Use of sulfonamide compound in preparation of drug for treating cancers

Abstract

The use of a sulfonamide compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, a tautomer thereof, or a stereoisomer thereof as a WDR5 inhibitor. The compound has a significant effect as a WDR5 and Myc interaction blocker, and is conducive to cancer treatment. A1 and A2 are ring structures, and R1 and R2 are substituents.

Description

Use of sulfonamide compounds as drugs for treating cancer Technical Field

[0001] The present disclosure belongs to the field of pharmaceutical chemistry and relates to the medical use of sulfonamide derivatives, and particularly to the use of a sulfonamide compound as an anti-neuroblastoma drug for preparing a cancer treatment drug. Background Art

[0002] Neuroblastoma (NB) is one of the most common extracranial malignant tumors in children. It originates from the neural crest cells of the sympathetic nervous system and is prone to occur in the adrenal glands (Non-Patent Document 1). It has an insidious onset and is prone to metastasis. The mortality rate of high-risk cases is high, seriously threatening the life and health of children. Clinically, there are great differences in the prognosis of children at different stages. In low-risk children under the age of 18 months, the tumor often regresses naturally or can be cured with chemotherapy alone; however, the prognosis of children with tumors with unfavorable pathological types, risk factors such as MYCN gene amplification, 11q abnormalities, or distant metastasis is extremely poor (Non-Patent Document 2). Although current treatment options include comprehensive measures such as surgery, chemoradiotherapy, and biological therapy, there are still disadvantages such as difficulty in eradicating small lesions, large toxic side effects, and easy drug resistance, which greatly reduce the treatment effect and are a major problem in clinical pediatric surgery. Therefore, the development of a new, safe and effective drug for the treatment of neuroblastoma is urgent.

[0003] WD40 repeat domain protein 5 (WDR5) belongs to the WD40 protein family and is a protein containing a circular seven-bladed β-propeller domain. WDR5 is highly conserved across different vertebrates, with approximately 90% sequence identity. WDR5 was first discovered to regulate osteoblast differentiation and promote bone formation during skeletal development. In recent years, an increasing number of studies have revealed the biological functions of WDR5, finding that it not only regulates biological behaviors such as cell proliferation, division, apoptosis, signal transduction, gene transcription, and DNA damage repair under physiological conditions, but is also highly correlated with the occurrence and development of various tumors, making it a popular choice as a target for tumor treatment.

[0004] WDR5's most important function in vivo is epigenetic regulation. As a member of the histone methyltransferase (HMT) complex, it regulates histone methylation levels and activates target gene transcription. Dysfunction of WDR5 can upregulate the expression of multiple tumor-promoting factors and activate tumor-related signaling pathways, thereby enhancing tumor cell proliferation, metastasis, and drug resistance, driving the epithelial-mesenchymal transition (EMT). WDR5 also acts as a cofactor for the myelocytokine viral oncogene homolog (Myc). As a transcription factor, Myc regulates the transcription of downstream genes by binding to the promoter regions of target genes. This function is limited by Myc's ability to localize to chromatin. Studies have found that approximately 80% of Myc binding to its downstream target gene sequences requires WDR5. Disruption of the WDR5-Myc binding significantly diminishes Myc's ability to induce pluripotent stem cells, thus making WDR5 a key player in Myc-driven tumorigenesis. This mechanism has been confirmed in a variety of Myc-related tumors. In glioblastoma and neuroblastoma, WDR5 can promote the binding of Myc to the coactivator protein-associated arginine methyltransferase 1 (CARM1) promoter, enhancing the proliferation and self-renewal ability of tumor cells. In neuroblastoma, WDR5 co-localizes with N-Myc in the double minute homology gene 2 (MDM2) promoter region, activating MDM2 transcription and inhibiting the expression of the tumor suppressor protein p53. In cholangiocarcinoma, WDR5 maintains high levels of HIF-1α in the body through epigenetic regulation, while also increasing HIF-1α expression through Myc in the transcriptional process, promoting EMT, metastasis, and invasion of tumor cells.

[0005] There are two interaction sites on the surface of WDR5: the WDR5 binding domain (WBM) and the WDR5 interaction domain (WIN). The WBM is a shallow, relatively hydrophobic binding pocket primarily composed of Asn225, Tyr228, Leu240, Phe266, Val268, and Gln289. Proteins such as retinoblastoma binding protein 5 (RBBP5), C-myc, L-myc, N-myc, and KAT8-regulated NSL complex subunit 2 (KANSL2) all interact with WDR5 through this site. The WIN is an arginine-binding pocket composed of amino acids Ala65, Ser91, Asp107, Phe133, Tyr191, Tyr260, and Phe263. Proteins such as mixed lineage leukemia 1-4 (MLL1-4), KAT8-regulated NSL complex subunit 1 (KANSL1), H3, methylphosphoguanosine phosphate binding protein (MBD3), and kinesin heavy chain member 2A (KIF2A) have been reported to interact with WDR5 through this site. Key biological functions of WDR5 rely on the mediation of these two sites, such as direct binding with RBBP5 and SET1 / MLL, and indirect binding with ash2 (lack, small, or homolog)-like (Drosophila) protein (ASH2L) and dpy-30 homolog protein (DPY30), which then assemble into a complex with histone methyltransferase catalytic activity, epigenetically regulating the transcription of target genes (non-patent literature 4). Furthermore, WDR5 interacts with the transcription factor Myc, recruiting Myc to chromatin and enhancing its binding to target gene promoter regions, greatly enhancing its tumor-promoting function (non-patent literature 5, 6). Therefore, targeting the WBM or WIN sites on the surface of WDR5 to design specific protein-protein interaction blockers has become the main strategy for the development of new WDR5 inhibitors.

[0006] Currently, it has been reported that protein-protein interaction blockers designed and developed for the WIN site of WDR5 have strong affinity and good drugability, but their application is limited to the treatment of MLL gene translocation rearrangement leukemia and is not effective for solid tumors. There are few studies on WBM site blockers. Stephen's research team at Vanderbilt University School of Medicine in the United States has conducted multiple rounds of optimization and modification, and the obtained compound No. 12 can specifically bind to the WBM site and interact with the K of WDR5. D The value was 0.10±0.01 μM (Non-patent Documents 7 and 8), but its antitumor effect was not evaluated.

[0007] In summary, the design and synthesis of highly active candidate compounds that specifically block the interaction between WDR5 and Myc for the treatment of diseases such as neuroblastoma has important research significance and application prospects, and is an important direction for potential drug targets and the search for lead compounds.

[0008] References

[0009] 1 Matthay KK, Maris JM, Schleiermacher G, Nakagawara A, Mackall CL, Diller L, et al. Neuroblastoma. Nature reviews. Disease primers 2016; 2:16078.

[0010] 2 Kholodenko IV, Kalinovsky DV, Doronin, II, Deyev SM, Kholodenko RV. Neuroblastoma Origin and Therapeutic Targets for Immunotherapy. Journal of immunology research 2018; 2018:7394268.

[0011] 3 Migliori V, Mapelli M, Guccione E. On WD40 proteins: propelling our knowledge of transcriptional control? Epigenetics 2012; 7:815 - 22.

[0012] 4 Ernst P, Vakoc CR. WRAD: enabler of the SET1 - family of H3K4 methyltransferases. Briefings in functional genomics 2012; 11:217 - 26.

[0013] 5 Thomas LR, Wang Q, Grieb BC, Phan J, Foshage AM, Sun Q, et al. Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC. Molecular cell 2015; 58:440 - 52.

[0014] 6 Sun Y, Bell JL, Carter D, Gherardi S, Poulos RC, Milazzo G, et al. WDR5 Supports an N-Myc Transcriptional Complex That Drives a Protumorigenic Gene Expression Signature in Neuroblastoma. Cancer research 2015;75:5143-54.

[0015] Summary of the Invention

[0016] Based on the above research background, the purpose of the present disclosure is to provide a sulfonamide compound or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, so as to screen out compounds that have excellent performance in terms of efficacy, safety and selectivity as WDR5 inhibitors.

[0017] More specifically, the present disclosure provides a sulfonamide compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a tautomer thereof or a stereoisomer thereof,

[0018] in:

[0019] A 1 Ring and A 2 The rings are each independently selected from one of a C6-C30 aryl ring, a C6-C30 aliphatic hydrocarbon ring, a C3-C30 heteroaryl ring, and a C3-C30 aliphatic heterocycle, where "ring" includes monocyclic and polycyclic rings;

[0020] R 1 A 1 Ring substituent, m = 0-3; R 1 independently selected from halogen, C3-C5 cycloalkyl, C1-C3 haloalkyl, -CN, -S(=O)2-NH2, optionally substituted by 1-3 R b Substituted C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; R b Independently selected from substituted or unsubstituted C1-C3 alkoxy, where "substituted" means optionally substituted with 1-3 hydroxyl, halogen or C1-C3 alkoxy substituents;

[0021] R 2 A 2 Ring substituent, n = 0-3; R 2 Selected from -OH, halogen, C1-C3 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 haloalkyl, -C(O)NHRc 、-NHC(O)CH2NHC(O)R c , 3-5 membered cycloalkyl optionally substituted by 1-3 "-CN", 5-7 membered aryl optionally substituted by 1-3 "-CN"; R c is a C1-C3 alkyl group;

[0022] L is a chemical bond or selected from C1-6 alkylene, saturated or partially unsaturated C3-10 cycloalkylene, -O-, -NR a -、-NR a - a divalent group composed of one or more combinations of C1-6 alkylene groups; R a R is independently selected from H, C1-C10 alkyl, saturated or partially unsaturated C3-6 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-10 aryl group, a CH2 in can be replaced by -O- or -S-, R a The H in the group can be substituted by hydroxy, halogen or C1-C3 alkoxy.

