Sulfonamide compound and use thereof

Abstract

A sulfonamide compound represented by formula (I) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, a preparation method for same and a use of same, and a pharmaceutical composition comprising same. The compound serves as a WDR5 inhibitor, has a remarkable effect as a WDR5 and Myc interaction blocker, and is beneficial to cancer treatment. A1 and A2 each are of a ring structure, and R1 and R2 are substituents.

Description

Sulfonamide compounds and uses thereof Technical Field

[0001] The present disclosure belongs to the field of pharmaceutical chemistry and relates to the technical field of sulfonamide derivatives, and particularly to a sulfonamide compound as an anti-neuroblastoma agent, a preparation method thereof, and uses thereof. Background Art

[0002] WD40 repeat domain protein 5 (WDR5) is a member of the WD40 protein family and contains a circular seven-bladed β-propeller domain. WDR5 is highly conserved across vertebrates, with approximately 90% sequence identity. WDR5 was first discovered to regulate osteoblast differentiation and promote bone formation during skeletal development. In recent years, an increasing number of studies have revealed the biological functions of WDR5, finding that it not only regulates biological behaviors such as cell proliferation, division, apoptosis, signal transduction, gene transcription, and DNA damage repair under physiological conditions, but is also highly correlated with the occurrence and development of various tumors, making it a popular target for tumor therapy.

[0003] WDR5's most important function in vivo is epigenetic regulation. As a member of the histone methyltransferase (HMT) complex, it regulates histone methylation levels and activates target gene transcription. Dysfunction of WDR5 can upregulate the expression of multiple tumor-promoting factors and activate tumor-related signaling pathways, thereby enhancing tumor cell proliferation, metastasis, and drug resistance, driving the epithelial-mesenchymal transition (EMT). WDR5 also acts as a cofactor for the myelocytokine viral oncogene homolog (Myc). As a transcription factor, Myc regulates the transcription of downstream genes by binding to the promoter regions of target genes. This function is limited by Myc's ability to localize to chromatin. Studies have found that approximately 80% of Myc binding to its downstream target gene sequences requires WDR5. Disruption of the WDR5-Myc binding significantly diminishes Myc's ability to induce pluripotent stem cells, thus making WDR5 a key player in Myc-driven tumorigenesis. This mechanism has been confirmed in a variety of Myc-related tumors. In glioblastoma and neuroblastoma, WDR5 can promote the binding of Myc to the coactivator protein-associated arginine methyltransferase 1 (CARM1) promoter, enhancing the proliferation and self-renewal ability of tumor cells. In neuroblastoma, WDR5 co-localizes with N-Myc in the double minute homology gene 2 (MDM2) promoter region, activating MDM2 transcription and inhibiting the expression of the tumor suppressor protein p53. In cholangiocarcinoma, WDR5 maintains high levels of HIF-1α in the body through epigenetic regulation, while also increasing HIF-1α expression through Myc in the transcriptional process, promoting EMT, metastasis, and invasion of tumor cells.

[0004] There are two interaction sites on the surface of WDR5: the WDR5 binding domain (WBM) and the WDR5 interaction domain (WIN). The WBM is a shallow, relatively hydrophobic binding pocket primarily composed of Asn225, Tyr228, Leu240, Phe266, Val268, and Gln289. Proteins such as retinoblastoma binding protein 5 (RBBP5), C-myc, L-myc, N-myc, and KAT8-regulated NSL complex subunit 2 (KANSL2) all interact with WDR5 through this site. The WIN is an arginine-binding pocket composed of amino acids Ala65, Ser91, Asp107, Phe133, Tyr191, Tyr260, and Phe263. Proteins such as mixed lineage leukemia 1-4 (MLL1-4), KAT8-regulated NSL complex subunit 1 (KANSL1), H3, methylphosphoguanosine phosphate binding protein (MBD3), and kinesin heavy chain member 2A (KIF2A) have been reported to interact with WDR5 through this site. Key biological functions of WDR5 rely on the mediation of these two sites, such as direct binding with RBBP5 and SET1 / MLL, and indirect binding with ash2 (lack, small, or homolog)-like (Drosophila) protein (ASH2L) and dpy-30 homolog protein (DPY30), which then assemble into a complex with histone methyltransferase catalytic activity, epigenetically regulating the transcription of target genes (non-patent literature 4). Furthermore, WDR5 interacts with the transcription factor Myc, recruiting Myc to chromatin and enhancing its binding to target gene promoter regions, greatly enhancing its tumor-promoting function (non-patent literature 5, 6). Therefore, targeting the WBM or WIN sites on the surface of WDR5 to design specific protein-protein interaction blockers has become the main strategy for the development of new WDR5 inhibitors.

[0005] Currently, it has been reported that protein-protein interaction blockers designed and developed for the WIN site of WDR5 have strong affinity and good drugability, but their application is limited to the treatment of MLL gene translocation rearrangement leukemia and is not effective for solid tumors. There are few studies on WBM site blockers. Stephen's research team at Vanderbilt University School of Medicine in the United States has conducted multiple rounds of optimization and modification, and the obtained compound No. 12 can specifically bind to the WBM site and interact with the K of WDR5. D The value was 0.10±0.01 μM (Non-patent Documents 7 and 8), but its antitumor effect was not evaluated.

[0006] Therefore, designing and synthesizing highly active compounds that specifically block the interaction between WDR5 and Myc for the treatment of malignant tumors, especially neuroblastoma, has important research significance and application prospects, and is an important direction for potential drug targets and the search for lead compounds.

[0007] Non-Patent References

[0008] 1Matthay KK, Maris JM, Schleiermacher G, Nakagawara A, Mackall CL, Diller L, et al. Neuroblastoma. Nature reviews. Disease primers 2016; 2:16078.

[0009] 2Kholodenko IV, Kalinovsky DV, Doronin, II, Deyev SM, Kholodenko RV. Neuroblastoma Origin and Therapeutic Targets for Immunotherapy. Journal of immunology research 2018; 2018:7394268.

[0010] 3Migliori V, Mapelli M, Guccione E.On WD40 proteins: propelling our knowledge of transcriptional control? Epigenetics 2012; 7:815-22.

[0011] 4Ernst P, Vakoc CR. WRAD: enabler of the SET1-family of H3K4 methyltransferases. Briefings in functional genomics 2012; 11:217-26.

[0012] 5Thomas 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.

[0013] 6Sun 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.

[0014] 7Chen X, Xu J, Wang

[0015] 8Chacón Simon S, Wang F, Thomas LR, Phan J, Zhao B, Olejniczak ET, et al. Discovery of WD Repeat-Containing Protein 5(WDR5)-MYC Inhibitors Using Fragment-Based Methods and Structure-Based Design. Journal of medicinal chemistry 2020;63:4315-33.

[0016] Summary of the Invention

[0017] Based on the above research background, the purpose of the present disclosure is to provide a sulfonamide compound or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, so as to screen out compounds that have excellent performance in terms of efficacy, safety and selectivity as WDR5 inhibitors.

[0018] 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,

[0019] in:

[0020] A 1 Ring and A 2The rings are each independently selected from one of a C6-C30 aryl ring, a C6-C30 aliphatic hydrocarbon ring, a C3-C30 heteroaryl ring, and a C3-C30 aliphatic heterocycle, where "ring" includes monocyclic and polycyclic rings;

[0021] R 1 A 1 Ring substituent, m = 0-3; R 1 independently selected from halogen, C3-C5 cycloalkyl, C1-C3 haloalkyl, -CN, optionally substituted by 1-3 R b Substituted C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; R b Independently selected from substituted or unsubstituted C1-C3 alkoxy, where "substituted" means optionally substituted with 1-3 hydroxyl, halogen or C1-C3 alkoxy substituents;

[0022] R 2 A 2 Ring substituent, n = 0-3; R 2 Selected from -OH, halogen, C1-C3 alkoxy, C1-C3 haloalkyl, -C(O)NHR c 、-NHC(O)CH2NHC(O)R c , 3-5 membered cycloalkyl optionally substituted by 1-3 "-CN", 5-7 membered aryl optionally substituted by 1-3 "-CN"; R c is a C1-C3 alkyl group;

[0023] L is a chemical bond or selected from C1-6 alkylene, saturated or partially unsaturated C3-10 cycloalkylene, -O-, -NR a -、-NR a - a divalent group composed of one or more combinations of C1-6 alkylene groups; R a R is independently selected from H, C1-C10 alkyl, saturated or partially unsaturated C3-6 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-10 aryl group, a CH2 in can be replaced by -O- or -S-, R a The H in the group can be substituted by hydroxy, halogen or C1-C3 alkoxy.

[0024] The compounds disclosed herein are compounds that specifically bind to the WBM site of WDR5, 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. According to the results of crystal complex structure analysis, 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.

[0025] In an optional embodiment of the present disclosure, A 1 Ring represents a cyclic group selected from 5-7 membered cycloalkyl, 5-7 membered cycloalkenyl, 5-7 membered aryl, 5-7 membered heterocyclyl, 5-7 membered heteroaryl, A 2 Ring represents a cyclic group selected from 5-7 membered cycloalkyl, 5-7 membered cycloalkenyl, 5-7 membered aryl, 5-7 membered heterocyclyl, and 5-10 membered heteroaryl; R 1 and R 2 There is at least one halogen as a substituent.

[0026] In an optional embodiment of the present disclosure, A 1 Ring or A 2 The ring is one of the following cyclic structures:

[0027] * indicates the site of connection with the parent nucleus, R as a substituent 1 and R 2 Substitution may be performed at any chemically substitutable site.

[0028] In an optional embodiment of the present disclosure, R 1 or R 2 is selected from H, F, Cl, Br, I, hydroxyl, methyl, methoxy, trifluoromethyl, ethyl, ethynyl, cyclopropyl, cyclopentyl, cyclohexyl, cyano, formamido, cyano-substituted cyclopropyl, cyano-substituted cyclopentyl, cyano-substituted cyclohexyl, phenyl, cyano-substituted phenyl, naphthyl, cyano-substituted naphthyl and one of the following groups:

[0029] *Indicates the site of attachment to the parent nucleus.

[0030] In an optional embodiment of the present disclosure, A 1 Ring and its substituent R 1 The combination is one selected from the following groups:

[0031] In an optional embodiment of the present disclosure, A 2 Ring and its substituent R 2 The combination is one selected from the following groups:

[0032] *Indicates the site of attachment to the parent nucleus.

[0033] The compounds disclosed herein can be used as WDR5-Myc interaction blockers. Specifically, pharmacological experimental results demonstrate that the compounds disclosed herein can specifically bind to the WBM domain of WDR5, blocking the interaction between WDR5 and Myc. Based on this use, the compounds disclosed herein can be used in the preparation of drugs for treating diseases associated with abnormal WDR5 expression leading to abnormal activation of signaling pathways related to Myc, RBBP5, KANSL2, and others.

[0034] It is well known that diseases associated with abnormal expression of WDR5 leading to abnormal activation of signaling pathways such as Myc, RBBP5, and KANSL2 include but are not limited to neuroblastoma, gangliocytoma, ganglioblastoma, ganglioneuroma, ganglioneuroma, sympathetic neuroblastoma, schwannoma, neurofibroma, prostate cancer, triple-negative breast cancer, nasopharyngeal cancer, esophageal cancer, laryngeal cancer, lung cancer, gastric cancer, liver cancer, colorectal cancer, cervical cancer, pancreatic cancer, bladder cancer, retinoblastoma, osteosarcoma, chondrosarcoma, chordoma, rhabdomyosarcoma, multiple myeloma, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and the like. In particular, the drug is suitable for the treatment and relief of neurogenic tumors including neuroblastoma, gangliocytoma, ganglioblastoma, ganglioneuroma, ganglioneuroma, sympathetic neuroblastoma, schwannoma, and neurofibroma.

[0035] Representative compounds of the present disclosure include, but are not limited to, the following compounds:

[0036] Another aspect of the present disclosure provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises the sulfonamide compound disclosed above or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, and a pharmaceutically acceptable carrier and / or excipient, and the pharmaceutical composition can be a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation;

[0037] The pharmaceutical composition may be in the form of an oral dosage form or an injection, wherein the oral dosage form includes capsules, tablets, pills, powders, and granules. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures, and the injection includes physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions.

[0038] In this disclosure, a "pharmaceutically acceptable" ingredient is a substance that is suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic response), ie, at a reasonable benefit / risk ratio.

[0039] In the present disclosure, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent or excipient used to deliver the active substance of the present disclosure or a physiologically acceptable salt thereof to animals or humans. The carrier can be liquid or solid.

[0040] In the present disclosure, the pharmaceutical composition contains a safe and effective amount (such as 0.001-99.9 parts by weight, 0.01-99 parts by weight, or 0.1-90 parts by weight) of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient, wherein the total weight of the composition is 100 parts by weight.

[0041] Alternatively, the pharmaceutical composition disclosed herein contains 0.001-99.9 wt %, more preferably 0.01-99 wt %, and more preferably 0.1-90 wt % of the total weight of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient, wherein the total weight of the composition is 100 wt %.

[0042] In another optional embodiment, the optional ratio of the compound of formula (I) to the pharmaceutically acceptable carrier, excipient or sustained-release agent is that the active ingredient of formula (I) accounts for more than 70% of the total weight ratio, and the remaining part accounts for 0.5-30% of the total weight ratio, or better 1-15%, or most preferably 2-10%.

[0043] The various formulations of the pharmaceutical composition disclosed herein may contain, in a unit dose, 0.5 mg to 200 mg, 2 mg to 100 mg, or even 5 mg to 50 mg of the compound of formula (I), its enantiomers, racemates, pharmaceutically acceptable salts, or mixtures thereof.

[0044] 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.

[0045] The pharmaceutical composition of the present disclosure may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, wherein the compound of formula (I) may be present in a suitable solid or liquid carrier or diluent. The pharmaceutical composition of the present disclosure may also be stored in a suitable sterilizing apparatus for injection or infusion. The pharmaceutical composition may also contain odorants, flavoring agents, and the like.

[0046] The compound of formula (I) disclosed herein or a pharmaceutical composition comprising the compound of formula (I) can be used clinically in mammals (including humans) via oral, nasal, skin, lung or gastrointestinal tract administration routes. An optional route of administration is oral. An optional daily dose is 0.5 mg-100 mg / kg body weight, taken once or in divided doses. Regardless of the method of administration, the optimal dose for an individual should be determined based on the specific treatment. Typically, the dose is started with a small dose and gradually increased until the most suitable dose is found.

[0047] The effective dose of the active ingredient used may vary depending on the compound used, the mode of administration, and the severity of the disease to be treated. However, generally, satisfactory results are achieved when the compounds of the present disclosure are administered at a dose of about 1-100 mg / kg of animal body weight per day, preferably in 1-3 divided doses per day, or in a sustained-release form. For most large mammals, the total daily dose is about 5-500 mg, preferably about 10-250 mg. A dosage form suitable for oral administration comprises about 1-100 mg of the active compound intimately mixed with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to provide the optimal therapeutic response. For example, depending on the exigencies of the treatment condition, several divided doses may be administered daily, or the dose may be reduced proportionally.

[0048] The compound or its pharmaceutically acceptable salt and composition thereof can be administered orally as well as intravenously, intramuscularly or subcutaneously. From the standpoint of ease of preparation and administration, the pharmaceutical composition of choice is a solid composition, particularly a tablet and a solid-filled or liquid-filled capsule. Oral administration of the pharmaceutical composition is optional.

[0049] Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycol, nonionic surfactants and edible oils (such as corn oil, peanut oil and sesame oil), as long as they are suitable for the characteristics of the active ingredient and the specific mode of administration desired. Adjuvants commonly used in the preparation of pharmaceutical compositions may also be advantageously included, such as flavoring agents, coloring agents, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA.

[0050] The active compounds or pharmaceutically acceptable salts thereof and compositions thereof may also be administered parenterally or intraperitoneally. Solutions or suspensions of the active compounds (as free base or pharmaceutically acceptable salts) may also be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquids, polyethylene glycols, and mixtures thereof in oils. Under conventional storage and use conditions, these formulations contain a preservative to prevent the growth of microorganisms.

[0051] The pharmaceutical forms adapted for injection include: sterile aqueous solutions or dispersions and sterile powders (for the temporary preparation of sterile injection solutions or dispersions). In all cases, these forms must be sterile and must be fluid to facilitate syringe discharge of fluid. Must be stable under manufacturing and storage conditions and must be able to prevent the contamination effects of microorganisms (such as bacteria and fungi). Carrier can be a solvent or dispersion medium, wherein containing such as water, alcohol (such as glycerol, propylene glycol and liquid polyethylene glycol), their appropriate mixture and vegetable oil.

[0052] The compound represented by formula (I) or its pharmaceutically acceptable salt and composition thereof can also be administered in combination with other active ingredients or drugs for treating or preventing cancer. When two or more drugs are administered in combination, the effect is generally better than that of the two drugs administered alone.

[0053] Another aspect of the present disclosure provides the use of the compounds of the present disclosure and corresponding pharmaceutical compositions in the preparation of cancer treatment or relief drugs. The compositions and methods provided by the present disclosure can be used to treat a variety of cancers, including prostate, breast, brain, skin, cervical cancer, testicular cancer, etc. More specifically, the cancers that can be treated by the compositions and methods of the present disclosure include, but are not limited to, tumor types such as astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, stomach cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, and sarcoma.More specifically, these compounds are useful in the treatment of: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, VIPoma), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyomas, hemangiomas, lipomas, neurofibromas, fibromas), Colorectal: adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma; Genitourinary: kidney (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia); bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma); prostate (adenocarcinoma, sarcoma); testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary: gallbladder cancer, ampullary carcinoma, bile duct cancer; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma); Tumors), multiple myeloma, malignant giant cell tumor, chordoma, chronic bone metastases (osteochondrosarcoma), benign tumors, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis), meninges (meningiomas, meningosarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal cord fibromas, meningiomas, gliomas, sarcomas; Gynecological: uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma) , unclassified carcinoma), granulosa cell tumor, Sertoli cell tumor, germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, cystosarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma); Hematology: blood (acute and chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, lipoma, hemangioma, dermatofibroma, lupus erythematosus, psoriasis and Adrenal gland: neuroblastoma.In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0054] In an optional embodiment, a compound having a structure represented by the following formula (I) or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof is provided as a drug for treating neurogenic tumors. The present disclosure also provides a compound having a structure represented by the following formula (I) or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof as a drug for treating and alleviating neuroblastoma, gangliocytoma, ganglioblastoma, ganglioneuroma, sympathetic neuroblastoma, schwannoma, and neurofibroma.

