WO2025031361A1 - Use of sulfonamide compound in preparation of drug for treating cancers - Google Patents

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

The present invention belongs to the field of pharmaceutical chemistry and relates to the medical use of sulfonamide derivatives, and specifically relates to the use of a sulfonamide compound as an anti-neuroblastoma drug for preparing a cancer treatment drug.

Background Art

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). Its onset is insidious, and it is prone to metastasis. The mortality rate of high-risk cases is high, which seriously threatens 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 by chemotherapy alone; while the prognosis of children with tumors with poor pathological types, accompanied by risk factors such as MYCN gene amplification, 11q abnormalities, or distant metastasis is extremely poor (Non-patent Document 2). Although current treatment methods 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 reduces the treatment effect and is a major problem in clinical pediatric surgery. Therefore, it is urgent to develop a new, safe and effective drug for the treatment of neuroblastoma.

WD40 repeat domain protein 5 (WDR5) belongs to the WD40 protein family and is a protein containing a circular seven-blade β-propeller domain. WDR5 is highly conserved among different vertebrates, with a sequence identity of about 90%. WDR5 was first discovered to be involved in regulating osteoblast differentiation and promoting bone formation during skeletal development. In recent years, more and more 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 a variety of tumors, making it a popular choice for tumor treatment targets.

The most important function of WDR5 in vivo is epigenetic regulation. As a member of the histone methyltransferase (HMT) complex, it regulates histone methylation levels and activates the transcription of target genes. Abnormal WDR5 function can upregulate the expression of multiple tumor-promoting factors, activate tumor-related signaling pathways, and then enhance tumor cell proliferation, metastasis and drug resistance, driving the occurrence of epithelial-mesenchymal transition (EMT). WDR5 is also an auxiliary factor of myelocytoma viral oncogene homolog (Myc). As a transcription factor, Myc regulates the transcription of downstream genes by binding to the promoter region of the target gene. The limiting factor of this function is the ability of Myc to localize to chromatin. Studies have found that about 80% of the binding of Myc to its downstream target gene sequence requires the participation of WDR5. After the binding of WDR5 and Myc is destroyed, the ability of Myc to induce pluripotent stem cells is greatly weakened. Therefore, WDR5 is a key factor in the process of 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 homolog gene 2 (MDM2) promoter region, activates the transcription of MDM2, and inhibits the expression of tumor suppressor protein p53. In cholangiocarcinoma, WDR5 maintains a high level of HIF-1α in the body through epigenetic regulation, and also increases the expression of HIF-1α through Myc in the transcription link, promoting the EMT, metastasis and invasion of tumor cells.

There are two interaction sites on the surface of WDR5, namely the WDR5 binding domain (WBM) site and the WDR5 interaction domain (WIN). The WBM site is a shallow and relatively hydrophobic binding pocket, mainly composed of Asn225, Tyr228, Leu240, Phe266, Val268 and Gln289. Retinoblastoma binding protein 5 (RBBP5), C-myc, L-myc, N-myc, KAT8 regulatory NSL complex subunit 2 (KANSL2), etc. all interact with WDR5 through this site. The WIN site is an arginine binding pocket, composed of amino acids such as Ala65, Ser91, Asp107, Phe133, Tyr191, Tyr260 and Phe263. It has been reported that 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) interact with WDR5 through this site. The key biological functions of WDR5 rely on the mediation of the above two sites, such as direct binding with RBBP5 and SET1/MLL, indirect binding with ash2 (lack, small, or homologous)-like (Drosophila) protein (ASH2L) and dpy-30 homolog protein (DPY30) to assemble into a complex with histone methyltransferase catalytic activity, regulating the transcription of target genes through epigenetic regulation (non-patent document 4); and interacting with the transcription factor Myc, recruiting Myc to chromatin, improving its binding to the promoter region of the target gene, and greatly enhancing its tumor-promoting function (non-patent documents 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.

At present, 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 they are not effective for solid tumors, while there are few studies on WBM site blockers. Stephen's research team at Vanderbilt University School of Medicine in the United States conducted multiple rounds of optimization and modification, and the obtained compound No. 12 can specifically bind to the WBM site, and the _KD value with WDR5 is 0.10±0.01μM (non-patent literature 7,8), but its anti-tumor effect has not been evaluated.

In summary, designing and synthesizing 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.

References

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

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.

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

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

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.

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.

Summary of the invention

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 thereof or a stereoisomer thereof, so as to screen out compounds having excellent performance in terms of effectiveness, safety and selectivity as WDR5 inhibitors.

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,

in:

^A1 ring and ^A2 ring 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 is a substituent of the A ¹ ring, m=0-3; R ¹ is independently selected from halogen, C3-C5 cycloalkyl, C1-C3 haloalkyl, -CN, -S(=O) ₂ -NH ₂ , C1-C3 alkyl optionally substituted by 1-3 R ^b , C2-C6 alkenyl, C2-C6 alkynyl; R ^b is independently selected from substituted or unsubstituted C1-C3 alkoxy, where "substituted" means optionally substituted by 1-3 hydroxyl, halogen or C ₁ -C ₃ alkoxy substituents;

^R2 is a substituent of the ^A2 ring, n=0-3; ^R2 is selected from -OH, halogen, _C1 - _C3 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, _C1 - _C3 haloalkyl, -C(O) ^NHRc , -NHC(O) _CH2NHC (O) ^Rc , 3-5 membered cycloalkyl optionally substituted by 1-3 "-CN", 5-7 membered aryl optionally substituted by 1-3 "-CN"; ^Rc is _C1 - _C3 alkyl;

L is a chemical bond or a divalent group selected from one or more combinations of C1-6 alkylene, saturated or partially unsaturated C3-10 cycloalkylene, -O-, -NR ^a -, and -NR ^a -C1-6 alkylene; ^Ra 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, CH ₂ in ^Ra can be replaced by -O- or -S-, and H in ^Ra can be replaced by hydroxyl, halogen or C1-C3 alkoxy.

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 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.

The compounds disclosed herein can be used as WDR5-Myc interaction blockers. Specifically, the pharmacological experimental results show that the compounds disclosed herein can specifically bind to the WBM domain of WDR5 and block 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 related to abnormal activation of Myc, RBBP5, KANSL2 and other related signaling pathways caused by abnormal expression of WDR5.