[0023] The present disclosure provides a class of compounds that specifically bind to the WBM site of WDR5, which can block the interaction between WDR5 and Myc, thereby regulating Myc-mediated oncogene transcription and achieving tumor treatment effects. Pharmacological experiments have shown that the disclosed embodiment compounds have a strong affinity for the WDR5 protein. In neuroblastoma cell lines with high MYCN amplification, the compounds can significantly inhibit cell proliferation, while having no significant effect on the survival of human embryonic kidney cells HEK293T, showing good selectivity and safety. The results of complex crystal structure analysis show that the representative compounds of the present disclosure can specifically bind to the WBM domain of WDR5, blocking the interaction between WDR5 and Myc, thereby exerting anti-tumor activity.

[0024] The compounds disclosed herein can be used as WDR5-Myc interaction blockers. Specifically, pharmacological experimental results demonstrate that the compounds disclosed herein can specifically bind to the WBM domain of WDR5, blocking the interaction between WDR5 and Myc. Based on this use, the compounds disclosed herein can be used in the preparation of drugs for treating diseases associated with abnormal WDR5 expression leading to abnormal activation of signaling pathways related to Myc, RBBP5, KANSL2, and others.

[0025] Diseases associated with abnormal expression of WDR5 leading to abnormal activation of Myc, RBBP5, KANSL2 and other related signaling pathways include but are not limited to neuroblastoma, gangliocytoma, ganglioblastoma, ganglioneuroma, ganglioneuroma, sympathetic neuroblastoma, schwannoma, neurofibroma, prostate cancer, triple-negative breast cancer, nasopharyngeal cancer, esophageal cancer, laryngeal cancer, lung cancer, gastric cancer, liver cancer, colorectal cancer, cervical cancer, pancreatic cancer, bladder cancer, retinoblastoma, osteosarcoma, chondrosarcoma, chordoma, rhabdomyosarcoma, multiple myeloma, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia and other diseases, and are especially suitable for the treatment and relief of neurogenic tumors including: neuroblastoma, gangliocytoma, ganglioblastoma, ganglioneuroma, ganglioneuroma, sympathetic neuroblastoma, schwannoma, and neurofibroma.

[0026] The following representative compounds of the present disclosure have WDR5-Myc interaction inhibitory activity and have broad application prospects in tumor treatment:

[0027] In one embodiment of the present disclosure, the optional ratio of the compound of formula (I) to the pharmaceutically acceptable carrier, excipient or sustained-release agent is that the active ingredient of formula (I) accounts for more than 70% of the total weight ratio, and the remaining part accounts for 0.5-30% of the total weight ratio, or better 1-15%, or most preferably 2-10%.

[0028] The various formulation forms of the pharmaceutical composition disclosed herein contain, in a unit dose, 0.5 mg to 200 mg, 2 mg to 100 mg, or 5 mg to 50 mg of the compound of formula (I), its enantiomers, racemates, pharmaceutically acceptable salts, or mixtures thereof.

[0029] When the pharmaceutical composition contains an additional active pharmaceutical ingredient for treating or preventing cancer, the dosage of the active ingredient can generally be the conventional dosage in the prior art or lower.

[0030] The pharmaceutical composition of the present disclosure may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, wherein the compound of formula (I) may be present in a suitable solid or liquid carrier or diluent. The pharmaceutical composition of the present disclosure may also be stored in a suitable sterilizing apparatus for injection or infusion. The pharmaceutical composition may also contain odorants, flavoring agents, and the like.

[0031] The compound of formula (I) disclosed herein or a pharmaceutical composition comprising the compound of formula (I) can be used clinically in mammals (including humans) via oral, nasal, skin, lung or gastrointestinal tract administration routes. An optional route of administration is oral. An optional daily dose is 0.5 mg-100 mg / kg body weight, taken once or in divided doses. Regardless of the method of administration, the optimal dose for an individual should be determined based on the specific treatment. Typically, the dose is started with a small dose and gradually increased until the most suitable dose is found.

[0032] The effective dose of the active ingredient used may vary depending on the compound used, the mode of administration, and the severity of the disease to be treated. However, generally, satisfactory results are achieved when the compounds of the present disclosure are administered at a dose of about 1-100 mg / kg of animal body weight per day, preferably in 1-3 divided doses per day, or in a sustained-release form. For most large mammals, the total daily dose is about 5-500 mg, preferably about 10-250 mg. A dosage form suitable for oral administration comprises about 1-100 mg of the active compound intimately mixed with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to provide the optimal therapeutic response. For example, depending on the exigencies of the treatment condition, several divided doses may be administered daily, or the dose may be reduced proportionally.

[0033] The compound or its pharmaceutically acceptable salt and composition thereof can be administered orally as well as intravenously, intramuscularly or subcutaneously. From the standpoint of ease of preparation and administration, the pharmaceutical composition of choice is a solid composition, particularly a tablet and a solid-filled or liquid-filled capsule. Oral administration of the pharmaceutical composition is optional.

[0034] Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycol, nonionic surfactants and edible oils (such as corn oil, peanut oil and sesame oil), as long as they are suitable for the characteristics of the active ingredient and the specific mode of administration desired. Adjuvants commonly used in the preparation of pharmaceutical compositions may also be advantageously included, such as flavoring agents, coloring agents, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA.

[0035] The active compounds or pharmaceutically acceptable salts thereof and compositions thereof may also be administered parenterally or intraperitoneally. Solutions or suspensions of the active compounds (as free base or pharmaceutically acceptable salts) may also be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquids, polyethylene glycols, and mixtures thereof in oils. Under conventional storage and use conditions, these formulations contain a preservative to prevent the growth of microorganisms.

[0036] The pharmaceutical forms adapted for injection include: sterile aqueous solutions or dispersions and sterile powders (for the temporary preparation of sterile injection solutions or dispersions). In all cases, these forms must be sterile and must be fluid to facilitate syringe discharge of fluid. Must be stable under manufacturing and storage conditions and must be able to prevent the contamination effects of microorganisms (such as bacteria and fungi). Carrier can be a solvent or dispersion medium, wherein containing such as water, alcohol (such as glycerol, propylene glycol and liquid polyethylene glycol), their appropriate mixture and vegetable oil.

[0037] Another aspect of the present disclosure provides the use of the compounds of the present disclosure and corresponding pharmaceutical compositions in the preparation of cancer treatment or relief drugs. The compositions and methods provided by the present disclosure can be used to treat a variety of cancers, including prostate, breast, brain, skin, cervical cancer, testicular cancer, etc. More specifically, the cancers that can be treated by the compositions and methods of the present disclosure include, but are not limited to, tumor types such as astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, stomach cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, and sarcoma.More specifically, these compounds are useful in the treatment of: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, VIPoma), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyomas, hemangiomas, lipomas, neurofibromas, fibromas), Colorectal: adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma; Genitourinary: kidney (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia); bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma); prostate (adenocarcinoma, sarcoma); testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary: gallbladder cancer, ampullary carcinoma, bile duct cancer; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma); Tumors), multiple myeloma, malignant giant cell tumor, chordoma, chronic bone metastases (osteochondrosarcoma), benign tumors, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis), meninges (meningiomas, meningosarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal cord fibromas, meningiomas, gliomas, sarcomas; Gynecological: uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma) , unclassified carcinoma), granulosa cell tumor, Sertoli cell tumor, germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, cystosarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma); Hematology: blood (acute and chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, lipoma, hemangioma, dermatofibroma, lupus erythematosus, psoriasis and Adrenal gland: neuroblastoma.In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0038] In an alternative embodiment, the cancer is selected from neuroblastoma, gangliocytoma, ganglioneuroma, ganglioneuroma, sympathetic neuroblastoma, neurilemmoma, neurofibroma, prostate cancer, triple-negative breast cancer, nasopharyngeal cancer, esophageal cancer, laryngeal cancer, lung cancer, gastric cancer, liver cancer, colorectal cancer, cervical cancer, pancreatic cancer, bladder cancer, retinoblastoma, osteosarcoma, chondrosarcoma, chordoma, rhabdomyosarcoma, multiple myeloma, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia;

[0039] From a chemical and pharmaceutical perspective, the compounds of the present disclosure also include esters, optical isomers, tautomers, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, chelates, complexes, inclusion compounds, or pharmaceutical compositions thereof.

[0040] Explanation of terms

[0041] Unless otherwise stated, some terms used in the specification and claims of this disclosure are defined as follows:

[0042] definition

[0043] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain this disclosure.