[0055] In an optional embodiment, the cancer is selected from neuroblastoma, gangliocytoma, ganglioblastoma, ganglioneuroma, sympathetic neuroblastoma, schwannoma, neurofibroma, prostate cancer, triple-negative breast cancer, nasopharyngeal cancer, esophageal cancer, laryngeal cancer, lung cancer, gastric cancer, liver cancer, colorectal cancer, cervical cancer, pancreatic cancer, bladder cancer, retinoblastoma, osteosarcoma, chondrosarcoma, chordoma, rhabdomyosarcoma, multiple myeloma, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia; in an optional embodiment, the cancer is selected from neurogenic tumors including: neuroblastoma, gangliocytoma, ganglioblastoma, ganglioneuroma, ganglioneuroma, sympathetic neuroblastoma, schwannoma, neurofibroma.

[0056] The present disclosure also provides a method for treating and / or preventing cancer, comprising administering to a human or animal body a therapeutically effective amount of the sulfonamide compound of the present disclosure or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the pharmaceutical composition thereof.

[0057] Explanation of terms

[0058] Unless otherwise stated, some terms used in the specification and claims of this disclosure are defined as follows:

[0059] definition

[0060] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain this disclosure.

[0061] In the present disclosure, the terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps.

[0062] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group, and may refer to a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, such as methylene, ethylene, propylene, or butylene.

[0063] An aliphatic cyclic group refers to a cycloalkyl, cycloalkenyl, cycloalkynyl, etc., which are cyclic structures composed of C and H. If C is replaced by a heteroatom, it becomes an aliphatic heterocyclic group; it also includes the bridged ring and spiro ring forms described below.

[0064] As used herein, term " alkyl " is defined as linear or branched saturated aliphatic hydrocarbon.In some embodiments, alkyl has 1 to 12, for example 1 to 6 carbon atom.For example, as used herein, term " C1-6 alkyl " refers to the linear or branched group (for example methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl, sec-butyl, the tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl) of 1 to 6 carbon atom, it is optionally replaced (this moment this group is referred to as " haloalkyl ") (for example CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl or-CH2CH2CF3 etc.) by 1 or more (such as 1 to 3) applicable substituents such as halogen. The term "C1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0065] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon radical containing one double bond and having 2 to 6 carbon atoms ("C 2-6 The alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present disclosure contain an alkenyl group, the compounds may exist in pure E (entgegen) form, pure Z (zusammen) form, or any mixture thereof.

[0066] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group containing one or more triple bonds, which may be of 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.

[0067] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.), which is optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-6 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl.

[0068] As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including but not limited to (cyclo)propyl, (cyclo)butyl, (cyclo)pentyl, (cyclo)hexyl, (cyclo)heptyl, (cyclo)octyl, (cyclo)nonyl, (cyclo)hexenyl, and the like.

[0069] As used herein, the terms "heterocyclyl", "heterocyclylene" and "heterocycle" refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) cyclic group having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C. For example, a "3-10 membered heterocyclyl" is a saturated or partially unsaturated heterocyclyl having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms independently selected from N, O and S. Examples of heterocyclylene and heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl. The group also encompasses bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc.). The heterocyclylene and heterocyclyl groups may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.

[0070] As used herein, the terms "arylene" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, as used herein, the term "C 6-10 (E)aryl" and "C 6-10 The term "aromatic ring" means an aromatic group containing 6 to 10 carbon atoms, such as (ene)phenyl (phenyl ring) or (ene)naphthyl (naphthalene ring). The (ene)aryl group and the aromatic ring are optionally substituted by one or more (such as one to three) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.) substituted.

[0071] As used herein, the terms "heteroaryl(ene)" and "heteroaromatic ring" refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being for example oxygen, nitrogen or sulfur) and, in each case, may additionally be benzo-fused. In particular, “heteroaryl” or “heteroaromatic ring” is selected from thiophenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof.

[0072] As used herein, the term "aralkyl" preferably refers to an alkyl group substituted with an aryl or heteroaryl group, wherein the aryl, heteroaryl, and alkyl groups are as defined herein. Typically, the aryl group may have 6-14 carbon atoms, the heteroaryl group may have 5-14 ring atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0073] As a more specific terminology explanation is as follows:

[0074] "Alkyl" refers to a saturated aliphatic hydrocarbon group, comprising 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, a saturated straight or branched monovalent hydrocarbon group, wherein the alkyl group may be independently optionally substituted with one or more substituents described in the present disclosure. Further examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group can be optionally substituted or unsubstituted.

[0075] "Alkenyl" refers to a linear or branched monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one C—C is sp 2Double bond, wherein the alkenyl group can be independently optionally substituted with one or more substituents described in the present disclosure, specific examples of which include, but are not limited to, vinyl, allyl, and butylene, etc. The alkenyl group can be optionally substituted or unsubstituted.

[0076] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring comprises 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls. Cycloalkyls may be optionally substituted or unsubstituted.

[0077] "Spiroalkyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Spiroalkyl is divided into single spiro, double spiro or multiple spiroalkyl according to the number of shared spiro atoms between the rings, preferably single spiro and double spiroalkyl, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Non-limiting examples of "spiroalkyl" include, but are not limited to:

[0078] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system. It is preferably 6- to 12-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic or tricyclic, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to:

[0079] "Bridged cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures that share two carbon atoms that are not directly connected to each other. One or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system. It is preferably 6- to 12-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, and more preferably a bicyclic or tricyclic group. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to:

[0080] The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like.

[0081] "Heterocyclyl," "heterocycle," or "heterocyclic" are used interchangeably herein to refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic non-aromatic heterocyclic group containing 3 to 12 ring atoms, wherein at least one ring atom is a heteroatom, such as an oxygen, nitrogen, or sulfur atom. Preferably, the heterocyclic group has a 5- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring, which may contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, and piperazinyl. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl. The heterocyclyl group may be optionally substituted or unsubstituted.

[0082] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) m The heteroatom of m=1 or 2, the remaining ring atoms are carbon, and m=1 or 2. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a bispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a bispiro heterocyclic group. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiro heterocyclic group. Non-limiting examples of "spiro heterocyclic group" include, but are not limited to:

[0083] "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) m The heteroatom of the ring is 1, the remaining ring atoms are carbon, and m = 1 or 2. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclic group" include but are not limited to:

[0084] "Bridged heterocyclic group" refers to a polycyclic group of 5 to 18 members, containing two or more ring structures, sharing two atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) m The heteroatom of the cyclic ring is 1 or 2, and the remaining ring atoms are carbon atoms, and m = 1 or 2. It is preferably 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, and more preferably a bicyclic or tricyclic group. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to:

[0085] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused manner. The term "aryl" includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl. Preferably, aryl is C6-C 10 Aryl, more preferably phenyl and naphthyl, most preferably phenyl. Aryl can be substituted or unsubstituted. The "aryl" can be fused with a heteroaryl, a heterocyclic group or a cycloalkyl group, wherein the aryl ring is connected to the parent structure. Non-limiting examples include but are not limited to:

[0086] "Heteroaryl" refers to an aromatic 5 to 6-membered monocyclic or 9 to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. The embodiment of "heteroaryl" includes, but is not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl and benzisoxazolyl. Heteroaryl can be optionally substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:

[0087] "Alkoxy" refers to a group (alkyl-O-). Alkyl is defined herein. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0088] "Haloalkyl" refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as described in this disclosure. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.

[0089] "Carboxylate" refers to -C(O)O(alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0090] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and at least one nitrogen atom in the ring, which may optionally further contain one or more (e.g., one, two, three or four) ring members selected from N, O, C=O, S, S=O and S(=O)2, which is connected to the rest of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atoms, and the nitrogen-containing heterocycle is optionally benzo-fused and can be 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.

[0091] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0092] If a substituent is described as being "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0093] 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.

[0094] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0095] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0096] 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.

[0097] The present disclosure also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present disclosure except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of suitable isotopes for inclusion in the compounds of the present disclosure include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the present disclosure (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e., 14C) are particularly useful for this purpose because of their ease of incorporation and ease of detection. 11 C. 18 F. 15 O and 13 N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present disclosure can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present disclosure include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0098] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0099] As used herein, "substituted" or "substituted", unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -C(O)R b 、-OC(O)R b 、-NR b R b 、-C(O)NR b R b 、-NR b C(O)R b 、-S(O)NR b R b or -S(O)2NR b R b , where R b The definition of is as described in the general formula (I).

[0100] As used herein, a "therapeutically effective dose" of a compound is an amount sufficient to ameliorate or in some way reduce the symptoms, halt or reverse the progression of a condition. Such a dose may be administered as a single dose or according to a regimen to be effective. As used herein, "treat" means to ameliorate or otherwise modify the symptoms or pathology of a patient's condition, disorder, or disease in any way.

[0101] As used herein, "amelioration of the symptoms of a particular disease by administration of a particular compound or pharmaceutical composition" refers to any reduction, whether permanent or temporary, long-lasting or transient, attributable to or associated with the administration of that composition.

[0102] The compounds of the present disclosure may contain asymmetric or chiral centers and, therefore, exist as different stereoisomers. All stereoisomeric forms of the compounds of the present disclosure, including but not limited to diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute part of the present disclosure. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity.

[0103] "Tautomers" or "tautomeric forms" refer to structural isomers of different energies that are interconvertible via a low energy barrier. Single stereochemical isomers of the disclosed compounds or mixtures of their enantiomers, diastereomers, or geometric isomers are within the scope of the present disclosure.

[0104] In this article, solid lines can be used Solid wedge or virtual wedge The chemical bonds of the compounds of the present disclosure are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomer shown exists. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present disclosure are intended to exist in the form of stereoisomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present disclosure may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0105] The present disclosure encompasses all possible crystalline forms or polymorphs of the compounds of the present disclosure, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0106] It should also be understood that certain compounds of the present disclosure may exist in free form for treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present disclosure, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, chelates, complexes, inclusion compounds, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present disclosure or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present disclosure," the various derivative forms of the compounds described above are also intended to be encompassed.

[0107] 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.

[0108] Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyphenate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate.

[0109] Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. Methods for preparing pharmaceutically acceptable salts of the compounds of the present disclosure are known to those skilled in the art.

[0110] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present disclosure in the form of free acid or alcohol). The compounds of the present disclosure themselves can also be esters.

[0111] 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.

[0112] Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane.

[0113] Also included within the scope of the present disclosure are metabolites of the compounds of the present disclosure, i.e., substances formed in vivo upon administration of the compounds of the present disclosure. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Thus, the present disclosure includes metabolites of the compounds of the present disclosure, including compounds produced by contacting the compounds of the present disclosure with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0114] 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 to or on the body. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted in vivo into the desired therapeutically active compound.

[0115] The present disclosure also encompasses compounds of the present disclosure that contain protecting groups. In any process for preparing the compounds of the present disclosure, it may be necessary and / or desirable to protect sensitive or reactive groups on any related molecules, thereby forming a chemically protected form of the compounds of the present disclosure. This can be achieved by conventional protecting groups, for example, those described in TW Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0116] The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0117] The present disclosure provides a novel WDR5 / Myc interaction blocker. Experimental results show that this type of derivative exhibits excellent anti-neuroblastoma activity, as well as excellent safety and selectivity, and can be used to prepare drugs for treating cancer, especially neuroblastoma and other diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0118] FIG1 is a schematic diagram of the crystal structure of the complex of the disclosed compound and WDR5. DETAILED DESCRIPTION

[0119] The method of the present disclosure is described below through specific examples to make the technical solution of the present disclosure easier to understand and grasp, but the present disclosure is not limited to this. 1 H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are in Hz.

[0120] Mass spectra were obtained using an LC / MS instrument with ESI ionization. High-performance liquid chromatograph models: Agilent 1260, Thermo Fisher Scientific U3000; chromatographic column: Waters xbrige C18 (4.6*150 mm, 3.5 μm); mobile phase: A: ACN, B: Water (0.1% H₃PO₄); flow rate: 1.0 mL / min; gradient: 5% A for 1 min, increase to 20% A within 4 min, increase to 80% A within 8 min, 80% A for 2 min, back to 5% A within 0.1 min; wavelength: 220 nm; column oven: 35°C. Thin-layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used for thin-layer chromatography (TLC) are 0.2mm-0.3mm in size, and the plates used for TLC separation and purification products are 0.4mm-0.5mm in size. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0121] In the following examples, all temperatures are in degrees Celsius unless otherwise indicated. Starting materials and reagents were commercially available or synthesized according to known methods, and were used without further purification unless otherwise indicated. Commercial suppliers include, but are not limited to, Sinopharm Group, J&K Technology Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Shanghai Bidex Pharmaceutical Technology Co., Ltd., and Shanghai Myrel Chemical Technology Co., Ltd. CD3OD: deuterated methanol; CDCl3: deuterated chloroform; DMSO-d6: deuterated dimethyl sulfoxide; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos: 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl; HATU: 2-(7-benzotriazole oxide) -N,N,N',N'-tetramethyluronium hexafluorophosphate; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBT: 1-hydroxybenzotriazole; BINAP: 1,1'-binaphthyl-2,2'-bis(diphenylphosphine); DCM: dichloromethane; PE: petroleum ether; EA: ethyl acetate; MeOH: methanol; DMF: N,N-dimethylformamide; TLC: thin layer chromatography; HPLC: high performance liquid chromatography; purity: purity; R f In thin-layer chromatography, the ratio of the distance from the origin to the center of the spot to the distance from the origin to the solvent front. A hydrogen atmosphere refers to a hydrogen balloon with a capacity of approximately 1 L connected to the reaction flask.

[0122] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C-30°C. The reaction progress in the examples is monitored by thin layer chromatography (TLC). The developing solvent used in the reaction and the eluent system for column chromatography or thin layer chromatography used to purify the compound include: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane:ethyl acetate; the volume ratio of the solvent varies according to the polarity of the compound and can be adjusted by adding a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine. The reagent providing alkaline conditions is selected from organic bases or inorganic bases, the organic bases are one or more of triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium tert-butoxide, sodium methoxide and potassium tert-butoxide, and the inorganic bases are 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 providing acidic conditions is one or more of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a methanol solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid and phosphoric acid;

[0123] The metal catalyst is one or more of palladium / carbon, Raney nickel, tetrakistriphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, bistriphenylphosphine palladium dichloride (Pd(PPh3)2Cl2) and tris(dibenzylideneacetone)dipalladium (Pd2(dba)3);

[0124] 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'-bisdiphenylphosphine (BINAP);

[0125] The reducing agent is one or more of sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and lithium aluminum tetrahydride;

[0126] The oxidizing agent is one or more of potassium permanganate, manganese dioxide, potassium dichromate, sodium dichromate and potassium osmate;

[0127] 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.

[0128] Pharmaceutical chemical synthesis

[0129] Preparation of intermediates

[0130] Intermediate 1

[0131] 2,4-Dichlorobenzoyl chloride IN-1

[0132] Step 1: 2,4-dichlorobenzoyl chloride IN-1

[0133] N,N-dimethylformamide (3 drops) was slowly added dropwise to a mixture of 2,4-dichlorobenzoic acid IN-1a (300 mg, 1.57 mmol) and oxalyl chloride (3 mL, 35.5 mmol) in anhydrous tetrahydrofuran (15 mL) at 0°C. The mixture was allowed to react at room temperature for 2 hours. TLC indicated the disappearance of the starting material. The reaction mixture was concentrated to afford the title compound IN-1 (320 mg, crude) as a white solid, which was used directly in the next step.

[0134] Example 1

[0135] 2,4-Dichloro-N-((2,4-dimethylthiazol-5-yl)sulfonyl)benzamide 1

[0136] Step 1: 2,4-Dimethyl-1,3-thiazole-5-sulfonyl chloride 1b

[0137] 2,4-Dimethylthiazole 1a (5.00 g, 44.2 mmol) was slowly added dropwise to chlorosulfonic acid (10 mL) at room temperature. The reaction mixture was heated to 140°C and allowed to react for 18 hours. The reaction mixture cooled to room temperature and phosphorus pentachloride (18.4 g, 88.4 mmol) was slowly added. A vigorous exotherm occurred (be careful to prevent spraying). After the addition, the temperature was raised to 120°C and the reaction continued for 3 hours. TLC indicated the disappearance of the starting material. The reaction mixture was cooled to room temperature and slowly added dropwise to ice water (100 mL). Dichloromethane (20 mL x 3) was added for extraction. The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound 1b (9.3 g, crude) as a brownish-yellow oil, which was used directly in the next step.

[0138] Step 2: 2,4-Dimethylthiazole-5-sulfonamide 1c

[0139] Compound 1b (8.8 g, crude) was dissolved in 1,4-dioxane (50 mL), cooled to 0°C, and aqueous ammonia (15 mL) was slowly added dropwise. After completion of the dropwise addition, the reaction was continued at 0°C for 10 minutes. TLC indicated the disappearance of the starting material. The reaction solution was slowly poured into ice water (100 mL) and acidified to approximately pH 3 with dilute hydrochloric acid (3N). Extraction was performed with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 1c (7.2 g, crude) as a brown-yellow oil, which was used directly in the next step.

[0140] Step 3 2,4-dichloro-N-((2,4-dimethylthiazol-5-yl)sulfonyl)benzamide 1

[0141] Compound 1c (230 mg, crude) was dissolved in ethyl acetate (10 mL). 4-Dimethylaminopyridine (5 mg, 0.04 mmol), triethylamine (2 mL, 14.4 mmol), and a toluene solution of intermediate IN-1 (320 mg, crude) (15 mL) were added sequentially at room temperature. The mixture was allowed to react at room temperature for 10 hours. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-HPLC to afford the title compound 1 (116 mg, 23.73% yield over three steps) as a white solid.