Diseases related to abnormal activation of Myc, RBBP5, KANSL2 and other related signaling pathways caused by abnormal expression of WDR5 include, but are not limited to, neuroblastoma, gangliocytoma, ganglioblastoma, ganglioneuroma, 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 and other diseases, especially suitable for the treatment and relief of neurogenic tumors including: neuroblastoma, gangliocytoma, ganglioblastoma, ganglioneuroma, ganglioblastoma, sympathetic neuroblastoma, schwannoma, neurofibroma.

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

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: The active ingredients account for more than 70% of the total weight, and the rest accounts for 0.5-30% of the total weight, or better 1-15%, or most preferably 2-10%.

The various formulation forms of the pharmaceutical composition disclosed herein have a unit dose containing 0.5 mg-200 mg, 2 mg-100 mg, or 5 mg-50 mg of the compound of formula (I), enantiomers, racemates, pharmaceutically acceptable salts or mixtures thereof.

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.

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

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

The effective dose of the active ingredient used may vary with the compound used, the mode of administration, and the severity of the disease to be treated. However, generally, satisfactory results can be obtained 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 active compound closely mixed with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to provide the best therapeutic response. For example, several divided doses may be administered per day, or the dose may be reduced proportionally, depending on the urgency of the treatment condition.

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 optional pharmaceutical composition is a solid composition, especially a tablet and a solid-filled or liquid-filled capsule. Oral administration of the pharmaceutical composition is optional.

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 administration method required. Adjuvants commonly used in the preparation of pharmaceutical compositions may also be advantageously included, such as flavoring agents, pigments, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA.

The active compounds or their pharmaceutically acceptable salts and compositions thereof may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds (as free bases 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 preparations contain preservatives to prevent the growth of microorganisms.

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 the discharge of fluid from a syringe. Must be stable under manufacturing and storage conditions, and must be able to prevent the contamination effects of microorganisms (such as bacteria and fungi). The carrier can be a solvent or dispersion medium, which contains, for example, water, alcohol (such as glycerol, propylene glycol and liquid polyethylene glycol), their appropriate mixtures and vegetable oils.

Another aspect of the present disclosure provides the use of the compounds of the present disclosure and the 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, head and neck, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer and 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: bronchial 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, glucagon, gastrinoma) , carcinoid, VIPoma), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); genitourinary tract: 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, glandular Tumor-like tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, chronic bone tumor (osteochondrosarcoma), benign tumor, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Nervous system: skull (osteoma, hemangioma, granuloma, Xanthomas, osteitis), meninges (meningioma, meningeal sarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, neurothecoma, retinoblastoma, congenital tumors), spinal cord fibroma, meningioma, glioma, sarcoma; Gynecology: uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa cell tumor, supporting cell tumor, germ cell tumor, malignant In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

In an optional embodiment, the cancer is selected from neuroblastoma, gangliocytoma, ganglioblastoma, ganglioneuroma, ganglioblastoma, 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;

From a chemical and pharmaceutical point of view, 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 the above-mentioned pharmaceutical compositions formed by the compounds of the present disclosure.

Explanation of terms

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

definition

Unless otherwise defined below, the meanings of all technical and scientific terms used herein are intended to be the same as those generally understood by those skilled in the art. Reference to the technology used herein is intended to refer to the technology generally understood in the art, including those changes in technology or replacement of equivalent technology that are obvious to those skilled in the art. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present disclosure.

In the present disclosure, the terms "includes," "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.

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.

The aliphatic cyclic group refers to a cycloalkyl, cycloalkenyl, cycloalkynyl, etc. composed of a ring structure of C and H, wherein C is replaced by a heteroatom to form an aliphatic heterocyclic group; it also includes the bridged ring and spiro ring forms described later.

As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl has 1 to 12, for example 1 to 6 carbon atoms. For example, as used herein, the term "C1-6 alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to ₃ ) suitable substituents such as halogen (in this case, the group is referred to as "haloalkyl") (e.g., _CH2F , _CHF2 , _CF3 , _CCl3 , _{C2F5 , C2Cl5} , _{CH2CF3 , CH2Cl} or _{-CH2CH2CF3 , etc.} ). 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).

As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon group containing one double bond and having 2 to 6 carbon atoms (" _C2-6 alkenyl"). 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 alkenyl, the compounds may exist in pure E (entgegen) form, pure Z (zusammen) form or any mixture thereof.

As used herein, the term "alkynyl" denotes 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.

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 spiro, 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, decalinyl, etc.), optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl has 3 to 15 carbon atoms. For example, the term " _C3-6 cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl.

As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" refer to a 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 ring having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including but not limited to (cyclo)propyl (ring), (cyclo)butyl (ring), (cyclo)pentyl (ring), (cyclo)hexyl (ring), (cyclo)heptyl (ring), (cyclo)octyl (ring), (cyclo)nonyl (ring), (cyclo)hexenyl (ring) and the like.

As used herein, the terms "heterocyclyl", "heterocyclylene" and "heterocycle" refer to a saturated (i.e., C) ring 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. The term "heterocycloalkyl" refers to a saturated or partially unsaturated (i.e., having one or more double and/or triple bonds in the ring) cyclic group. For example, a "3-10 membered (sub)heterocyclic (group)" is a saturated or partially unsaturated (sub)heterocyclic (group) 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 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.

As used herein, the terms "(ylidene)aryl" 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 terms "C _6-10 (ylidene)aryl" and "C _6-10 aromatic ring" mean an aromatic group containing 6 to 10 carbon atoms, such as (ylidene)phenyl (benzene ring) or (ylidene)naphthyl (naphthalene ring). The (ylidene)aryl group and the aromatic ring are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO ₂ , C _1-6 alkyl, etc.).

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 additionally may 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.

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

As a more specific explanation of the terms are as follows:

"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 may be optionally substituted or unsubstituted.

"Alkenyl" refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one CC is an ^sp2 double bond, wherein the alkenyl group may be independently optionally substituted with one or more substituents described in the present disclosure, wherein specific examples include, but are not limited to, vinyl, allyl, and butylene, etc. Alkenyl may be optionally substituted or unsubstituted.

"Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, more preferably includes 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes cycloalkyl of spiro ring, condensed ring and bridge ring. Cycloalkyl can be optionally substituted or unsubstituted.

"Spirocycloalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic 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, and more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spirocycloalkyl is divided into single spiro, double spiro or multi-spirocycloalkyl, preferably single spiro and double spirocycloalkyl, preferably 4/5 members, 4/6 members, 5/5 members or 5/6 members. Non-limiting examples of "spirocycloalkyl" include, but are not limited to:

"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, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to:

"Bridged cycloalkyl" refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures, sharing 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, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to:

The cycloalkyl ring may 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.

"Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably in this application and refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic non-aromatic heterocyclic group containing 3-12 ring atoms, wherein at least one ring atom is a heteroatom, such as an oxygen, nitrogen, sulfur atom, etc. Preferably, it has a 5-7 membered monocyclic ring or a 7-10 membered bi- 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 may be optionally substituted or unsubstituted.

"Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one 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, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) _m heteroatoms, and the remaining ring atoms are carbon, m = 1 or 2. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between rings, spiro heterocyclyl is divided into single spiro heterocyclyl, double spiro heterocyclyl or multi-spiro heterocyclyl, preferably single spiro heterocyclyl and double spiro heterocyclyl. More preferably 4/4, 4/5, 4/6, 5/5 or 5/6 monospiro heterocyclyl. Non-limiting examples of "spiro heterocyclyl" include, but are not limited to:

"Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more cyclic structures that share 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 heteroatoms, and the remaining ring atoms are carbon, m = 1 or 2. Preferably 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, 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:

"Bridged heterocyclic group" refers to a polycyclic group with 5 to 18 members, containing two or more cyclic 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 heteroatoms, and the remaining ring atoms are carbon, m = 1 or 2. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to:

"Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl. Preferably, the aryl group is a C ₆ -C ₁₀ aryl group, more preferably, the aryl group is phenyl and naphthyl, and most preferably, Preferably, phenyl is used. Aryl may be substituted or unsubstituted. The "aryl" may be fused with heteroaryl, heterocyclic or cycloalkyl, wherein the aryl ring is connected to the parent structure, and non-limiting examples include but are not limited to:

"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 may 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:

"Alkoxy" refers to a group of (alkyl-O-), wherein alkyl is as defined herein. _{C 1} -C ₆ alkoxy is preferred, and examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

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

"Hydroxy" refers to an -OH group. "Halogen" refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine. "Amino" refers to -NH _2. "Cyano" refers to -CN.

"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), wherein alkyl and cycloalkyl are as defined above. As used herein, the term "halo" or "halogen" groups are defined to include F, Cl, Br or I.

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 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 connected to the rest of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atoms, the nitrogen-containing heterocycle is optionally benzo-fused, and is preferably connected to the rest of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring.

The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form stable compounds.

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

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.

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

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

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.

The present disclosure also includes all pharmaceutically acceptable isotope-labeled compounds, which are identical to the compounds of the present disclosure except for one or more An atom is 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 isotopes suitable for inclusion in the compounds of the present disclosure include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( ^2H ), tritium ( ^3H )); isotopes of carbon (e.g., ^11C , ^13C , and ^14C ); isotopes of chlorine (e.g., ^36Cl ); isotopes of fluorine (e.g., ^18F ); isotopes of iodine (e.g., ^123I and ^125I ); isotopes of nitrogen (e.g., ^13N and ^15N ); isotopes of oxygen (e.g., ^15O , ^17O , and ^18O ); isotopes of phosphorus (e.g., ^32P ); and isotopes of sulfur (e.g., ^35S ). 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 isotopes tritium (i.e., ³ H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because of their ease of incorporation and ease of detection. Substitution with positron emitting isotopes (e.g., ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present disclosure may be prepared by methods analogous to those described in the accompanying schemes and/or in the examples and preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvates of the present disclosure include those in which the crystallization solvent may be isotopically substituted, for example, D ₂ O, acetone- _{d 6} or DMSO-d ₆ .

"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms in the group are replaced independently of each other 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, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

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: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -C(O) ^Rb , ^-OC (O) ^Rb , ^-NRbRb , ^-C (O) ^NRbRb , -NRbC(O) ^{Rb , -S} (O) ^NRbRb or -S(O ⁾ _2NRbRb ^, wherein ^Rb is as defined in the general formula (I).

As used herein, a "therapeutically effective dose" of a compound refers to 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.

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

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, lasting or transitory, attributable to or associated with the administration of that composition.

"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 through 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 the present 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 the present disclosure or mixtures of their enantiomers, diastereomers, or geometric isomers are all within the scope of the present disclosure.

"Pharmaceutically acceptable salts" refer to salts of the disclosed compounds which are safe and effective for use in humans or animals. Salts of compounds can be obtained by using a sufficient amount of a base or acid in a pure solution or a suitable inert solvent to obtain 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 acid salts and organic acid salts, and the inorganic and organic acids include 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, butenedioic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid and methanesulfonic acid, and the like.

In this article, solid lines can be used Solid wedge Virtual wedge Depict the chemical bonds of the compounds of the present disclosure. 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 is present. 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 diastereoisomer pairs).

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

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, which, after being administered to a patient in need thereof, can directly or indirectly provide a compound of the present disclosure or its metabolite or residue. Therefore, when referring to "compounds of the present disclosure" herein, it is also intended to cover the above-mentioned various derivative forms of the compound.

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.

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

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.

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, including 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.

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 a process of contacting the compounds of the present disclosure with a mammal for a period of time sufficient to produce a metabolic product thereof.

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 having the desired activity when administered into or onto the body. Typically such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compound in vivo.

The present disclosure also encompasses compounds of the present disclosure containing 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 of the molecules involved, 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 T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.

The term "about" means within ±10%, within ±5%, or within ±2% of the stated value.

The present disclosure provides a WDR5/Myc interaction blocker with a new structure. 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

FIG1 is a schematic diagram of the crystal structure of the complex of the disclosed compound and WDR5.