[0044] In the present disclosure, the terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps.

[0045] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0046] An aliphatic cyclic group refers to a cycloalkyl, cycloalkenyl, cycloalkynyl, etc., which are cyclic structures composed of C and H. If C is replaced by a heteroatom, it becomes an aliphatic heterocyclic group; it also includes the bridged ring and spiro ring forms described below.

[0047] As used herein, term " alkyl " is defined as linear or branched saturated aliphatic hydrocarbon.In some embodiments, alkyl has 1 to 12, for example 1 to 6 carbon atom.For example, as used herein, term " C1-6 alkyl " refers to the linear or branched group (for example methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl, sec-butyl, the tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl) of 1 to 6 carbon atom, it is optionally replaced (this moment this group is referred to as " haloalkyl ") (for example CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl or-CH2CH2CF3 etc.) by 1 or more (such as 1 to 3) applicable substituents such as halogen. The term "C1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0048] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon radical containing one double bond and having 2 to 6 carbon atoms ("C 2-6 The alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present disclosure contain an alkenyl group, the compounds may exist in pure E (entgegen) form, pure Z (zusammen) form, or any mixture thereof.

[0049] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.

[0050] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.), which is optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-6 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl.

[0051] As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including but not limited to (cyclo)propyl, (cyclo)butyl, (cyclo)pentyl, (cyclo)hexyl, (cyclo)heptyl, (cyclo)octyl, (cyclo)nonyl, (cyclo)hexenyl, and the like.

[0052] As used herein, the terms "heterocyclyl", "heterocyclylene" and "heterocycle" refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) cyclic group having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C. For example, a "3-10 membered heterocyclyl" is a saturated or partially unsaturated heterocyclyl having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms independently selected from N, O and S. Examples of heterocyclylene and heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl. The group also encompasses bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc.). The heterocyclylene and heterocyclyl groups may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.

[0053] As used herein, the terms "arylene" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, as used herein, the term "C 6-10 (E)aryl" and "C 6-10The term "aromatic ring" means an aromatic group containing 6 to 10 carbon atoms, such as (ene)phenyl (phenyl ring) or (ene)naphthyl (naphthalene ring). The (ene)aryl group and the aromatic ring are optionally substituted by one or more (such as one to three) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.) substituted.

[0054] As used herein, the terms "heteroaryl(ene)" and "heteroaromatic ring" refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being for example oxygen, nitrogen or sulfur) and, in each case, may additionally be benzo-fused. In particular, “heteroaryl” or “heteroaromatic ring” is selected from thiophenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof.

[0055] As used herein, the term "aralkyl" preferably refers to an alkyl group substituted with an aryl or heteroaryl group, wherein the aryl, heteroaryl, and alkyl groups are as defined herein. Typically, the aryl group may have 6-14 carbon atoms, the heteroaryl group may have 5-14 ring atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0056] As a more specific terminology explanation is as follows:

[0057] "Alkyl" refers to a saturated aliphatic hydrocarbon group, comprising 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, a saturated straight or branched monovalent hydrocarbon group, wherein the alkyl group may be independently optionally substituted with one or more substituents described in the present disclosure. Further examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group can be optionally substituted or unsubstituted.

[0058] "Alkenyl" refers to a linear or branched monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one C—C is sp 2 Double bond, wherein the alkenyl group can be independently optionally substituted with one or more substituents described in the present disclosure, specific examples of which include, but are not limited to, vinyl, allyl, and butylene, etc. The alkenyl group can be optionally substituted or unsubstituted.

[0059] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring comprises 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls. Cycloalkyls may be optionally substituted or unsubstituted.

[0060] "Spiroalkyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Spiroalkyl is divided into single spiro, double spiro or multiple spiroalkyl according to the number of shared spiro atoms between the rings, preferably single spiro and double spiroalkyl, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Non-limiting examples of "spiroalkyl" include, but are not limited to:

[0061] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system. It is preferably 6- to 12-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic or tricyclic, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to:

[0062] "Bridged cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures that share two carbon atoms that are not directly connected to each other. One or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system. It is preferably 6- to 12-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, and more preferably a bicyclic or tricyclic group. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to:

[0063] The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like.

[0064] "Heterocyclyl," "heterocycle," or "heterocyclic" are used interchangeably herein to refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic non-aromatic heterocyclic group containing 3 to 12 ring atoms, wherein at least one ring atom is a heteroatom, such as an oxygen, nitrogen, or sulfur atom. Preferably, the heterocyclic group has a 5- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring, which may contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, and piperazinyl. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl. The heterocyclyl group may be optionally substituted or unsubstituted.

[0065] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) mThe heteroatom of m=1 or 2, the remaining ring atoms are carbon, and m=1 or 2. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a bispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a bispiro heterocyclic group. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiro heterocyclic group. Non-limiting examples of "spiro heterocyclic group" include, but are not limited to:

[0066] "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) m The heteroatom of the ring is 1, the remaining ring atoms are carbon, and m = 1 or 2. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclic group" include but are not limited to:

[0067] "Bridged heterocyclic group" refers to a polycyclic group of 5 to 18 members, containing two or more ring structures, sharing two atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) m The heteroatom of the cyclic ring is 1 or 2, and the remaining ring atoms are carbon atoms, and m = 1 or 2. It is preferably 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, and more preferably a bicyclic or tricyclic group. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to:

[0068] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused manner. The term "aryl" includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl. Preferably, aryl is C6-C 10 Aryl, more preferably phenyl and naphthyl, most preferably phenyl. Aryl can be substituted or unsubstituted. The "aryl" can be fused with a heteroaryl, a heterocyclic group or a cycloalkyl group, wherein the aryl ring is connected to the parent structure. Non-limiting examples include but are not limited to:

[0069] "Heteroaryl" refers to an aromatic 5 to 6-membered monocyclic or 9 to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. The embodiment of "heteroaryl" includes, but is not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl and benzisoxazolyl. Heteroaryl can be optionally substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:

[0070] "Alkoxy" refers to a group (alkyl-O-). Alkyl is defined herein. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0071] "Haloalkyl" refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as described in this disclosure. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.

[0072] "Hydroxy" refers to an -OH group. "Halogen" refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine. "Amino" refers to -NH2. "Cyano" refers to -CN.

[0073] "Nitro" refers to -NO2. "Benzyl" refers to -CH2-phenyl. "Carboxyl" refers to -C(O)OH. "Acetyl" refers to -C(O)CH3 or Ac. "Carboxylate" refers to -C(O)O(alkyl) or (cycloalkyl), where alkyl and cycloalkyl are as defined above. As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0074] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and at least one nitrogen atom in the ring, which may optionally further contain one or more (e.g., one, two, three or four) ring members selected from N, O, C=O, S, S=O and S(=O)2, which is linked to the rest of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atoms, the nitrogen-containing heterocycle being optionally benzo-fused and preferably linked to the rest of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring.

[0075] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0076] If a substituent is described as being "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0077] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0078] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0079] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0080] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0081] The present disclosure also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present disclosure except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of suitable isotopes for inclusion in the compounds of the present disclosure include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the present disclosure (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e., 14C) are particularly useful for this purpose because of their ease of incorporation and ease of detection. 11 C. 18 F. 15 O and 13 N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present disclosure can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present disclosure include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0082] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0083] As used herein, "substituted" or "substituted", unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -C(O)R b 、-OC(O)R b 、-NR b R b 、-C(O)NR b R b 、-NR b C(O)R b 、-S(O)NR b R b or -S(O)2NR b R b , where R b The definition of is as described in the general formula (I).

[0084] As used herein, a "therapeutically effective dose" of a compound is an amount sufficient to improve or in some way reduce symptoms, stop or reverse the progression of a disease. Such a dose can be used as a single dose or taken according to a regimen to be effective.

[0085] As used herein, "treat" or "treating" means ameliorating or otherwise altering in any way the symptoms or pathology of a patient's condition, disorder or disease.

[0086] As used herein, "amelioration of the symptoms of a particular disease by administration of a particular compound or pharmaceutical composition" refers to any reduction, whether permanent or temporary, long-lasting or transient, attributable to or associated with the administration of that composition.

[0087] "Tautomers" or "tautomeric forms" refer to structural isomers of different energies that can be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence (chemical valence) tautomers include interconversions by reorganization of bonding electrons. Unless otherwise indicated, the structural formulas described in this disclosure include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of this disclosure or mixtures of their enantiomers, diastereomers, or geometric isomers are within the scope of this disclosure.

[0088] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure that are safe and effective for use in humans or animals. Salts of the compounds can be prepared by using a sufficient amount of a base or acid in a pure solution or a suitable inert solvent to form the corresponding addition salt. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, and pharmaceutically acceptable acid addition salts include inorganic and organic acid salts, such as hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, and methanesulfonic acid.

[0089] In this article, solid lines can be used Solid wedge or virtual wedge The chemical bonds of the compounds of the present disclosure are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomer shown exists. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present disclosure are intended to exist in the form of stereoisomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present disclosure may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0090] The present disclosure encompasses all possible crystalline forms or polymorphs of the compounds of the present disclosure, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0091] It should also be understood that certain compounds of the present disclosure may exist in free form for treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present disclosure, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, chelates, complexes, inclusion compounds, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present disclosure or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present disclosure," the various derivative forms of the compounds described above are also intended to be encompassed.

[0092] Pharmaceutically acceptable salts of the compounds of the present disclosure include acid addition salts and base addition salts thereof, including but not limited to salts containing hydrogen bonds or coordinate bonds.

[0093] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present disclosure in the form of free acid or alcohol). The compounds of the present disclosure themselves can also be esters.

[0094] The compounds of the present disclosure may exist in the form of solvates (preferably hydrates), wherein the compounds of the present disclosure contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of the polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0095] Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane.

[0096] Also included within the scope of the present disclosure are metabolites of the compounds of the present disclosure, i.e., substances formed in vivo upon administration of the compounds of the present disclosure. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Thus, the present disclosure includes metabolites of the compounds of the present disclosure, including compounds produced by contacting the compounds of the present disclosure with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0097] The present disclosure further includes within its scope prodrugs of the compounds of the present disclosure, which are certain derivatives of the compounds of the present disclosure that may themselves have little or no pharmacological activity but are converted, for example, by hydrolytic cleavage, into compounds of the present disclosure that have the desired activity when administered to or on the body. Typically such prodrugs will be functional group derivatives of the compounds that are readily converted in vivo into the desired therapeutically active compound.

[0098] The present disclosure also encompasses compounds of the present disclosure that contain protecting groups. In any process for preparing the compounds of the present disclosure, it may be necessary and / or desirable to protect sensitive or reactive groups on any related molecules, thereby forming a chemically protected form of the compounds of the present disclosure. This can be achieved by conventional protecting groups, for example, those described in TW Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0099] The term "about" means within ±10%, may be within ±5%, or may be within ±2% of the stated value.

[0100] The present disclosure provides a novel WDR5 / Myc interaction blocker. Experimental results show that this type of derivative exhibits excellent anti-neuroblastoma activity, as well as excellent safety and selectivity, and can be used to prepare drugs for treating cancer, especially neuroblastoma and other diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0101] FIG1 is a schematic diagram of the crystal structure of the complex of the disclosed compound and WDR5. DETAILED DESCRIPTION

[0102] The method of the present disclosure is described below through specific examples to make the technical solution of the present disclosure easier to understand and grasp, but the present disclosure is not limited to this. 1 H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are in Hz.

[0103] Mass spectra were obtained using LC / MS instrumentation, using ESI as the ionization method.

[0104] HPLC model: Agilent 1260, Thermo Fisher U3000; chromatographic column model: Waters xbrige C18 (4.6*150 mm, 3.5 μm); mobile phase: A:ACN, B:Water (0.1% H3PO4); flow rate: 1.0 mL / min; gradient: 5%A for 1 min, increase to 20%A within 4 min, increase to 80%A within 8 min, 80%A for 2 min, back to 5%A ​​within 0.1 min; wavelength: 220 nm; column oven: 35°C.

[0105] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.2mm-0.3mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0106] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0107] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are used directly without further purification. Unless otherwise indicated, commercial manufacturers include but are not limited to Sinopharm Group, J&K Technology Co., Ltd., Tokyo Pharmaceuticals (Shanghai) Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd. and Shanghai Myrel Chemical Technology Co., Ltd.

[0108] CD3OD: deuterated methanol; CDCl3: deuterated chloroform; DMSO-d6: deuterated dimethyl sulfoxide; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos: 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl; HATU: 2-(7-benzotriazole oxide)-N ,N,N',N'-tetramethyluronium hexafluorophosphate; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBT: 1-hydroxybenzotriazole; BINAP: 1,1'-binaphthyl-2,2'-bis(diphenylphosphine); DCM: dichloromethane; PE: petroleum ether; EA: ethyl acetate; MeOH: methanol; DMF: N,N-dimethylformamide; TLC: thin layer chromatography; HPLC: high performance liquid chromatography; purity: purity; &: and; R f: The ratio of the distance from the origin to the center of the spot to the distance from the origin to the solvent front in thin layer chromatography. The hydrogen atmosphere can be, for example, connected to a hydrogen balloon with a volume of about 1 L through the reaction bottle. Unless otherwise specified in the embodiments, the solution in the reaction refers to an aqueous solution. Unless otherwise specified in the embodiments, the reaction temperature is room temperature, which is 20°C-30°C. The reaction progress in the embodiments is monitored by thin layer chromatography (TLC), and the developing solvent used in the reaction, the eluent system of the column chromatography used to purify the compound, or the developing solvent system of thin layer chromatography includes: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagent can also be added for adjustment, such as acetic acid or triethylamine.The reagent providing alkaline conditions is selected from organic bases or inorganic bases, the organic bases are triethylamine, N, N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium tert-butoxide, sodium methoxide and potassium tert-butoxide, and the inorganic bases are sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and lithium hydroxide. One or more reagents providing acidic conditions are hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a methanol solution of hydrogen chloride, trifluoroacetic acid, One or more of formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid and phosphoric acid; the metal catalyst is one or more of palladium / carbon, Raney nickel, tetrakistriphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, bistriphenylphosphine palladium dichloride (Pd(PPh3)Cl2) and tris(dibenzylideneacetone)dipalladium (Pd2(dba)3); the ligand is 2-dicyclohexylphosphine One or more of: -2,6'-dimethoxybiphenyl (SPhos), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (XantPhos), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (DavePhos), 1,1'-bis(diphenylphosphino)ferrocene (Dppf) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), preferably 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP) INAP); the reducing agent is one or more of sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and lithium aluminum tetrahydride; the oxidizing agent is one or more of potassium permanganate, manganese dioxide, potassium dichromate, sodium dichromate, and potassium osmate; the above reaction is preferably carried out in a solvent, and the solvent used is one or more of N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-dioxane, water, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, methanol, ethanol, toluene, petroleum ether, ethyl acetate, n-hexane, and acetone.

[0109] Drug chemical synthesis experiment part

[0110] Preparation of intermediates

[0111] Intermediate 1

[0112] 2,4-Dichlorobenzoyl chloride IN-1

[0113] Step 1: 2,4-dichlorobenzoyl chloride IN-1

[0114] N,N-dimethylformamide (3 drops) was slowly added dropwise to a mixture of 2,4-dichlorobenzoic acid IN-1a (300 mg, 1.57 mmol) and oxalyl chloride (3 mL, 35.5 mmol) in anhydrous tetrahydrofuran (15 mL) at 0°C. The mixture was allowed to react at room temperature for 2 hours. TLC indicated the disappearance of the starting material. The reaction mixture was concentrated to afford the title compound IN-1 (320 mg, crude) as a white solid, which was used directly in the next step.

[0115] Intermediate 2

[0116] 2-Methylthiazole-5-sulfonamide IN-2

[0117] Step 1: 2-Methylthiazole-5-sulfonyl chloride IN-2a

[0118] 2-Methylthiazole IN-2a (2.03 g, 20.2 mmol) was slowly added to chlorosulfonic acid (10 ml) at room temperature. After addition, the temperature was raised to 120°C and the mixture was reacted for 24 hours. The mixture was then cooled to room temperature and phosphorus pentachloride (3.18 g, 40.3 mmol) was slowly added. After addition, the mixture was reacted at 120°C for 3 hours. The mixture was cooled to room temperature and the reaction mixture was slowly poured into ice water (20 mL) to quench the mixture. The temperature was maintained below 5°C. TLC indicated the disappearance of the starting material. The reaction mixture was extracted with dichloromethane (60 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound IN-2b (576 mg, crude) as a yellow oil, which was used directly in the next step.

[0119] Step 2 2-Methylthiazole-5-sulfonamide IN-2

[0120] Compound IN-2b (656 mg, crude) was dissolved in 1,4-dioxane (5 mL). Ammonia (2 mL) was slowly added at room temperature. The reaction solution became increasingly turbid. The reaction was continued at room temperature for 30 minutes. TLC indicated the disappearance of the starting material. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to afford the title compound IN-2 (102 mg, 2.79% yield over two steps) as a gray solid.

[0121] LC-MS: m / z = 179.0 [M+H] +

[0122] Example 1

[0123] 2,4-Dichloro-N-((2-methylthiazol-5-yl)sulfonyl)benzamide 1

[0124] Step 1: 2,4-dichloro-N-((2-methylthiazol-5-yl)sulfonyl)benzamide 1

[0125] Compound IN-2 (30 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), and 4-dimethylaminopyridine (2.1 mg, 0.02 mmol) and triethylamine (51.1 mg, 0.51 mmol) were added. After the addition, the reaction solution was cooled to 0°C and intermediate IN-1 (68 mg, crude product) was added. The reaction was allowed to react at room temperature for 1 hour. TLC showed that the starting material had reacted completely. The reaction solution was concentrated, and the crude product was diluted with water (5 mL) and acidified with dilute hydrochloric acid to pH = 5. Ethyl acetate (10 mL x 2) was added for extraction. The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-TLC (MeOH / DCM = 1 / 8) to obtain the title compound 1 as a white solid (12.1 mg, yield 20.47%).

[0126] LCMS: m / z=350.9[M+H] + (93.30% purity, 210nm)

[0127] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 8.0, 1.6 Hz, 1H), 2.76 (s, 3H). The active hydrogen of the sulfonamide was not detected.

[0128] Example 2

[0129] 2,4-Dichloro-N-((5-ethynylthiophen-2-yl)sulfonyl)benzamide

[0130] Step 1: (Z)-N'-((5-bromothiophen-2-yl)sulfonyl)-N,N-dimethylformimide 2b

[0131] 5-Bromothiophene-2-sulfonamide 2a (2.40 g, 9.92 mmol) was added to dichloromethane (10 mL). N,N-dimethylformamide dimethyl acetal (2 mL) was added at room temperature. After addition, the mixture was allowed to react at room temperature for 20 minutes. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound 2b (3.01 g, crude) as a pale yellow solid, which was used directly in the next step.

[0132] Step 2 (Z)-N,N-dimethyl-N'-((5-((trimethylsilyl)ethynyl)2-thienyl)sulfonyl)carboximide 2c

[0133] Compound 2b (2.00 g, 6.734 mmol) was added to dry N,N-dimethylformamide (20 mL). Triethylamine (4.70 mL, 33.8 mmol), iodide (130 mg, 0.68 mmol), bistriphenylphosphine palladium dichloride (240 mg, 0.34 mmol), and trimethylethynylsilane (1.35 mL, 9.46 mmol) were added sequentially at room temperature. After addition, the atmosphere was purged with nitrogen three times and the reaction was allowed to proceed at room temperature for 24 hours. TLC indicated the disappearance of the starting material. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL x 2). The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-TLC (petroleum ether / ethyl acetate = 10 / 1) to afford the title compound 2c (1.15 g, 37% yield over two steps) as a pale yellow solid.

[0134] Step 3 5-ethynylthiophene-2-sulfonamide 2d

[0135] Compound 2c (1.15 g, 3.66 mmol) was added to dry N,N-dimethylformamide (20 mL), followed by the addition of tetrabutylammonium fluoride solution (7.3 mL, 1 M). The reaction was allowed to react at room temperature for 4 hours, after which TLC indicated the disappearance of the starting material. The reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-TLC (petroleum ether / ethyl acetate = 10 / 1) to afford the title compound 2d (450 mg, 66% yield) as a pale yellow solid.

[0136] Step 4: 2,4-dichloro-N-((5-ethynylthiophen-2-yl)sulfonyl)benzamide 2

[0137] 2,4-Dichlorobenzoic acid (204 mg, 1.07 mmol) was dissolved in dichloromethane (4 mL). HATU (609 mg, 1.60 mmol) and N,N-diisopropylethylamine (276 mg, 2.14 mmol) were added at room temperature. The mixture was allowed to react at room temperature for 2 hours. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (4 mL) and extracted with dichloromethane (2 mL x 3). The combined organic phases were washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in dichloromethane (4 mL). N,N-diisopropylethylamine (276 mg, 2.14 mmol) and compound 2d (200 mg, 1.61 mmol) were added sequentially at room temperature. The mixture was allowed to react at room temperature for 10 hours. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (4 mL) and extracted with dichloromethane (2 mL x 3). The organic phases were combined, washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-HPLC to give the title compound 2 as a white solid (75 mg, yield 19%).

[0138] LC-MS: m / z = 359.9 [M+H] + (99.94% purity by HPLC, 254nm)

[0139] 1 H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 7.82 (d, J = 4.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.36 (dd, J = 8.4, 1.6 Hz, 1H), 7.24 (d, J = 4.0 Hz, 1H), 3.55 (s, 1H). The active hydrogen of the sulfonamide was not revealed.

[0140] Example 3

[0141] 2-Chloro-4-cyano-N-((2-methylthiazol-5-yl)sulfonyl)benzamide 3

[0142] Step 1: 2-Chloro-4-cyanobenzoyl chloride 3b

[0143] Disperse 2-chloro-4-cyanobenzoic acid 3a (50 mg, 0.28 mmol) in tetrahydrofuran (3 mL). Add oxalyl chloride (69.9 mg, 0.55 mmol) and one drop of N,N-dimethylformamide at 0°C. After addition, warm to 25°C and react for 1 hour. TLC confirms complete reaction. The reaction mixture is concentrated to afford the title compound 3b (72 mg, crude) as a yellow oil, which is used directly in the next step.

[0144] Step 2: 2-chloro-4-cyano-N-((2-methylthiazol-5-yl)sulfonyl)benzamide 3

[0145] Intermediate IN-2 (30 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), and 4-dimethylaminopyridine (2.1 mg, 0.02 mmol) and triethylamine (51.1 mg, 0.51 mmol) were added. After the addition was complete, the reaction mixture was cooled to 0°C and compound 3b (72 mg, crude) was added. After the addition was complete, the reaction mixture was warmed to 25°C for 1 hour. TLC indicated complete reaction of the starting material. The reaction mixture was concentrated, and the crude product was diluted with water (5 mL), acidified to pH 5 with dilute hydrochloric acid, and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-TLC (MeOH / DCM = 1 / 8) to afford 40 mg of a pale yellow solid. This was then purified by Prep-HPLC to afford the title compound 3 (12.6 mg, 21.9% yield) as a white solid.

[0146] LC-MS: m / z=342.0[M+H] + (99.31% purity, 210nm)

[0147] 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.11 (s, 1H), 7.87 (dd, J = 8.0, 1.2 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 2.74 (s, 3H). The active hydrogen of the sulfonamide was not revealed.

[0148] Example 4

[0149] 2-Chloro-4-ethynyl-N-((2-methylthiazol-5-yl)sulfonyl)benzamide

[0150] Step 1: 2-Chloro-4-ethynylbenzoyl chloride 4b

[0151] Disperse 2-chloro-4-ethynylbenzoic acid 4a (50 mg, 0.28 mmol) in tetrahydrofuran (3 mL). Add oxalyl chloride (70.3 mg, 0.55 mmol) and one drop of N,N-dimethylformamide at 0°C. After addition, warm to 25°C and react for 1 hour. TLC confirms complete reaction. The reaction mixture is concentrated to afford the title compound 4b (65 mg, crude) as a yellow oil, which is used directly in the next step.

[0152] Step 2: 2-chloro-4-ethynyl-N-((2-methylthiazol-5-yl)sulfonyl)benzamide 4

[0153] Intermediate IN-2 (30 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), and 4-dimethylaminopyridine (2.1 mg, 0.02 mmol) and triethylamine (51.1 mg, 0.51 mmol) were added. After the addition was complete, the reaction mixture was cooled to 0°C and compound 4b (65 mg, crude) was added. After the addition was complete, the reaction mixture was warmed to 25°C and allowed to react for 1 hour. TLC indicated complete reaction of the starting material. The reaction mixture was concentrated, diluted with water (5 mL), and acidified to pH 5 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-TLC (MeOH / DCM = 1 / 8) to afford the title compound 4 (8.2 mg, 14.3% yield) as a white solid.

[0154] LC-MS: m / z=341.0[M+H] + (99.38% purity, 210nm)

[0155] 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.46-7.41 (m, 2H), 7.35 (dd, J = 7.6, 1.6 Hz, 1H), 4.31 (s, 1H), 2.63 (s, 3H). The active hydrogen of the sulfonamide was not revealed.

[0156] Example 5

[0157] 2,4-Dichloro-N-((4-sulfamoylphenyl)sulfonyl)benzamide 5

[0158] Step 1: 4-sulfamoylbenzenediazonium chloride 5b

[0159] Disperse 4-aminobenzenesulfonamide 5a (6.4 g, 37.17 mmol) in a 35 mL aqueous solution of hydrochloric acid (6.3 mL, 205.68 mmol) at 0°C. Add sodium nitrate (2.65 g, 38.41 mmol) in a 10 mL aqueous solution. After addition, react at 0°C for 1 hour. TLC confirms complete reaction. The reaction solution becomes transparent yellow, yielding a solution of the title compound 5b (45 mL, crude product), which is used directly in the next step.

[0160] Step 2: 4-Sulfamoylbenzenesulfonyl chloride 5c

[0161] Sulfur dioxide gas was passed through acetic acid (35 mL) for 40 minutes. Anhydrous copper chloride (1.5 g, 13.74 mmol) was added, stirred for 10 minutes, and compound 5b (45 mL, crude) was added dropwise. The mixture was allowed to react at 25°C for 0.5 hours. TLC confirmed complete reaction. The reaction mixture was diluted with water (10 mL), adjusted to a pH of 7-8 with saturated sodium carbonate solution, and extracted with dichloromethane (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford the title compound 5c (1 g, crude) as a yellow solid, which was used directly in the next step.

[0162] Step 3 Benzene-1,4-disulfonamide 5d

[0163] Compound 5c (1 g, crude) was dispersed in 1,4-dioxane (10 mL) and aqueous ammonia (5 mL) was added. The mixture was allowed to react at 25°C for 16 hours. TLC confirmed complete reaction. The reaction mixture was concentrated, and the crude product was slurried with MeOH / DCM (1 / 2, 10 mL) to afford the title compound 5d (835 mg, 9.5% yield over three steps) as a white solid.

[0164] LC-MS: m / z = 235.0 [MH] -

[0165] Step 4: 2,4-dichloro-N-((4-sulfamoylphenyl)sulfonyl)benzamide 5

[0166] Compound 5d (60 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 4-dimethylaminopyridine (46.5 mg, 0.38 mmol) and triethylamine (154.2 mg, 1.52 mmol) were added. The mixture was stirred for 10 minutes, cooled to 0°C, and intermediate IN-1 (64.5 mg, crude product, 82.5% content) was added. After addition, the mixture was heated to 25°C and allowed to react for 16 hours. LC-MS showed approximately 20% of the starting material remaining and 40% of the product. The reaction solution was purified by Prep-HPLC to afford the title compound 5 as a white solid (36.5 mg, 35.1% yield).

[0167] LC-MS: m / z = 409.0 [M+H] + (99.92% purity, 220nm)

[0168] 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 1.6 Hz, 1H), 7.66 (s, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 8.0, 1.6 Hz, 1H). The active hydrogen of the sulfonamide was not revealed.

[0169] Example 6

[0170] 4-Bromo-2-chloro-N-((2-methylthiazol-5-yl)sulfonyl)benzamide 6

[0171] Step 1: 4-Bromo-2-chlorobenzoyl chloride 6b

[0172] Dissolve 4-bromo-2-chlorobenzoic acid 6a (79 mg, 0.34 mmol) in dichloromethane (2 mL). Add oxalyl chloride (52 mg, 0.41 mmol) and N,N-dimethylformamide (1 drop) dropwise. Under nitrogen, react at room temperature for 1 hour. TLC confirms complete reaction. Concentrate to afford the title compound 6b (crude, 0.34 mmol) as a yellow solid, which is used directly in the next step.

[0173] Step 2 4-bromo-2-chloro-N-((2-methylthiazol-5-yl)sulfonyl)benzamide 6

[0174] Intermediate IN-2 (50 mg, 0.28 mmol) was dissolved in tetrahydrofuran (2 mL), and 4-dimethylaminopyridine (34 mg, 0.028 mmol) and triethylamine (85 mg, 0.84 mmol) were added. Compound 6b (crude product, 0.34 mmol) was dissolved in tetrahydrofuran (2 mL) and added dropwise to the reaction mixture under nitrogen atmosphere at room temperature for 1 hour. TLC confirmed the complete reaction. Water (10 mL) was added, and the pH was adjusted to 3 with dilute hydrochloric acid (3 M, 1.0 mL). The product was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and concentrated. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 10) to afford the title compound 6 (17 mg, 15% yield over two steps) as a white solid.

[0175] LC-MS: m / z=396.9[M+H] + (98.03% purity, 210nm)

[0176] 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.48-7.41 (m, 2H), 2.63 (s, 3H). The active hydrogen of the sulfonamide was not revealed.

[0177] Example 7

[0178] N-((4-aminophenyl)sulfonyl)-2,4-dichlorobenzamide 7

[0179] Step 1: 2,4-dichloro-N-((4-nitrophenyl)sulfonyl)benzamide 7b

[0180] 4-Nitrobenzenesulfonamide 7a (404 mg, 2.00 mmol) was dissolved in tetrahydrofuran (8 mL), and 4-dimethylaminopyridine (24 mg, 0.20 mmol) and triethylamine (607 mg, 6.00 mmol) were added. Intermediate IN-1 (503 mg, crude) was dissolved in tetrahydrofuran (4 mL) and added dropwise to the reaction mixture under nitrogen atmosphere at room temperature for 1 hour. TLC confirmed the complete reaction. Water (40 mL) was added, and dilute hydrochloric acid (3 M, 4 mL) was added to adjust the pH to 3. The mixture was extracted with ethyl acetate (20 mL x 3) and concentrated. The crude product was purified by TLC-Prep (methanol / dichloromethane = 1 / 10) to afford the title compound 7b (196 mg, 26% yield) as a white solid.

[0181] 1 H NMR (400MHz, DMSO-d6) δ8.28(dt,J=8.8,2.4Hz,2H),8.05(dd,J=8.8,2.4Hz,2H),7.49(d,J=8.4Hz,1H),7.46(d,J=2.4Hz,1H),7.33(dd,J=8.0,2.0Hz,1H).

[0182] Step 2 N-((4-aminophenyl)sulfonyl)-2,4-dichlorobenzamide 7

[0183] Compound 7b (404 mg, 0.52 mmol) was dissolved in ethanol (5 mL) and palladium on carbon (10%, 20 mg) was added. The mixture was hydrogenated at room temperature for 2 hours. TLC confirmed the complete reaction. The reaction mixture was filtered through celite and rinsed with methanol (5 mL). The filtrate was concentrated and purified by TLC-Prep (7 M ammonia in methanol / dichloromethane = 1 / 20) to afford the title compound 7 (41 mg, 23% yield) as a white solid.

[0184] LCMS: m / z=345.0[M+H] +

[0185] 1H NMR (400 MHz, DMSO-d6) δ 7.49-7.42 (m, 4H), 7.30 (dd, J = 8.2, 2.0 Hz, 1H), 6.50-6.48 (m, 2H), 5.47 (s, 2H). The active hydrogen of the sulfonamide was not revealed.

[0186] Example 8

[0187] 2,4-Dichloro-N-((4-hydroxyphenyl)sulfonyl)benzamide 8

[0188] Step 1: 2,4-dichloro-N-((4-methoxyphenyl)sulfonyl)benzamide 8b

[0189] 4-Methoxybenzenesulfonamide 8a (187 mg, 1.00 mmol) was dissolved in tetrahydrofuran (4 mL), and 4-dimethylaminopyridine (12 mg, 0.10 mmol) and triethylamine (303 mg, 3.00 mmol) were added. Intermediate IN-1 (251 mg, crude) was dissolved in tetrahydrofuran (2 mL) and added dropwise to the reaction mixture under nitrogen atmosphere at room temperature for 1 hour. TLC confirmed the complete reaction. Water (20 mL) was added, and dilute hydrochloric acid (3 M, 2 mL) was added to adjust the pH to 3. The reaction was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and concentrated. The crude product was purified by TLC-Prep (methanol / dichloromethane = 1 / 10) to afford the title compound 8b (245 mg, 68% yield) as a white solid.

[0190] LC-MS: m / z = 360.0 [M+H] +

[0191] Step 2 2,4-dichloro-N-((4-hydroxyphenyl)sulfonyl)benzamide 8

[0192] Compound 8b (245 mg, 0.68 mmol) was dissolved in dichloromethane (12 mL) under nitrogen atmosphere. Boron tribromide (308 mg, 1.23 mmol) was added dropwise and allowed to react at room temperature for 2 hours. TLC confirmed the reaction was complete, and methanol / dichloromethane (1 / 10, 20 mL) was added dropwise to quench the reaction. Water (30 mL) was added to separate the layers, and the aqueous phase was extracted with dichloromethane (30 mL x 2). The combined organic phases were concentrated. The crude product was purified by TLC-Prep (methanol / dichloromethane = 1 / 10) and then by TLC-Prep (ethyl acetate) to obtain the title compound 8 (84 mg, 36% yield) as a white solid.

[0193] LCMS: m / z=346.0[M+H] +

[0194] 1H NMR (400MHz, DMSO-d6) δ12.58(s,1H),10.63(s,1H),7.83-7.79(m,2H),7.71-7.67(m 1H),7.49-7.46(m,2H),6.97-6.93(m,2H).

[0195] Pharmacological activity test part

[0196] Test Example 1: Affinity test of compounds with WDR5 at the molecular level

[0197] The affinity test of the compounds in the present disclosure to WDR5 at the molecular level was conducted by the following method:

[0198] Compound Preparation: Accurately weigh the compound and dissolve it in DMSO (Sigma, D5879) to a 10 mM stock solution. Serially dilute the stock solution two-fold using 1x HBS-EP buffer (10 mM HEPES, pH 7.4, 150 mM NaCl, 3.0 mM EDTA, and 0.005% (v / v) TW-20) to a final concentration of 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, and 0.39 μM. The final DMSO concentration was 5%. A certain amount of compound sample was transferred to a 96-well plate (Greiner, 650101) according to the experimental protocol.

[0199] Surface Plasmon Resonance (SPR) Assay: WDR5 protein was coupled to a CM5 chip (Cytiva, BR100530) using the amino coupling method, yielding a signal of approximately 9000 response units (RU). Three initialization cycles were performed, followed by injection of test compounds. Association times were set to 120 seconds and dissociation times to 100 seconds. Residual compound on the chip was subsequently washed away with a solution containing 50% DMSO. Solvent correction was performed every 48 cycles using 1x HBS-EP buffer containing 4.5%-5.8% DMSO.

[0200] Detection and Analysis: Biacore8K was used for signal detection, data collection, processing and analysis. The raw data generated by the experiment were processed using Biacore8K data processing software by subtracting the control group parameters and solvent correction, and the corresponding K was fitted using the static affinity model. D For details, see Table 1.