[0142] LC-MS: m / z=364.9[M+H] + (99.30% purity by HPLC, 210nm)

[0143] 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 2.0 Hz, 1H), 7.56-7.50 (m, 2H), 2.69 (s, 3H), 2.58 (s, 3H). (Active hydrogen of sulfonamide is not shown)

[0144] Example 2

[0145] N 1 -((5-bromothien-2-yl)sulfonyl)-5-(1-cyanocyclopentyl)-2-hydroxy-N 3 -Methylisophthalamide 2

[0146] Step 1: 3-Bromo-5-formyl-2-hydroxybenzoic acid 2b

[0147] 5-Formylsalicylic acid 2a (10.10 g, 60.19 mmol) was dissolved in DMF (100 mL), and the temperature was lowered to 0°C. N-bromosuccinimide (NBS) (10.87 g, 61.07 mmol) was slowly added thereto. After the addition, the temperature was slowly raised to 70°C and the reaction was continued for 2 hours. The reaction was monitored by TLC (DCM / MeOH = 5 / 1, R f =0.2) The starting material reacted completely, and the reaction solution was quenched by adding water (300 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound 2b (15.02 g, crude product) as a yellow solid, which was used directly in the next step.

[0148] Step 2: Methyl 3-bromo-5-formyl-2-methoxybenzoate 2c

[0149] Compound 2b (15.02 g, crude product) was added to DMF (100 mL), and potassium carbonate (25.34 g, 183.62 mmol) and iodomethane (21.73 g, 153.05 mmol) were added. After the addition was complete, the reaction solution was stirred at room temperature for 18 hours. The reaction mixture was detected by TLC (DCM / MeOH=5 / 1, R f =0.2) The starting material reacted completely, and the reaction solution was quenched by adding water (300 mL), extracted with ethyl acetate (100 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain the title compound 2c (5.40 g, two-step yield 32%) as a white solid.

[0150] 1 H NMR (400MHz, CDCl3) δ9.93 (s, 1H), 8.26 (dd, J = 4.8, 2.4Hz, 2H), 4.01 (s, 3H), 3.97 (s, 3H).

[0151] Step 3: Methyl 3-bromo-5-(hydroxymethyl)-2-methoxybenzoate 2d

[0152] Compound 2c (10.00 g, 36.62 mmol) was added to methanol (200 mL), and the temperature was lowered to 0-5°C. Sodium borohydride (813 mg, 21.9 mmol) was slowly added thereto. Stirring was continued for 30 minutes after addition. TLC analysis (PE / EA=4 / 1, R f =0.6) The starting material reacted completely, and the reaction solution was quenched by adding water (200 mL), extracted with ethyl acetate (100 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 2d (10.50 g, crude product) as a yellow oil, which was used directly in the next step.

[0153] Step 4: Methyl 3-bromo-2-methoxy-5-(((methylsulfonyl)oxy)methyl)benzoate 2e

[0154] Compound 2d (10.50 g, crude product) was added to dichloromethane (100 mL), and triethylamine (5.50 g, 54.4 mmol) was added thereto. The reaction solution was cooled to 0-5°C, and methylsulfonyl chloride (4.68 g, 40.8 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was stirred for 30 minutes and monitored by TLC (PE / EA=4 / 1, R f =0.2) was reacted completely, and the reaction solution was quenched by adding saturated brine (100 mL), extracted with dichloromethane (50 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound 2e (11.82 g, crude product) as a yellow oil, which was used directly in the next step.

[0155] Step 5: Methyl 3-bromo-5-(cyanomethyl)-2-methoxybenzoate 2f

[0156] Compound 2e (11.82 g, crude product) was added to acetonitrile (100 mL), and potassium carbonate (9.24 g, 66.95 mmol) and trimethylsilyl cyanide (5.00 g, 50.39 mmol) were added thereto. After the addition was complete, the reaction solution was stirred at room temperature for 18 hours. The reaction mixture was detected by TLC (PE / EA=4 / 1, R f =0.6) the reaction was complete, the reaction solution was quenched with water (100 mL), extracted with ethyl acetate (100 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated, and the crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain the title compound 2f (4.24 g, three-step yield 40.76%) as a white solid

[0157] Step 6: 2g of methyl 3-bromo-5-(1-cyanocyclopentyl)-2-methoxybenzoate

[0158] Compound 2f (104 mg, 0.385 mmol) was added to dry tetrahydrofuran (5 mL), and the reaction solution was cooled to 0°C. Sodium bis(trimethylsilyl)amide tetrahydrofuran solution (0.45 mL, 0.90 mmol, 2 M / L) was slowly added dropwise. After the addition was complete, the reaction solution was allowed to react at 0°C for 30 minutes. 1,4-dibromobutane (83 mg, 0.39 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was allowed to react at 0°C for 30 minutes. TLC (PE / EA=4 / 1, R f=0.3) to monitor the reaction completion. The reaction solution was quenched by adding saturated brine (20 mL), extracted with dichloromethane (20 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain 2 g (30 mg, 24.23% yield) of the title compound as a colorless oil.

[0159] 1 H NMR (400MHz, CDCl3) δ7.81(s,2H),3.94(s,3H),3.93(s,3H),2.53-2.46(m,2H),2.08-1.94(m,6H).

[0160] Step 7: 3-Bromo-5-(1-cyanocyclopentyl)-2-methoxybenzoic acid 2h

[0161] Compound 2g (2.94g, 8.69mmol) was added to a mixed solution of methanol (15mL) and water (5mL), and sodium hydroxide (452mg, 11.3mmol) was added thereto. The reaction solution was reacted at room temperature for 4 hours. The reaction was monitored by TLC (PE / EA=4 / 1, R f =0.6) The reaction was complete. The reaction solution was concentrated under reduced pressure at 20°C to remove the methanol. Dilute hydrochloric acid (1M / L) was slowly added dropwise to acidify to pH 4-5. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 2h (2.81 g, 99%) as a white solid.

[0162] LC-MS: m / z = 326.0 [M+H] + .

[0163] Step 8: 3-Bromo-5-(1-cyanocyclopentyl)-2-methoxy-N-methylbenzamide 2i

[0164] Compound 2h (2.81 g, 8.67 mmol) was added to dichloromethane (30 mL), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (6.60 g, 17.3 mmol), methylamine hydrochloride (877 mg, 13.0 mmol) and N,N-diisopropylethylamine (4.47 g, 34.6 mmol) were added thereto. The reaction solution was reacted at room temperature for 18 hours. The reaction mixture was detected by TLC (DCM / MeOH=10 / 1, R f =0.2) was completed, the reaction solution was quenched with water (20 mL), extracted with dichloromethane (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated, and the crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain the title compound 2i (2.62 g, yield 89.73%) as a colorless oily liquid.

[0165] Step 9: Methyl 5-(1-cyanocyclopentyl)-2-methoxy-3-(methylcarbamoyl)benzoate 2j

[0166] Compound 2i (284 mg, 0.842 mmol) was dissolved in a mixed solution of methanol (10 mL) and DMF (2 mL), and the mixture was transferred to an autoclave. Bistriphenylphosphine palladium dichloride (100 mg, 0.142 mmol) was added thereto. Carbon monoxide was replaced three times. Carbon monoxide was flushed into the mixture while maintaining the pressure at 3-4 atmospheres. The reaction solution was heated to 90°C for 18 hours and monitored by TLC (PE / EA=1 / 1, R f =0.4) A large amount of starting material remained, and the reaction solution was concentrated to dryness. The crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to obtain the title compound 2j (21 mg, yield 7.88%) as a colorless oily liquid.

[0167] LC-MS: m / z = 317.2 [M+H] +

[0168] Step 10: 5-(1-cyanocyclopentyl)-2-methoxy-3-(methylcarbamoyl)benzoic acid 2k

[0169] Compound 2j (61 mg, 0.19 mmol) was added to a mixed solution of methanol (2 mL) and water (2 mL), and sodium hydroxide (15 mg, 0.37 mmol) was added thereto. The reaction was continued at room temperature for 18 hours after the addition was completed. The reaction was monitored by TLC (PE / EA=1 / 1, R f =0.5) and the reaction was complete. The methanol in the reaction solution was concentrated and removed, and water (20 mL) was added to quench the reaction. Dilute hydrochloric acid (1 M / L) was slowly added dropwise to acidify to a pH of 4-5. Extraction was performed with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford the title compound 2k (30 mg, crude) as a white solid, which was used directly in the next step.

[0170] LC-MS: m / z = 301.1 [MH] -

[0171] Step 11N 1 -((5-bromothien-2-yl)sulfonyl)-5-(1-cyanocyclopentyl)-2-methoxy-N 3 -Methylisophthalamide 2L

[0172] Compound 2k (30 mg, 0.099 mmol) was added to dichloromethane (5 mL), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (60 mg, 0.15 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.5 mmol) were added thereto. After the addition was complete, the reaction solution was reacted at room temperature for 18 hours and monitored by TLC (DCM / MeOH=10 / 1, R f =0.2) reaction was complete. The reaction solution was quenched with water (10 mL), extracted with dichloromethane (5 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was dissolved in dichloromethane (5 mL), and 5-bromothiophene-2-sulfonamide (30 mg, 0.12 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.5 mmol) were added in sequence, and reacted at room temperature for 4 hours. The reaction was monitored by TLC (DCM / MeOH=20 / 1, R f =0.4) was completed, the reaction solution was quenched with water (5 mL), extracted with dichloromethane (10 mL x 2), the organic phases were combined and concentrated, and the crude product was purified by silica gel column chromatography (DCM / MeOH = 60 / 1) to give the title compound 2L (30 mg, two-step yield 30.00%) as a white solid.

[0173] LC-MS: m / z = 526.0 [M+H] +

[0174] Step 12N 1 -((5-bromothien-2-yl)sulfonyl)-5-(1-cyanocyclopentyl)-2-hydroxy-N 3 -Methylisophthalamide 2

[0175] Compound 2L (30 mg, 0.056 mmol) was added to dichloromethane (4 mL), and a boron tribromide-dichloromethane solution (2 mL, 2 mmol, 1 M / L) was added thereto. After the addition was complete, the reaction solution was reacted at room temperature for 1 hour and monitored by TLC (DCM / MeOH = 20 / 1, R f =0.5) The reaction was complete. The reaction solution was quenched with water (10 mL) and extracted with dichloromethane (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain the title compound 2 as a white solid (20 mg, yield 68.49%).

[0176] LC-MS: m / z = 512.0 [MH] + (97.35% purity, 220nm)

[0177] 1H NMR (400 MHz, DMSO-d6) δ 15.98 (s, 1H), 8.51 (d, J = 4.4 Hz, 1H), 8.02 (dd, J = 6.8, 2.8 Hz, 2H), 7.41 (d, J = 3.6 Hz, 1H), 7.19 (d, J = 4.0 Hz, 1H), 2.83 (d, J = 4.8 Hz, 3H), 2.36 (dd, J = 17.6, 4.8 Hz, 2H), 2.05-1.95 (m, 2H), 1.91-1.84 (m, 4H). (The active hydrogen of the sulfonamide is not shown).

[0178] Example 3

[0179] 2,4-Dichloro-N-((2-chloro-4-methylthiazol-5-yl)sulfonyl)benzamide 3

[0180] Step 1: 2-Chloro-4-methylthiazole-5-sulfonamide 3b

[0181] Dissolve 2-chloro-4-methylthiazole-5-sulfonyl chloride 3a (160 mg, 0.689 mmol) in 1,4-dioxane (1 mL). Cool to 0°C and slowly add aqueous ammonia (0.5 mL) dropwise. After addition, warm the reaction mixture to room temperature and allow to react for 10 minutes. TLC indicated complete reaction. The reaction mixture was concentrated to afford the title compound 3b (169 mg, crude) as a white solid, which was used directly in the next step.

[0182] LC-MS: m / z = 212.9 [M+H] +

[0183] Step 2 2,4-dichloro-N-((2-chloro-4-methylthiazol-5-yl)sulfonyl)benzamide 3

[0184] Compound 3b (213 mg, 1.02 mmol) was dissolved in ethyl acetate (2 mL). Triethylamine (322 mg, 3.18 mmol) and 4-dimethylaminopyridine (10 mg, 0.079 mmol) were added sequentially at room temperature. Compound IN-1 (214 mg, 1.02 mmol) in toluene (1 mL) was then added. The reaction was allowed to react overnight at room temperature. TLC indicated complete reaction. The reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (1 mL x 3). The combined organic phases were washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether = 1 / 3) to afford the title compound 3 (60 mg, 23% yield over two steps) as a white solid.

[0185] LC-MS: m / z=384.9[M+H] +(98.43% purity by HPLC, 210nm)

[0186] 1 H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 8.4, 2.0 Hz, 1H), 2.53 (s, 3H). (The active hydrogen of the sulfonamide is not shown).

[0187] Example 4

[0188] 2,4-Dichloro-N-((2-chloro-4-cyclopropylthiazol-5-yl)sulfonyl)benzamide

[0189] Step 1-Cyclopropyl-2-thiocyanate-1-one 4b

[0190] Compound α-bromocyclopropylethyl ketone 4a (20.1 g, 123 mmol) was dissolved in anhydrous ethanol (170 mL). Sodium thiocyanate (12.1 g, 149 mmol) was added at room temperature and allowed to react for 10 hours. TLC monitoring revealed the disappearance of the starting material. The mixture was filtered, and the filter cake was washed with anhydrous ether (50 mL x 2). The filtrate was concentrated, and the crude product was dissolved in anhydrous ether (50 mL x 2). The mixture was filtered and the filtrate was concentrated to afford the title compound 4b (10.2 g, crude) as a dark brown liquid, which was directly carried to the next step.

[0191] Step 2: 2-Chloro-4-cyclopropylthiazole 4c

[0192] Compound 4b (10.2 g, crude product) was dissolved in dichloromethane (120 mL). Dry hydrogen chloride gas was slowly introduced at 0°C for 1 hour. The mixture was then slowly warmed to room temperature and the reaction continued for 10 hours. TLC indicated the disappearance of the starting material. The reaction solution was quenched with water (200 mL) and extracted with dichloromethane (60 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to obtain the title compound 4c (4.11 g, 20.4% yield for two steps) as a light yellow liquid.

[0193] LCMS: m / z = 160.1 [M+H] +

[0194] 1 H NMR (400MHz, CDCl3) δ6.73 (s, 1H), 1.96 (tt, J = 8.2, 5.2Hz, 1H), 0.95-0.86 (m, 4H).

[0195] Step 3: 2-Chloro-4-cyclopropylthiazole-5-sulfonyl chloride 4d

[0196] Under nitrogen, compound 4c (300 mg, 1.88 mmol) was dissolved in anhydrous tetrahydrofuran (7 mL), cooled to -70°C, and n-butyllithium (2.5 M in n-hexane, 1 mL) was slowly added dropwise, with a slight temperature increase. After addition, the reaction was continued at -70°C for 10 minutes. Dry sulfur dioxide gas was introduced for 20 minutes, and the reaction was continued for 10 minutes before returning to room temperature for 1 hour. The reaction solution was concentrated, and the residue was dissolved in dichloromethane (3 mL). N-chlorosuccinimide (376 mg, 2.82 mmol) was added and allowed to react at room temperature for 10 hours. TLC indicated the disappearance of the starting material. The reaction solution was quenched with water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound 4d (322 mg, crude) as a colorless oil, which was used directly in the next step.

[0197] Step 4: 2-chloro-4-cyclopropylthiazole-5-sulfonamide 4e

[0198] Compound 4d (322 mg, crude product) was dissolved in 1,4-dioxane (2 mL) and aqueous ammonia (25%, 0.5 mL) was added at room temperature. After addition, the mixture was allowed to react at room temperature for 10 minutes. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to obtain the title compound 4e (178 mg, 40% yield for two steps) as a white solid.

[0199] LCMS: m / z = 238.9 [M+H] +

[0200] 1 H NMR (400MHz, CDCl3) δ5.10 (s, 2H), 2.52 (dq, J = 8.0, 5.2Hz, 1H), 1.18-1.08 (m, 4H).

[0201] Step 5: 2,4-dichloro-N-((2-chloro-4-cyclopropylthiazol-5-yl)sulfonyl)benzamide 4

[0202] 2,4-Dichlorobenzoic acid (80 mg, 0.42 mmol) was dissolved in dichloromethane (2 mL). HATU (239 mg, 0.63 mmol) and N,N-diisopropylethylamine (108 mg, 0.84 mmol) were added at room temperature. After addition, the mixture was allowed to react at room temperature for 2 hours. TLC showed the disappearance of the starting material. The reaction solution was quenched with water (2 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was dissolved in dichloromethane (2 mL), and compound 4e (100 mg, 0.42 mmol) was added. The mixture was allowed to react at room temperature for 10 hours. TLC showed the disappearance of the starting material. The reaction solution was quenched with water (2 mL), extracted with dichloromethane (1 mL x 3), and the organic phases were combined, washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Pre-HPLC (acetonitrile / water = 60 / 40) to obtain the title compound 4 as a white solid (35 mg, yield 20%).

[0203] LC-MS: m / z = 408.9 [MH] - (99.38% purity by HPLC, 210nm)

[0204] 1 H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.8, 2.0 Hz, 1H), 2.72-2.65 (m, 1H), 1.21-1.13 (m, 4H). (The active hydrogen of the sulfonamide is not shown).

[0205] Example 5

[0206] N-((5-bromothiophen-2-yl)sulfonyl)-2-chloro-4-(trifluoromethyl)benzamide 5

[0207] Step 1: 2-Chloro-4-(trifluoromethyl)benzoyl chloride 5b

[0208] 2-Chloro-4-(trifluoromethyl)benzoic acid 5a (202 mg, 0.90 mmol) was added to tetrahydrofuran (10 mL), cooled to 0°C, and N,N-dimethylformamide (4 drops) was added. After reacting at 0°C for 2 minutes, oxalyl chloride (2 mL, 23.6 mmol) was slowly added dropwise. After addition, the mixture was warmed to room temperature and reacted for 4 hours. TLC indicated the disappearance of the starting material. The reaction solution was concentrated to dryness to obtain the title compound 5b (230 mg, crude) as a white solid, which was used directly in the next step.

[0209] Step 2 N-((5-bromothiophen-2-yl)sulfonyl)-2-chloro-4-(trifluoromethyl)benzamide 5

[0210] 5-Bromothiophene-2-sulfonamide (258 mg, 1.06 mmol) was dissolved in dichloromethane (10 mL). 4-Dimethylaminopyridine (5 mg, 0.04 mmol), compound 5b (230 mg, crude), and triethylamine (2 mL, 14.4 mmol) were added sequentially at room temperature. The reaction was allowed to react at room temperature for 2 hours. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-HPLC to afford the title compound 5 (25 mg, 6% yield) as a white solid.