DETAILED DESCRIPTION

The method of the present disclosure is described below by specific examples to make the technical solution of the present disclosure easier to understand and grasp, but the present disclosure is not limited thereto. In the following examples, ¹ H NMR spectra were measured using a Bruker instrument (400 MHz), and chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. ¹ H NMR expression method: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplet. If coupling constants are provided, the unit is Hz.

The mass spectrum was obtained by LC/MS using ESI as the ionization method.

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% H ₃ PO ₄ ); 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.

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

Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

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

CD ₃ OD: deuterated methanol; CDCl ₃ : deuterated chloroform; DMSO-d ₆ : deuterated dimethyl sulfoxide; Pd ₂ (dba) ₃ : tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl ₂ ：[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; XantPhos: 4,5-bis(diphenylphosphino)ferrocene-9,9-dimethylxanthene; XPhos: 2-dicyclohexylphospho-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 connected to a hydrogen balloon with a volume of about 1 L through the reaction bottle. Unless otherwise specified, the solution in the reaction refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C-30°C. The reaction progress in the examples is monitored by thin layer chromatography (TLC), and the developing solvent used in the reaction, the column chromatography eluent system used for purifying 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 reagents, such as acetic acid or triethylamine, can also be added for adjustment. The reagent for providing alkaline conditions is selected from organic bases or inorganic bases, the organic base is one or more of triethylamine, N,N-diisopropylethylamine, n-butyl lithium, diisopropyl lithium amide, bistrimethylsilyl lithium amide, sodium tert-butoxide, sodium methoxide and potassium tert-butoxide, the inorganic base is one or more of sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and lithium hydroxide; the reagent for providing acidic conditions is one or more of hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, methanol solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid and phosphoric acid; the metal catalyst is palladium/carbon, Raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (Pd(dppf)Cl ₂ ), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, bistriphenylphosphine palladium dichloride (Pd(PPh ₃ )Cl ₂ ) and tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ ); the ligand is one or more of 2-dicyclohexylphosphino-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'-bis(diphenylphosphine) (BINAP); 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.

Drug Chemical Synthesis Experiment Section

Preparation of intermediates

Intermediate 1

2,4-Dichlorobenzoyl chloride IN-1

Step 1 2,4-Dichlorobenzoyl chloride IN-1

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, and reacted at room temperature for 2 hours. TLC showed that the starting material disappeared. The reaction solution was directly concentrated to obtain the title compound IN-1 (320 mg, crude product) as a white solid, which was directly used in the next step.

Intermediate 2

2-Methylthiazole-5-sulfonamide IN-2

Step 1: 2-Methylthiazole-5-sulfonyl chloride IN-2a

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 for reaction for 24 hours, then the temperature was lowered to room temperature, phosphorus pentachloride (3.18 g, 40.3 mmol) was slowly added, and after addition, the temperature was 120 ° C for reaction for 3 hours. After cooling to room temperature, the reaction solution was slowly poured into ice water (20 mL) for quenching, and the temperature was controlled below 5 ° C. TLC showed that the raw material disappeared. The reaction solution 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 obtain the title compound IN-2b (576 mg, crude product) as a yellow oil, which was directly used in the next step.

Step 2 2-Methylthiazole-5-sulfonamide IN-2

Compound IN-2b (656 mg, crude product) was dissolved in 1,4-dioxane (5 mL), and aqueous ammonia (2 mL) was slowly added at room temperature. The reaction solution gradually became turbid. The reaction was continued at room temperature for 30 minutes. TLC showed that the raw material disappeared. The reaction solution was concentrated, and the crude product was chromatographed on a silica gel column (PE/EA=5/1) to obtain the title compound IN-2 (102 mg, two-step yield 2.79%) as a gray solid.

LC-MS: m/z = 179.0 [M + H] ⁺

Example 1

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

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

Compound IN-2 (30 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), 4-dimethylaminopyridine (2.1 mg, 0.02 mmol) and triethylamine (51.1 mg, 0.51 mmol) were added, and the reaction solution was cooled to 0 ° C, and intermediate IN-1 (68 mg, crude product) was added. The reaction was reacted at room temperature for 1 hour. TLC showed that the raw material was completely reacted. The reaction solution was concentrated, the crude product was diluted with water (5 mL), acidified with dilute hydrochloric acid to pH = 5, and 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%).

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.29 (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 sulfonamide was not shown.

Example 2

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

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

5-Bromothiophene-2-sulfonamide 2a (2.40 g, 9.92 mmol) was added to dichloromethane (10 mL), and N,N-dimethylformamide dimethyl acetal (2 mL) was added at room temperature. After addition, the mixture was reacted at room temperature for 20 minutes. TLC showed that the raw material disappeared. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (10 mL x 3), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 2b (3.01 g, crude product) as a light yellow solid, which was used directly in the next step.

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

Compound 2b (2.00 g, 6.734 mmol) was added to dry N,N-dimethylformamide (20 mL), and 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 in sequence at room temperature. After addition, nitrogen was replaced 3 times, and the reaction was carried out at room temperature for 24 hours. TLC showed that the raw material disappeared. The reaction solution was filtered, 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 obtain the title compound 2c (1.15 g, two-step yield 37%) as a light yellow solid.

Step 3 5-ethynylthiophene-2-sulfonamide 2d

Compound 2c (1.15 g, 3.66 mmol) was added to dry N,N-dimethylformamide (20 mL), and tetrabutylammonium fluoride solution (7.3 mL, 1 M) was added thereto. After addition, the mixture was reacted at room temperature for 4 hours. TLC showed that the raw material disappeared. The reaction solution was quenched with water (100 mL), 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 obtain the title compound 2d (450 mg, yield 66%) as a light yellow solid.

