 2H), 2.80 - 2.57 (m, 2H), 2.44 - 2.35 (m, 2H), 0.99 - 0.89 (m, 6H); MS (ESI): m / z 443.4 (M+H) + .

[0641] Example 158:

[0642]

[0643] Compound 158 was obtained by the synthesis of compound 24 from (S)-2-amino-3- methoxypropan-1-ol hydrochloride. 1H NMR (500 MHz, DMSO-d6) δ 8.74 - 8.59 (m, 1H), 8.13 - 7.82 (m, 6H), 7.50 - 7.31 (m, 3H), 5.94 - 5.79 (m, 1H), 5.00 - 4.80 (m, 1H), 4.59 - 4.26 (m, 3H), 3.59 - 3.35 (m, 4H), 3.30 - 3.12 (m, 3H); MS (ESI): m / z 434.5 (M+H) + .

[0644] Example 159:

[0645]

[0646] Compound 159 was obtained from (R)-2-amino-2-cyclopropyl ethanol hydrochloride following the synthesis of Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.75 - 8.49 (m, 1H), 8.12 - 8.01 (m, 3H), 7.98 - 7.73 (m, 3H), 7.44 - 7.36 (m, 2H), 7.36 - 7.30 (m, 1H), 6.15 - 5.82 (m, 1H), 4.87 - 4.70 (m, 1H), 4.61 - 4.37 (m, 2H), 3.77 - 3.45 (m, 3H), 1.09 - 0.97 (m, 1H), 0.52 - 0.25 (m, 2H), 0.22 - 0.06 (m, 2H); MS (ESI): m / z 430.4 (M+H) + .

[0647] Example 160:

[0648]

[0649] Compound 160-a was obtained from (2-chloro-6-methylpyridin-4-yl)methanol following the synthesis of Compound 12-c.

[0650] 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (20.00 g, 92.18 mmol) was dissolved in tetrahydrofuran (400 mL), and zinc chloride (16.33 g, 119.8 mmol) was added in portions at 0 °C. After stirring the mixture at 0 °C for 0.5 hours, a 20% sodium methanethiol aqueous solution (48.45 g, 138.3 mmol) was slowly added, and the mixture was stirred for another 5 hours at room temperature. 400 mL of water and 400 mL of ethyl acetate were added to the reaction mixture, which was then filtered. The filtrate was separated, and the aqueous phase was extracted twice with 200 mL of ethyl acetate. The combined organic phases were washed three times with water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 160-b (8.44 g, 36.9 mmol), in a yield of 40.0%.

[0651] Compound 160-b (100 mg, 0.437 mmol) and (2R,3R)-2-aminobutane-1,3-diol (48.3 mg, 0.459 mmol) were dissolved in N-methylpyrrolidone (3 mL), and N,N-diisopropylethylamine (170 mg, 1.31 mmol) was added. The mixture was stirred at 90 °C for 16 hours. 20 mL of water was added to the reaction mixture, and the mixture was extracted twice with 20 mL of ethyl acetate. The combined organic phases were washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 160-c (110 mg, 0.37 mmol), in 84.6% yield. MS (ESI): m / z 298.4 (M+H) + .

[0652] Compound 160-b (100 mg, 0.437 mmol) was dissolved in ethyl acetate (4 mL), and 3-chloroperoxybenzoic acid (192 mg, 1.11 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 7 hours. 20 mL of ethyl acetate was added to the reaction mixture, followed by washing three times with 5 mL of saturated sodium thiosulfate and 5 mL of saturated sodium bicarbonate, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product compound 160-d (100 mg, 0.304 mmol), in 84.6% yield. MS (ESI): m / z 330.5 (M+H) + .

[0653] Compound 160-d (37.31 mg, 0.113 mmol) and 160-a (30 mg, 0.113 mmol) were dissolved in N-methylpyrrolidone (3 mL), and N,N-diisopropylethylamine (73.2 mg, 0.567 mmol) was added. The mixture was stirred at 90 °C for 3 hours. After the reaction solution was cooled to room temperature, compound 160 (10 mg, 20.9 μmol) was obtained by purification through preparative liquid chromatography, with a yield of 18.5%. 1 HNMR (500 MHz, DMSO-d6) δ 8.15-7.78 (m, 4H), 7.67-7.61 (m, 1H), 7.53-7.35 (m, 2H), 7.20-7.11 (m, 1H), 5.70-5.63 (m, 1H), 5.45-5.39 (m, 1H), 5.03-4.92 (m, 1H), 4.81-4.73 (m, 1H), 4.63-4.45 (m, 4H), 4.11-4.02 (m, 2H), 3.56-3.41 (m, 2H), 2.53-2.51 (m, 3H), 1.09-0.93 (m, 3H); MS (ESI): m / z 478.5 (M+H) + .

[0654] Example 161:

[0655]

[0656] Compound 161 was obtained by referring to the synthesis of compound 160 from (2-chloro-6-methylpyridin-4-yl)methanol and R-2-aminobutyramide hydrochloride. 1 HNMR (500 MHz, DMSO-d6) δ 8.15-7.78 (m, 4H), 7.67-7.61 (m, 1H), 7.53-7.35 (m, 2H), 7.20-7.11 (m, 1H), 5.70-5.63 (m, 1H), 5.45-5.39 (m, 1H), 5.03-4.92 (m, 1H), 4.81-4.73 (m, 1H), 4.63-4.45 (m, 4H), 4.11-4.02 (m, 2H), 3.56-3.41 (m, 2H), 2.53-2.51 (m, 3H), 1.09-0.93 (m, 3H); MS (ESI): m / z 478.5 (M+H) + .

[0657] Example 161:

[0658]

[0659] Compound 162 was obtained from (6-chloro-4-methylpyridin-2-yl)methanol and L- threoninol hydrochloride, referring to the synthesis of Compound 160. 1 H NMR (500 MHz, DMSO-d6) δ 8.11 - 7.98 (m, 4H), 7.62 (s, 1H), 7.47 - 7.36 (m, 2H), 7.25 (s, 1H), 5.66 (d, J = 7.8 Hz, 1H), 5.41 - 5.35 (m, 1H), 5.04 - 4.93 (m, 1H), 4.82 - 4.72 (m, 1H), 4.62 - 4.47 (m, 4H), 4.12 - 4.02 (m, 2H), 3.52 - 3.39 (m, 2H), 2.39 (s, 3H), 1.09 - 0.93 (m, 3H); MS (ESI): m / z 478.4 (M+H) + .

[0660] Example 163:

[0661]

[0662] Compound 163 was obtained from (6-chloro-4-methylpyridin-2-yl)methanol and R-2- aminobutyramide hydrochloride, referring to the synthesis of Compound 160. 1 H NMR (500 MHz, DMSO-d6) δ 8.11 - 7.98 (m, 4H), 7.62 (s, 1H), 7.47 - 7.36 (m, 2H), 7.25 (s, 1H), 5.66 (d, J = 7.8 Hz, 1H), 5.41 - 5.35 (m, 1H), 5.04 - 4.93 (m, 1H), 4.82 - 4.72 (m, 1H), 4.62 - 4.47 (m, 4H), 4.12 - 4.02 (m, 2H), 3.52 - 3.39 (m, 2H), 2.39 (s, 3H), 1.09 - 0.93 (m, 3H); MS (ESI): m / z 478.4 (M+H) + .

[0663] Example 164:

[0664]

[0665] Compound 164-a was obtained from cis-tetrahydrofuran-3,4-diol, referring to the synthesis of Compound 26. Compound 164 was obtained from Compound 164-a, referring to the synthesis of Compound 101. 1H NMR (500 MHz, DMSO-d6) δ 8.65 (d, J = 4.9 Hz, 1H), 8.58 - 8.27 (m, 2H), 8.07 - 8.00 (m, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.90 - 7.83 (m, 1H), 7.48 - 7.39 (m, 2H), 7.33 (dd, J = 7.3, 4.9 Hz, 1H), 5.50 - 5.12 (m, 1H), 4.77 - 4.36 (m, 3H), 4.30 - 4.04 (m, 1H), 3.24 - 2.54 (m, 4H); MS (ESI): m / z 432.5 (M+H) + .

[0666] Example 165:

[0667]

[0668] Compound 165 was obtained by the synthesis of compound 149 with reference to the synthesis of compound 149 from R-l-tert-butyldimethylsilyloxy-2-propanol. 1 H NMR (500 MHz, DMSO-d6) δ 8.68 - 8.63 (m, 1H), 8.63 - 8.40 (m, 1H), 8.38 - 8.28 (m, 1H), 8.07 - 8.01 (m, 2H), 7.95 - 7.84 (m, 2H), 7.48 - 7.39 (m, 2H), 7.36 - 7.31 (m, 1H), 5.38 - 4.21 (m, 4H), 4.19 - 3.41 (m, 2H), 1.28 - 1.03 (m, 3H); MS (ESI): m / z 404.1 (M+H) + .

[0669] Example 166:

[0670]

[0671] Compound 166 was obtained by the synthesis of compound 26 with reference to the synthesis of compound 26 from (R)-2-hydroxypropanamide. 1 H NMR (500 MHz, DMSO-d6) δ 8.69 - 8.63 (m, 1H), 8.58 - 8.26 (m, 2H), 8.08 - 7.99 (m, 2H), 7.96 - 7.83 (m, 2H), 7.47 - 7.44 (m, 1H), 7.43 - 7.38 (m, 1H), 7.35 - 7.31 (m, 1H), 7.27 - 7.14 (m, 2H), 5.39 - 5.22 (m, 1H), 4.62 - 4.45 (m, 2H), 1.47 - 1.40 (m, 3H); MS (ESI): m / z 418.3 (M+H) + .

[0672] Example 167:

[0673]

[0674] Compound 167 was obtained from (R)-2-methylbutane-2,3-diol following the synthesis of Reference Compound 26. 1 H NMR (500 MHz, DMSO-d6) δ 8.69 - 8.62 (m, 1H), 8.60 - 8.28 (m, 2H), 8.08 - 7.99 (m, 2H), 7.97 - 7.90 (m, 1H), 7.90 - 7.82 (m, 1H), 7.49 - 7.38 (m, 2H), 7.37 - 7.29 (m, 1H), 5.14 - 4.99 (m, 1H), 4.64 - 4.46 (m, 3H), 1.27 - 1.05 (m, 9H); MS (ESI): m / z 433.7 (M+H) + .

[0675] Example 168:

[0676]

[0677] Compound 168 was obtained from (6-chloropyridin-2,4-yl)dimethanol and (2R,3R)-butane-2,3-diol following the synthesis of Reference Compound 160. 1 H NMR (500 MHz, DMSO-d6) δ 8.57 - 8.27 (m, 2H), 8.04 - 7.98 (m, 2H), 7.71 - 7.67 (m, 1H), 7.46 - 7.37 (m, 3H), 5.45 (t, J = 5.8 Hz, 1H), 5.41 (t, J = 5.9 Hz, 1H), 5.32 - 5.12 (m, 1H), 4.83 - 4.73 (m, 1H), 4.68 - 4.45 (m, 6H), 3.84 - 3.73 (m, 1H), 1.24 - 0.98 (m, 6H); MS (ESI): m / z 479.7 (M+H) + .

[0678] Example 169:

[0679]

[0680] Compound 169 was obtained from (6-chloropyridin-2,4-yl)dimethanol and R-2-aminobutyramide hydrochloride following the synthesis of Reference Compound 160. 1H NMR (500 MHz, DMSO-d6) δ 8.20 - 7.98 (m, 4H), 7.76 - 7.60 (m, 2H), 7.54 - 7.28 (m, 4H), 6.38 - 6.23 (m, 1H), 5.49 - 5.40 (m, 2H), 4.65 - 4.45 (m, 7H), 2.09 - 1.74 (m, 2H), 0.86 - 0.69 (m, 3H); MS (ESI): m / z 491.4 (M+H) + .

[0681] Example 170:

[0682]

[0683] Compound 170 was obtained by the synthesis of Compound 160 from (6-chloropyridin-2,4- yl)methanol and L-threonine hydrochloride. 1 H NMR (500 MHz, DMSO-d6) δ 8.20 - 7.98 (m, 4H), 7.76 - 7.60 (m, 2H), 7.54 - 7.28 (m, 4H), 6.38 - 6.23 (m, 1H), 5.49 - 5.40 (m, 2H), 4.65 - 4.45 (m, 7H), 2.09 - 1.74 (m, 2H), 0.86 - 0.69 (m, 3H); MS (ESI): m / z 491.4 (M+H) + .

[0684] Example 171:

[0685]

[0686] Compound 171 was obtained by the synthesis of Compound 160 from (6-chloropyridin-2- yl)methanol and L-threonine hydrochloride. 1 H NMR (500 MHz, DMSO-d6) δ 8.20 - 7.98 (m, 4H), 7.76 - 7.60 (m, 2H), 7.54 - 7.28 (m, 4H), 6.38 - 6.23 (m, 1H), 5.49 - 5.40 (m, 2H), 4.65 - 4.45 (m, 7H), 2.09 - 1.74 (m, 2H), 0.86 - 0.69 (m, 3H); MS (ESI): m / z 491.4 (M+H) + .

[0687] Example 172:

[0688]

[0689] Compound 172 was obtained from (6-chloropyridin-2-yl)methanol and R-2- aminobutyramide hydrochloride, referring to the synthesis of Compound 160. 1 H NMR (500 MHz, DMSO-d6) δ 8.14 - 7.99 (m, 4H), 7.90 - 7.77 (m, 2H), 7.67 - 7.60 (m, 1H), 7.47 - 7.28 (m, 4H), 6.30 - 6.22 (m, 1H), 5.45 - 5.37 (m, 1H), 4.64 - 4.61 (m, 2H), 4.60 - 4.47 (m, 3H), 1.91 - 1.64 (m, 2H), 0.82 - 0.69 (m, 3H); MS (ESI): m / z 461.4 (M+H) + .