[0211] LC-MS: m / z = 447.8 [M+H] + (96.61% purity by HPLC, 254nm)

[0212] 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.78 (q, J = 8.4 Hz, 2H), 7.70 (d, J = 4.0 Hz, 1H), 7.42 (d, J = 4.4 Hz, 1H). (Active hydrogen of sulfonamide is not shown)

[0213] Example 6

[0214] N1-((5-bromothiophen-2-yl)sulfonyl)-4-chloro-2-hydroxy-N3-methylisophthalamide 6

[0215] Step 1: 4-Chloro-3-formyl-2-hydroxybenzoic acid 6b

[0216] 4-Chloro-3-formyl-2-hydroxybenzoic acid 6a (3.01 g, 17.4 mmol) was added to trifluoroacetic acid (70 mL). Hexamethylenetetramine (4.86 g, 34.71 mmol) and cuprous oxide (2.48 g, 17.3 mmol) were added at room temperature. After addition, the reaction mixture was heated to 80°C for 10 hours. TLC indicated the disappearance of the starting material. The reaction mixture was cooled to room temperature and hydrochloric acid (3N, 70 mL) was slowly added dropwise. After addition, the reaction mixture was allowed to continue at room temperature for 2 hours. The mixture was concentrated and the residue was added to water (100 mL). The mixture was filtered and the filter cake was rinsed again with water (300 mL). The resulting mixture was dried to obtain the title compound 6b (7.02 g, crude) as a white solid, which was used directly in the next step.

[0217] Step 2: Methyl 4-chloro-3-formyl-2-hydroxybenzoate 6c

[0218] Compound 6b (7.02 g, crude product) was added to anhydrous methanol (70 mL), and concentrated sulfuric acid (7 mL) was added at room temperature. After the addition was complete, the reaction solution was heated to 80°C for 10 hours. TLC showed that the starting material disappeared. The reaction solution was cooled to room temperature and quenched with water (100 mL). It was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to obtain the title compound 6c (3.47 g, two-step yield 93%) as a white solid.

[0219] Step 3: Methyl 4-chloro-3-formyl-2-(methoxymethoxy)benzoate 6d

[0220] Compound 6c (3.47 g, 16.2 mmol) was added to dichloromethane (100 mL). Triethylamine (3.26 g, 30.3 mmol) was added at room temperature. After the addition was complete, the ice bath was cooled to 0°C and chloromethyl methyl ether (1.95 g, 24.2 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 2 hours. TLC showed the disappearance of the starting material. The reaction mixture was quenched 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 silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain the title compound 6d (2.56 g, 61% yield) as a white solid.

[0221] Step 4: 6-chloro-2-hydroxy-3-(methoxycarbonyl)benzoic acid 6e

[0222] Compound 6d (1.00 g, 3.86 mmol) was added to acetonitrile (20 mL). Sodium chlorite (487 mg, 5.41 mmol), sodium dihydrogen phosphate (650 mg, 5.42 mmol), and hydrogen peroxide (3 mL, 30%) were added at room temperature. The reaction was allowed to react at room temperature for 10 hours. TLC indicated the disappearance of the starting material. Saturated aqueous sodium sulfite (40 mL) was added to the reaction solution, which was concentrated to a small amount of solvent. Hydrochloric acid (3 N) was slowly added dropwise to a pH of 1-2. The mixture was stirred for 2 hours, then filtered and the filter cake dried to afford the title compound 6e (500 mg, 56% yield) as a white solid.

[0223] Step 5: Methyl 4-chloro-2-hydroxy-3-(methylcarbamoyl)benzoate 6f

[0224] Compound 6e (527 mg, 2.28 mmol) was added to dichloromethane (20 mL). Methylamine hydrochloride (246 mg, 3.64 mmol), HATU (1.74 mg, 4.57 mmol), and triethylamine (1 mL, 7.15 mmol) were added at room temperature. The mixture was allowed to react at room temperature for 10 hours. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound 6f (450 mg, crude) as an off-white solid, which was used directly in the next step.

[0225] Step 6: 4-chloro-2-hydroxy-3-(methylcarbamoyl)benzoic acid 6g

[0226] Compound 6f (310 mg, crude product) was dissolved in tetrahydrofuran (6 mL) and aqueous sodium hydroxide solution (15%, 1 mL) was added at room temperature. After addition, the reaction was continued at room temperature for 10 hours. TLC showed that the starting material disappeared. The reaction solution was quenched with water (6 mL) and acidified to pH = 3 with dilute hydrochloric acid (3N). The mixture was concentrated and filtered. The filter cake was washed with water (5 mL x 2) and dried to obtain the title compound 6g (190 mg, 52% yield for two steps) as a white solid.

[0227] Step 7N 1 -((5-bromothiophen-2-yl)sulfonyl)-4-chloro-2-hydroxy-N3-methylisophthalamide 6

[0228] Compound 6g (190 mg, 0.83 mmol) was dissolved in dichloromethane (4 mL). N,N-diisopropylethylamine (214 mg, 1.65 mmol), HATU (472 mg, 1.24 mmol), and 5-bromo-2-thiophenesulfonamide (220 mg, 0.91 mmol) were added sequentially at room temperature. After addition, the mixture was reacted at room temperature for 3 hours. TLC showed that the starting material disappeared. The reaction solution was quenched with water (2 mL) and extracted with dichloromethane (1 mL x 3). The organic phases were combined and washed with saturated brine (1 mL). The organic phases were concentrated to obtain the title compound 6 (4.51 mg, yield 1.2%) as a white solid.

[0229] LC-MS: m / z = 450.9 [MH] - (97.75% purity by HPLC,220nm)

[0230] 1H NMR (400 MHz, CDCl3) δ 11.02 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H), 7.71 (d, J = 4.0 Hz, 1H), 7.09 (d, J = 4.0 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 3.09 (d, J = 4.8 Hz, 3H). (Active hydrogen of sulfonamide is not shown)

[0231] Example 7

[0232] N-((3-bromo-5-methylthiophen-2-yl)sulfonyl)-2,4-dichlorobenzamide 7

[0233] Step 1: 3-Bromo-5-methylthiophene-2-sulfonyl chloride 7b

[0234] Dissolve 3-bromo-5-methylthiophene 7a (500 mg, 2.82 mmol) in dichloromethane (5 mL) and cool to 0°C. Slowly add chlorosulfonic acid (3 mL) diluted in dichloromethane (3 mL). After addition, continue the reaction at 0°C for 10 minutes. TLC indicates the disappearance of the starting material. The reaction mixture is slowly poured into ice water (20 mL) for quenching. Extract with dichloromethane (6 mL x 3). The combined organic phases are washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound 7b (916 mg, crude) as a colorless oil, which is used directly in the next step.

[0235] Step 2: 3-Bromo-5-methylthiophene-2-sulfonamide 7c

[0236] Compound 7b (916 mg, crude) was dissolved in 1,4-dioxane (9 mL). Aqueous ammonia (25%, 1 mL) was added at room temperature. After 30 minutes of reaction, the starting material disappeared as monitored by TLC. The reaction solution was directly concentrated to afford the title compound 7c (778 mg, crude) as a white solid, which was used directly in the next step.

[0237] Step 3 N-((3-bromo-5-methylthiophen-2-yl)sulfonyl)-2,4-dichlorobenzamide 7

[0238] Compound 7c (293 mg, crude) was dissolved in ethyl acetate (2 mL), and triethylamine (386 mg, 3.82 mmol) was added. The mixture was allowed to react at room temperature for 10 minutes. The mixture was cooled to 0°C, and a mixture of intermediate IN-1 (200 mg, 0.95 mmol) in toluene (1 mL) was added. The reaction was allowed to react at room temperature for 10 hours. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (8 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The crude product was purified by Prep-TLC (dichloromethane / methanol = 10 / 1) to afford the title compound 7 (110 mg, 35% yield over three steps) as a white solid.

[0239] LC-MS: m / z = 427.8 [MH] - (99.88% purity by HPLC, 210nm)

[0240] 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 1.2 Hz, 1H), 7.57-7.50 (m, 2H), 7.10 (s, 1H), 2.52 (s, 3H). (The active hydrogen of the sulfonamide is not shown).

[0241] Example 8

[0242] N-((5-bromothiophen-2-yl)sulfonyl)-2-chloro-4-(1-cyanocyclopropyl)-6-methoxybenzamide 8

[0243] Step 1: 3-Chloro-4-hydroxy-5-methoxybenzaldehyde 8b

[0244] Vanillin 8a (15.1 g, 99.3 mmol) was added to N,N-dimethylformamide (100 mL), followed by N-chlorosuccinimide (19.9 g, 149 mmol) at room temperature. After addition, the reaction was continued at room temperature for 10 hours. TLC indicated the disappearance of the starting material. The reaction solution was quenched with water (600 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 15) to afford the title compound 8b (8.22 g, 44% yield) as a white solid, which was used directly in the next step.

[0245] Step 2: 3-Chloro-4-trifluoromethanesulfonyl-5-methoxybenzaldehyde 8c

[0246] Compound 8b (8.22 g, 44.0 mmol) was added to dichloromethane (150 mL). Triethylamine (13.4 mg, 132 mmol) and 4-dimethylaminopyridine (269 mg, 2.20 mmol) were added at room temperature. After addition, the reaction solution was cooled to 0°C and N-phenylbis(trifluoromethanesulfonyl)imide solution (20.5 g, 57.3 mmol, dissolved in 40 mL of dichloromethane) was added dropwise. The mixture was warmed to room temperature and allowed to react for 10 hours. TLC indicated the disappearance of the starting material. The reaction solution was quenched with water (200 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound 8c (15.3 g, crude) as an off-white solid, which was used directly in the next step.

[0247] Step 3: Methyl 2-chloro-4-formyl-6-methoxybenzoate 8d

[0248] Compound 8c (15.3 g, crude) was added to methanol (465 mL) and N,N-dimethylformamide (20 mL). Triethylamine (19.5 g, 192 mmol), palladium acetate (2.70 g, 12.0 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (2.66 g, 4.81 mmol) were added at room temperature. Carbon monoxide was replaced three times. The autoclave was maintained at 0.3-0.5 MPa and heated to 80°C for 12 hours. TLC indicated the disappearance of the starting material. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (80 mL x 2). The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 15) to obtain the title compound 8d (8.49 g, 85% yield over two steps) as a white solid.

[0249] Step 4: Methyl 2-chloro-4-(hydroxymethyl)-6-methoxybenzoate 8e

[0250] Compound 8d (8.49 g, 37.1 mmol) was added to methanol (10 mL), followed by the addition of sodium borohydride (702 mg, 18.6 mmol) at room temperature. The reaction mixture was allowed to react for 30 minutes. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (80 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound 8e (6.81 g, crude) as a pale yellow oil, which was used directly in the next step.

[0251] Step 5: Methyl 2-chloro-6-methoxy-4-(((methylsulfonyl)oxy)methyl)benzoate 8f

[0252] Compound 8e (6.81 g, crude) was added to dichloromethane (50 mL), cooled to 0°C, and triethylamine (6.01 g, 59.1 mmol) was added. After stirring for 10 minutes, methylsulfonyl chloride (4.06 g, 35.4 mmol) was added. After the addition, the mixture was warmed to room temperature and reacted for 30 minutes. TLC showed the disappearance of the starting material. The reaction solution was quenched with water (100 mL) and extracted with dichloromethane (20 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 8f (7.26 g, crude) as a colorless oil, which was used directly in the next step.

[0253] Step 6: 8g of methyl 2-chloro-4-(cyanomethyl)-6-methoxybenzoate

[0254] Compound 8f (7.26 g, crude) was added to acetonitrile (40 mL). Anhydrous potassium carbonate (3.90 g, 28.2 mmol) and trimethylsilyl cyanide (3.50 g, 35.2 mmol) were added sequentially at room temperature. The mixture was heated to 50°C and reacted for 12 hours. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to afford the title compound 8f (1.81 g, 20% yield over three steps) as a colorless oil.

[0255] Step 7: Methyl 2-chloro-4-(1-cyanocyclopropyl)-6-methoxybenzoate 8h

[0256] Compound 8g (1.22 g, 5.09 mmol) was added to tetrahydrofuran (10 mL), cooled to 0°C, and potassium tert-butoxide (1.26 mg, 11.2 mmol) was slowly added portionwise. The mixture was allowed to react at 0°C for 30 minutes. 1,2-Dibromoethane (956 mg, 5.09 mmol) was added and the mixture was allowed to react at room temperature for 30 minutes. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to afford the title compound 8h (224 mg, 16% yield) as a white solid.

[0257] Step 8: 2-chloro-4-(1-cyanocyclopropyl)-6-methoxybenzoic acid 8i

[0258] Compound 8h (224 mg, 0.84 mmol) was dissolved in anhydrous methanol (2 mL). Sodium hydroxide solution (15%, 1 mL) and water (0.5 mL) were added at room temperature. After addition, the mixture was heated to 80°C and reacted for 10 hours. TLC indicated the disappearance of the starting material. The reaction solution was cooled to room temperature and acidified with hydrochloric acid (3N) to pH 7. The methanol was removed by concentration. The residue was diluted with water (1 mL) and acidified with hydrochloric acid (3N) to pH 1. A large amount of white solid precipitated. The filter cake was washed with water (1 mL x 2) and dried to obtain the title compound 8i (110 mg, 52% yield) as a white solid.

[0259] Step 9: N-((5-bromothiophen-2-yl)sulfonyl)-2-chloro-4-(1-cyanocyclopropyl)-6-methoxybenzamide 8

[0260] Compound 8i (110 mg, 0.44 mmol) was dissolved in dichloromethane (2 mL), and HATU (250 mg, 0.66 mmol), N,N-diisopropylethylamine (113 mg, 0.87 mmol), and 5-bromo-2-thiophenesulfonamide (106 mg, 0.44 mmol) were added sequentially at room temperature. The reaction was allowed to proceed at room temperature for 10 hours, and TLC showed the disappearance of the starting material. The reaction solution was quenched with water (3 mL) and extracted with dichloromethane (1 mL x 3). The organic phases were combined, washed with saturated brine (2 mL), and dried over anhydrous sodium sulfate. The crude product was purified by Prep-HPLC to obtain the title compound 8 (33 mg, 16% yield) as a white solid.

[0261] LC-MS: m / z = 474.9 [MH] - (98.05% purity by HPLC, 254nm)

[0262] 1 H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J = 3.6 Hz, 1H), 7.42 (d, J = 4.0 Hz, 1H), 7.03 (d, J = 1.2 Hz, 1H), 6.90 (s, 1H), 3.79 (s, 3H), 1.79 (dd, J = 8.4, 5.2 Hz, 2H), 1.63 (dd, J = 8.0, 4.8 Hz, 2H). (The active hydrogen of the sulfonamide is not shown).

[0263] Example 9

[0264] N-((5-bromothiophen-2-yl)sulfonyl)-2-chloro-4-(1-cyanocyclopropyl)-6-hydroxybenzamide 9

[0265] The first step is N-((5-bromothiophen-2-yl)sulfonyl)-2-chloro-4-(1-cyanocyclopropyl)-6-hydroxybenzamide 9

[0266] Compound 8 (20 mg, 42 mmol) was dissolved in dichloromethane (1 mL). A solution of boron tribromide in dichloromethane (1 mL, 1 mmol, 1 N) was added at room temperature. The mixture was allowed to react for 30 minutes. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (1 mL) and extracted with ethyl acetate (1 mL x 3). The combined organic phases were washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-HPLC to afford the title compound 9 (8.51 mg, 43% yield) as a white solid.

[0267] LC-MS: m / z = 488.9 [MH] - (98.77% purity by HPLC,220nm)

[0268] 1 H NMR (400 MHz, DMSO-d6) δ 13.78 (s, 1H), 7.38 (s, 1H), 7.19 (s, 1H), 6.70 (d, J = 2.0 Hz, 1H), 6.68 (s, 1H), 1.74 (dd, J = 8.4, 5.2 Hz, 2H), 1.55 (dd, J = 8.0, 5.2 Hz, 2H). (The active hydrogen of the sulfonamide is not shown).

[0269] Example 10

[0270] (3R,4S,5R)-N-((5-bromothiophen-2-yl)sulfonyl)-3,4,5-trihydroxycyclohexyl-1-ene-1-carboxamide 10

[0271] Step 1: (3R,4S,5R)-3,4,5-triacetoxycyclohex-1-ene-1-carboxylic acid 10b

[0272] (3R,4S,5R)-3,4,5-triacetoxycyclohex-1-ene-1-carboxylic acid 10a (1.02 g, 5.74 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (1.16 g, 11.5 mmol) was added at room temperature. The mixture was allowed to react for 10 minutes. The reaction mixture was cooled to 0°C and acetic anhydride (2.34 g, 23.0 mmol) was slowly added dropwise, with a slight temperature increase. After the addition, the mixture was allowed to react for 30 minutes at room temperature. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (2 mL x 3). The organic phases were combined, washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound 10b (1.21 g, crude) as a colorless oil, which was used directly in the next step.

[0273] Step 2: (1R,2S,3R)-5-(Chlorocarbonyl)cyclohex-4-ene-1,2,3-triacetic acid triester 10c

[0274] Compound 10b (1.21 g, crude) was dissolved in tetrahydrofuran (10 mL), cooled to 0°C, and oxalyl chloride (1.42 g, 11.2 mmol) was slowly added dropwise. The mixture was allowed to react at 0°C for 10 minutes. Subsequently, N,N-dimethylformamide (3 drops) was slowly added dropwise. The reaction was vigorous, with significant gas evolution. After addition, the mixture was warmed to room temperature and reacted for 30 minutes. TLC confirmed complete reaction. The reaction solution was concentrated to afford the title compound 10c (725 mg, crude) as a white solid, which was used directly in the next step.