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

Dissolve 2,4-dichlorobenzoic acid (204 mg, 1.07 mmol) in dichloromethane (4 mL), add HATU (609 mg, 1.60 mmol) and N,N-diisopropylethylamine (276 mg, 2.14 mmol) at room temperature, react at room temperature for 2 hours, TLC shows that the raw material disappears. Add water (4 mL) to the reaction solution Quench, extract with dichloromethane (2mL x3), combine the organic phases, wash with saturated brine (2mL), dry with anhydrous sodium sulfate, concentrate, dissolve the residue in dichloromethane (4mL), add N,N-diisopropylethylamine (276mg, 2.14mmol) and compound 2d (200mg, 1.61mmol) in turn at room temperature, react at room temperature for 10 hours, TLC shows that the raw material disappears. The reaction solution is quenched with water (4mL), extracted with dichloromethane (2mL x3), combine the organic phases, wash with saturated brine (2mL), dry with anhydrous sodium sulfate, concentrate, and the crude product is purified by Prep-HPLC to obtain the title compound 2 as a white solid (75mg, yield 19%).

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

¹ H NMR (400 MHz, CDCl ₃ ) δ9.16 (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 sulfonamide was not revealed.

Example 3

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

Step 1: 2-Chloro-4-cyanobenzoyl chloride 3b

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 a drop of N,N-dimethylformamide at 0°C, heat to 25°C and react for 1 hour, TLC detection shows that the reaction of the raw material is complete. The reaction solution is concentrated to obtain the title compound 3b (72 mg, crude product) as a yellow oil, which is used directly in the next step.

Step 2 2-Chloro-4-cyano-N-((2-methylthiazol-5-yl)sulfonyl)benzamide 3

The 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, the reaction solution was cooled to 0 ° C, and compound 3b (72 mg, crude product) was added. After the addition, the reaction solution was heated to 25 ° C for 1 hour. TLC showed that the raw material was completely reacted. The reaction solution was concentrated, the crude product was diluted with water (5 mL), acidified with dilute hydrochloric acid to pH = 5, and 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 40 mg of a light yellow solid, and then purified by Prep-HPLC to obtain the title compound 3 as a white solid (12.6 mg, yield 21.9%).

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.20 (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 sulfonamide was not revealed.

Example 4

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

Step 1 2-Chloro-4-ethynylbenzoyl chloride 4b

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 a drop of N,N-dimethylformamide at 0°C, heat to 25°C and react for 1 hour, TLC detection shows that the reaction of the raw material is complete. The reaction solution is concentrated to obtain the title compound 4b (65 mg, crude product) as a yellow oil, which is used directly in the next step.

Step 2 2-Chloro-4-ethynyl-N-((2-methylthiazol-5-yl)sulfonyl)benzamide 4

The 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 completed, the reaction solution was cooled to 0°C and compound 4b (65 mg, crude product) was added. After the addition was completed, the reaction solution was heated to 25°C for 1 hour. TLC showed that the raw material was completely reacted. The reaction solution was concentrated, diluted with water (5 mL), acidified with dilute hydrochloric acid to pH = 5, extracted with ethyl acetate (10 mL x2), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC. The title compound 4 (8.2 mg, yield 14.3%) was obtained as a white solid by purification with MeOH/DCM=1/8.

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.84 (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 sulfonamide was not revealed.

Example 5

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

Step 1 4-sulfamoylbenzene diazonium chloride 5b

Disperse 4-aminobenzenesulfonamide 5a (6.4 g, 37.17 mmol) in a hydrochloric acid (6.3 mL, 205.68 mmol) aqueous solution (35 mL) at 0°C, then add a sodium nitrate (2.65 g, 38.41 mmol) aqueous solution (10 mL), and react at 0°C for 1 hour. TLC shows that the reaction of the raw material is complete. The reaction solution is transparent yellow, and a solution of the title compound 5b (45 mL, crude product) is obtained, which is used directly in the next step.

Step 2 4-Sulfamoylbenzenesulfonyl chloride 5c

Sulfur dioxide gas was passed into 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 product) was added dropwise, and reacted at 25°C for 0.5 hours. TLC detected that the raw material reacted completely. The reaction solution was diluted with water (10 mL), the pH was adjusted to 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 obtain the title compound 5c (1 g, crude product) as a yellow solid, which was directly used in the next step.

Step 3 Benzene-1,4-disulfonamide 5d

Compound 5c (1 g, crude product) was dispersed in 1,4-dioxane (10 mL), and then ammonia water (5 mL) was added to complete the addition. The reaction was carried out at 25°C for 16 hours. TLC showed that the reaction of the raw material was complete. The reaction solution was concentrated, and the crude product was slurried with (MeOH/DCM=1/2, 10 mL) to obtain the title compound 5d (835 mg, three-step yield 9.5%) as a white solid.

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

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

Compound 5d (60 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (5 mL), 4-dimethylaminopyridine (46.5 mg, 0.38 mmol) and triethylamine (154.2 mg, 1.52 mmol) were added, stirred for 10 minutes, cooled to 0°C, and intermediate IN-1 (64.5 mg, crude product, content 82.5%) was added. After the addition, the temperature was raised to 25°C and reacted for 16 hours. LC-MS showed that about 20% of the raw materials remained and 40% of the products were obtained. The reaction solution was purified by Prep-HPLC to obtain the title compound 5 (36.5 mg, yield 35.1%) as a white solid.

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.18 (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 sulfonamide was not revealed.

Example 6

4-Bromo-2-chloro-N-((2-methylthiazol-5-yl)sulfonyl)benzamide

Step 1 4-Bromo-2-chlorobenzoyl chloride 6b

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), and react at room temperature for 1 hour under nitrogen protection. TLC shows that the raw material reacts completely, and the mixture is concentrated to obtain the title compound 6b (crude product, 0.34 mmol) as a yellow solid, which is used directly in the next step.

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

Intermediate IN-2 (50 mg, 0.28 mmol) was dissolved in tetrahydrofuran (2 mL), 4-dimethylaminopyridine (34 mg, 0.028 mmol) was added, and the mixture was stirred for 2 h. Ethylamine (85 mg, 0.84 mmol), compound 6b (crude product, 0.34 mmol) was dissolved in tetrahydrofuran (2 mL), added dropwise to the reaction solution, nitrogen protection, and reacted at room temperature for 1 hour. TLC detected that the raw material reacted completely, water (10 mL) was added, dilute hydrochloric acid (3M, 1.0 mL) was adjusted to pH 3, ethyl acetate (10 mL x 3) was added for extraction, and the organic phases were combined and concentrated. The crude product was purified by silica gel column chromatography (methanol/dichloromethane = 1/10) to obtain the title compound 6 as a white solid (17 mg, two-step yield 15%).