[0201] Conclusion: The compounds of the examples disclosed herein have a strong affinity with the WDR5 protein at the molecular level.

[0202] Table 1. Affinity test results of the compounds disclosed herein and WDR5 protein

[0203] Note: ND means the compound has no significant binding to WDR5; NT means the affinity of the compound has not been tested

[0204] Test Example 2: Anti-proliferative activity test of compounds on neuroblastoma cells

[0205] The anti-proliferative activity of the compounds of the present disclosure on neuroblastoma cells was tested by the following method:

[0206] Compound preparation: Accurately weigh the compound and dissolve it in DMSO to a 10 mM stock solution for later use. Dilute the compound to a final concentration of 10 μM in DMEM or IMDM medium, with a final DMSO concentration of 0.1%. Transfer the compound to a 96-well plate for subsequent experiments.

[0207] Cell Counting Kit-8 test (CCK-8): 293T, SK-N-AS, IMR32, and LAN5 cells were seeded into 96-well cell culture plates at a seeding volume of 2 x 10 cells per well. 4 Each well was incubated with the corresponding compound and DMSO control for 72 hours. Then, 10 μL of CCK-8 reagent was added to each well and incubated at 37°C for another 2 hours. The absorbance of the cells was measured at 450 nm using a microplate reader.

[0208] Detection and analysis: Collect the absorbance data corresponding to the cells in each well and calculate the corresponding cell survival rate and inhibition rate. See Table 2 for details.

[0209] Conclusion: The compounds disclosed in the examples have good anti-proliferative activity against neuroblastoma cells.

[0210] Table 2. Antiproliferative activity test results of some compounds in the present disclosure on neuroblastoma cells

[0211] “-”: No significant effect.

[0212] Test Example 3: Structural analysis of the complex between some compounds disclosed herein and WDR5

[0213] The complex structure of some compounds 2 in the present disclosure was elucidated by the following method:

[0214] Protein crystal preparation: WDR5 expression vector-containing Rosetta2 competent cells were cultured in a 37°C shaking incubator until the OD value reached 0.6-0.8. IPTG was added to a final concentration of 0.1 mM and cultured at 16°C for 20 hours before harvesting. Cells were disrupted using a high-pressure cell disruptor and centrifuged at high speed for 30 minutes. The supernatant was collected after adding 10 mL of Ni-NTA affinity chromatography gel resin and binding was allowed to proceed at 4°C with stirring for 1 hour. The supernatant was then centrifuged and treated with a decontamination buffer (50 mM Tris pH 7.5, 150 mM NaCl, 50 mM imidazole, 1 mM TCEP) and an elution buffer (50 mM Tris pH 7.5, 150 mM NaCl, 300 mM imidazole, 1 mM TCEP) to obtain the initial target protein. High-purity WDR5 protein was then obtained using anion exchange chromatography and size exclusion chromatography columns, respectively. The sample was then collected and protein purity was verified by SDS-polyacrylamide gel electrophoresis.

[0215] The obtained highly pure WDR5 protein was concentrated to 11 mg / mL using an ultrafiltration tube and centrifuged at 12,000 rpm for 30 minutes. Crystallization buffer was prepared: 0.1 M Bis-Tris, pH 5.8, 0.2 M ammonium acetate, and 30% (w / v) pEG3350. Crystallization conditions were optimized using a 24-well hanging drop plate. 1 mL of buffer was used per well. The two solutions were mixed at a ratio of 1.5 μL crystallization buffer and 1.5 μL protein solution. After 2-3 days in an 18°C ​​incubator, crystals grew in a flake-like shape. Crystals of the WDR5-active compound complex were obtained by immersion.

[0216] Detection and analysis: The diffraction data of the crystals were collected at the microcrystal complex beamline BL18U1 of the Shanghai Synchrotron Radiation Facility (SSRF). The collected data were processed using HKL3000, including steps such as data point selection, indexing, correction, integration, data merging and normalization, to generate MTZ files. The WDR5 empty protein crystal structure resolved by our laboratory was used as a template, and the Phaser module in CCP4 was used for molecular replacement to generate the initial structural coordinates. COOT was used for model construction and optimization, and then Phenix was used to further optimize the model, and the R factor in the structural parameters was repeatedly reduced to less than 0.25. The results are shown in Figure 1.

[0217] Test Example 4: In vitro efficacy test of some compounds of the present disclosure on acute myeloid leukemia, hepatoma cell lines and pancreatic cancer cell lines

[0218] Compound preparation: Accurately weigh the compound and dissolve it in DMSO to a 10 mM stock solution for later use. Dilute the compound to a final concentration of 10 μM in MEM or RPMI 1640 medium with a final DMSO concentration of 0.1%. Transfer the compound to a 96-well plate for subsequent experiments.

[0219] Cell Counting Kit-8 test (CCK-8): Hep3B, Huh-7, MV4-11, and Mia-Paca2 cells were seeded into 96-well cell culture plates at a seeding volume of 2 x 10 cells per well. 4 Each well was incubated with the corresponding compound and DMSO control for 72 hours. Then, 10 μL of CCK-8 reagent was added to each well and incubated at 37°C for another 2 hours. The absorbance of the cells was measured at 450 nm using a microplate reader.

[0220] Detection and analysis: Collect the absorbance data corresponding to the cells in each well and calculate the corresponding inhibition rate. See Table 3 for details.

[0221] Table 3. In vitro efficacy test results of some compounds of the present disclosure on acute myeloid leukemia, hepatoma cell lines and pancreatic cancer cell lines

[0222] Conclusion: The compounds of the examples disclosed herein have good anti-proliferative activity against hepatoma cells, acute myeloid leukemia cells and pancreatic cancer cells.

[0223] Test Example 5: Pharmacokinetic test of some compounds disclosed herein on normal mice

[0224] This test investigated the pharmacokinetic properties of Compound 2 in mice. Female Balb / c mice, 6-8 weeks old, were gavage- or tail-vein-administered with Compound 2. Whole blood was collected 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration. After centrifugation at 8000 rpm for 5 minutes, the upper plasma layer was collected. HPLC-MS / MS was used to determine plasma exposure at different time points, and pharmacokinetic parameters were calculated. The specific experimental results are as follows:

[0225] Table 4. Pharmacokinetic test results of some compounds of the present disclosure on normal mice

[0226] Conclusion: The compounds of the present disclosure are rapidly absorbed orally and have a very high bioavailability. The plasma half-life is T 1 / 2 With a duration of up to 15.9 hours, it is an ideal potential oral drug candidate.

[0227] Test Example 6: Efficacy test of some compounds disclosed herein on the IMR32 CDX mouse neuroblastoma model

[0228] This test case studied the efficacy of Compound 1 and Compound 2 in a neuroblastoma model. Human neuroblastoma IMR32 cells were cultured in a monolayer in vitro and routinely digested and passaged twice a week using trypsin-EDTA. When the cell saturation reached 80%-90%, the cells were harvested, counted, and the inoculation concentration was adjusted to 10,000,000 cells / animal. The cells were inoculated subcutaneously on the upper right back of the animal and allowed to grow until the tumor grew to approximately 120 mm. 3 Animals were randomly divided into groups and dosed according to body weight and tumor volume. Animal body weight and tumor volume were measured twice a week. Efficacy data were expressed as tumor volume (TV), tumor inhibition rate (TGI), and relative volume (T / C). Specific experimental data are as follows:

[0229] Table 5. Efficacy test results of some compounds of the present disclosure on IMR32 CDX mouse neuroblastoma model

[0230] n=6

[0231] n=5

[0232] The experimental results showed no significant abnormalities in the animals' health during the dosing period. Compared with the vehicle control group, the low, medium, and high dose groups of the disclosed compounds all demonstrated significant antitumor efficacy with a favorable dose-response relationship, with TGIs reaching 85.5%, 107.1%, and 107.1%, respectively. In some animals in the high and medium dose groups, tumors completely disappeared in the late stages of dosing. This demonstrates the significant efficacy of the disclosed compounds in the IMR32 human neuroblastoma model.

[0233] Test Example 7: Efficacy test of some compounds disclosed herein on Hep3B CDX mouse hepatoma model

[0234] This test case studied the efficacy of compound 2 in a liver cancer model. Human liver cancer Hep3B cells were cultured in a monolayer in vitro and routinely digested and passaged twice a week using trypsin-EDTA. When the cell saturation reached 80%-90%, the cells were harvested, counted, and the inoculation concentration was adjusted to 10,000,000 cells / animal. The cells were inoculated subcutaneously on the upper right back of the animal and allowed to grow until the tumor grew to approximately 110 mm. 3 Animals were randomly divided into groups and dosed according to body weight and tumor volume. Animal body weight and tumor volume were measured twice a week. Efficacy data were expressed as tumor volume (TV), tumor inhibition rate (TGI), and relative volume (T / C). Specific experimental data are as follows:

[0235] Table 6. Efficacy test results of some compounds of the present disclosure on Hep3B CDX mouse hepatoma model

[0236] n=5

[0237] The experimental results showed no significant abnormalities in the animals' health during the dosing period. Compared with the vehicle control group, both the low- and high-dose groups of the disclosed compounds demonstrated significant antitumor efficacy with a good dose-response relationship, with TGIs reaching 40% and 106.8%, respectively. In the high-dose 90 mg / kg group, tumors in some animals completely disappeared in the late stages of dosing. This demonstrates the significant efficacy of the disclosed compounds in the Hep3B liver cancer xenograft model.