[0275] Step 3 (1R,2S,3R)-5-(((5-bromothiophen-2-yl)sulfonyl)carbamoyl)cyclohex-4-ene-1,2,3-triacetate 10d

[0276] 5-Bromothiophene-2-sulfonamide (826 mg, 3.41 mmol) was dissolved in ethyl acetate (5 mL). Triethylamine (1.15 g, 11.4 mmol) and 4-dimethylaminopyridine (28 mg, 0.23 mmol) were added at room temperature. The mixture was allowed to react for 10 minutes. A solution of compound 10c (725 mg, 2.27 mmol) in toluene (2 mL) was added and the reaction continued at room temperature for 12 hours. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (2 mL x 3). The organic phases were combined, washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound 10d (1.20 g, crude) as a colorless oil, which was used directly in the next step.

[0277] Step 4: (3R, 4S, 5R)-N-((5-bromothiophen-2-yl)sulfonyl)-3,4,5-trihydroxycyclohexyl-1-ene-1-carboxamide 10

[0278] Compound 10d (1.20 g, crude) was dissolved in anhydrous methanol (10 ml). Anhydrous potassium carbonate (1.26 g, 9.15 mmol) was added at room temperature. The mixture was allowed to react for 2 hours. TLC indicated the disappearance of the starting material. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL x 2). The filtrate was concentrated, and the crude product was purified by Prep-HPLC to afford the title compound 10 (47 mg, 2% yield over four steps) as a white solid.

[0279] LC-MS: m / z = 397.9 [M+H] + (99.86% purity by HPLC, 254nm)

[0280] 1H NMR (400 MHz, CD3OD) δ 7.52 (d, J = 4.0 Hz, 1H), 7.11 (d, J = 4.4 Hz, 1H), 6.46-6.45 (m, 1H), 4.28 (s, 1H), 3.88 (dt, J = 6.7, 4.8 Hz, 1H), 3.60 (dd, J = 6.8, 4.0 Hz, 1H), 2.58-2.52 (m, 1H), 2.02 (dd, J = 18.0, 4.8 Hz, 1H). (The active hydrogen of the sulfonamide is not shown).

[0281] Example 11

[0282] 2,4-Dichloro-N-((5-ethynylthiophen-2-yl)sulfonyl)benzamide 11

[0283] Step 1 (Z)-N'-((5-bromothiophen-2-yl)sulfonyl)-N,N-dimethylformimide 11b

[0284] 5-Bromothiophene-2-sulfonamide 11a (2.40 g, 9.92 mmol) was added to dichloromethane (10 mL). N,N-dimethylformamide dimethyl acetal (2 mL) was added at room temperature. After addition, the mixture was allowed to react at room temperature for 20 minutes. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound 11b (3.01 g, crude) as a pale yellow solid, which was used directly in the next step.

[0285] Step 2 (Z)-N,N-dimethyl-N'-((5-((trimethylsilyl)ethynyl)2-thienyl)sulfonyl)carboximide 11c

[0286] Compound 11b (2.00 g, 6.734 mmol) was added to dry N,N-dimethylformamide (20 mL). Triethylamine (4.70 mL, 33.8 mmol), iodide (130 mg, 0.68 mmol), bistriphenylphosphine palladium dichloride (240 mg, 0.34 mmol), and trimethylethynylsilane (1.35 mL, 9.46 mmol) were added sequentially at room temperature. After addition, the atmosphere was purged with nitrogen three times and the reaction was allowed to proceed at room temperature for 24 hours. TLC indicated the disappearance of the starting material. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL x 2). The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-TLC (petroleum ether / ethyl acetate = 10 / 1) to afford the title compound 11c (1.15 g, 37% yield over two steps) as a pale yellow solid.

[0287] Step 3 5-ethynylthiophene-2-sulfonamide 11d

[0288] Compound 11c (1.15 g, 3.66 mmol) was added to dry N,N-dimethylformamide (20 mL), followed by the addition of tetrabutylammonium fluoride solution (7.3 mL, 1 M). The reaction was allowed to react at room temperature for 4 hours. TLC indicated the disappearance of the starting material. The reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-TLC (petroleum ether / ethyl acetate = 10 / 1) to afford the title compound 11d (450 mg, 66% yield) as a pale yellow solid.

[0289] Step 4: 2,4-dichloro-N-((5-ethynylthiophen-2-yl)sulfonyl)benzamide 11

[0290] 2,4-Dichlorobenzoic acid (204 mg, 1.07 mmol) was dissolved in dichloromethane (4 mL). HATU (609 mg, 1.60 mmol) and N,N-diisopropylethylamine (276 mg, 2.14 mmol) were added at room temperature. The mixture was allowed to react at room temperature for 2 hours. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (4 mL) and extracted with dichloromethane (2 mL x 3). The combined organic phases were washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in dichloromethane (4 mL). N,N-diisopropylethylamine (276 mg, 2.14 mmol) and compound 11d (200 mg, 1.61 mmol) were added sequentially at room temperature. The mixture was allowed to react at room temperature for 10 hours. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (4 mL) and extracted with dichloromethane (2 mL x 3). The organic phases were combined, washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-HPLC to give the title compound 11 as a white solid (75 mg, yield 19%).

[0291] LC-MS: m / z = 359.9 [M+H] + (99.94% purity by HPLC, 254nm)

[0292] 1 H NMR (400MHz, CDCl3) δ9.16 (s, 1H), 7.82 (d, J = 4.0Hz, 1H), 7.72 (d, J = 8.4Hz, 1H), 7.4 4(d,J=1.6Hz,1H),7.36(dd,J=8.4,1.6Hz,1H),7.24(d,J=4.0Hz,1H),3.55(s,1H).

[0293] Example 12

[0294] 2,4-Dichloro-N-((5-iodothien-2-yl)sulfonyl)benzamide 12

[0295] Step 1: 5-iodothiophene-2-sulfonyl chloride 12b

[0296] 2-Iodothiophene 12a (4.01 g, 19.0 mmol) was added to dichloromethane (20 mL), cooled to -60°C, and chlorosulfonic acid (5 mL) was slowly added dropwise. The mixture was allowed to react at -60°C for 10 minutes, then warmed to room temperature for 2 hours. TLC indicated the disappearance of the starting material. The reaction mixture was quenched by adding ice water (50 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound 12b (3.02 g, crude) as a pale yellow oil, which was used directly in the next step.

[0297] Step 2 5-Iodothiophene-2-sulfonamide 12c

[0298] Compound 12b (3.02 g, crude) was added to 1,4-dioxane (10 mL). Ammonia (2 mL) was added at room temperature and allowed to react for 20 minutes. TLC indicated the disappearance of the starting material. The reaction mixture was poured into water (20 mL) for quenching and extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound 12c (3.35 g, crude) as a pale yellow oil, which was used directly in the next step.

[0299] Step 3 2,4-dichloro-N-((5-iodothiophen-2-yl)sulfonyl)benzamide 12

[0300] Compound 12c (200 mg, crude) was dissolved in ethyl acetate (1 mL). Triethylamine (2 mL, 14.4 mmol) and a toluene solution (1 mL) of intermediate IN-1 (320 mg, crude) were added sequentially at room temperature. The mixture was allowed to react at room temperature for 2 hours. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (1 mL x 3). The combined organic phases were washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-HPLC to afford the title compound 12 (28 mg, 5.34% yield over three steps) as a white solid.

[0301] LC-MS: m / z = 459.8 [MH] - (99.89% purity by HPLC, 210nm)

[0302] 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 4.0, 3.2 Hz, 2H), 7.48 (d, J = 3.6 Hz, 1H). (The active hydrogen of the sulfonamide is not shown).

[0303] Example 13

[0304] 6-Bromo-N-((5-bromothiophen-2-yl)sulfonyl)benzo[b]thiophene-2-carboxamide 13

[0305] Step 1: 6-Bromo-N-((5-bromothiophen-2-yl)sulfonyl)benzo[b]thiophene-2-carboxamide 13

[0306] 5-Bromothiophene-2-sulfonamide 13a (87 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (1 mL). N,N-diisopropylethylamine (85 mg, 0.65 mmol), HATU (186 mg, 0.49 mmol), and 6-bromobenzo[B]thiophene-2-carboxylic acid (84 mg, 0.33 mmol) were added sequentially at room temperature. The mixture was allowed to react at room temperature for 12 hours. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The organic phases were combined, washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether = 1 / 8) to afford the title compound 13 (48 mg, 28% yield) as a white solid.

[0307] LCMS: m / z = 477.8 [MH] - (99.63% purity by HPLC,254nm)

[0308] 1 H NMR (400 MHz, DMSO-d6) δ: 8.22 (d, J = 1.6 Hz, 1H), 7.84-7.77 (m, 2H), 7.50 (dd, J = 1.6, 2.0 Hz, 1H), 7.33 (d, J = 4.0 Hz, 1H), 7.14 (d, J = 4.0 Hz, 1H). (The active hydrogen of the sulfonamide is not shown).

[0309] Example 14

[0310] 2,4-Dichloro-N-((4,5-dichlorothiophen-2-yl)sulfonyl)benzamide 14

[0311] Step 1: 2,4-dichloro-N-((4,5-dichlorothiophen-2-yl)sulfonyl)benzamide 14

[0312] Intermediate IN-1 (185 mg, crude) was dissolved in dichloromethane (10 mL). 2,3-Dichlorothiophene-5-sulfonamide 14a (193 mg, 0.83 mmol) and 4-dimethylaminopyridine (5 mg, 0.05 mmol) were added sequentially at room temperature. The mixture was allowed to react for 1 hour. TLC confirmed the complete reaction. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-HPLC to afford the title compound 14 (65 mg, 19.34% yield) as a white solid.

[0313] LCMS: m / z = 403.8 [MH] - (99.97% purity by HPLC, 254nm)

[0314] 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 8.4, 2.0 Hz, 1H). (The active hydrogen of the sulfonamide is not shown).

[0315] Example 15

[0316] N-((5-bromothiophen-2-yl)sulfonyl)-6-chloro-2'-cyano-4-hydroxy-[1,1'-biphenyl]-3-carboxamide 15

[0317] Step 1: 5-Bromo-4-chloro-2-hydroxybenzoic acid 15b

[0318] 4-Chloro-2-hydroxybenzoic acid 15a (5.40 g, 31.3 mmol) was added to dichloromethane (120 mL). Triethylamine (3.50 g, 34.6 mmol) was added at room temperature. After the addition was complete, the reaction solution was cooled to -60°C and bromine (5.01 g, 31.3 mmol, dissolved in 20 mL of dichloromethane) was slowly added dropwise. The reaction was continued at -60°C for 1 hour. TLC showed the disappearance of the starting material. The reaction solution was concentrated, the residue was diluted with water (150 mL), and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with dilute hydrochloric acid (1N, 50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain the title compound 15b (2.20 g, 28% yield) as a white solid.

[0319] Step 2: Ethyl 5-bromo-4-chloro-2-hydroxybenzoate 15c

[0320] Compound 15b (1.00 g, 3.98 mmol) was dissolved in anhydrous ethanol (20 mL). Concentrated sulfuric acid (2 mL) was added at room temperature. Under nitrogen, the mixture was heated to 80°C for 10 hours. TLC indicated the disappearance of the starting material. The reaction mixture was cooled to room temperature and quenched with water (20 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to afford the title compound 15c (1.02 g, 92% yield) as a colorless oil.

[0321] Step 3 6-chloro-2'-cyano-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid ethyl ester 15d

[0322] Compound 15c (769 mg, 2.75 mmol) was added to dry N,N-dimethylformamide (20 mL). 2-Cyanophenylboronic acid (566 mg, 3.85 mmol), potassium phosphate (1.16 mg, 5.47 mmol), and Pd(dppf)2Cl2 (200 mg, 0.27 mmol) were added sequentially at room temperature. After addition, the reaction mixture was warmed to 90°C for 2 hours. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 8) to afford the title compound 15d (230 mg, 28% yield) as an off-white solid.

[0323] Step 4: 6-chloro-2'-cyano-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid 15e

[0324] Compound 15d (125 mg, 0.41 mmol) was added to a mixture of ethanol (3 mL) and water (3 mL). Solid sodium hydroxide (50 mg, 1.25 mmol) was added at room temperature. After addition, the reaction mixture was allowed to react at room temperature for 12 hours. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (3 mL) and extracted with ethyl acetate (1 mL x 3). The combined organic phases were washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to afford the title compound 15e (85 mg, 76% yield) as a white solid.

[0325] Step 5: N-((5-bromothiophen-2-yl)sulfonyl)-6-chloro-2'-cyano-4-hydroxy-[1,1'-biphenyl]-3-carboxamide 15

[0326] Compound 15e (85 mg, 0.31 mmol) was dissolved in dichloromethane (2 mL). HATU (177 mg, 0.47 mmol), N,N-diisopropylethylamine (80 mg, 0.62 mmol), and 5-bromo-2-thiophenesulfonamide (75 mg, 0.31 mmol) were added sequentially at room temperature. After addition, the reaction mixture was allowed to react at room temperature for 12 hours. The reaction mixture was quenched with water (3 mL) and extracted with dichloromethane (1 mL x 3). The organic phases were combined, washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-HPLC to obtain the title compound 15 (40 mg, 26% yield) as a white solid.

[0327] LC-MS: m / z = 494.9 [MH] - (98.92% purity by HPLC, 254nm)

[0328] 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.6 Hz, 1H), 7.70-7.66 (m, 2H), 7.55-7.51 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 7.11 (d, J = 3.6 Hz, 1H). (The active hydrogens of the sulfonamide and phenolic hydroxyl groups are not shown).

[0329] Example 16

[0330] N-((5-bromothien-2-yl)sulfonyl)-2-chloro-4-(1-cyanocyclopentyl)-6-methoxybenzamide 16

[0331] Step 1: Methyl 2-chloro-4-(1-cyanocyclopentyl)-6-methoxybenzoate 16a

[0332] Compound 8g (1.13 g, 4.71 mmol) was added to tetrahydrofuran (20 mL). The mixture was cooled to 0°C and potassium tert-butoxide (1.17 g, 10.4 mmol) was slowly added portionwise. After reacting at 0°C for 30 minutes, 1,4-dibromobutane (1.02 g, 4.73 mmol) was added. After addition, the reaction solution was slowly warmed to room temperature and reacted for 30 minutes. TLC indicated the disappearance of the starting material. The reaction solution was quenched with water (30 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to obtain the title compound 16a (1.02 g, 74% yield) as a white solid.

[0333] Step 2: 2-Chloro-4-(1-cyanocyclopentyl)-6-methoxybenzoic acid 16b

[0334] Compound 16a (200 mg, 0.68 mmol) was dissolved in anhydrous methanol (6 mL). Sodium hydroxide solution (15%, 1 mL) and water (1 mL) were added at room temperature. After addition, the reaction mixture was heated to 80°C for 10 hours. TLC indicated the disappearance of the starting material. The reaction mixture was cooled to room temperature and acidified to pH 7 by dilute hydrochloric acid (3 N). The methanol was concentrated to a minimum volume, and the residue was diluted with water (1 mL). The residue was acidified to pH 1 by hydrochloric acid (3 N). A large amount of white solid precipitated. The filter cake was washed with water (1 mL x 2) and dried to obtain the title compound 16b (165 mg, 87% yield) as a white solid.

[0335] Step 3 N-((5-bromothiophen-2-yl)sulfonyl)-2-chloro-4-(1-cyanocyclopentyl)-6-methoxybenzamide 16

[0336] Compound 16b (165 mg, 0.59 mmol) was dissolved in dichloromethane (2 mL). HATU (336 mg, 0.885 mmol), N,N-diisopropylethylamine (152 mg, 1.18 mmol), and 5-bromo-2-thiophenesulfonamide (143 mg, 0.590 mmol) were added sequentially at room temperature. The mixture was allowed to react at room temperature for 10 hours. TLC indicated the disappearance of the starting material. The reaction solution was quenched with water (3 mL) and extracted with dichloromethane (1 mL x 3). The organic phases were combined, washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-HPLC to afford the title compound 16 (60 mg, 20.19% yield) as a white solid.

[0337] LC-MS: m / z = 501.0 [MH] - (98.32% purity by HPLC,220nm)

[0338] 1 H NMR (400MHz, CDCl3) δ8.44(s,1H),7.71(d,J=4.0Hz,1H),7.13(d,J=4.0Hz,1H),7.04(d,J =1.2Hz,1H),6.96(d,J=1.2Hz,1H),3.86(s,3H),2.47(d,J=5.2Hz,2H),2.10-1.93(m,6H).

[0339] Example 17

[0340] N-((5-bromothiophen-2-yl)sulfonyl)-2-chloro-4-(1-cyanocyclopentyl)-6-hydroxybenzamide 17

[0341] The first step is N-((5-bromothien-2-yl)sulfonyl)-2-chloro-4-(1-cyanocyclopentyl)-6-methoxybenzamide 17

[0342] Compound 16 (20 mg, 40 mmol) was dissolved in dichloromethane (1 mL). A dichloromethane solution of boron tribromide (1 mL, 1 mmol, 1 N) was added at room temperature. After addition, the mixture was allowed to react at room temperature for 30 minutes. TLC indicated the disappearance of the starting material. The reaction mixture was quenched with water (1 mL) and extracted with ethyl acetate (1 mL x 3). The organic phases were combined, washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-HPLC to afford the title compound 17 (10 mg, 53% yield) as a white solid.

[0343] LC-MS: m / z = 486.9 [MH] - (98.77% purity by HPLC,220nm)

[0344] 1 H NMR (400MHz, CDCl3) δ11.77(s,1H),10.04(s,1H),7.74(d,J=4.0Hz,1H),7.14(d,J=4.0Hz ,1H),7.07(d,J=2.0Hz,1H),7.03(d,J=2.0Hz,1H),2.50-2.40(m,2H),2.07-1.95(m,6H).

[0345] Example 18

[0346] 2,4-Dichloro-N-((1-ethyl-1H-imidazol-4-yl)sulfonyl)benzamide 18

[0347] Step 1-Ethyl-1H-imidazole-4-sulfonyl chloride 18b

[0348] 1-Ethylimidazole 18a (20.00 g, 208.0 mmol) was slowly added dropwise to chlorosulfonic acid (60 mL), maintaining the addition temperature below 30°C. After completion of the addition, the temperature was raised to 120°C for 24 hours. The reaction solution was cooled to room temperature, and thionyl chloride (60 mL) was added. After completion of the addition, the temperature was raised to 120°C for 24 hours. The reaction was complete as determined by TLC (DCM / MeOH = 20 / 1, R f=0.2). The reaction solution was cooled to 0-10°C and slowly added dropwise to ice water (200 mL) for quenching. The mixture was extracted with dichloromethane (50 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (EA = 100%) to obtain the title compound 18b as a yellow oil (15.02 g, two spots could not be separated by TLC).

[0349] Step 2: 1-Ethyl-1H-imidazole-4-sulfonamide 18c

[0350] 25% to 28% ammonia water (100 mL) was cooled to -15°C, and a tetrahydrofuran solution of compound 18b (15.02 g, crude product, dissolved in 50 mL of tetrahydrofuran) was added dropwise thereto, with the addition temperature maintained below -10°C. After completion of the addition, the mixture was analyzed by TLC (DCM / MeOH = 20 / 1, R f =0.4) The reaction of the starting material was complete. The reaction solution was concentrated and the crude product was purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain 6.52 g of crude product. Ethyl acetate (65 mL) was added and heated to reflux for 30 minutes. The mixture was cooled to room temperature and filtered. The solid was washed with ethyl acetate (20 mL). The gray solid was dried to obtain 3.10 g. 1 H NMR analysis revealed impurities in the product. The crude product was further purified by silica gel column chromatography (DCM / MeOH = 15 / 1) to afford 2.01 g. Ethyl acetate (20 mL) was added and heated to reflux for 30 minutes. The mixture was cooled to room temperature, filtered, rinsed with ethyl acetate (10 mL), and dried to afford the title compound 18c (1.60 g, 4.3% yield over two steps) as an off-white solid.

[0351] 1 H NMR (400MHz, DMSO-d6) δ7.82(d,J=0.8Hz,1H),7.71(d,J=0.4Hz,1H),7.14(s,2H),4.03(q,J=7.2Hz,2H),1.35(t,J=7.2Hz,3H)

[0352] Step 3 2,4-dichloro-N-((1-ethyl-1H-imidazol-4-yl)sulfonyl)benzamide 18

[0353] 2,4-Dichlorobenzoic acid (191 mg, 1.00 mmol) was added to tetrahydrofuran (5 mL), and N,N'-carbonyldiimidazole (370 mg, 2.30 mmol) was added. After the addition, the reaction solution was heated to 60°C for 2 hours. The reaction solution was naturally cooled to room temperature and compound 18c (352 mg, 2.00 mmol) was added. The reaction solution was stirred at room temperature for 10 minutes, and then 1,8-diazabicyclo[5.4.0]undec-7-ene (300 mg, 1.97 mmol) was added. After the addition, the mixture was stirred at room temperature for 18 hours. The mixture was detected by TLC (DCM / MeOH=20 / 1, R f =0.2) was completely reacted, and the reaction solution was quenched with water (50 mL), extracted with ethyl acetate (20 mL x 2), and the aqueous phase was collected. Dilute hydrochloric acid (3 M / L) was slowly added dropwise to the aqueous phase to acidify to pH = 4-5. Ethyl acetate (40 mL x 2) was then extracted, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate and concentrated. The crude product was added with ethyl acetate (20 mL) and heated to reflux for 0.5 hours. The mixture was cooled to room temperature, filtered, and the solid was rinsed with ethyl acetate (10 mL). Drying gave the title compound 18 as a white solid (250 mg, 71.8% yield).

[0354] LC-MS: m / z = 348.0 [M+H] + (98.09% purity, 220nm)

[0355] 1 H NMR (400MHz, DMSO-d6) δ12.63(s,1H),8.13(d,J=1.2Hz,1H),7.94(s,1H),7.72(d,J=2.0Hz,1H), 7.51(dd,J=8.4,2.0Hz,1H),7.45(d,J=8.0Hz,1H),4.09(q,J=7.2Hz,2H),1.37(t,J=7.2Hz,3H).

[0356] Example 19

[0357] N-(1,4-oxazacyclyl-4-ylsulfonyl)-2,4-dichlorobenzamide 19

[0358] Step 1,4-Oxazoline-4-sulfonamide 19b

[0359] 1,4-Oxazacyclohexane 19a (400 mg, 3.95 mmol) was dissolved in 1,4-dioxane (6 mL), and sulfonamide (456 mg, 4.74 mmol) was added at room temperature. After the addition was complete, the reaction solution was heated to 120°C and reacted for 18 hours. TLC analysis (DCM / MeOH = 20 / 1, R f=0.1) The starting material reacted completely. The reaction solution cooled naturally to room temperature and was concentrated to dryness. The residue was added with ethyl acetate (10 mL) and heated under reflux until completely dissolved. The residue was filtered while hot. The filtrate cooled naturally to room temperature, whereupon a large amount of solid precipitated. This solid was filtered and the filter cake was rinsed with ethyl acetate (10 mL). The filter cake was dried to afford the title compound 19b (250 mg, 35.11% yield) as a yellow solid.

[0360] Step 2 N-(1,4-oxazacyclo-4-ylsulfonyl)-2,4-dichlorobenzamide 19

[0361] 2,4-Dichlorobenzoic acid (300 mg, 1.57 mmol) was added to dichloromethane (10 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (900 mg, 2.36 mmol) and N,N-diisopropylethylamine (1 mL, 5.42 mmol) were added in sequence at room temperature. The reaction was continued for 18 hours after the addition. TLC detection (DCM / MeOH=20 / 1, R f =0.2) The reaction was complete. The reaction mixture was quenched with water (10 mL), separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was dissolved in dichloromethane (10 mL), and compound 19b (250 mg, 1.38 mmol) and N,N-diisopropylethylamine (1 mL, 5.42 mmol) were added in sequence at room temperature. After the addition was complete, the reaction was continued for 18 hours. TLC was performed (DCM / MeOH = 20 / 1, R f =0.5) The starting material reacted completely, and the reaction solution was quenched with water (20 mL), extracted with dichloromethane (20 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 80 / 1) to obtain the title compound 19 (102 mg, 20.9% yield) as a yellow solid.

[0362] LC-MS: m / z=355.0[M+H] + (97.44% purity, 220nm)

[0363] 1 H NMR (400MHz, DMSO-d6) δ12.19(s,1H),7.76(d,J=2.0Hz,1H),7.58(d,J=8.4Hz,1H),7 .53(dd,J=8.4,2.0Hz,1H),3.79-3.65(m,4H),3.60-3.53(m,4H),1.92-1.82(m,2H).

[0364] Example 20

[0365] N-(3-bromo-4-fluorophenylsulfonyl)-2,4-dichlorobenzamide 20

[0366] Step 1: 3-Bromo-4-fluorobenzenesulfonamide 20b

[0367] 3-Bromo-4-fluorobenzenesulfonyl chloride 20a (235 mg, 0.859 mmol) was dissolved in 1,4-dioxane (4 mL), and 25%-28% ammonia water (0.5 mL) was slowly added dropwise. After the addition was complete, the mixture was reacted at room temperature for 30 minutes. The reaction was detected by TLC (DCM / MeOH = 20 / 1, R f =0.8) The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound 20b (229 mg, crude product) as a white solid, which was used directly in the next step.

[0368] LC-MS: m / z = 251.9 [MH] -

[0369] Step 2 N-(3-bromo-4-fluorobenzenesulfonyl)-2,4-dichlorobenzamide 20

[0370] 2,4-Dichlorobenzoic acid (172 mg, 0.900 mmol) was added to dichloromethane (10 mL), and N, N, N′, N′-tetramethyl-oxy-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (513 mg, 1.35 mmol) and N, N-diisopropylethylamine (0.2 mL, 1.08 mmol) were added in sequence at room temperature. The reaction was continued for 18 hours after the addition was completed. The reaction was detected by TLC (DCM / MeOH=20 / 1, R f =0.2) The raw material reacted completely, and the reaction solution was extracted with water (10 mL), separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was dissolved in dichloromethane (10 mL), and compound 20b (229 mg, 0.901 mmol) and N,N-diisopropylethylamine (0.2 mL, 1.08 mmol) were added in sequence at room temperature. After the addition was complete, the reaction was continued for 4 hours. TLC detection (DCM / MeOH=20 / 1, R f =0.5) The starting material reacted completely. The reaction mixture was quenched with water (15 mL) and extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 30 / 1) to obtain the title compound 20 (180 mg, 49.07% yield over two steps) as a white solid.

[0371] LC-MS: m / z = 425.9 [M+H] + (98.97% purity, 210nm)

[0372] 1H NMR (400MHz, CDCl3) δ8.96(s,1H),8.37(dd,J=6.0,2.4Hz,1H),8.13(ddd,J=8.8,4.4,2.4Hz,1H),7. 72(d,J=8.0Hz,1H),7.45(d,J=4.0Hz,1H),7.36(dd,J=8.8,2.0Hz,1H),7.31(dd,J=8.4,8.0Hz,1H).

[0373] Example 21

[0374] N-((3-bromo-4,5-difluorophenyl)sulfonyl)-2,4-dichlorobenzamide 21

[0375] Step 1 4-Bromo-2,3-difluoro-6-nitroaniline 21b

[0376] 2,3-Difluoro-6-nitroaniline 21a (10.0 g, 57.43 mmol) was dissolved in DMF (230 mL) and N-bromosuccinimide (12.30 g, 69.10 mmol) was slowly added. After the addition, the reaction solution was heated to 90°C and reacted for 5 hours. TLC analysis (PE / EA = 10 / 1, R f =0.4) The starting material reacted completely. The reaction mixture was cooled to room temperature and quenched with ice water (500 mL). The mixture was extracted with ethyl acetate (300 mL x 3). The organic phases were combined, washed with water (400 mL x 2), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 7 / 1) to obtain the title compound 21b (13.55 g, 93.12% yield) as a yellow solid.

[0377] 1 H NMR (400MHz, CDCl3) δ8.23 (dd, J=6.4, 2.4Hz, 1H), 6.25 (s, 2H).

[0378] Step 2 1-Bromo-2,3-difluoro-5-nitrobenzene 21c

[0379] Compound 21b (12.55 g, 49.60 mmol) was dissolved in tetrahydrofuran (90 mL) and isoamyl nitrite (11.62 g, 98.89 mmol) was slowly added. After the addition, the reaction solution was heated to 55°C and reacted for 18 hours. TLC analysis (PE / EA = 4 / 1, R f=0.5) The starting material reacted completely, and the reaction solution was cooled to room temperature. Water (100 mL) was added for quenching, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE = 100%) to afford the title compound 21c (10.38 g, 87.96% yield) as a yellow oil.

[0380] Step 3 1-Bromo-2,3-difluoro-5-nitrobenzene 21d

[0381] Compound 21c (10.38 g, 43.61 mmol) was dissolved in ethanol (100 mL), and reduced iron powder (24.42 g, 436.1 mmol), ammonium chloride (23.32 g, 436.0 mmol) and water (50 mL) were added in sequence at room temperature. After the addition, the reaction solution was heated to 80°C for 18 hours. The reaction was detected by TLC (PE / EA=4 / 1, R f =0.8) The starting material reacted completely. The reaction mixture was cooled to room temperature, filtered, and the solid was rinsed with ethanol (100 mL x 3). The filtrate was concentrated. The residue was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic phases were combined. The mixture was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 7 / 1) to afford the title compound 21d (4.80 g, 52.9% yield) as a yellow solid.

[0382] LC-MS: m / z = 210.0 [M+H] +

[0383] Step 4: 3-Bromo-4,5-difluorobenzenesulfonyl chloride 21e

[0384] Compound 21d (1.01 g, 4.85 mmol) was added to a mixture of concentrated hydrochloric acid (10 mL) and water (10 mL) and stirred evenly. The mixture was cooled to -5°C and a sodium nitrite solution (497 mg, 7.20 mmol, dissolved in 4 mL of water) was slowly added dropwise. The temperature was maintained and the reaction was continued for 1 hour. The solution was set aside. Anhydrous copper dichloride (192 mg, 1.42 mmol) was added to acetic acid (15 mL) and sulfur dioxide gas was continuously introduced into the mixture for 1 hour. The mixture was cooled to 5°C. The above diazonium salt solution was added to the reaction mixture and the mixture was reacted at -5°C to 0°C for 2 hours. The reaction was detected by TLC (PE / EA=4 / 1, R f =0.3) The reaction was complete. The reaction solution was quenched by adding ice water (100 mL), extracted with dichloromethane (50 mL x 3), and the organic phases were combined, washed with water (100 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 21e (1.20 g, crude) as a brown oil, which was used directly in the next step.

[0385] Step 5: 3-Bromo-4,5-difluorobenzenesulfonamide 21f

[0386] A 25%-28% ammonia solution (10 mL) was cooled to -5°C, and a tetrahydrofuran solution of compound 21e (1.20 g crude product, dissolved in 5 mL tetrahydrofuran) was added dropwise thereto. After the addition was complete, the reaction solution was slowly warmed to room temperature and reacted for 30 minutes. The reaction mixture was detected by TLC (PE / EA=4 / 1, R f =0.8) The starting material reacted completely. The reaction mixture was quenched by adding saturated brine (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 40 / 1) to afford the title compound 21f (735 mg, 55.6% yield over two steps) as a yellow solid.

[0387] 1 H NMR (400MHz, DMSO-d6) δ7.95 (dt, J = 5.6, 2.0Hz, 1H), 7.09-7.85 (m, 1H), 7.66 (s, 2H).

[0388] Step 6: N-((3-bromo-4,5-difluorophenyl)sulfonyl)-2,4-dichlorobenzamide 21

[0389] 2,4-Dichlorobenzoic acid (210 mg, 1.10 mmol) was added to dichloromethane (10 mL), and oxalyl chloride (1 mL, 11.8 mmol) and DMF (1 drop) were added in sequence at room temperature. After the addition was complete, the mixture was reacted at room temperature for 4 hours. The reaction was detected by TLC (DCM / MeOH=20 / 1, R f =0.2) The raw material reacted completely, the reaction solution was concentrated to dryness, and the residue was dissolved in dichloromethane (15 mL). Compound 21f (300 mg, 1.10 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.71 mmol) were added in sequence at room temperature. After the addition was complete, the mixture was reacted at room temperature for 2 hours. TLC detection (DCM / MeOH=20 / 1, R f =0.5) The starting material reacted completely. The reaction solution was quenched with water (15 mL) and extracted with dichloromethane (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 30 / 1) to obtain a white solid (325 mg, HPLC 95%). The crude product was further purified by prep-HPLC to obtain the title compound 21 as a white solid (200 mg, 40% yield).

[0390] LC-MS: m / z = 443.8 [MH] - (99.91% purity, 210nm)

[0391] 1H NMR (400 MHz, DMSO-d6) δ 8.15-8.02 (m, 2H), 7.74 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.52 (dd, J = 8.4, 2.0 Hz, 1H). (The active hydrogen of the sulfonamide is not shown).

[0392] Example 22

[0393] 2,4-Dichloro-N-(morpholinosulfonyl)benzamide 22

[0394] Step 1: Morpholine-4-sulfonamide 22b

[0395] Morpholine 22a (800 mg, 9.18 mmol) was added to 1,4-dioxane (6 mL), and sulfonamide (1.06 g, 11.0 mmol) was added thereto. After the addition was complete, the reaction solution was heated to 120°C for 18 hours and monitored by TLC (DCM / MeOH = 20 / 1, R f =0.2) was complete, and the reaction solution was cooled to room temperature. The reaction solution was concentrated to dryness, and ethyl acetate (20 mL) was added. After the addition was complete, the reaction solution was heated under reflux until complete dissolution. The solution was filtered while hot, and the filtrate was collected. The filtrate naturally cooled to room temperature, whereupon a large amount of solid precipitated. This solid was filtered, rinsed with ethyl acetate (10 mL), and dried to obtain the title compound 22b (805 mg, 54.12% yield) as a yellow solid.

[0396] LC-MS: m / z = 167.1 [M+H] +

[0397] 1 H NMR (400MHz, DMSO-d6) δ6.82(s,2H),3.65(t,J=4.8Hz,4H),2.92(t,J=4.8Hz,4H)

[0398] Step 2: 2,4-dichloro-N-(morpholinosulfonyl)benzamide 22

[0399] 2,4-Dichlorobenzoic acid (300 mg, 1.57 mmol) was added to dichloromethane (10 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (900 mg, 2.36 mmol) and N,N-diisopropylethylamine (1 mL, 5.42 mmol) were added thereto. After the addition was complete, the reaction solution was stirred at room temperature for 18 hours and monitored by TLC (DCM / MeOH=20 / 1, R f=0.2) reaction was complete, water (10 mL) was added to extract the liquid, dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness. Dichloromethane (10 mL) was added to dissolve it, and then compound 22b (240 mg, 1.44 mmol) and N,N-diisopropylethylamine (1 mL, 5.42 mmol) were added. After the addition was complete, the mixture was stirred at room temperature for 18 hours and monitored by TLC (DCM / MeOH=20 / 1, R f =0.6) was completed, and the reaction solution was quenched with water (10 mL), extracted with dichloromethane (10 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 80 / 1) to obtain the title compound 22 (50 mg, 10.25% yield) as a yellow solid.

[0400] LC-MS: m / z = 339.0 [M+H] + (99.82% purity, 254nm)

[0401] 1 H NMR (400MHz, DMSO-d6) δ12.25(s,1H),7.77(d,J=1.6Hz,1H),7.61(d,J=8.4Hz,1H),7.53(dd,J=8.4,2.0Hz,1H),3.69-3.62(m,4H),3.32-3.28(m,4H).

[0402] Example 23

[0403] N-((5-bromo-3-(2-methoxyethyl)thiophen-2-yl)sulfonyl)-2,4-dichlorobenzamide 23

[0404] Step 1 3-(2-methoxyethyl)thiophene 23b

[0405] Under ice bath conditions, sodium hydride (9.36 g, 60%) was added to anhydrous tetrahydrofuran (100 mL), and 3-thiopheneethanol 23a (10.0 g, 78.0 mmol) was slowly added. After the addition was complete, iodomethane (33.0 g, 234 mmol) was slowly added at 0°C. After the addition was complete, the reaction solution was heated to 60°C under nitrogen protection for 2 hours. The raw material (ethyl acetate / petroleum ether = 1 / 10, R f =0.2) the reaction was complete, and a new point appeared (ethyl acetate / petroleum ether=1 / 10, R f=0.6). The reaction solution was cooled to room temperature and slowly poured into a saturated aqueous ammonium chloride solution (150 mL) at 0°C. Extraction was performed with ethyl acetate (60 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 23b (13.6 g, crude product) as a pale yellow liquid, which was directly carried to the next step.