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.84 (s, 1H), 7.59 (d, J＝1.6 Hz, 1H), 7.48-7.41 (m, 2H), 2.63 (s, 3H). The active hydrogen of sulfonamide was not revealed.

Example 7

N-((4-aminophenyl)sulfonyl)-2,4-dichlorobenzamide 7

Step 1: 2,4-Dichloro-N-((4-nitrophenyl)sulfonyl)benzamide 7b

4-nitrobenzenesulfonamide 7a (404 mg, 2.00 mmol) was dissolved in tetrahydrofuran (8 mL), 4-dimethylaminopyridine (24 mg, 0.20 mmol) and triethylamine (607 mg, 6.00 mmol) were added, and intermediate IN-1 (503 mg, crude product) was dissolved in tetrahydrofuran (4 mL), and added dropwise to the reaction solution, nitrogen was protected, and the reaction was carried out at room temperature for 1 hour. TLC detected that the raw material reacted completely, water (40 mL) was added, dilute hydrochloric acid (3 M, 4 mL) was added to adjust the pH to 3, ethyl acetate (20 mL x 3) was added to extract, and concentrated. The crude product was purified by TLC-Prep (methanol/dichloromethane = 1/10) to obtain the title compound 7b (196 mg, yield 26%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )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).

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

Compound 7b (404 mg, 0.52 mmol) was dissolved in ethanol (5 mL), palladium carbon (10%, 20 mg) was added, and hydrogenation was performed at room temperature for 2 hours. TLC detected that the raw material reaction was complete, the reaction solution was filtered through diatomaceous earth, washed with methanol (5 mL), and the filtrate was concentrated and purified by TLC-Prep (7M ammonia-methanol solution/dichloromethane = 1/20) to obtain the title compound 7 (41 mg, yield 23%) as a white solid.

LCMS: m/z = 345.0 [M + H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.49-7.42 (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 sulfonamide was not revealed.

Example 8

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

Step 1: 2,4-Dichloro-N-((4-methoxyphenyl)sulfonyl)benzamide 8b

4-Methoxybenzenesulfonamide 8a (187 mg, 1.00 mmol) was dissolved in tetrahydrofuran (4 mL), 4-dimethylaminopyridine (12 mg, 0.10 mmol) and triethylamine (303 mg, 3.00 mmol) were added, and intermediate IN-1 (251 mg, crude product) was dissolved in tetrahydrofuran (2 mL), and added dropwise to the reaction solution, nitrogen was protected, and the reaction was carried out at room temperature for 1 hour. TLC detected that the raw material reacted completely, water (20 mL) was added, dilute hydrochloric acid (3M, 2 mL) was added to adjust the pH to 3, ethyl acetate (10 mL x 3) was added for extraction, and the organic phases were combined and concentrated. The crude product was purified by TLC-Prep (methanol/dichloromethane = 1/10) to obtain the title compound 8b (245 mg, yield 68%) as a white solid.

LC-MS: m/z = 360.0 [M + H] ⁺

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

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

LCMS: m/z = 346.0 [M + H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.58 (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).

Pharmacological activity test part

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

The affinity test of the compounds in the present disclosure to WDR5 at the molecular level was carried out by the following method:

Compound preparation: Weigh the compound accurately and dissolve it in DMSO (Sigma, D5879) to 10mM stock solution for use. Use 1x HBS-EP buffer (10mM HEPES, pH 7.4, 150mM NaCl, 3.0mM EDTA, and 0.005% (v/v) TW-20) to dilute the stock solution 2-fold to 9 concentrations. The final concentration of the compound in the reaction system is 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39μM, and the final DMSO concentration of the compound is 5%. According to the corresponding experimental procedure design, a certain amount of compound samples are transferred to a 96-well plate (Greiner, 650101) in sequence.

Surface plasmon resonance experiment (SPR): WDR5 protein was coupled to a CM5 chip (Cytiva, BR100530) using the amino coupling method, with a signal value of approximately 9000 response units (RU). Three initialization cycles were first run, followed by sequential injection of the test compounds, with the binding time set to 120 seconds and the dissociation time set to 100 seconds, followed by washing the residual compounds in the chip with a solution containing 50% DMSO. Solvent correction was performed every 48 cycles using 1x HBS-EP buffer containing 4.5%-5.8% DMSO.

Detection and analysis: Biacore8K was used for signal detection, data collection, processing and analysis. The raw data generated by the experiment was processed by Biacore8K data processing software by subtracting the control group parameters and solvent correction, and the static affinity model was used to fit the corresponding _KD value, as shown in Table 1.

Conclusion: The compounds of the embodiments of the present disclosure have a strong affinity with the WDR5 protein at the molecular level.

Table 1. Affinity test results of the compounds disclosed in the present invention and WDR5 protein

Note: N.D. indicates that the compound has no significant binding to WDR5; N.T. indicates that the affinity of the compound has not been tested

Test Example 2: Anti-proliferation activity test of compounds on neuroblastoma cells

The antiproliferative activity of the compounds of the present disclosure on neuroblastoma cells was tested by the following method:

Compound preparation: Weigh the compound accurately and dissolve it in DMSO to 10 mM stock solution for later use. Use DMEM or IMDM medium to dilute the compound to a final test concentration of 10 μM and a final DMSO concentration of 0.1%, and transfer the compound to a 96-well plate for subsequent experiments.

Cell Counting Kit-8 Test (CCK-8): 293T, SK-N-AS, IMR32 and LAN5 cells were inoculated into 96-well cell culture plates at a seeding volume of 2x10 ⁴ cells/well. The corresponding compounds and DMSO control were added to each well and cultured for 72 hours. Then 10 μL of CCK-8 reagent was added to each well and incubated at 37 degrees for 2 hours. The absorbance of the cells at 450 nm was measured using a microplate reader.

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.

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

Table 2. Test results of the antiproliferative activity of some compounds in the present disclosure on neuroblastoma cells

“-”: No significant effect.