[0238] Test Example 8: Safety test of some compounds disclosed herein on normal mice

[0239] This test case investigated the safety of Compound 1 and Compound 2. Female, 6-8 week old ICR mice were selected as research subjects. The animals were randomly divided into groups based on body weight and then orally administered at doses of 100 mg / kg, 300 mg / kg, 400 mg / kg, and 500 mg / kg, respectively. The changes in animal weight, morbidity, and mortality were observed. The specific results are as follows:

[0240] Table 7. Safety test results of some compounds of the present disclosure on normal mice

[0241] The experimental results showed that, in ICR mice, oral administration of the disclosed embodiment compound 1 at doses of 100 mg / kg and 300 mg / kg did not cause illness or death in all animals. Oral administration of the disclosed embodiment compound 2 at doses of 100 mg / kg, 300 mg / kg and 400 mg / kg did not cause illness or death in all animals. In the 500 mg / kg group, only one animal died on the third day of the experiment. It can be seen that the expected tolerable dose of the disclosed embodiment compound is as high as 400 mg / kg, and the safety is good.

[0242] Test Example 9: Protein Binding Rate Test of Some Compounds Disclosed

[0243] The plasma protein binding rates of Compound 1 and Compound 2 in human plasma were determined using equilibrium dialysis. A semipermeable membrane was used to separate the left and right chambers. A drug-containing protein solution was added to the left chamber, while a blank buffer solution was added to the right chamber. Unbound free drug was allowed to freely pass through the semipermeable membrane. After a certain incubation period, equilibrium was reached between the two chambers, and the free drug concentrations were equal. The plasma protein binding rate was calculated by measuring the drug concentrations on both chambers. The results are shown in Table 8:

[0244] Table 8. Protein binding test results of some compounds disclosed herein

[0245] The experimental results show that the free drug content of the compound of the embodiment of the present disclosure reaches 1.48%, which is sufficient to meet the therapeutic drug concentration requirement in vivo.

[0246] Test Example 10: Hepatocyte Stability Test of Some Compounds of the Disclosure

[0247] Transfer 198 μL of live cell suspension to a 96-well deep-well plate, place the deep-well plate on a vortex and preheat in an incubator for 10 minutes. The experiment was performed in duplicate. Add 2 μL of 100 μM test substance or positive drug verapamil to each well to start the reaction, and place the deep-well plate back on the incubator vortexer. Incubate the sample, take 25 μL of the suspension at 0, 15, 30, 60, 90 and 120 minutes, and add 150 μL of acetonitrile containing the internal standard to terminate the reaction. Vortex for 10 minutes and centrifuge at 3220 g and 4°C for 45 minutes. Transfer 100 μL of supernatant to the sample plate, add 100 μL of pure water to mix, and use for UPLC-MS / MS analysis. The results are shown in Table 9:

[0248] Table 9. Hepatocyte stability test results of some compounds of the present disclosure

[0249] The experimental results show that the compounds of the embodiments of the present disclosure are easily metabolized and eliminated in the human liver and are less likely to produce cumulative toxicity.

[0250] The applicant declares that the present disclosure uses the above-mentioned embodiments to illustrate a sulfonamide compound disclosed herein as an inhibitor of the interaction between WDR5 and Myc, its preparation method and application, but the present disclosure is not limited to the above-mentioned embodiments, that is, it does not mean that the present disclosure must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement to the present disclosure, the equivalent replacement of the raw materials of the products disclosed herein, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the present disclosure. The preferred embodiments of the present disclosure are described in detail above, but the present disclosure is not limited to the specific details in the above-mentioned embodiments. Within the scope of the technical concept of the present disclosure, the technical solutions of the present disclosure can be subjected to various simple modifications, and these simple modifications all fall within the scope of protection of the present disclosure. It should also be noted that the various specific technical features described in the above-mentioned specific embodiments can be combined in any suitable manner if there is no contradiction. In order to avoid unnecessary repetition, the present disclosure will no longer separately describe various possible combinations.

Claims

1. Use of a sulfonamide compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a tautomer thereof or a stereoisomer thereof as an inhibitor of the interaction between WDR5 and Myc, in: A 1 Ring and A 2 The rings are each independently selected from one of a C6-C30 aryl ring, a C6-C30 aliphatic hydrocarbon ring, a C3-C30 heteroaryl ring, and a C3-C30 aliphatic heterocycle, and the "ring" herein includes a monocyclic ring and a polycyclic ring; R 1 A 1 Ring substituent, m = 0-3; R 1 independently selected from halogen, C3-C5 cycloalkyl, C1-C3 haloalkyl, -CN, -S(=O)2-NH2, optionally substituted by 1-3 R b Substituted C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; R b Independently selected from substituted or unsubstituted C1-C3 alkoxy, where "substituted" means optionally substituted with 1-3 hydroxyl, halogen or C1-C3 alkoxy substituents; R 2 A 2 Ring substituent, n = 0-3; R 2 Selected from -OH, halogen, C1-C3 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 haloalkyl, -C(O)NHR c 、-NHC(O)CH2NHC(O)R c , 3-5 membered cycloalkyl optionally substituted by 1-3 "-CN", 5-7 membered aryl optionally substituted by 1-3 "-CN"; R c is a C1-C3 alkyl group; L is a chemical bond or selected from C1-6 alkylene, saturated or partially unsaturated C3-10 cycloalkylene, -O-, -NR a -、-NR a - a divalent group composed of one or more of C1-6 alkylene groups; R a R is independently selected from H, C1-C10 alkyl, saturated or partially unsaturated C3-6 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-10 aryl, a The CH2 in R can be replaced by -O- or -S-. a The H in the R can be substituted by hydroxy, halogen or C1-C3 alkoxy.

2. The use according to claim 1, wherein the sulfonamide compound represented by formula (I) is the following compound:

3. The use according to claim 1, characterized in that It specifically binds to the WBM site of WDR5, thereby blocking the interaction between WDR5 and Myc.

4. Use of the sulfonamide compound represented by formula (I) or its pharmaceutically acceptable salt, its tautomer or its stereoisomer in the preparation of a drug for treating or alleviating cancer, in: A 1 Ring and A 2 The rings are each independently selected from one of a C6-C30 aryl ring, a C6-C30 aliphatic hydrocarbon ring, a C3-C30 heteroaryl ring, and a C3-C30 aliphatic heterocycle, and the "ring" herein includes a monocyclic ring and a polycyclic ring; R 1 A 1 Ring substituent, m = 0-3; R 1 independently selected from halogen, C3-C5 cycloalkyl, C1-C3 haloalkyl, -CN, -S(=O)2-NH2, optionally substituted by 1-3 R b Substituted C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; R b Independently selected from substituted or unsubstituted C1-C3 alkoxy, where "substituted" means optionally substituted with 1-3 hydroxyl, halogen or C1-C3 alkoxy substituents; R 2 A 2 Ring substituent, n = 0-3; R 2 Selected from -OH, halogen, C1-C3 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 haloalkyl, -C(O)NHR c 、-NHC(O)CH2NHC(O)R c , 3-5 membered cycloalkyl optionally substituted by 1-3 "-CN", 5-7 membered aryl optionally substituted by 1-3 "-CN"; R c is a C1-C3 alkyl group; L is a chemical bond or selected from C1-6 alkylene, saturated or partially unsaturated C3-10 cycloalkylene, -O-, -NR a -、-NR a - a divalent group composed of one or more of C1-6 alkylene groups; R a R is independently selected from H, C1-C10 alkyl, saturated or partially unsaturated C3-6 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-10 aryl, a The CH2 in R can be replaced by -O- or -S-. a The H in the R can be substituted by hydroxy, halogen or C1-C3 alkoxy.

5. The use according to claim 4, wherein the sulfonamide compound represented by formula (I) is the following compound:

6. The use according to claim 4, characterized in that The cancer is selected from neuroblastoma, gangliocytoma, ganglioblastoma, ganglioneuroma, ganglioblastoma, sympathetic neuroblastoma, schwannoma, neurofibroma, prostate cancer, triple-negative breast cancer, nasopharyngeal carcinoma, esophageal cancer, laryngeal cancer, lung cancer, gastric cancer, liver cancer, colorectal cancer, cervical cancer, pancreatic cancer, bladder cancer, retinoblastoma, osteosarcoma, chondrosarcoma, chordoma, rhabdomyosarcoma, multiple myeloma, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia; preferably, the cancer is selected from neurogenic tumors including: neuroblastoma, gangliocytoma, ganglioblastoma, ganglioneuroma, ganglioblastoma, sympathetic neuroblastoma, schwannoma, neurofibroma, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, pancreatic cancer.

7. The sulfonamide compound represented by formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, a tautomer thereof or a stereoisomer thereof, characterized in that: The sulfonamide compound is the following compound:

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