[0406] Step 2 3-(2-Methoxyethyl)thiophene-2-sulfonyl chloride 23c

[0407] The temperature of the dry ice / ethanol bath was lowered to -10°C, and a dichloromethane solution (50 mL) of compound 23b (11.0 g, crude product) was slowly added dropwise to a dichloromethane solution (50 mL) of chlorosulfonic acid (10 mL) (the temperature may rise sharply, so the addition should be controlled below 0°C). After the addition, the raw material (ethyl acetate / petroleum ether = 1 / 10, R f =0.6) disappeared, and a new spot appeared (ethyl acetate / petroleum ether = 1 / 10, R f The reaction solution was slowly poured into ice water (80 mL) for quenching, extracted with dichloromethane (40 mL x 3), and the organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 23c (4.46 g, crude product) as a pale yellow liquid, which was directly carried out to the next step.

[0408] Step 3 3-(2-methoxyethyl)thiophene-2-sulfonamide 23d

[0409] A tetrahydrofuran solution (20 mL) of compound 23c (4.46 g, crude product) was slowly added dropwise to aqueous ammonia (20 mL) and reacted at 20°C for 30 minutes. The raw material (ethyl acetate / petroleum ether = 1 / 10, R f =0.3) disappeared. The reaction solution was concentrated, the crude product was diluted with water (50 mL), extracted with ethyl acetate (20 mL x 2), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain the title compound 23d as a white solid (200 mg, three-step yield 1%).

[0410] 1 H NMR (400MHz, CDCl3) δ7.45(d,J=4.8Hz,1H),6.97(d,J=5.2Hz,1H),5.39(s,2H),3.66(t,J=5.6Hz,2H),3.32(s,3H),3.27(t,J=5.6Hz,2H).

[0411] Step 4: 5-bromo-3-(2-methoxyethyl)thiophene-2-sulfonamide 23e

[0412] Compound 23d (200 mg, 0.90 mmol) was dissolved in dichloromethane (2 mL), and bromine (159 mg, 0.99 mmol) was slowly added at 0°C. After the addition was complete, the mixture was reacted at 20°C for 12 hours. The starting material disappeared after TLC monitoring (ethyl acetate / petroleum ether = 1 / 3, R f =0.3). The reaction solution was quenched with water (5 mL) and extracted with ethyl acetate (2 mL x 2). The organic phases were combined, washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Pre-TLC (ethyl acetate / petroleum ether = 1 / 3) to obtain the title compound 23e (40 mg, yield 15%) as a light yellow solid.

[0413] LCMS: m / z = 299.9 [M+H] +

[0414] 1 H NMR (400MHz, CDCl3) δ6.95 (s, 1H), 5.39 (s, 2H), 3.63 (t, J = 5.2Hz, 2H), 3.32 (s, 3H), 3.21 (t, J = 5.2Hz, 2H).

[0415] Step 5: N-((5-bromo-3-(2-methoxyethyl)thiophen-2-yl)sulfonyl)-2,4-dichlorobenzamide 23

[0416] 2,4-Dichlorobenzoic acid (25 mg, 0.133 mmol) was added to dichloromethane (0.5 mL), and EDCI (33 mg, 0.173 mmol) and HOBT (24 mg, 0.173 mmol) were added in sequence at 20°C. After the addition, the reaction solution was stirred for 1 hour. The starting material disappeared after TLC monitoring (dichloromethane / methanol = 1 / 15, R f =0.2). The reaction solution was quenched with water (2 mL) and extracted with dichloromethane (1 mL x 2). The organic phases were combined, washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, and concentrated. Compound 23e (40 mg, 0.133 mmol), N,N-diisopropylethylamine (35 mg, 0.266 mmol) and dichloromethane (0.5 mL) were added to the crude product. After addition, the mixture was reacted at 20°C for 10 hours. The reaction mixture was monitored by TLC for the reaction mixture of compound 24e (ethyl acetate / petroleum ether = 1 / 3, R f =0.3) disappeared, the reaction solution was quenched with water (2 mL), extracted with dichloromethane (1 mL x 2), the organic phases were combined, washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Pre-TLC (dichloromethane / methanol = 15 / 1) to give the title compound 23 as a white solid (4 mg, yield 6%).

[0417] LCMS: m / z = 471.8 [MH] - (97.70% purity, 204nm)

[0418] 1 H NMR(400MHz,DMSO-d6)δ7.72(s,1H),7.58-7.47(m,2H),7.32(s,1H),7.08( t,J=51.2Hz,1H),3.56(t,J=6.4Hz,2H),3.23(s,3H),3.10(t,J=6.4Hz,2H).

[0419] Example 24

[0420] 5-(2-acetamidoacetamido)-N-((5-bromothien-2-yl)sulfonyl)-2,4-dichlorobenzamide 24

[0421] Step 1: Methyl 5-((tert-Butoxycarbonyl)amino)-2,4-dichlorobenzoate 24b

[0422] Methyl 2,4-dichloro-5-bromobenzoate 24a (12.3 g, 43.3 mmol) was dissolved in toluene (120 mL), and palladium acetate (486 mg, 2.17 mmol), tert-butyl carbamate (6.59 g, 56.3 mmol), BINAP (2.70 g, 4.33 mmol) and cesium carbonate (28.2 g, 86.6 mmol) were added in sequence. After the addition was complete, the atmosphere was replaced with nitrogen three times, and the reaction solution was heated to 120 °C for 20 hours. The starting material disappeared after TLC monitoring (ethyl acetate / petroleum ether = 1 / 5, R f =0.5), a new point was generated (ethyl acetate / petroleum ether=1 / 5, R f =0.4). The reaction solution was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (30 mL x 2). The organic phases were combined and diluted with water (100 mL). The mixture was extracted with ethyl acetate (50 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 silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 8) to obtain the title compound 24b (6.65 g, yield 47%) as a white solid.

[0423] Step 2: 5-amino-2,4-dichlorobenzoic acid methyl ester 24c

[0424] Compound 24b (6.65 g, 20.8 mmol) was dissolved in dichloromethane (30 mL), trifluoroacetic acid (60 mL) was added at 20°C, and the mixture was kept warm for 1 hour. The starting material disappeared after monitoring by TLC (ethyl acetate / petroleum ether = 1 / 5, R f=0.4), a new point was generated (ethyl acetate / petroleum ether=1 / 5, R f =0.2). The reaction solution was concentrated to about 30 mL, diluted with water (50 mL), and basified to pH 8-9 by adding 30% sodium hydroxide solution dropwise at 0°C. The mixture was 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 to obtain the title compound 24c (4.77 g, crude product) as a white solid, which was directly carried out to the next step.

[0425] Step 3: 5-(2-acetamidoacetamido)-2,4-dichlorobenzoic acid methyl ester 24d

[0426] Compound 24c (4.67 g, crude product) was dissolved in dichloromethane (45 mL), and acetylglycine (2.61 g, 22.3 mmol), HATU (12.1 g, 31.8 mmol) and N,N-diisopropylethylamine (5.48 g, 42.4 mmol) were added in sequence at 20°C. After the addition was complete, the reaction solution was reacted at 20°C for 10 hours. The disappearance of the starting material was monitored by TLC (ethyl acetate / petroleum ether = 1 / 1, R f =0.6), a new point was generated (ethyl acetate / petroleum ether=1 / 1, R f =0.2). The reaction solution was quenched with water (70 mL) and extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain the title compound 24d (11.2 g, crude product) as a light yellow solid, which was used directly in the next step.

[0427] LCMS: m / z=319.0 [M+H] +

[0428] Step 4: 5-(2-acetamidoacetamido)-2,4-dichlorobenzoic acid 24e

[0429] Compound 24d (10.7 g, crude product) was dissolved in anhydrous methanol (100 mL), and solid sodium hydroxide (1.34 g, 33.5 mmol) and water (100 mL) were added at 10°C. After the addition was complete, the reaction was continued at 20°C for 3 hours. The starting material disappeared after TLC monitoring (dichloromethane / methanol = 10 / 1, R f =0.7), a new point was generated (dichloromethane / methanol=5 / 1, R f=0.1). The reaction solution was concentrated and acidified to pH 2-3 by the addition of hydrochloric acid (25 mL, 6N) at 0°C. The mixture was extracted with ethyl acetate (40 mL x 4). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, concentrated, and slurried at room temperature (ethyl acetate / petroleum ether = 1 / 3, 50 mL), filtered, and the filter cake was dried to obtain the title compound 24e (7.46 g, 73% yield for three steps) as a light yellow solid.

[0430] Step 5: 5-(2-acetamidoacetamido)-N-((5-bromothiophen-2-yl)sulfonyl)-2,4-dichlorobenzamide 24

[0431] Compound 24e (300 mg, 0.98 mmol) was added to dichloromethane (3 mL), and 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (767 mg, 1.47 mmol) and N,N-diisopropylethylamine (254 mg, 1.97 mmol) were added in sequence at room temperature. After the addition was complete, the reaction was continued for 2 hours. The starting material disappeared after TLC monitoring (dichloromethane / methanol = 5 / 1, R f =0.1). The reaction solution was quenched with water (5 mL), extracted with dichloromethane (1 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. 5-Bromo-2-thiophenesulfonamide (262 mg, 1.08 mmol), N,N-diisopropylethylamine (254 mg, 1.966 mmol), and dichloromethane (3 mL) were added to the crude product. After addition, the reaction was continued at room temperature for 10 hours. LCMS monitoring showed that the active ester of compound 25e disappeared. The reaction solution was quenched with water (5 mL), extracted with dichloromethane (2 mL), and the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by pre-TLC (dichloromethane / methanol = 10 / 1) to obtain the title compound 24 (120 mg, 23% yield) as a light yellow solid.

[0432] LCMS: m / z=527.8[M+H] + (99.78% purity, 210nm)

[0433] 1 H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.30(t,J=5.6Hz,1H),7.95(s,1H),7.77(s,1H),7.65(d,J =4.0Hz,1H),7.39(d,J=4.1Hz,1H),7.10(t,J=50.8Hz,1H),3.94(d,J=6.0Hz,2H),1.89(s,3H).

[0434] Example 25

[0435] 5-(2-acetamidoacetamido)-N-((5-bromo-3-(2-methoxyethyl)thiophen-2-yl)sulfonyl)-2,4-dichlorobenzamide 25

[0436] The first step is 5-(2-acetamidoacetamido)-N-((5-bromothiophen-2-yl)sulfonyl)-2,4-dichlorobenzamide 25

[0437] Compound 24e (97 mg, 0.32 mmol) was added to dichloromethane (1 mL), and EDCI (80 mg, 0.41 mmol) and HOBT (56 mg, 0.0.41 mmol) were added in sequence at 20°C. After the addition, the reaction solution was stirred for 1 hour. The starting material disappeared after TLC monitoring (dichloromethane / methanol = 1 / 15, R f =0.2). The reaction solution was quenched with water (2 mL) and extracted with dichloromethane (1 mL x 2). The organic phases were combined, washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, and concentrated. Compound 23e (100 mg, 0.33 mmol), N,N-diisopropylethylamine (205 mg, 1.58 mmol) and dichloromethane (1 mL) were added to the crude product. After the addition was complete, the reaction was continued at 20°C for 10 hours. The reaction of compound 24e (ethyl acetate / petroleum ether = 1 / 3, R f =0.3) disappeared, the reaction solution was quenched with water (2 mL), extracted with dichloromethane (1 mL x 2), the organic phases were combined, washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Pre-TLC (dichloromethane / methanol = 1 / 10) to obtain the title compound 25 as a white solid (20 mg, yield 11%).

[0438] LCMS: m / z = 585.9 [M+H] + (95.27% purity, 204nm)

[0439] 1 H NMR (400MHz, DMSO-d6) δ9.67(s,1H),8.31(t,J=5.6Hz,1H),7.95(s,1H),7.77(s,1H),7.31(s,1H),7.09(t,J =51.2Hz,1H),3.94(d,J=6.0Hz,2H),3.55(t,J=6.8Hz,2H),3.22(s,3H),3.09(t,J=6.8Hz,2H),1.89(s,3H).

[0440] Example 26

[0441] N-((5-bromothiazol-2-yl)sulfonyl)-2,4-dichlorobenzamide 26

[0442] Step 1: 2-(Benzylthio)-5-bromothiazole 26b

[0443] Benzyl mercaptan (6.14 g, 49.40 mmol) was added to a DMF (50 mL) solution of 2,5-dibromothiazole 26a (10.0 g, 41.17 mmol) and potassium carbonate (11.38 g, 82.33 mmol), and stirred at 25°C for 16 hours. TLC showed that the reaction was complete (PE / EA = 15 / 1, starting material R f =0.5, product R f =0.55). The reaction solution was quenched by adding water (50 mL), extracted with ethyl acetate (50 mL), washed with water (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated and purified by silica gel column chromatography to obtain the title compound 26b (10.6 g, yield 90.0%) as a light yellow liquid.

[0444] Step 2 5-Bromothiazole-2-sulfonyl chloride 26c

[0445] At 0°C, N-chlorosuccinimide (9.42 g, 70.58 mmol) was added to a mixed solution of compound 26b (10.1 g, 35.29 mmol) in acetic acid / water (3:1, 200 mL). The reaction mixture was heated to 25°C and stirred for 2 hours. TLC showed that the reaction was complete (PE / EA = 10 / 1, starting material R f =0.5, product R f =0.3). The reaction solution was quenched with water (150 mL), extracted with ethyl acetate (150 mL), washed with water (150 mL x 2), washed with saturated sodium bicarbonate solution (150 mL x 2), and washed with saturated brine (150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated and purified by silica gel column chromatography to obtain the title compound 26c (8.75 g, crude product) as a light yellow liquid, which was used directly in the next reaction.

[0446] Step 3 5-bromothiazole-2-sulfonyl chloride 26d

[0447] At 0°C, ammonia (5 mL) was added to a solution of compound 26c (8.75 g, crude product) in tetrahydrofuran (50 mL). The reaction mixture was heated to 25°C and stirred for 30 minutes. TLC showed that the reaction was complete (PE / EA = 3 / 1, starting material R f =0.5, product R f=0.3). The reaction solution was concentrated, acidified with 2M hydrochloric acid to pH = 3-4, extracted with ethyl acetate (50 mL), washed with water (5 mL x 2), washed with saturated brine (50 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated and purified by silica gel column chromatography to obtain the title compound 26d (2.76 g, two-step yield 32.2%) as a white solid.

[0448] LC-MS: m / z = 242.9 [M+H] +

[0449] Step 4: N-((5-bromothiazol-2-yl)sulfonyl)-2,4-dichlorobenzamide 26

[0450] Oxalyl chloride (206 mg, 1.62 mmol) and DMF (1 drop) were added to a suspension of 2,4-dichlorobenzoic acid (155 mg, 0.81 mmol) in DCM (2 mL) at 0°C. The reaction mixture was heated to 25°C for 1 hour. The reaction mixture was concentrated and the concentrate was dissolved in DCM (2 mL). The concentrate in DCM was added to a solution of compound 26d (150 mg, 0.62 mmol) and triethylamine (187 mg, 1.85 mmol) in DCM (3 mL) at 0°C. The mixture was heated to 25°C and stirred for 30 minutes. TLC showed that the reaction was complete (PE / EA = 2 / 1, starting material R f =0.3, DCM / MeOH=10:1, product R f =0.1), the reaction solution was concentrated, the crude product was dissolved in water (15 mL), extracted with PE / EA (3 / 1, 15 mL x 3), the aqueous phase was acidified with 2M hydrochloric acid to pH = 3-4, extracted with ethyl acetate (15 mL), washed with water (5 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was suspended in DCM (5 mL), PE (15 mL) was added, stirred for 15 minutes, filtered, and the filter cake was washed with PE / EA (3 / 1, 2 mL), drained, and dried to obtain the title compound 26 (128 mg, yield 57.6%) as a white solid.

[0451] LC-MS: m / z = 414.8 [M+H] + (97.46% purity by HPLC,254nm)

[0452] 1 H NMR (400MHz, DMSO-d6) δ8.24(s,1H),7.72(d,J=1.6Hz,1H),7.59(d,J=8.0Hz,1H),7.51(dd,J=8.4,2.0Hz,1H).

[0453] Example 27

[0454] 2,4-Dichloro-N-((5-ethynylthiazol-2-yl)sulfonyl)benzamide 27

[0455] Step 1 5-((Trimethylsilyl)ethynyl)thiazole-2-sulfonamide 27a

[0456] Cuprous iodide CuI (20 mg, 0.1 mmol) and Pd(PPh3)2Cl2 (72 mg, 0.1 mol) were added to a DMF (5 mL) solution of compound 26d (500 mg, 2.06 mmol) and triethylamine (624 mg, 6.17 mmol). The atmosphere was replaced with nitrogen three times for protection. Trimethylethynylsilane (1.14 g, 11.57 mmol) was added to the reaction solution via syringe. The reaction solution was heated to 80°C and stirred for 30 minutes. TLC showed that the reaction was complete (PE / EA = 1 / 1, starting material R f =0.3, product R f =0.35). EA (50 mL) was added to the reaction solution, and a solid precipitated. The solid was filtered, and the filter cake was washed with EA (5 mL). The filtrate was washed with water (50 mL x 3). The EA phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain the title compound 27a (310 mg, 57.9%) as a light yellow liquid.

[0457] LC-MS: m / z = 261.0 [M+H] +

[0458] Step 2 5-ethynylthiazole-2-sulfonamide 27b

[0459] Potassium carbonate (119 mg, 0.86 mmol) was added to a solution of compound 27a (150 mg, 0.57 mmol) in methanol (5 mL) at 25°C. The reaction mixture was stirred for 30 minutes. TLC showed that the reaction was complete (PE / EA = 5 / 1, starting material R f =0.5, product R f =0.3). The reaction solution was diluted with water (10 mL), acidified to pH = 3 with 2M hydrochloric acid, extracted with ethyl acetate (15 mL), washed with water (15 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound 27b (108 mg, 100%) as a light yellow liquid.