Test Example 3: Structural analysis of the complex of some compounds disclosed herein and WDR5

The complex structure analysis of some compounds 2 in the present disclosure was carried out by the following method:

Protein crystal preparation: The expression vector Rosetta2 competent cells of WDR5 were placed in a 37°C constant temperature shaking incubator and cultured until the OD value was 0.6-0.8. IPTG with a final concentration of 0.1 mM was added and cultured at 16°C for 20 hours before the cells were collected. The cells were crushed using a high-pressure cell disruptor and the supernatant was collected after high-speed centrifugation for 30 minutes. 10 mL of Ni-NTA affinity chromatography gel resin was added, stirred and bound at 4°C for 1 hour, and the supernatant was collected by centrifugation and then purified using a decontamination buffer (50 mM Tris pH 7.5, 150 mM NaCl, 50 mM imidazole, The resin was treated with 50 mM Tris pH 7.5, 1 mM TCEP) and elution buffer (50 mM Tris pH 7.5, 150 mM NaCl, 300 mM imidazole, 1 mM TCEP) to obtain the preliminary target protein. After that, an anion exchange chromatography column and a molecular exclusion chromatography column were used to obtain high-purity WDR5 protein, and the sample was collected and the protein purity was identified by SDS-polyacrylamide gel electrophoresis.

The obtained high-purity WDR5 protein was concentrated to 11 mg/mL using an ultrafiltration tube and centrifuged at 12000 rpm for 30 minutes. Crystallization buffer was prepared: 0.1 M Bis-Tris, pH 5.8, 0.2 M ammonium acetate, 30% (w/v) pEG3350. Crystallization conditions were optimized using a 24-well hanging drop plate. 1 mL of buffer per well. The two solutions were mixed in a ratio of 1.5 μL crystallization buffer + 1.5 μL protein solution, and crystals were grown in a constant temperature incubator at 18°C for 2-3 days. The crystals were in the form of flakes. The complex crystals of WDR5 and active compounds were obtained by immersion method.

Detection and analysis: The diffraction data of the crystals were collected at the microcrystal complex beamline BL18U1 of the Shanghai Synchrotron Radiation Source (SSRF). The collected data were processed using HKL3000, including data point selection, indexing, correction, integration, data merging and normalization, to generate MTZ files. The WDR5 empty protein crystal structure resolved by this 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 made less than 0.25. The results are shown in Figure 1.

Test Example 4: In vitro efficacy test of some compounds disclosed herein on acute myeloid leukemia, hepatoma cell lines and pancreatic cancer cell lines

Compound preparation: Weigh the compound accurately and dissolve it in DMSO to 10mM stock solution for later use. Use MEM or RPMI 1640 medium to dilute the compound to a final test concentration of 10μM and a final DMSO concentration of 0.1%, and transfer the compound to a 96-well plate for subsequent experiments.

Cell Counting Kit-8 Test (CCK-8): Hep3B, Huh-7, MV4-11 and Mia-Paca2 cells were inoculated into 96-well cell culture plates at a seeding volume of 2x10 ⁴ cells/well. The corresponding compounds and DMSO control were added to each well and cultured for 72 hours. Then 10 μL of CCK-8 reagent was added to each well and incubated at 37 degrees for 2 hours. The absorbance of the cells at 450 nm was measured using a microplate reader.

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.

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

Conclusion: The compounds of the examples disclosed herein have good antiproliferative activity against hepatoma cells, acute myeloid leukemia cells and pancreatic cancer cells. “-” No significant effect.

Test Example 5: Pharmacokinetic test of some compounds disclosed in the present invention on normal mice

This test case studied the pharmacokinetic properties of compound 2 in mice. Balb/c female mice, 6-8 weeks old, were selected and injected with compound 2 by gavage or tail vein. Whole blood was collected at 5min, 15min, 30min, 1h, 2h, 4h, 8h, and 24h after administration. After centrifugation at 8000rpm for 5min, the upper plasma was collected. The plasma exposure of the drug at different time points was tested by HPLC-MS/MS method, and the pharmacokinetic parameters were calculated. The specific experimental results are as follows:

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

Conclusion: The compound of the embodiment of the present disclosure is rapidly absorbed orally, has extremely high bioavailability, and has a plasma half-life T _1/2 of up to 15.9 h, making it an ideal potential oral drug candidate molecule.

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

This test example studies the efficacy of compound 1 and compound 2 in a neuroblastoma model. Human neuroblastoma IMR32 cells were selected for in vitro monolayer culture and routine digestion and passage with trypsin-EDTA twice a week. When the cell saturation was 80%-90%, the cells were collected, counted, and the inoculation concentration was adjusted to 10,000,000 cells/mouse. The cells were inoculated subcutaneously on the upper right back of the animal. When the tumor grew to about 120 mm ³ , the animals were randomly grouped and dosed according to their weight and tumor volume. The animal weight and tumor volume were measured twice a week. The efficacy data are expressed in terms of tumor volume (TV), tumor inhibition rate (TGI), and relative volume (T/C). The specific experimental data are as follows:

Table 5. Results of efficacy tests of some compounds disclosed herein on the IMR32 CDX mouse neuroblastoma model

n＝6

n＝5

The experimental results showed that there was no obvious abnormality in the health status of the animals during the administration period; compared with the solvent control (Vehicle) group, the low, medium and high dose groups of the disclosed embodiment compound all showed obvious anti-tumor efficacy and had a good dose-effect relationship, with TGI reaching 85.5%, 107.1% and 107.1% respectively, and the tumors of some animals in the high and medium dose groups completely disappeared in the late stage of administration. It can be seen that the disclosed embodiment compound has significant efficacy in the IMR32 human neuroblastoma model.