[0690] Example 173:

[0691]

[0692] Compound 173 was obtained from (6-chloropyridin-2-yl)methanol and (2R,3R)-butane-2,3-diol, referring to the synthesis of Compound 160. 1 H NMR (500 MHz, DMSO-d6) δ 8.59 - 8.28 (m, 2H), 8.07 - 7.73 (m, 4H), 7.49 - 7.38 (m, 3H), 5.45 - 5.39 (m, 1H), 5.28 - 5.14 (m, 1H), 4.83 - 4.74 (m, 1H), 4.65 - 4.49 (m, 4H), 3.90 - 3.68 (m, 1H), 1.24 - 1.00 (m, 6H); MS (ESI): m / z 449.4 (M+H) + .

[0693] Example 174:

[0694]

[0695] Compound 174 was obtained from 2,4-dichloro-5-cyanopyrimidine, referring to the synthesis of Compound 169. 1 H NMR (500 MHz, DMSO-d6) δ 8.51 - 8.10 (m, 2H), 8.00 (d, J = 8.2 Hz, 2H), 7.76 (s, 1H), 7.60 - 7.38 (m, 4H), 7.17 (s, 1H), 4.83 - 4.42 (m, 8H), 2.04 - 1.70 (m, 3H), 0.88 - 0.79 (m, 4H); MS (ESI): m / z 448.3 (M+H)+ .

[0696] Example 175:

[0697]

[0698] Compound 175 was obtained from 2,4-dichloro-5-cyanopyrimidine following the synthesis of Compound 170. 1 H NMR (500 MHz, DMSO-d6) δ 8.34 - 7.97 (m, 4H), 7.69 (s, 1H), 7.57 - 7.36 (m, 3H), 5.53 - 5.39 (m, 2H), 4.90 - 4.54 (m, 7H), 4.53 - 4.43 (m, 1H), 4.17 - 3.80 (m, 2H), 3.54 - 3.41 (m, 2H), 0.96 (d, J = 6.7 Hz, 3H); MS (ESI): m / z 451.3 (M+H) + .

[0699] Example 176

[0700]

[0701] Compound 176 was obtained from tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate following the synthesis of Compound 169. 1 H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.45 (d, J = 8.6 Hz, 2H), 8.25 (s, 1H), 7.84 - 7.79 (m, 1H), 7.68 - 7.61 (m, 1H), 7.56 - 7.46 (m, 2H), 7.40 - 7.29 (m, 1H), 4.79 - 4.44 (m, 8H), 2.06 - 1.44 (m, 2H), 0.85 - 0.61 (m, 3H); MS (ESI): m / z 492.3 (M+H) + .

[0702] Example 177:

[0703]

[0704] Compound 177 was obtained from tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate following the synthesis of Compound 170. 1H NMR (500 MHz, DMSO-d6) δ 9.22 (d, J = 2.2 Hz, 1H), 8.94 - 8.51 (m, 2H), 8.38 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 6.78 - 6.62 (m, 1H), 4.88 - 4.73 (m, 3H), 4.68 - 4.64 (m, 5H), 3.98 - 3.94 (m, 2H), 3.57 - 3.41 (m, 4H), 0.94 - 0.88 (m, 3H); MS (ESI): m / z 495.2 (M+H) + .

[0705] Example 178:

[0706]

[0707] Compound 178 was obtained from 6-chloro-4-(hydroxymethyl)picolinonitrile following the synthesis of Reference Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.72 - 8.40 (m, 2H), 8.19 (d, J = 8.7 Hz, 1H), 8.15 - 7.86 (m, 3H), 7.47 (d, J = 7.9 Hz, 2H), 5.73 - 5.52 (m, 2H), 4.92 - 4.66 (m, 4H), 4.63 - 4.42 (m, 4H); MS (ESI): m / z 458.3 (M+H) + .

[0708] Example 179:

[0709]

[0710] Compound 179 was obtained from 2-chloro-6-(hydroxymethyl)isonicotinonitrile following the synthesis of Reference Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.73 - 8.39 (m, 2H), 8.35 - 8.08 (m, 3H), 7.79 - 7.71 (m, 1H), 7.52 - 7.41 (m, 2H), 5.74 - 5.50 (m, 2H), 4.92 - 4.66 (m, 4H), 4.63 - 4.40 (m, 4H): m / z 458.3 (M+H) + .

[0711] Example 180:

[0712]

[0713] Compound 180 was obtained from 2-chloro-6-(hydroxymethyl)isonicotinamide following the synthesis of Compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.71 - 8.40 (m, 2H), 8.34 (s, 1H), 8.20 - 8.06 (m, 3H), 7.91 - 7.69 (m, 2H), 7.43 (d, J = 8.1 Hz, 2H), 5.66 - 5.53 (m, 2H), 4.90 - 4.66 (m, 4H), 4.61 - 4.41 (m, 4H); MS (ESI): m / z 476.3 (M+H) + .

[0714] Example 181 :

[0715]

[0716] Compound 181 was obtained from [(R)-1-(4-bromophenyl)ethyl] tert-butyl carbamate following the synthesis of Compound 125. 1 H NMR (500 MHz, DMSO-d6) δ 8.73 - 8.33 (m, 2H), 8.06 - 7.64 (m, 3H), 7.52 - 7.38 (m, 3H), 5.71 - 5.33 (m, 3H), 5.26 - 4.18 (m, 9H), 1.55 - 1.44 (m, 3H); MS (ESI): m / z 477.3 (M+H) + .

[0717] Example 182 :

[0718]

[0719] Compound 182 was obtained from ((5-bromopyridin-2-yl)methyl) tert-butyl carbamate following the synthesis of Compound 168. 1 H NMR (500 MHz, DMSO-d6) δ 9.17 - 8.32 (m, 3H), 7.80 - 6.96 (m, 4H), 5.60 - 4.56 (m, 8H), 3.84 - 3.59 (m, 1H), 1.28 - 1.24 (m, 3H), 1.01 - 0.83 (m, 3H); MS (ESI): m / z 480.2 (M+H) + .

[0720] Example 183 :

[0721]

[0722] Compound 183 was obtained from (5-chloropyridin-3-yl)methanol and (2R,3R)-butane-2,3-diol following the synthesis of Compound 160.1 H NMR (500 MHz, DMSO-d6) δ 8.78 - 8.72 (m, 1H), 8.59 - 8.28 (m, 3H), 7.95 (s, 1H), 7.70 - 7.65 (m, 2H), 7.49 - 7.41 (m, 2H), 5.40 - 5.35 (m, 1H), 5.29 - 5.13 (m, 1H), 4.83 - 4.74 (m, 1H), 4.66 - 4.46 (m, 4H), 3.82 - 3.72 (m, 1H), 1.24 - 1.09 (m, 3H), 1.09 - 1.00 (m, 3H); MS (ESI): m / z 449.2 (M+H) + .

[0723] Example 184:

[0724]

[0725] Compound 184 was obtained by the synthesis of compound 168 with reference to the synthesis of compound 184 from [(R)-1-(4-bromophenyl)ethyl] tert-butyl carbamate. 1 H NMR (500 MHz, DMSO-d6) δ 8.78 - 8.72 (m, 1H), 8.59 - 8.28 (m, 3H), 7.95 (s, 1H), 7.70 - 7.65 (m, 2H), 7.49 - 7.41 (m, 2H), 5.40 - 5.35 (m, 1H), 5.29 - 5.13 (m, 1H), 4.83 - 4.74 (m, 1H), 4.66 - 4.46 (m, 4H), 3.82 - 3.72 (m, 1H), 1.24 - 1.09 (m, 3H), 1.09 - 1.00 (m, 3H); MS (ESI): m / z 449.2 (M+H) + .

[0726] Example 185:

[0727]

[0728] Compound 185 was obtained by the synthesis of compound 24 with reference to the synthesis of compound 185 from (S)-pyrrolidin-2-ylmethanol hydrochloride. 1 H NMR (500 MHz, DMSO-d6) δ 8.78 - 8.72 (m, 1H), 8.59 - 8.28 (m, 3H), 7.95 (s, 1H), 7.70 - 7.65 (m, 2H), 7.49 - 7.41 (m, 2H), 5.40 - 5.35 (m, 1H), 5.29 - 5.13 (m, 1H), 4.83 - 4.74 (m, 1H), 4.66 - 4.46 (m, 4H), 3.82 - 3.72 (m, 1H), 1.24 - 1.09 (m, 3H), 1.09 - 1.00 (m, 3H); MS (ESI): m / z 449.2 (M+H) + .

[0729] Example 186:

[0730]

[0731] Compound 186 was obtained from (R)-1-aminopropan-2-ol following the synthesis of Reference Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.66 - 8.63 (m, 1H), 8.11 - 7.96 (m, 4H), 7.94 - 7.90 (m, 1H), 7.88 - 7.84 (m, 1H), 7.44 - 7.37 (m, 2H), 7.35 - 7.31 (m, 1H), 6.54 - 6.33 (m, 1H), 4.85 - 4.68 (m, 1H), 4.56 - 4.45 (m, 2H), 3.90 - 3.70 (m, 1H), 3.47 - 3.35 (m, 1H), 3.25 - 3.14 (m, 1H), 1.10 - 0.92 (m, 3H); MS (ESI): m / z 403.8 (M+H) + .

[0732] Example 187:

[0733]

[0734] Compound 187 was obtained from (3R,5S)-5-(hydroxymethyl)pyrrolidin-3-ol hydrochloride following the synthesis of Reference Compound 24. 11 H NMR (500 MHz, DMSO-d6) δ 8.70 - 8.63 (m, 1H), 8.24 - 8.15 (m, 1H), 8.11 - 7.90 (m, 4H), 7.89 - 7.84 (m, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.36 - 7.31 (m, 1H), 4.95 - 4.84 (m, 1H), 4.64 - 4.44 (m, 4H), 4.35 - 4.26 (m, 1H), 3.70 - 3.42 (m, 3H), 3.31 - 3.26 (m, 1H), 2.07 - 1.91 (m, 2H); MS (ESI): m / z 446.2 (M+H) + .

[0735] Example 188:

[0736]

[0737] Compound 188 was obtained from R-2-aminopropanamide hydrochloride following the synthesis of Reference Compound 24. 1H NMR (500 MHz, DMSO-de) δ 8.69 - 8.60 (m, 1H), 8.17 - 7.81 (m, 6H), 7.68 - 7.24 (m, 5H), 6.47 - 6.33 (m, 1H), 4.66 - 4.42 (m, 3H), 1.41 - 1.25 (m, 3H); MS (ESI): m / z 417.2 (M+H) + .

[0738] Example 189:

[0739]

[0740] Compound 179 (10 mg, 21.9 μmol) was dissolved in methanol (2 mL), concentrated ammonia and Raney nickel (1 mg) were added. The mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. The mixture was filtered through celite, concentrated, and the residue was purified by preparative liquid chromatography to give compound 189 (3.0 mg, 6.5 μmol), 29.7% yield. 1 H NMR (500 MHz, DMSO-de) δ 8.72 - 8.39 (m, 2H), 8.12 - 8.00 (m, 2H), 7.85 - 7.63 (m, 1H), 7.46 - 7.38 (m, 3H), 5.67 - 5.52 (m, 1H), 5.50 - 5.38 (m, 1H), 5.35 - 4.86 (m, 1H), 4.76 - 4.56 (m, 5H), 4.55 - 4.20 (m, 3H), 3.89 - 3.78 (m, 2H): m / z 462.4 (M+H) + .

[0741] Example 190:

[0742]

[0743] Compound 190 was obtained from D-allothionol following the synthesis of compound 24. 1 H NMR (500 MHz, DMSO-de) δ 8.72 - 8.39 (m, 2H), 8.12 - 8.00 (m, 2H), 7.85 - 7.63 (m, 1H), 7.46 - 7.38 (m, 3H), 5.67 - 5.52 (m, 1H), 5.50 - 5.38 (m, 1H), 5.35 - 4.86 (m, 1H), 4.76 - 4.56 (m, 5H), 4.55 - 4.20 (m, 3H), 3.89 - 3.78 (m, 2H): m / z 462.4 (M+H) + .

[0744] Example 191:

[0745]

[0746] Compound 191 was obtained from L-allothreonolol by the synthesis of Reference Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.72 - 8.56 (m, 1H), 8.10 - 7.99 (m, 4H), 7.95 - 7.91 (m, 1H), 7.89 - 7.84 (m, 1H), 7.44 - 7.38 (m, 2H), 7.35 - 7.31 (m, 1H), 5.93 - 5.77 (m, 1H), 4.82 - 4.42 (m, 4H), 4.20 - 4.06 (m, 1H), 3.83 - 3.65 (m, 2H), 3.63 - 3.48 (m, 1H), 1.10 - 0.96 (m, 3H); MS (ESI): m / z 434.4 (M+H) + .

[0747] Example 192:

[0748]

[0749] Compound 192 was obtained from (R)-2-amino-N,N-dimethylpropanamide hydrochloride by the synthesis of Reference Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.72 - 8.56 (m, 1H), 8.14 - 7.83 (m, 6H), 7.49 - 7.26 (m, 3H), 6.51 - 6.35 (m, 1H), 5.07 - 4.77 (m, 1H), 4.59 - 4.46 (m, 2H), 3.12 - 2.90 (m, 3H), 2.90 - 2.73 (m, 3H), 1.34 - 1.14 (m, 3H); MS (ESI): m / z 445.3 (M+H) + .

[0750] Example 192:

[0751]

[0752] Compound 193 was obtained from (R)-2-amino-N-methylpropanamide by the synthesis of Reference Compound 24. 1H NMR (500 MHz, DMSO-d6) δ 8.74 - 8.59 (m, 1H), 8.14 - 8.00 (m, 5H), 7.94 - 7.84 (m, 2H), 7.46 - 7.31 (m, 3H), 6.45 - 6.30 (m, 1H), 4.61 - 4.46 (m, 3H), 2.64 - 2.57 (m, 3H), 1.36 - 1.20 (m, 3H); MS (ESI): m / z 431.3 (M+H) + .

[0753] Example 194:

[0754]

[0755] Compound 194 was obtained by reference to the synthesis of Compound 160 from (6-chloropyridine-2,4-diyl)dimethanol and (2R,3R)-3-aminobutan-2-ol. 1 H NMR (500 MHz, DMSO-d6) δ 8.11 - 7.96 (m, 4H), 7.73 - 7.66 (m, 1H), 7.45 - 7.36 (m, 3H), 5.79 - 5.66 (m, 1H), 5.51 - 5.42 (m, 2H), 5.08 - 4.98 (m, 1H), 4.66 - 4.59 (m, 4H), 4.59 - 4.40 (m, 2H), 4.17 - 4.00 (m, 1H), 3.80 - 3.64 (m, 1H), 1.10 - 0.92 (m, 6H); MS (ESI): m / z 478.4 (M+H) + .

[0756] Example 195:

[0757]

[0758] Compound 195 was obtained by reference to the synthesis of Compound 24 from (2R,3R)-3-aminopentan-2-ol. 1 H NMR (500 MHz, DMSO-d6) δ 8.67 - 8.63 (m, 1H), 8.10 - 7.99 (m, 4H), 7.91 (d, J = 7.9 Hz, 1H), 7.89 - 7.83 (m, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.36 - 7.31 (m, 1H), 5.69 - 5.59 (m, 1H), 4.99 - 4.89 (m, 1H), 4.56 - 4.41 (m, 2H), 4.05 - 3.91 (m, 1H), 3.87 - 3.73 (m, 1H), 1.54 - 1.38 (m, 2H), 0.93 - 0.70 (m, 6H); MS (ESI): m / z 432.3 (M+H)+ .

[0759] Example 196:

[0760]

[0761] Compound 196 was obtained from (1R,2R)-2-amino-1-cyclopropylpropan-1-ol following the synthesis of Compound 24. 1 HNMR (500 MHz, DMSO-d6) δ 8.72 - 8.61 (m, 1H), 8.14 - 7.83 (m, 6H), 7.48 - 7.28 (m, 3H), 5.81 - 5.70 (m, 1H), 5.19 - 5.02 (m, 1H), 4.60 - 4.45 (m, 2H), 4.35 - 4.20 (m, 1H), 2.98 - 2.85 (m, 1H), 1.22 - 1.07 (m, 3H), 0.87 - 0.65 (m, 1H), 0.44 - 0.04 (m, 4H); MS (ESI): m / z 444.2 (M+H) + .

[0762] Example 197:

[0763]

[0764] Compound 197 was obtained from (1S,2R)-2-amino-1-cyclopropylpropan-1-ol following the synthesis of Compound 24. 1 HNMR (500 MHz, DMSO-d6) δ 8.72 - 8.59 (m, 1H), 8.12 - 7.83 (m, 6H), 7.55 - 7.30 (m, 3H), 5.82 - 5.71 (m, 1H), 5.19 - 5.00 (m, 1H), 4.70 - 4.46 (m, 2H), 4.37 - 4.18 (m, 1H), 2.97 - 2.85 (m, 1H), 1.20 - 1.03 (m, 3H), 0.90 - 0.67 (m, 1H), 0.47 - 0.08 (m, 4H); MS (ESI): m / z 444.2 (M+H) + .

[0765] Example 198:

[0766]

[0767] Compound 198 was obtained from (6-chloropyridine-2,4-diyl)dimethanol and (2R,3R)-3-aminopentan-2-ol following the synthesis of Compound 160. 1H NMR (500 MHz, DMSO-d6) δ 8.12 - 7.96 (m, 4H), 7.67 (s, 1H), 7.43 - 7.36 (m, 3H), 5.67 - 5.59 (m, 1H), 5.47 - 5.43 (m, 1H), 5.43 - 5.38 (m, 1H), 5.00 - 4.87 (m, 1H), 4.63 - 4.59 (m, 4H), 4.55 - 4.41 (m, 2H), 4.06 - 3.90 (m, 1H), 3.90 - 3.72 (m, 1H), 1.52 - 1.42 (m, 2H), 0.90 - 0.71 (m, 6H); MS (ESI): m / z 492.4 (M+H) + .

[0768] Example 199:

[0769]

[0770] Compound 199 was obtained from (2R,3S)-2-aminopentan-3-ol following the synthesis of Reference Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.76 - 8.60 (m, 1H), 8.13 - 7.97 (m, 4H), 7.93 - 7.89 (m, 1H), 7.88 - 7.83 (m, 1H), 7.47 - 7.28 (m, 3H), 6.03 - 5.88 (m, 1H), 4.98 - 4.78 (m, 1H), 4.62 - 4.46 (m, 2H), 4.31 - 4.10 (m, 1H), 3.52 - 3.36 (m, 1H), 1.45 - 1.21 (m, 2H), 1.12 - 0.70 (m, 6H); MS (ESI): m / z 432.2 (M+H) + .

[0771] Example 200:

[0772]

[0773] Compound 200 was obtained from (2R,3R)-2-aminopentan-3-ol following the synthesis of Reference Compound 24. 1H NMR (500 MHz, DMSO-d6) δ 8.69 - 8.62 (m, 1H), 8.14 - 7.98 (m, 4H), 7.96 - 7.89 (m, 1H), 7.89 - 7.82 (m, 1H), 7.46 - 7.36 (m, 2H), 7.36 - 7.30 (m, 1H), 5.74 - 5.62 (m, 1H), 5.15 - 4.99 (m, 1H), 4.60 - 4.42 (m, 2H), 4.27 - 4.09 (m, 1H), 3.45 - 3.35 (m, 1H), 1.43 - 1.13 (m, 3H), 1.11 - 1.00 (m, 2H), 0.92 - 0.65 (m, 3H); MS (ESI): m / z 432.2 (M+H) + .

[0774] Example 201:

[0775]

[0776] Compound 201 was obtained from (2R,3R)-3-amino-4-(piperidin-l-yl)butan-2-ol following the synthesis of Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.58 (d, J = 4.5 Hz, 1H), 8.08 - 7.93 (m, 4H), 7.88 - 7.83 (m, 1H), 7.83 - 7.68 (m, 1H), 7.35 - 7.24 (m, 3H), 5.56 (d, J = 8.0 Hz, 1H), 5.18 - 4.92 (m, 1H), 4.54 - 4.37 (m, 2H), 4.12 - 3.86 (m, 2H), 2.34 - 1.98 (m, 6H), 1.31 - 1.21 (m, 4H), 1.21 - 1.16 (m, 2H), 1.03 - 0.94 (m, 1H), 0.86 - 0.82 (m, 2H); MS (ESI): m / z 501.6 (M+H) + .

[0777] Example 202:

[0778]

[0779] Compound 202 was obtained from (2R,3R)-3-amino-4-(pyrrolidin-l-yl)butan-2-ol following the synthesis of Compound 24. 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.16 - 7.98 (m, 4H), 7.95 - 7.83 (m, 2H), 7.46 - 7.28 (m, 3H), 5.77 - 5.52 (m, 1H), 5.35 - 5.00 (m, 1H), 4.63 - 4.41 (m, 2H), 4.19 - 3.93 (m, 2H), 3.15 (d, J = 9.5 Hz, 2H), 2.32 - 2.19 (m, 4H), 1.71 - 1.51 (m, 4H), 1.34 - 1.27 (m, 3H); MS (ESI): m / z 487.2 (M+H) + .

[0780] Example 203:

[0781]

[0782] Compound 203 was obtained from (2R,3R)-3-amino-4-((R)-3- hydroxypyrrolidin-l-yl)butan-2-ol following the synthesis of compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.66 - 8.53 (m, 1H), 8.13 - 7.73 (m, 6H), 7.39 - 7.23 (m, 3H), 5.69 - 5.57 (m, 1H), 5.21 - 4.80 (m, 2H), 4.50 - 4.07 (m, 5H), 3.96 - 3.81 (m, 2H), 3.12 - 3.03 (m, 4H), 1.25 - 1.16 (m, 5H); MS (ESI): m / z 503.3 (M+H) + .

[0783] Example 204:

[0784]

[0785] Compound 204-a was obtained from (2-chloro-6- (hydroxymethyl)isonicotinic acid and R-2-aminobutyramide hydrochloride following the synthesis of compound 160. Compound 204 was obtained from compound 204-a following the synthesis of compound 189. 1H NMR (500 MHz, DMSO-d6) δ 8.17 - 7.98 (m, 4H), 7.78 (s, 1H), 7.62 (s, 1H), 7.51 - 7.37 (m, 3H), 7.36 - 7.21 (m, 1H), 6.31 - 6.21 (m, 1H), 4.65 - 4.60 (m, 2H), 4.60 - 4.54 (m, 2H), 4.54 - 4.45 (m, 1H), 3.95 - 3.87 (m, 2H), 1.86 - 1.62 (m, 2H), 0.84 - 0.64 (m, 3H); MS (ESI): m / z 490.7 (M+H) + .

[0786] Example 205:

[0787]

[0788] Compound 205 was obtained by the synthesis of Reference Compound 204 from tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate. 1 H NMR (500 MHz, DMSO-d6) δ 9.21 - 9.12 (m, 1H), 8.39 - 8.31 (m, 1H), 8.12 - 8.09 (m, 1H), 8.09 - 7.77 (m, 2H), 7.68 - 7.58 (m, 1H), 7.46 (s, 1H), 7.41 - 7.38 (m, 1H), 7.31 - 7.22 (m, 1H), 6.32 - 6.21 (m, 1H), 5.45 - 5.38 (m, 1H), 4.74 - 4.53 (m, 5H), 3.84 (s, 2H), 2.06 - 1.95 (m, 2H), 0.82 - 0.57 (m, 3H); MS (ESI): m / z 491.8 (M+H) + .

[0789] Example 206:

[0790]

[0791] Compound 206 was obtained by the synthesis of Reference Compound 24 from (R)-2-amino-2-cyclopropylacetamide hydrochloride. 1 H NMR (500 MHz, DMSO-d6) δ 8.69 - 8.61 (m, 1H), 8.16 - 7.78 (m, 6H), 7.63 - 7.24 (m, 5H), 6.28 - 6.19 (m, 1H), 4.66 - 4.43 (m, 2H), 4.28 - 4.17 (m, 1H), 1.22 - 1.13 (m, 1H), 0.53 - 0.16 (m, 4H); MS (ESI): m / z 443.7 (M+H)+ .

[0792] Example 207:

[0793]

[0794] Compound 207 was obtained from (2S,3R)-2-amino-3-hydroxybutyric amide hydrochloride following the synthesis of Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.72 - 8.60 (m, 1H), 8.18 - 7.80 (m, 6H), 7.52 - 7.13 (m, 5H), 6.17 - 5.97 (m, 1H), 5.28 - 5.12 (m, 1H), 4.62 - 4.40 (m, 3H), 4.28 - 4.10 (m, 1H), 1.10 - 0.94 (m, 3H); MS (ESI): m / z 447.7 (M+H) + .

[0795] Example 208:

[0796]

[0797] Compound 208 was obtained from (R)-2-amino-2-phenyl ethan-1-ol following the synthesis of Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.68 - 8.62 (m, 1H), 8.13 - 8.03 (m, 1H), 8.02 - 7.71 (m, 5H), 7.39 - 7.14 (m, 8H), 6.63 - 6.51 (m, 1H), 5.38 - 5.03 (m, 2H), 4.61 - 4.24 (m, 2H), 3.85 - 3.65 (m, 2H); MS (ESI): m / z 466.7 (M+H) + .

[0798] Example 209:

[0799]

[0800] Compound 209 was obtained from (2S,3S)-2-amino-3-hydroxybutyric amide hydrochloride following the synthesis of Compound 24. 1H NMR (500 MHz, DMSO-d6) δ 8.70 - 8.61 (m, 1H), 8.18 - 7.80 (m, 6H), 7.52 - 7.21 (m, 5H), 6.26 - 6.13 (m, 1H), 5.11 - 4.98 (m, 1H), 4.66 - 4.43 (m, 3H), 4.11 - 3.90 (m, 1H), 1.12 - 1.04 (m, 3H); MS (ESI): m / z 447.6 (M+H) + .

[0801] Example 210:

[0802]

[0803] Compound 210 was obtained from (R)-2-amino-3-methylbutyramide hydrochloride following the synthesis of Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.68 - 8.61 (m, 1H), 8.18 - 7.96 (m, 4H), 7.94 - 7.90 (m, 1H), 7.86 (td, J = 7.7, 1.9 Hz, 1H), 7.61 (s, 1H), 7.49 - 7.37 (m, 2H), 7.35 - 7.27 (m, 2H), 6.10 - 5.90 (m, 1H), 4.70 - 4.57 (m, 2H), 4.54 - 4.40 (m, 1H), 2.11 - 1.92 (m, 1H), 0.92 - 0.76 (m, 6H); MS (ESI): m / z 445.6 (M+H) + .

[0804] Example 211:

[0805]

[0806] Compound 211 was obtained from (R)-2-amino-2-cyclobutylacetamide hydrochloride following the synthesis of Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.64 (dd, J = 5.0, 1.6 Hz, 1H), 8.14 - 7.74 (m, 6H), 7.55 (s, 1H), 7.50 - 7.36 (m, 2H), 7.36 - 7.29 (m, 1H), 7.27 - 7.17 (m, 1H), 6.14 - 6.02 (m, 1H), 4.70 - 4.42 (m, 3H), 2.67 - 2.58 (m, 1H), 1.89 - 1.50 (m, 6H); MS (ESI): m / z 457.6 (M+H) + .

[0807] Example 212:

[0808]

[0809] Compound 212 was obtained from (2R,3S)-2-amino-3-hydroxybutyric amide hydrochloride, referring to the synthesis of Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J = 4.7 Hz, 1H), 8.22 - 7.98 (m, 4H), 7.94 - 7.89 (m, 1H), 7.89 - 7.83 (m, 1H), 7.49 - 7.29 (m, 4H), 7.19 (s, 1H), 6.10 - 6.01 (m, 1H), 5.22 - 5.16 (m, 1H), 4.57 - 4.43 (m, 3H), 4.26 - 4.12 (m, 1H), 1.09 - 0.98 (m, 3H); MS (ESI): m / z 447.6 (M+H) + .

[0810] Example 213:

[0811]

[0812] Compound 213 was obtained from (2R,3R)-2-amino-3-hydroxybutyric amide hydrochloride, referring to the synthesis of Compound 24. 1 H NMR (500 MHz, DMSO-d6) δ 8.68 - 8.60 (m, 1H), 8.26 - 7.98 (m, 4H), 7.95 - 7.89 (m, 1H), 7.89 - 7.79 (m, 1H), 7.51 - 7.30 (m, 4H), 7.25 - 7.13 (m, 1H), 6.11 - 5.99 (m, 1H), 5.20 (s, 1H), 4.52 - 4.43 (m, 3H), 4.26 - 4.13 (m, 1H), 1.09 - 0.96 (m, 3H); MS (ESI): m / z 447.6 (M+H) + .

[0813] Example 214:

[0814]

[0815] Compound 214 was obtained from (R)-(2-aminobutyl)carbamic acid tert-butyl ester, referring to the synthesis of Compound 101. 1H NMR (500 MHz, DMSO-d6) δ 8.67 - 8.59 (m, 1H), 8.11 - 7.94 (m, 4H), 7.93 - 7.89 (m, 1H), 7.88 - 7.83 (m, 1H), 7.45 - 7.37 (m, 2H), 7.35 - 7.30 (m, 1H), 6.32 - 6.20 (m, 1H), 4.61 - 4.41 (m, 2H), 4.19 - 4.09 (m, 1H), 2.89 - 2.63 (m, 2H), 1.60 - 1.40 (m, 2H), 0.87 - 0.65 (m, 3H); MS (ESI): m / z 417.6 (M+H) + .

[0816] Test Examples

[0817] Bioactivity test of HGC27 (human gastric cancer cell) cell growth inhibition

[0818] The test method is used for the evaluation of the biological activity of the compounds at the cellular level.

[0819] Harvest HGC27 cells (purchased from Chinese Academy of Sciences), resuspend with complete medium and adjust the cell density to 0.2 x 10 6 cells per milliliter. According to 100 μL per well, the cell suspension is added to the 96-well plate, and cultured overnight at 37°C, 5% CO2 incubator. Prepare the test compound, add it to the cell well plate, so that the highest concentration of the compound is 10 μM. According to 3-fold dilution, set 8 concentration points. At the same time, set 100% inhibition control wells, i.e. no cells are added, only wells with equal volume of complete medium; and 0% inhibition control wells, i.e. 0.1% DMSO is added to the cell wells. The above cell plate is incubated at 37°C, 5% CO2 for 24 hours. Take out the cell culture plate, add 25 μl Luminescent Cell Viability reagent (promega cat#G7573) to each well, avoid light incubation for 10 minutes, then transfer 100 μL to white plate, use Molecular Devices SpectraMax i3 to detect chemiluminescence. The data is processed by the following formula to calculate the inhibition rate: Compound inhibition rate = (0% inhibition control well signal - compound treatment well signal) / (0% inhibition control well signal - 100% inhibition control well signal) * 100%. The calculated data is used to perform four-parameter fitting by graphpad prism software and calculate the corresponding IC 50 .

[0820] The cellular biological activity of the compounds described in this invention was evaluated using the above-described detection methods. The activity results are shown in the table below. CR8 is a literature compound, purchased from Shanghai Bid Pharmaceuticals, and its specific structure is as follows:

[0821]

[0822]

[0823]

[0824]

[0825] As can be seen from the above results, the compounds of the present invention have good tumor cell growth inhibitory activity.

[0826] Western blot detection of Cyclin K (CCNK) degradation

[0827] HEK293 cells (ATCC, cat#CRL-1573) were harvested and the cell density was adjusted to 1 x 10⁻⁶ cells / mL. 6 Cells were cultured overnight in 6-well plates with 1 ml of cell suspension per well. The compound stock solution was diluted to a suitable concentration with DMSO. The diluted compound was added to the cell wells at a ratio of 1:1000 with culture medium, ensuring a DMSO concentration of 0.1% per well. A negative control well was also included, containing 0.1% DMSO in complete culture medium. After fixation at the concentrations shown in the figure and for different time periods, total cell protein was extracted using RIPA cell lysis buffer (Beyotime, cat#P0013B) with added PMSF. Protein quantification was performed using a BCA protein quantification kit (Thermo Fisher, cat#A53225). Each sample was loaded with 40 μg for subsequent SDS-PAGE and Western blot experiments. The specific conditions were: gel running at 120V for 90 minutes, followed by transfer at 320mA for 60 minutes. Antibody incubation was performed according to the recommended dilution ratio and incubation time. The antibodies used in the experiment are as follows: Anti-GAPDH antibody (abcam, cat#ab9485), Anti-CyclinK antibody (abcam, cat#ab85854), Goat anti-Rabbit IgG (H+L) Cross-Adsorbed Secondary Antibody, and HRP (invitrogen, cat#G-21234). ECL chemiluminescence was performed using Thermo Fisher (cat#32209). The final results were analyzed using a gel imaging system.

[0828] According to the above detection method, some compounds of the present application were evaluated.

[0829] Figure 1 It is shown that compound 1 can significantly induce the degradation of Cyclin K, and presents strong time and dose dependence. Specifically, after incubation of compound 1 with HEK293 cells for 6h, 14h and 24h, Cyclin K degradation is exhibited relative to the control, with the highest concentration (1 μM) being the most effective, followed by the medium concentration (0.3 μM), and the lowest concentration (0.1 μM) being the least effective. Meanwhile, the same concentration of compound is better at degrading Cyclin K as the incubation time is prolonged. For example, the degradation effect of Cyclin K after treatment with low concentration (0.1 μM) compound 1 for 24h is better than that after treatment for 14h and 6h.

[0830] Figure 2 It is shown that other compounds of the present application, such as compounds 3, 4, 5, 8, 13, 18, can significantly induce the degradation of Cyclin K after treatment of HEK293 cells with 1 μM for 6h.

[0831] As can be seen from the above results, the compounds of the present application can effectively degrade Cyclin K.

Claims

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof: in, Cy1 is selected from: The wavy line represents the point where Cy1 is connected to Equation (I); wherein, Cy1 is optionally bounded by 0, 1, 2 or 3 R. 0 replace; Cy2 is selected from: The wavy line represents the point where Cy2 is connected to equation (I); wherein, Cy2 is optionally bounded by 0, 1, 2 or 3 R... 1 replace; Among them, R L and R L’ Each can independently represent hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Among them, R 0 Each can independently represent hydrogen, halogen, nitro, cyano, -R a -OR a -SR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -S(O)2R a -NR a C(O)R b -S(O)2NR a -S(O)R a Or -P(O)R a R b ; In this context, W2 independently represents CR. 1 Or N; Among them, R 1 Each can independently represent hydrogen, halogen, nitro, cyano, -R a -OR a -SR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a -S(O)R a -S(O)2NR a R b -P(O)R a R b And C1-C6 alkyl, (C2-C6) alkenyl, or (C2-C6) ynyl groups substituted with 0, 1, 2, or 3 substituents, wherein the substituents are selected from OR a SR a NR a R b NR a C(O)R b C(O)R a C(O)OR a C(O)NR a R b S(O)2R a S(O)R a S(O)2NR a R b Or P(O)R a R b ; Among them, R 2 Represents halogens, C1-C6 alkyl groups or C3-C8 cycloalkyl groups optionally substituted with 0, 1, 2, or 3 halogen atoms, -OR a -SR a nitro, cyano, -NR a R b -NR a C(O)R b -C(O)R a -C(O)OR a -C(O)NR a R b -S(O)2R a -S(O)R a -S(O)2NR a R b -P(O)R a R b (C2-C6)alkenyl or (C2-C6)ynyl; Among them, R 3 Represents C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Benzyl, 5-10 heteroaryl, -NR M R N -NHR M 、or -OR M ; When R 3 Represents C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C 10 When cycloalkyl or 3-10 membered heterocycloalkyl, it may optionally be substituted with 0, 1, 2, or 3 substituents: nitro, halogen, cyano, -R a -(C0-C6 alkylene)OR a -(C0-C6 alkylene)SR a -(C0-C6 alkylene)NR a R b -(C0-C6 alkylene)NR a C(O)R b -(C0-C6 alkylene)C(O)R a -(C0-C6 alkylene)C(O)OR a -(C0-C6 alkylene)C(O)NR a R b -(C0-C6 alkylene)S(O)2R a -(C0-C6 alkylene)S(O)R a -(C0-C6 alkylene)S(O)2NR a R b -(C0-C6 alkylene)P(O)R a R b ; When R 3 Indicates C6-C 10 When it is a 5-10 membered heteroaryl group, it may optionally be substituted by 0, 1, 2, or 3 substituents: nitro, halogen, cyano, -R. a -(C0-C6 alkylene)OR a -(C0-C6 alkylene)SR a -(C0-C6 alkylene)NR a R b -(C0-C6 alkylene)NR a C(O)R b -(C0-C6 alkylene)C(O)R a -(C0-C6 alkylene)C(O)OR a -(C0-C6 alkylene)C(O)NR a R b -(C0-C6 alkylene)S(O)2R a -(C0-C6 alkylene)S(O)R a -(C0-C6 alkylene)S(O)2NR a R b -(C0-C6 alkylene)P(O)R a R b ; When R 3 Indicates -NR M R N -NHR M -OR M At that time, R M and R N Each is independently selected from C1-C6 alkyl, -(C0-C6 alkylene) (C3-C6 alkylene) 10 Cycloalkyl), -(C0-C6 alkylene) (3-10 membered heterocycloalkyl), -(C0-C6 alkylene) (C6-C 10 -(C0-C6 alkylene)(5-10 heteroaryl); Among them, R M and R N Optionally, it can be substituted by 0, 1, 2, or 3 substituents: oxo, -R a -OR a -SR a -NR a R b -NR a C(O)R b -C(O)R a -C(O)OR a -C(O)NR a R b -S(O)2R a -S(O)R a -S(O)2NR a R b Or -P(O)R a R b ; Among them, R a R b Each can independently represent hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl, which may optionally be substituted with 0, 1, 2 or 3 halogen atoms; The 3-10 membered heterocyclic alkyl group contains one or two heteroatoms selected from O, N, and S; The premise is that the compound of formula (I) does not include 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 It indicates halogen, trifluoromethyl, or cyano.

3. The compound as described in 1 or a pharmaceutically acceptable salt thereof, wherein the Cy1 is oxidized by 0 R groups. 0 replace.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Cy2 is selected from:

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the Cy2 is affected by 0 R 1 replace.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the Cy2 is affected by one or two R... 1 replace.

7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R 0 Each can independently represent hydrogen, halogen, and -R. a -OR a Or -SR a ; 8. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R 1 Each can independently represent hydrogen, halogen, and -R. a -OR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a -S(O)R a -P(O)R a R b -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C1-C6 alkylene)OR a -(C1-C6 alkylene)NR a R b -(C1-C6 alkylene)NR a C(O)R b -(C1-C6 alkylene)C(O)R a -(C1-C6 alkylene)C(O)OR a -(C1-C6 alkylene)C(O)NR a R b -(C1-C6 alkylene)S(O)2R a -(C1-C6 alkylene)S(O)R a Or -(C1-C6 alkylene)P(O)R a R b .

9. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R 3 Represents C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C 10 Cycloalkyl or 3-10-membered heterocyclic alkyl groups, optionally substituted with 0, 1, 2, or 3 substituents: nitro, halogen, cyano, -R a -(C0-C6 alkylene)OR a -(C0-C6 alkylene)SR a -(C0-C6 alkylene)NR a R b -NR a C(O)R b -C(O)R a -C(O)OR a -C(O)NR a R b -S(O)2R a -S(O)R a -S(O)2NR a R b -P(O)R a R b .

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein, R 3 Represents C1-C6 alkyl, C1-C6 alkenyl, C1-C6 ynyl C3-C 10 Cycloalkyl or 3-10-membered heterocyclic alkyl groups, optionally substituted with 0, 1, 2, or 3 substituents: halogen, -R a -(C0-C6 alkylene)OR a Or -(C0-C6 alkylene)SR a -(C0-C6 alkylene)NR a R b .

11. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R 3 Indicates C6-C 10 A 5-10 aryl group, optionally substituted with 0, 1, 2, or 3 substituents: nitro, halogen, cyano, -R. a -(C0-C6 alkylene)OR a -(C0-C6 alkylene)SR a -(C0-C6 alkylene)NR a R b -NR a C(O)R b -C(O)R a -C(O)OR a -C(O)NR a R b -S(O)2R a -S(O)R a -S(O)2NR a R b Or -P(O)R a R b .

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein, The R 3 Optionally, it can be substituted by 0, 1, 2, or 3 substituents: halogens, -R a -(C0-C6 alkylene)OR a -(C0-C6 alkylene)SR a -(C0-C6 alkylene)NR a R b -NR a C(O)R b -C(O)R a -C(O)OR a -C(O)NR a R b -S(O)2R a -S(O)R a -S(O)2NR a R b Or -P(O)R a R b .

13. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R 3 Indicates -NR M R N -NHR M -OR M R M and R N Each can be independently represented as a C1-C6 alkyl group, -(C0-C6 alkylene group), or (C3-C6 alkylene group). 10 Cycloalkyl), -(C0-C6 alkylene) (3-10 membered heterocycloalkyl), -(C0-C6 alkylene) (C6-C 10 (5-10-membered heteroaryl) or (C0-C6 alkylene) Among them, R M and R N Optionally, it can be substituted by 0, 1, 2, or 3 substituents: oxo, nitro, halogen, cyano, -R. a -OR a -SR a -NR a R b -NR a C(O)R b -C(O)R a -C(O)OR a -C(O)NR a R b -S(O)2R a -S(O)R a -S(O)2NR a R b -P(O)R a R b .

14. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R a R b Each can independently represent hydrogen, C1-C3 alkyl or C3-C6 cycloalkyl, which may optionally be substituted with 0, 1, 2 or 3 halogen atoms; 15. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R a R b Each can independently represent hydrogen or C1-C3 alkyl, which may optionally be substituted with 0, 1, 2, or 3 halogen atoms; 16. The compound of claim 1 or 2, wherein the compound is selected from:

17. A pharmaceutical composition comprising a compound as described in any one of the preceding claims or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

18. The use of the compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 17, in the preparation of a medicament for the prevention or treatment of diseases or conditions associated with Cyclin K protein.

19. The application as described in claim 18, wherein the disease or condition is selected from tumors, cancer, viral infections, inflammation-related diseases, and autoimmune diseases.

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