[0460] LC-MS: m / z = 189.0 [M+H] +

[0461] Step 3 2,4-dichloro-N-((5-ethynylthiazol-2-yl)sulfonyl)benzamide 27

[0462] At 0°C, oxalyl chloride (174 mg, 1.37 mmol) and DMF (1 drop) were added to a suspension of 2,4-dichlorobenzoic acid (131 mg, 0.69 mmol) in DCM (2 mL). The reaction solution was heated to 25°C and reacted for 1 hour. The reaction solution was concentrated and the concentrate was dissolved in DCM (2 mL). The above solution was added to a solution of compound 27b (108 mg, 0.57 mmol) and triethylamine (174 mg, 1.72 mmol) in DCM (3 mL) at 0°C. The reaction solution was heated to 25°C and stirred for 30 minutes. TLC showed that the reaction was complete (PE / EA = 2 / 1, starting material R f =0.3, DCM / MeOH=10:1, product R f = 0.1), the reaction solution was concentrated, the crude product was dissolved in water (15 mL), extracted with a PE / EA mixture (3 / 1, 15 mL x 3), the aqueous phase was acidified to pH = 3-4 with 2M hydrochloric acid, extracted with ethyl acetate (15 mL), washed with water (5 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was suspended in DCM (5 mL), petroleum ether (15 mL) was added, stirred for 15 minutes, filtered, and the filter cake was washed with PE / EA (3 / 1, 2 mL) and dried to obtain the title compound 27 (118 mg, yield 56.9%) as a white solid.

[0463] LC-MS: m / z=360.9[M+H] + (99.98% purity by HPLC,254nm)

[0464] 1 H NMR (400MHz, DMSO-d6) δ8.34(s,1H),7.71(d,J=2.0Hz,1H),7.59(d,J=8.4Hz,1H),7.51(dd,J=8.0,2.0Hz,1H),5.10(s,1H).

[0465] Pharmacological activity test

[0466] Test Example 1: Affinity test of compounds with WDR5 at the molecular level

[0467] The affinity test of the compounds in the present disclosure to WDR5 at the molecular level was conducted by the following method:

[0468] Compound Preparation: Accurately weigh the compound and dissolve it in DMSO (Sigma, D5879) to a 10 mM stock solution. Serially dilute the stock solution two-fold using 1x HBS-EP buffer (10 mM HEPES, pH 7.4, 150 mM NaCl, 3.0 mM EDTA, and 0.005% (v / v) TW-20) to a final concentration of 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, and 0.39 μM. The final DMSO concentration was 5%. A certain amount of compound sample was transferred to a 96-well plate (Greiner, 650101) according to the experimental protocol.

[0469] Surface Plasmon Resonance (SPR) Assay: WDR5 protein was coupled to a CM5 chip (Cytiva, BR100530) using the amino coupling method, yielding a signal of approximately 9000 response units (RU). Three initialization cycles were performed, followed by injection of test compounds. Association times were set to 120 seconds and dissociation times to 100 seconds. Residual compound on the chip was subsequently washed away with a solution containing 50% DMSO. Solvent correction was performed every 48 cycles using 1x HBS-EP buffer containing 4.5%-5.8% DMSO.

[0470] Detection and Analysis: Biacore8K was used for signal detection, data collection, processing and analysis. The raw data generated by the experiment were processed using Biacore8K data processing software by subtracting the control group parameters and solvent correction, and the corresponding K was fitted using the static affinity model. D For details, see Table 1.

[0471] Conclusion: The compounds of the examples disclosed herein have a strong affinity with the WDR5 protein at the molecular level.

[0472] Table 1. Affinity test results of the compounds disclosed herein and WDR5 protein

[0473] Test Example 2: Anti-proliferative activity test of compounds on neuroblastoma cells

[0474] The anti-proliferative activity of the compounds of the present disclosure on neuroblastoma cells was tested by the following method:

[0475] Compound preparation: Accurately weigh the compound and dissolve it in DMSO to a 10 mM stock solution for later use. Dilute the compound to a final concentration of 10 μM in MEM or RPMI 1640 medium with a final DMSO concentration of 0.1%. Transfer the compound to a 96-well plate for subsequent experiments.

[0476] Cell Counting Kit-8 test (CCK-8): 293T, SK-N-AS, IMR32, and LAN5 cells were seeded into 96-well cell culture plates at a seeding volume of 2 x 10 cells per well. 4 Each well was incubated with the corresponding compound and DMSO control for 72 hours. Then, 10 μL of CCK-8 reagent was added to each well and incubated at 37°C for another 2 hours. The absorbance of the cells was measured at 450 nm using a microplate reader.

[0477] 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.

[0478] Table 2. Antiproliferative activity test results of some compounds in the present disclosure on neuroblastoma cells

[0479] Conclusion: The compounds of the examples disclosed herein have good anti-proliferative activity against neuroblastoma cells. Wherein "-" indicates that the activity was not tested.

[0480] Test Example 3: Structural analysis of the complex between some compounds disclosed herein and WDR5

[0481] The structure of the complex of selected compounds 13 and 14 in the present disclosure was elucidated by the following method:

[0482] Protein crystal preparation: WDR5 expression vector-containing Rosetta2 competent cells were cultured in a 37°C shaking incubator until the OD value reached 0.6-0.8. IPTG was added to a final concentration of 0.1 mM and cultured at 16°C for 20 hours before harvesting. Cells were disrupted using a high-pressure cell disruptor and centrifuged at high speed for 30 minutes. The supernatant was collected after adding 10 mL of Ni-NTA affinity chromatography gel resin and binding was allowed to proceed at 4°C with stirring for 1 hour. The supernatant was then centrifuged and treated with a decontamination buffer (50 mM Tris pH 7.5, 150 mM NaCl, 50 mM imidazole, 1 mM TCEP) and an elution buffer (50 mM Tris pH 7.5, 150 mM NaCl, 300 mM imidazole, 1 mM TCEP) to obtain the initial target protein. High-purity WDR5 protein was then obtained using anion exchange chromatography and size exclusion chromatography, respectively. The sample was then collected and its purity was verified by SDS-polyacrylamide gel electrophoresis.

[0483] The obtained highly pure WDR5 protein was concentrated to 11 mg / mL using an ultrafiltration tube and centrifuged at 12,000 rpm for 30 minutes. Crystallization buffer was prepared: 0.1 M Bis-Tris, pH 5.8, 0.2 M ammonium acetate, and 30% (w / v) pEG3350. Crystallization conditions were optimized using a 24-well hanging drop plate. 1 mL of buffer was used per well. The two solutions were mixed at a ratio of 1.5 μL crystallization buffer and 1.5 μL protein solution. After 2-3 days in an 18°C ​​incubator, crystals grew in a flake-like shape. Crystals of the WDR5-active compound complex were obtained by immersion.

[0484] Detection and analysis: The diffraction data of the crystals were collected at the microcrystal complex beamline BL18U1 of the Shanghai Synchrotron Radiation Facility (SSRF). The collected data were processed using HKL3000, including steps such as data point selection, indexing, correction, integration, data merging and normalization, to generate MTZ files. The WDR5 empty protein crystal structure resolved by our laboratory was used as a template, and the Phaser module in CCP4 was used for molecular replacement to generate the initial structural coordinates. COOT was used for model construction and optimization, and then Phenix was used to further optimize the model, and the R factor in the structural parameters was repeatedly reduced to less than 0.25. The results are shown in Figure 1.

[0485] Conclusion: The compounds of the present invention bind to WDR5 by occupying the WBM site to block the interaction between WDR5 and Myc.

[0486] Test Example 4: In vitro efficacy test of some compounds of the present disclosure on acute myeloid leukemia, hepatoma cell lines and pancreatic cancer cell lines

[0487] Compound preparation: Accurately weigh the compound and dissolve it in DMSO to a 10 mM stock solution for later use. Dilute the compound to a final concentration of 10 μM in MEM or RPMI 1640 medium with a final DMSO concentration of 0.1%. Transfer the compound to a 96-well plate for subsequent experiments.

[0488] Cell Counting Kit-8 test (CCK-8): Hep3B, Huh-7, MV4-11, and Mia-Paca2 cells were seeded into 96-well cell culture plates at a seeding volume of 2 x 10 cells per well. 4 Each well was incubated with the corresponding compound and DMSO control for 72 hours. Then, 10 μL of CCK-8 reagent was added to each well and incubated at 37°C for another 2 hours. The absorbance of the cells was measured at 450 nm using a microplate reader.

[0489] 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.

[0490] 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

[0491] Conclusion: The compounds of the examples disclosed in the present invention have good anti-proliferative activity against hepatoma cells, acute myeloid leukemia cells and pancreatic cancer cells.

[0492] Test Example 5: Pharmacokinetic test of some compounds disclosed herein on normal mice

[0493] This test investigated the pharmacokinetic properties of compound 11 in mice. Female Balb / c mice, 6-8 weeks old, were gavage- or tail-vein-administered with compound 11. Whole blood was collected 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration. After centrifugation at 8000 rpm for 5 minutes, the upper plasma layer was collected. Plasma exposure at different time points was determined by HPLC-MS / MS, and pharmacokinetic parameters were calculated. The specific experimental results are as follows:

[0494] Table 4. Pharmacokinetic test results of some compounds of the present disclosure on normal mice

[0495] Conclusion: The compounds of the present disclosure are rapidly absorbed orally and have a very high bioavailability. The plasma half-life is T 1 / 2 With a duration of up to 15.9 hours, it is an ideal potential oral drug candidate.

[0496] Test Example 6: Efficacy test of some compounds disclosed herein on the IMR32 CDX mouse neuroblastoma model

[0497] The efficacy of compound 11 in a neuroblastoma model was studied. Human neuroblastoma IMR32 cells were cultured in monolayer in vitro and routinely digested and passaged twice a week using trypsin-EDTA. When the cell saturation reached 80%-90%, the cells were harvested, counted, and the inoculation concentration was adjusted to 10 million per animal. The cells were inoculated subcutaneously on the upper right back of the animal and allowed to grow until the tumor reached approximately 120 mm. 3 Animals were randomly divided into groups and dosed according to body weight and tumor volume. Animal body weight and tumor volume were measured twice a week. Efficacy data were expressed as tumor volume (TV), tumor inhibition rate (TGI), and relative volume (T / C). Specific experimental data are as follows:

[0498] Table 5. Results of efficacy test of some compounds of the present disclosure on IMR32 CDX mouse neuroblastoma model (n=6)

[0499] The experimental results showed no significant abnormalities in the animals' health during the dosing period. Compared with the vehicle control group, the low, medium, and high dose groups of the disclosed compounds all demonstrated significant antitumor efficacy with a favorable dose-response relationship, with TGIs reaching 85.5%, 107.1%, and 107.1%, respectively. In some animals in the high and medium dose groups, tumors completely disappeared in the late stages of dosing. This demonstrates the significant efficacy of the disclosed compounds in the IMR32 human neuroblastoma model.

[0500] Test Example 7: Efficacy test of some compounds disclosed herein on Hep3B CDX mouse hepatoma model

[0501] This test case investigated the efficacy of compound 11 in a liver cancer model. Human liver cancer Hep3B cells were cultured in a monolayer in vitro and routinely digested and passaged twice a week using trypsin-EDTA. When the cell saturation reached 80%-90%, the cells were harvested, counted, and the inoculation concentration was adjusted to 10 million cells / animal. The cells were inoculated subcutaneously on the upper right back of the animal and allowed to grow until the tumor reached approximately 110 mm. 3 Animals were randomly divided into groups and dosed according to body weight and tumor volume. Animal body weight and tumor volume were measured twice a week. Efficacy data were expressed as tumor volume (TV), tumor inhibition rate (TGI), and relative volume (T / C). Specific experimental data are as follows:

[0502] Table 6. Results of efficacy test of some compounds of the present disclosure on Hep3B CDX mouse hepatoma model (n=5)

[0503] The experimental results showed no significant abnormalities in the animals' health during the dosing period. Compared with the vehicle control group, both the low- and high-dose groups of the disclosed compounds demonstrated significant antitumor efficacy with a good dose-response relationship, with TGIs reaching 40% and 106.8%, respectively. In the high-dose 90 mg / kg group, tumors in some animals completely disappeared in the late stages of dosing. This demonstrates the significant efficacy of the disclosed compounds in the Hep3B liver cancer xenograft model.

[0504] Test Example 8: Safety test of some compounds disclosed herein on normal mice

[0505] This test case studied the safety of compound 11. Female, 6-8 week old ICR mice were selected as research subjects. The animals were randomly divided into groups according to their body weight and then orally administered at doses of 100 mg / kg, 300 mg / kg, 400 mg / kg, and 500 mg / kg, respectively. The changes in animal body weight, morbidity, and mortality were observed. The specific results are as follows:

[0506] Table 7. Safety test results of some compounds of the present disclosure on normal mice

[0507] The experimental results showed that in ICR mice, oral administration of the disclosed embodiment compound at doses of 100 mg / kg, 300 mg / kg and 400 mg / kg did not cause illness or death in all animals. 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 disclosed embodiment compound is as high as 400 mg / kg, and it has good safety.

[0508] Test Example 9: Protein Binding Rate Test of Some Compounds Disclosed

[0509] The plasma protein binding rate of compound 11 in human plasma was determined using equilibrium dialysis. A semipermeable membrane was used to separate the left and right chambers. A drug-containing protein solution was added to the left chamber, while a blank buffer solution was added to the right chamber. Unbound free drug was allowed to freely cross the semipermeable membrane. After a certain incubation period, equilibrium was reached between the two chambers, and the free drug concentration was equal. The plasma protein binding rate was calculated by measuring the drug concentrations on both sides. The results are shown in Table 8:

[0510] Table 8. Protein binding test results of some compounds disclosed herein

[0511] 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.

[0512] Test Example 10: Hepatocyte Stability Test of Some Compounds of the Disclosure

[0513] Transfer 198 μL of live cell suspension to a 96-well deep-well plate, place the deep-well plate on a vortex and preheat in an incubator for 10 minutes. The experiment was performed in duplicate. Add 2 μL of 100 μM test substance or positive drug verapamil to each well to start the reaction, and place the deep-well plate back on the incubator vortexer. Incubate the sample, take 25 μL of the suspension at 0, 15, 30, 60, 90 and 120 minutes, and add 150 μL of acetonitrile containing the internal standard to terminate the reaction. Vortex for 10 minutes and centrifuge at 3220 g and 4°C for 45 minutes. Transfer 100 μL of supernatant to the sample plate, add 100 μL of pure water to mix, and use for UPLC-MS / MS analysis. The results are shown in Table 9:

[0514] Table 9. Hepatocyte stability test results of some compounds of the present disclosure

[0515] The experimental results show that the compounds of the embodiments of the present disclosure are easily metabolized and eliminated in the human liver and are less likely to produce cumulative toxicity.

[0516] The applicant declares that the present disclosure uses the above-mentioned embodiments to illustrate a sulfonamide compound disclosed herein as an inhibitor of the interaction between WDR5 and Myc, its preparation method and application, but the present disclosure is not limited to the above-mentioned embodiments, that is, it does not mean that the present disclosure must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement to the present disclosure, the equivalent replacement of the raw materials of the products disclosed herein, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the present disclosure. The above describes in detail the optional embodiments of the present disclosure, but the present disclosure is not limited to the specific details in the above-mentioned embodiments. Within the scope of the technical concept of the present disclosure, the technical solution of the present disclosure can be subjected to a variety of simple modifications, and these simple modifications all fall within the scope of protection of the present disclosure. It should also be noted that the various specific technical features described in the above-mentioned specific embodiments can be combined in any suitable manner if there is no contradiction. In order to avoid unnecessary repetition, the present disclosure will no longer describe the various possible combinations separately.

Claims

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

2. The sulfonamide compound or a pharmaceutically acceptable salt thereof, a tautomer thereof or a stereoisomer thereof according to claim 1, wherein: A 1 Ring or A 2 The ring is one of the following cyclic structures: * indicates the connection site with the parent core, R as a substituent 1 and R 2 Any position that is chemically substitutable can be substituted. R 1 or R 2 is selected from H, F, Cl, Br, I, hydroxyl, methyl, methoxy, trifluoromethyl, ethyl, ethynyl, cyclopropyl, cyclopentyl, cyclohexyl, cyano, formamide, cyano-substituted cyclopropyl, cyano-substituted cyclopentyl, cyano-substituted cyclohexyl, phenyl, cyano-substituted phenyl, naphthyl, cyano-substituted naphthyl and one of the following groups: * indicates the site of attachment to the parent nucleus.

3. The sulfonamide compound or a pharmaceutically acceptable salt thereof, a tautomer thereof or a stereoisomer thereof according to claim 1, wherein: A 1 Ring and its substituent R 1 The combination is one selected from the following groups: A 2 Ring and its substituent R 2 The combination is one selected from the following groups: * indicates the site of attachment to the parent nucleus.

4. The sulfonamide compound according to claim 1 or a pharmaceutically acceptable salt thereof, a tautomer thereof or a stereoisomer thereof, wherein the sulfonamide compound represented by formula (I) is the following compound:

5. A pharmaceutical composition, comprising a sulfonamide compound as described in any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, and a pharmaceutically acceptable carrier and / or excipient, wherein the pharmaceutical composition is a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation; the dosage form of the pharmaceutical composition is preferably an oral dosage form or an injection, wherein the oral dosage form includes capsules, tablets, pills, powders and granules, and the liquid dosage form for oral administration includes a pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture, and the injection contains a physiologically acceptable sterile aqueous or anhydrous solution, dispersion, suspension or emulsion.

6. Use of the sulfonamide compound according to any one of claims 1 to 4 or its pharmaceutically acceptable salt, its tautomer or its stereoisomer or the pharmaceutical composition according to claim 5 in the preparation of an inhibitor of the interaction between WDR5 and Myc, preferably, by specifically binding to the WBM site of WDR5 to block the interaction between WDR5 and Myc.

7. Use of the sulfonamide compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, or the pharmaceutical composition according to claim 5 in the preparation of a drug for treating or alleviating cancer, Preferably, 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; further preferably, the cancer is selected from neuroblastoma, gangliocytoma, ganglioblastoma, ganglioneuroma, ganglioblastoma, sympathetic neuroblastoma, neurotheca, neurotheca, neurofibroma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, pancreatic cancer.

8. A method for treating and / or preventing cancer, comprising administering to a human or animal body a therapeutically effective amount of a sulfonamide compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, and a pharmaceutical composition according to claim 5.

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