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

This test example studies the efficacy of compound 2 in a liver cancer model. Human liver cancer Hep3B cells were selected for in vitro monolayer culture and routine digestion and passage with trypsin-EDTA twice a week. When the cell saturation was 80%-90%, the cells were collected, counted, and the inoculation concentration was adjusted to 10,000,000 cells/mouse. The cells were inoculated subcutaneously on the upper right back of the animal. When the tumor grew to about 110 mm ³ , the animals were randomly grouped and dosed according to their weight and tumor volume. The animal weight and tumor volume were measured twice a week. The efficacy data are expressed in terms of tumor volume (TV), tumor inhibition rate (TGI), and relative volume (T/C). The specific experimental data are as follows:

Table 6. Results of efficacy tests of some compounds disclosed herein on the Hep3B CDX mouse hepatoma model

n＝5

The experimental results showed that there was no obvious abnormality in the health status of the animals during the administration period; compared with the solvent control (Vehicle) group, the low-dose and high-dose groups of the disclosed embodiment compounds showed obvious anti-tumor efficacy and good dose-effect relationship, with TGI reaching 40% and 106.8% respectively, and the tumors of some animals in the high-dose 90 mg/kg group completely disappeared in the late stage of administration. It can be seen that the disclosed embodiment compounds have significant efficacy in the Hep3B liver cancer xenograft tumor model.

Test Example 8: Safety test of some compounds disclosed in the present invention on normal mice

This test example studied the safety of compound 1 and compound 2, using female, 6-8 week old ICR mice as the research subjects. The animals were randomly divided into groups according to their weight and orally administered with 100 mg/kg, 300 mg/kg, 400 mg/kg, and 500 mg/kg, respectively. The weight changes, morbidity, and mortality of the animals were observed. The specific results are as follows:

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

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

Test Example 9: Protein Binding Rate Test of Some Compounds Disclosed

The plasma protein binding rate of compound 1 and compound 2 in human plasma was determined by equilibrium dialysis. The left and right chambers were separated by a semipermeable membrane. The drug-containing protein solution was added to the left side, and the blank buffer was added to the right side. The unbound free drug can freely pass through the semipermeable membrane. After a certain period of incubation, the two sides reached equilibrium, and the free drug concentration was equal. The plasma protein binding rate can be calculated by measuring the drug concentration on both sides. The results are shown in Table 8:

Table 8. Protein binding test results of some compounds disclosed in this disclosure

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.

Test Example 10: Hepatocyte Stability Test of Some Compounds of the Disclosure

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 parallel. 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 3220g and 4°C for 45 minutes. Transfer 100 μL of supernatant to the sample injection plate, add 100 μL of pure water to mix, and use for UPLC-MS/MS analysis. The results are shown in Table 9:

Table 9. Results of the hepatocyte stability test of some compounds of the present disclosure

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 not prone to cumulative toxicity.

The applicant declares that the present disclosure uses the above-mentioned embodiments to illustrate the sulfonamide compounds disclosed as WDR5 and Myc interaction blockers and their preparation methods and applications, 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. It should be clear to those skilled in the art 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 protection scope and disclosure scope 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 technical concept of the present disclosure, the technical scheme of the present disclosure can be subjected to a variety of simple modifications, and these simple modifications all belong to the protection scope 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 without contradiction. In order to avoid unnecessary repetition, the present disclosure will no longer describe various possible combinations separately.

Claims (7)

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: ^A1 ring and ^A2 ring 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 is a substituent of the A ¹ ring, m=0-3; R ¹ is independently selected from halogen, C3-C5 cycloalkyl, C1-C3 haloalkyl, -CN, -S(=O) ₂ -NH ₂ , C1-C3 alkyl optionally substituted by 1-3 R ^b , C2-C6 alkenyl, C2-C6 alkynyl; R ^b is independently selected from substituted or unsubstituted C1-C3 alkoxy, where "substituted" means optionally substituted by 1-3 hydroxyl, halogen or C ₁ -C ₃ alkoxy substituents; ^R2 is a substituent of the ^A2 ring, n=0-3; ^R2 is selected from -OH, halogen, _C1 - _C3 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, _C1 - _C3 haloalkyl, -C(O) ^NHRc , -NHC(O) _CH2NHC (O) ^Rc , 3-5 membered cycloalkyl optionally substituted by 1-3 "-CN", 5-7 membered aryl optionally substituted by 1-3 "-CN"; ^Rc is _C1 - _C3 alkyl; L is a chemical bond or a divalent group selected from one or more combinations of C1-6 alkylene, saturated or partially unsaturated C3-10 cycloalkylene, -O-, -NR ^a -, and -NR ^a -C1-6 alkylene; ^Ra 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, CH ₂ in ^Ra can be replaced by -O- or -S-, and H in ^Ra can be replaced by hydroxyl, halogen or C1-C3 alkoxy. The use according to claim 1, wherein the sulfonamide compound represented by formula (I) is the following compound:
The use according to claim 1, characterized in that the interaction between WDR5 and Myc is blocked by specifically binding to the WBM site of WDR5. 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: ^A1 ring and ^A2 ring 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 is a substituent of the A ¹ ring, m=0-3; R ¹ is independently selected from halogen, C3-C5 cycloalkyl, C1-C3 haloalkyl, -CN, -S(=O) ₂ -NH ₂ , C1-C3 alkyl optionally substituted by 1-3 R ^b , C2-C6 alkenyl, C2-C6 alkynyl; R ^b is independently selected from substituted or unsubstituted C1-C3 alkoxy, where "substituted" means optionally substituted by 1-3 hydroxyl, halogen or C ₁ -C ₃ alkoxy substituents; ^R2 is a substituent of the ^A2 ring, n=0-3; ^R2 is selected from -OH, halogen, _C1 - _C3 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, _C1 - _C3 haloalkyl, -C(O) ^NHRc , -NHC(O) _CH2NHC (O) ^Rc , 3-5 membered cycloalkyl optionally substituted by 1-3 "-CN", 5-7 membered aryl optionally substituted by 1-3 "-CN"; ^Rc is _C1 - _C3 alkyl; L is a chemical bond or a divalent group selected from one or more combinations of C1-6 alkylene, saturated or partially unsaturated C3-10 cycloalkylene, -O-, -NR ^a -, and -NR ^a -C1-6 alkylene; ^Ra 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, CH ₂ in ^Ra can be replaced by -O- or -S-, and H in ^Ra can be replaced by hydroxyl, halogen or C1-C3 alkoxy. The use according to claim 4, wherein the sulfonamide compound represented by formula (I) is the following compound:
The use according to claim 4, characterized in that the cancer is selected from 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 Cell tumor, 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, neurotheca, neurofibroma, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, pancreatic cancer. 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: