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WO2025031361A1 - Utilisation d'un composé sulfonamide dans la préparation d'un médicament pour le traitement de cancers - Google Patents

Utilisation d'un composé sulfonamide dans la préparation d'un médicament pour le traitement de cancers Download PDF

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Publication number
WO2025031361A1
WO2025031361A1 PCT/CN2024/110126 CN2024110126W WO2025031361A1 WO 2025031361 A1 WO2025031361 A1 WO 2025031361A1 CN 2024110126 W CN2024110126 W CN 2024110126W WO 2025031361 A1 WO2025031361 A1 WO 2025031361A1
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Prior art keywords
ring
cancer
present disclosure
compounds
wdr5
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Chinese (zh)
Inventor
白芳
梅良和
李凯
曹宇
张斌
韩祺蕾
孟晓冬
王林
任鹏璇
王作鹏
张向磊
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Suzhou New Drug Incubator Biopharmaceutical Technology Co Ltd
ShanghaiTech University
Childrens Hospital of Fudan University
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Suzhou New Drug Incubator Biopharmaceutical Technology Co Ltd
ShanghaiTech University
Childrens Hospital of Fudan University
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Publication of WO2025031361A1 publication Critical patent/WO2025031361A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C15/02—Monocyclic hydrocarbons
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07—ORGANIC CHEMISTRY
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
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    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry and relates to the medical use of sulfonamide derivatives, and specifically relates to the use of a sulfonamide compound as an anti-neuroblastoma drug for preparing a cancer treatment drug.
  • Neuroblastoma is one of the most common extracranial malignant tumors in children. It originates from the neural crest cells of the sympathetic nervous system and is prone to occur in the adrenal glands (Non-patent Document 1). Its onset is insidious, and it is prone to metastasis. The mortality rate of high-risk cases is high, which seriously threatens the life and health of children. Clinically, there are great differences in the prognosis of children at different stages.
  • Non-patent Document 2 In low-risk children under the age of 18 months, the tumor often regresses naturally or can be cured by chemotherapy alone; while the prognosis of children with tumors with poor pathological types, accompanied by risk factors such as MYCN gene amplification, 11q abnormalities, or distant metastasis is extremely poor (Non-patent Document 2).
  • current treatment methods include comprehensive measures such as surgery, chemoradiotherapy, and biological therapy, there are still disadvantages such as difficulty in eradicating small lesions, large toxic side effects, and easy drug resistance, which greatly reduces the treatment effect and is a major problem in clinical pediatric surgery. Therefore, it is urgent to develop a new, safe and effective drug for the treatment of neuroblastoma.
  • WDR5 WD40 repeat domain protein 5
  • WDR5 belongs to the WD40 protein family and is a protein containing a circular seven-blade ⁇ -propeller domain. WDR5 is highly conserved among different vertebrates, with a sequence identity of about 90%. WDR5 was first discovered to be involved in regulating osteoblast differentiation and promoting bone formation during skeletal development. In recent years, more and more studies have revealed the biological functions of WDR5, finding that it not only regulates biological behaviors such as cell proliferation, division, apoptosis, signal transduction, gene transcription, and DNA damage repair under physiological conditions, but is also highly correlated with the occurrence and development of a variety of tumors, making it a popular choice for tumor treatment targets.
  • WDR5 The most important function of WDR5 in vivo is epigenetic regulation. As a member of the histone methyltransferase (HMT) complex, it regulates histone methylation levels and activates the transcription of target genes. Abnormal WDR5 function can upregulate the expression of multiple tumor-promoting factors, activate tumor-related signaling pathways, and then enhance tumor cell proliferation, metastasis and drug resistance, driving the occurrence of epithelial-mesenchymal transition (EMT). WDR5 is also an auxiliary factor of myelocytoma viral oncogene homolog (Myc). As a transcription factor, Myc regulates the transcription of downstream genes by binding to the promoter region of the target gene.
  • Myc myelocytoma viral oncogene homolog
  • WDR5 is a key factor in the process of Myc-driven tumorigenesis. This mechanism has been confirmed in a variety of Myc-related tumors. In glioblastoma and neuroblastoma, WDR5 can promote the binding of Myc to the coactivator protein-associated arginine methyltransferase 1 (CARM1) promoter, enhancing the proliferation and self-renewal ability of tumor cells.
  • CARM1 coactivator protein-associated arginine methyltransferase 1
  • WDR5 co-localizes with N-Myc in the double minute homolog gene 2 (MDM2) promoter region, activates the transcription of MDM2, and inhibits the expression of tumor suppressor protein p53.
  • MDM2 double minute homolog gene 2
  • WDR5 maintains a high level of HIF-1 ⁇ in the body through epigenetic regulation, and also increases the expression of HIF-1 ⁇ through Myc in the transcription link, promoting the EMT, metastasis and invasion of tumor cells.
  • WBM WDR5 binding domain
  • WIN WDR5 interaction domain
  • the WBM site is a shallow and relatively hydrophobic binding pocket, mainly composed of Asn225, Tyr228, Leu240, Phe266, Val268 and Gln289.
  • Retinoblastoma binding protein 5 (RBBP5), C-myc, L-myc, N-myc, KAT8 regulatory NSL complex subunit 2 (KANSL2), etc. all interact with WDR5 through this site.
  • the WIN site is an arginine binding pocket, composed of amino acids such as Ala65, Ser91, Asp107, Phe133, Tyr191, Tyr260 and Phe263.
  • MML1-4 mixed lineage leukemia 1-4
  • KANSL1 KAT8-regulated NSL complex subunit 1
  • MBD3 methylphosphoguanosine phosphate binding protein
  • KIF2A kinesin heavy chain member 2A
  • WDR5 The key biological functions of WDR5 rely on the mediation of the above two sites, such as direct binding with RBBP5 and SET1/MLL, indirect binding with ash2 (lack, small, or homologous)-like (Drosophila) protein (ASH2L) and dpy-30 homolog protein (DPY30) to assemble into a complex with histone methyltransferase catalytic activity, regulating the transcription of target genes through epigenetic regulation (non-patent document 4); and interacting with the transcription factor Myc, recruiting Myc to chromatin, improving its binding to the promoter region of the target gene, and greatly enhancing its tumor-promoting function (non-patent documents 5,6). Therefore, targeting the WBM or WIN sites on the surface of WDR5 to design specific protein-protein interaction blockers has become the main strategy for the development of new WDR5 inhibitors.
  • designing and synthesizing highly active candidate compounds that specifically block the interaction between WDR5 and Myc for the treatment of diseases such as neuroblastoma has important research significance and application prospects, and is an important direction for potential drug targets and the search for lead compounds.
  • the purpose of the present disclosure is to provide a sulfonamide compound or a pharmaceutically acceptable salt thereof, a tautomer thereof or a stereoisomer thereof, so as to screen out compounds having excellent performance in terms of effectiveness, safety and selectivity as WDR5 inhibitors.
  • the present disclosure provides a sulfonamide compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a tautomer thereof or a stereoisomer thereof,
  • A1 ring and A2 ring are each independently selected from one of a C6-C30 aryl ring, a C6-C30 aliphatic hydrocarbon ring, a C3-C30 heteroaryl ring, and a C3-C30 aliphatic heterocycle, and the "ring” herein includes a monocyclic ring and a polycyclic ring;
  • L is a chemical bond or a divalent group selected from one or more combinations of C1-6 alkylene, saturated or partially unsaturated C3-10 cycloalkylene, -O-, -NR a -, and -NR a -C1-6 alkylene;
  • Ra is independently selected from H, C1-C10 alkyl, saturated or partially unsaturated C3-6 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-10 aryl, CH 2 in Ra can be replaced by -O- or -S-, and H in Ra can be replaced by hydroxyl, halogen or C1-C3 alkoxy.
  • the present disclosure provides a class of compounds that specifically bind to the WBM site of WDR5, which can block the interaction between WDR5 and Myc, thereby regulating Myc-mediated oncogene transcription and achieving tumor treatment effects.
  • Pharmacological experiments have shown that the disclosed embodiment compounds have a strong affinity for WDR5 protein.
  • the compounds can significantly inhibit cell proliferation, while having no significant effect on the survival of human embryonic kidney cells HEK293T, showing good selectivity and safety.
  • the results of complex crystal structure analysis show that the representative compounds of the present disclosure can specifically bind to the WBM domain of WDR5, blocking the interaction between WDR5 and Myc, thereby exerting anti-tumor activity.
  • the compounds disclosed herein can be used as WDR5-Myc interaction blockers. Specifically, the pharmacological experimental results show that the compounds disclosed herein can specifically bind to the WBM domain of WDR5 and block the interaction between WDR5 and Myc. Based on this use, the compounds disclosed herein can be used in the preparation of drugs for treating diseases related to abnormal activation of Myc, RBBP5, KANSL2 and other related signaling pathways caused by abnormal expression of WDR5.
  • Diseases related to abnormal activation of Myc, RBBP5, KANSL2 and other related signaling pathways caused by abnormal expression of WDR5 include, but are not limited to, neuroblastoma, gangliocytoma, ganglioblastoma, ganglioneuroma, sympathetic neuroblastoma, schwannoma, neurofibroma, prostate cancer, triple-negative breast cancer, nasopharyngeal carcinoma, esophageal cancer, laryngeal cancer, lung cancer, gastric cancer, liver cancer, colorectal cancer, cervical cancer, pancreatic cancer, bladder cancer, retinoblastoma, osteosarcoma, chondrosarcoma, chordoma, rhabdomyosarcoma, multiple myeloma, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia and other diseases, especially suitable for the treatment and relief of neurogenic tumor
  • the optional ratio of the compound of formula (I) to the pharmaceutically acceptable carrier, excipient or sustained-release agent is:
  • the active ingredients account for more than 70% of the total weight, and the rest accounts for 0.5-30% of the total weight, or better 1-15%, or most preferably 2-10%.
  • the various formulation forms of the pharmaceutical composition disclosed herein have a unit dose containing 0.5 mg-200 mg, 2 mg-100 mg, or 5 mg-50 mg of the compound of formula (I), enantiomers, racemates, pharmaceutically acceptable salts or mixtures thereof.
  • the dosage of the active ingredient can generally be the conventional dosage in the prior art or lower.
  • the pharmaceutical composition of the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., wherein the compound of formula (I) can be present in a suitable solid or liquid carrier or diluent.
  • the pharmaceutical composition of the present invention can also be stored in a suitable sterilizing apparatus for injection or instillation.
  • the pharmaceutical composition can also contain odorants, flavoring agents, etc.
  • the compound of formula (I) disclosed herein or the pharmaceutical composition comprising the compound of formula (I) can be used clinically in mammals (including humans) through administration routes such as oral, nasal, skin, lung or gastrointestinal tract.
  • the optional administration route is oral.
  • the optional daily dose is 0.5mg-100mg/kg body weight, taken once or in divided doses. Regardless of the method of administration, the optimal dose for an individual should be determined according to the specific treatment. Usually, it is started with a small dose and the dose is gradually increased until the most suitable dose is found.
  • the effective dose of the active ingredient used may vary with the compound used, the mode of administration, and the severity of the disease to be treated. However, generally, satisfactory results can be obtained when the compounds of the present disclosure are administered at a dose of about 1-100 mg/kg of animal body weight per day, preferably in 1-3 divided doses per day, or in a sustained release form. For most large mammals, the total daily dose is about 5-500 mg, preferably about 10-250 mg.
  • a dosage form suitable for oral administration comprises about 1-100 mg of active compound closely mixed with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to provide the best therapeutic response. For example, several divided doses may be administered per day, or the dose may be reduced proportionally, depending on the urgency of the treatment condition.
  • the compound or its pharmaceutically acceptable salt and composition thereof can be administered orally as well as intravenously, intramuscularly or subcutaneously.
  • the optional pharmaceutical composition is a solid composition, especially a tablet and a solid-filled or liquid-filled capsule. Oral administration of the pharmaceutical composition is optional.
  • Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycol, nonionic surfactants and edible oils (such as corn oil, peanut oil and sesame oil), as long as they are suitable for the characteristics of the active ingredient and the specific administration method required.
  • Adjuvants commonly used in the preparation of pharmaceutical compositions may also be advantageously included, such as flavoring agents, pigments, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA.
  • the active compounds or their pharmaceutically acceptable salts and compositions thereof may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds (as free bases or pharmaceutically acceptable salts) may also be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquids, polyethylene glycols and mixtures thereof in oils. Under conventional storage and use conditions, these preparations contain preservatives to prevent the growth of microorganisms.
  • the pharmaceutical forms adapted for injection include: sterile aqueous solutions or dispersions and sterile powders (for the temporary preparation of sterile injection solutions or dispersions). In all cases, these forms must be sterile and must be fluid to facilitate the discharge of fluid from a syringe. Must be stable under manufacturing and storage conditions, and must be able to prevent the contamination effects of microorganisms (such as bacteria and fungi).
  • the carrier can be a solvent or dispersion medium, which contains, for example, water, alcohol (such as glycerol, propylene glycol and liquid polyethylene glycol), their appropriate mixtures and vegetable oils.
  • compositions and methods provided by the present disclosure can be used to treat a variety of cancers, including prostate, breast, brain, skin, cervical cancer, testicular cancer, etc. More specifically, the cancers that can be treated by the compositions and methods of the present disclosure include, but are not limited to, tumor types, such as astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, stomach, head and neck, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer and thyroid cancer and sarcoma.
  • tumor types such as astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, stomach, head and neck, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer and thyroid cancer and sarcoma.
  • Heart sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma;
  • Lung bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, mesothelioma;
  • Gastrointestinal esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,
  • 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;
  • the compounds of the present disclosure also include esters, optical isomers, tautomers, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, chelates, complexes, inclusion compounds or the above-mentioned pharmaceutical compositions formed by the compounds of the present disclosure.
  • alkylene refers to a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.
  • the aliphatic cyclic group refers to a cycloalkyl, cycloalkenyl, cycloalkynyl, etc. composed of a ring structure of C and H, wherein C is replaced by a heteroatom to form an aliphatic heterocyclic group; it also includes the bridged ring and spiro ring forms described later.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl has 1 to 12, for example 1 to 6 carbon atoms.
  • C1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3 ) suitable substituents such as halogen (in this case, the group is referred to as "haloalkyl”) (e.g., CH2F , CHF2 , CF3 , CCl3 , C2F5 , C2
  • haloalkyl e.g., CH2F
  • 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).
  • alkenyl means a linear or branched monovalent hydrocarbon group containing one double bond and having 2 to 6 carbon atoms (“ C2-6 alkenyl”).
  • the alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • the compounds of the present disclosure may exist in pure E (enthafen) form, pure Z (zusammen) form or any mixture thereof.
  • alkynyl denotes a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
  • a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloocty
  • the cycloalkyl has 3 to 15 carbon atoms.
  • C3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl.
  • cycloalkylene refers to a saturated (i.e., “cycloalkylene” and “cycloalkyl") or unsaturated (i.e., having one or more double bonds and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including but not limited to (cyclo)propyl (ring), (cyclo)butyl (ring), (cyclo)pentyl (ring), (cyclo)hexyl (ring), (cyclo)heptyl (ring), (cyclo)octyl (ring), (cyclo)nonyl (ring), (cyclo)hexenyl (ring) and the like.
  • heterocyclyl refers to a saturated (i.e., C) ring having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C.
  • heterocycloalkyl refers to a saturated or partially unsaturated (i.e., having one or more double and/or triple bonds in the ring) cyclic group.
  • a "3-10 membered (sub)heterocyclic (group)” is a saturated or partially unsaturated (sub)heterocyclic (group) having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms independently selected from N, O and S.
  • heterocyclylene and heterocyclyl include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.
  • the group also encompasses bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc.).
  • the heterocyclylene and heterocyclyl groups may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.
  • (ylidene)aryl and “aromatic ring” refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ electron system.
  • C 6-10 (ylidene)aryl and “C 6-10 aromatic ring” mean an aromatic group containing 6 to 10 carbon atoms, such as (ylidene)phenyl (benzene ring) or (ylidene)naphthyl (naphthalene ring).
  • the (ylidene)aryl group and the aromatic ring are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • suitable substituents e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.
  • heteroaryl(ene) and “heteroaromatic ring” refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being, for example, oxygen, nitrogen or sulfur) and, in each case additionally may be benzo-fused.
  • 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.
  • aralkyl preferably refers to an alkyl substituted with an aryl or heteroaryl, wherein the aryl, heteroaryl and alkyl are as defined herein.
  • the aryl may have 6-14 carbon atoms
  • the heteroaryl may have 5-14 ring atoms
  • the alkyl may have 1-6 carbon atoms.
  • Exemplary aralkyls include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • 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.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.
  • the alkyl group may be optionally substituted or unsubstituted.
  • Alkenyl refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one CC is an sp2 double bond, wherein the alkenyl group may be independently optionally substituted with one or more substituents described in the present disclosure, wherein specific examples include, but are not limited to, vinyl, allyl, and butylene, etc. Alkenyl may be optionally substituted or unsubstituted.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, more preferably includes 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes cycloalkyl of spiro ring, condensed ring and bridge ring. Cycloalkyl can be optionally substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated ⁇ electron aromatic system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members.
  • the spirocycloalkyl is divided into single spiro, double spiro or multi-spirocycloalkyl, preferably single spiro and double spirocycloalkyl, preferably 4/5 members, 4/6 members, 5/5 members or 5/6 members.
  • spirocycloalkyl include, but are not limited to:
  • “Fused cycloalkyl” refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • Non-limiting examples of "fused cycloalkyl” include, but are not limited to:
  • Bridged cycloalkyl refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include, but are not limited to:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like.
  • Heterocyclyl “heterocycle” or “heterocyclic” are used interchangeably in this application and refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic non-aromatic heterocyclic group containing 3-12 ring atoms, wherein at least one ring atom is a heteroatom, such as an oxygen, nitrogen, sulfur atom, etc. Preferably, it has a 5-7 membered monocyclic ring or a 7-10 membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl.
  • the heterocyclyl may be optionally substituted or unsubstituted.
  • spiro heterocyclyl is divided into single spiro heterocyclyl, double spiro heterocyclyl or multi-spiro heterocyclyl, preferably single spiro heterocyclyl and double spiro heterocyclyl. More preferably 4/4, 4/5, 4/6, 5/5 or 5/6 monospiro heterocyclyl.
  • spiro heterocyclyl include, but are not limited to:
  • the number of constituent rings it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic group include, but are not limited to:
  • bridged heterocyclic groups include, but are not limited to:
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner.
  • aryl includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl.
  • the aryl group is a C 6 -C 10 aryl group, more preferably, the aryl group is phenyl and naphthyl, and most preferably, Preferably, phenyl is used.
  • Aryl may be substituted or unsubstituted.
  • the "aryl” may be fused with heteroaryl, heterocyclic or cycloalkyl, wherein the aryl ring is connected to the parent structure, and non-limiting examples include but are not limited to:
  • Heteroaryl refers to an aromatic 5 to 6-membered monocyclic or 9 to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • the embodiment of “heteroaryl” includes, but is not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quino
  • Heteroaryl may be optionally substituted or unsubstituted.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:
  • Alkoxy refers to a group of (alkyl-O-), wherein alkyl is as defined herein.
  • C 1 -C 6 alkoxy is preferred, and examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Haloalkyl refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as described in the present disclosure.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.
  • Haldroxy refers to an -OH group.
  • Halogen refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
  • Amino refers to -NH 2.
  • Cyano refers to -CN.
  • halo refers to -NO2 .
  • Benzyl refers to -CH2 -phenyl.
  • Carboxyl refers to -C(O)OH.
  • Alcohol refers to -C(O) CH3 or Ac.
  • Carboxylate refers to -C(O)O(alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • halo or “halogen” groups are defined to include F, Cl, Br or I.
  • substituted means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form stable compounds.
  • substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the listed substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and/or together, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the listed substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.
  • each substituent is selected independently of the other.
  • each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • the present disclosure also includes all pharmaceutically acceptable isotope-labeled compounds, which are identical to the compounds of the present disclosure except for one or more An atom is replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature.
  • isotopes suitable for inclusion in the compounds of the present disclosure include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g., 11C , 13C , and 14C ); isotopes of chlorine (e.g., 36Cl ); isotopes of fluorine (e.g., 18F ); isotopes of iodine (e.g., 123I and 125I ); isotopes of nitrogen (e.g., 13N and 15N ); isotopes of oxygen (e.g., 15O , 17O , and 18O ); isotopes of phosphorus (e.g., 32P ); and isotopes of sulfur (e.g., 35S ).
  • isotopes of hydrogen e.g., deuterium ( 2H ), tritium ( 3H
  • Certain isotopically labeled compounds of the present disclosure are useful in drug and/or substrate tissue distribution studies (e.g., assays).
  • the radioactive isotopes tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
  • Substitution with positron emitting isotopes e.g., 11 C, 18 F, 15 O, and 13 N
  • PET positron emission tomography
  • Isotopically labeled compounds of the present disclosure may be prepared by methods analogous to those described in the accompanying schemes and/or in the examples and preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.
  • Pharmaceutically acceptable solvates of the present disclosure include those in which the crystallization solvent may be isotopically substituted, for example, D 2 O, acetone- d 6 or DMSO-d 6 .
  • Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.
  • a "therapeutically effective dose" of a compound refers to an amount sufficient to improve or in some way reduce symptoms, stop or reverse the progression of a disease. Such a dose can be used as a single dose or taken according to a regimen to be effective.
  • treating means ameliorating or otherwise altering in any way the symptoms or pathology of a patient's condition, disorder or disease.
  • amelioration of the symptoms of a particular disease by administration of a particular compound or pharmaceutical composition refers to any reduction, whether permanent or temporary, lasting or transitory, attributable to or associated with the administration of that composition.
  • Tautomers or “tautomeric forms” refer to structural isomers of different energies that can be interconverted through a low energy barrier.
  • proton tautomers i.e., prototropic tautomers
  • Valence (chemical valence) tautomers include interconversions by reorganization of bonding electrons.
  • the structural formulas described in the present disclosure include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present disclosure or mixtures of their enantiomers, diastereomers, or geometric isomers are all within the scope of the present disclosure.
  • “Pharmaceutically acceptable salts” refer to salts of the disclosed compounds which are safe and effective for use in humans or animals. Salts of compounds can be obtained by using a sufficient amount of a base or acid in a pure solution or a suitable inert solvent to obtain the corresponding addition salt.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts
  • pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts
  • the inorganic and organic acids include hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, butenedioic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid and methanesulfonic acid, and the like.
  • Solid wedge Virtual wedge Depict the chemical bonds of the compounds of the present disclosure.
  • the use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.).
  • the use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomer shown is present.
  • solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry.
  • the compounds of the present disclosure are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof.
  • the compounds of the present disclosure may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereoisomer pairs).
  • the present disclosure encompasses all possible crystalline forms or polymorphs of the compounds of the present disclosure, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the present disclosure may exist in free form for treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, chelates, complexes, inclusion compounds or prodrugs, which, after being administered to a patient in need thereof, can directly or indirectly provide a compound of the present disclosure or its metabolite or residue. Therefore, when referring to "compounds of the present disclosure” herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • Pharmaceutically acceptable salts of the compounds of the present disclosure include acid addition salts and base addition salts thereof, including but not limited to salts containing hydrogen bonds or coordinate bonds.
  • esters means an ester derived from the compounds of the general formula in the present application, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present disclosure in free acid or alcohol form).
  • physiologically hydrolyzable esters which can be hydrolyzed under physiological conditions to release the compounds of the present disclosure in free acid or alcohol form.
  • the compounds of the present disclosure themselves can also be esters.
  • the compounds of the present disclosure may exist in the form of solvates (preferably hydrates), wherein the compounds of the present disclosure contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol.
  • 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.
  • nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane.
  • peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA)
  • hydrogen peroxide alkyl hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxirane such as dimethyldioxirane
  • 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.
  • the present disclosure includes metabolites of the compounds of the present disclosure, including compounds produced by a process of contacting the compounds of the present disclosure with a mammal for a period of time sufficient to produce a metabolic product thereof.
  • the present disclosure further includes within its scope prodrugs of the compounds of the present disclosure, which are certain derivatives of the compounds of the present disclosure that may themselves have little or no pharmacological activity but are converted, for example, by hydrolytic cleavage, into compounds of the present disclosure having the desired activity when administered into or onto the body.
  • prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compound in vivo.
  • the present disclosure also encompasses compounds of the present disclosure containing protecting groups.
  • protecting groups In any process for preparing the compounds of the present disclosure, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present disclosure. This can be achieved by conventional protecting groups, for example, those described in T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
  • the present disclosure provides a WDR5/Myc interaction blocker with a new structure.
  • Experimental results show that this type of derivative exhibits excellent anti-neuroblastoma activity, as well as excellent safety and selectivity, and can be used to prepare drugs for treating cancer, especially neuroblastoma and other diseases.
  • FIG1 is a schematic diagram of the crystal structure of the complex of the disclosed compound and WDR5.
  • the mass spectrum was obtained by LC/MS using ESI as the ionization method.
  • HPLC model Agilent 1260, Thermo Fisher U3000; chromatographic column model: Waters xbrige C18 (4.6*150 mm, 3.5 ⁇ m); mobile phase: A: ACN, B: Water (0.1% H 3 PO 4 ); flow rate: 1.0 mL/min; gradient: 5% A for 1 min, increase to 20% A within 4 min, increase to 80% A within 8 min, 80% A for 2 min, back to 5% A within 0.1 min; wavelength: 220 nm; column oven: 35°C.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.2mm-0.3mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.
  • the hydrogen atmosphere can be connected to a hydrogen balloon with a volume of about 1 L through the reaction bottle.
  • the solution in the reaction refers to an aqueous solution.
  • the reaction temperature is room temperature, which is 20°C-30°C.
  • the column chromatography eluent system used for purifying the compound or the developing solvent system of thin layer chromatography includes: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, can also be added for adjustment.
  • the reagent for providing alkaline conditions is selected from organic bases or inorganic bases
  • the organic base is one or more of triethylamine, N,N-diisopropylethylamine, n-butyl lithium, diisopropyl lithium amide, bistrimethylsilyl lithium amide, sodium tert-butoxide, sodium methoxide and potassium tert-butoxide
  • the inorganic base is one or more of sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and lithium hydroxide
  • the reagent for providing acidic conditions is one or more of hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, methanol solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid and phosphoric acid
  • N,N-dimethylformamide (3 drops) was slowly added dropwise to a mixture of 2,4-dichlorobenzoic acid IN-1a (300 mg, 1.57 mmol) and oxalyl chloride (3 mL, 35.5 mmol) in anhydrous tetrahydrofuran (15 mL) at 0°C, and reacted at room temperature for 2 hours. TLC showed that the starting material disappeared.
  • the reaction solution was directly concentrated to obtain the title compound IN-1 (320 mg, crude product) as a white solid, which was directly used in the next step.
  • reaction solution was extracted with dichloromethane (60 mL x 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound IN-2b (576 mg, crude product) as a yellow oil, which was directly used in the next step.
  • Step 1 (Z)-N'-((5-bromothiophen-2-yl)sulfonyl)-N,N-dimethylformimide 2b
  • Step 2 (Z)-N,N-dimethyl-N'-((5-((trimethylsilyl)ethynyl)2-thienyl)sulfonyl)carboximide 2c
  • the reaction solution was filtered, the filter cake was washed with ethyl acetate (10 mL x 2), the filtrate was diluted with water (100 mL), and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated.
  • reaction solution is quenched with water (4mL), extracted with dichloromethane (2mL x3), combine the organic phases, wash with saturated brine (2mL), dry with anhydrous sodium sulfate, concentrate, and the crude product is purified by Prep-HPLC to obtain the title compound 2 as a white solid (75mg, yield 19%).
  • the intermediate IN-2 (30 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), and 4-dimethylaminopyridine (2.1 mg, 0.02 mmol) and triethylamine (51.1 mg, 0.51 mmol) were added. After the addition was completed, the reaction solution was cooled to 0°C and compound 4b (65 mg, crude product) was added. After the addition was completed, the reaction solution was heated to 25°C for 1 hour. TLC showed that the raw material was completely reacted.
  • 4-nitrobenzenesulfonamide 7a (404 mg, 2.00 mmol) was dissolved in tetrahydrofuran (8 mL), 4-dimethylaminopyridine (24 mg, 0.20 mmol) and triethylamine (607 mg, 6.00 mmol) were added, and intermediate IN-1 (503 mg, crude product) was dissolved in tetrahydrofuran (4 mL), and added dropwise to the reaction solution, nitrogen was protected, and the reaction was carried out at room temperature for 1 hour.
  • 4-Methoxybenzenesulfonamide 8a (187 mg, 1.00 mmol) was dissolved in tetrahydrofuran (4 mL), 4-dimethylaminopyridine (12 mg, 0.10 mmol) and triethylamine (303 mg, 3.00 mmol) were added, and intermediate IN-1 (251 mg, crude product) was dissolved in tetrahydrofuran (2 mL), and added dropwise to the reaction solution, nitrogen was protected, and the reaction was carried out at room temperature for 1 hour.
  • Test Example 1 Affinity test of compounds with WDR5 at the molecular level
  • Compound preparation Weigh the compound accurately and dissolve it in DMSO (Sigma, D5879) to 10mM stock solution for use.
  • the final concentration of the compound in the reaction system is 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39 ⁇ M, and the final DMSO concentration of the compound is 5%.
  • a certain amount of compound samples are transferred to a 96-well plate (Greiner, 650101) in sequence.
  • SPR Surface plasmon resonance experiment
  • Biacore8K was used for signal detection, data collection, processing and analysis.
  • the raw data generated by the experiment was processed by Biacore8K data processing software by subtracting the control group parameters and solvent correction, and the static affinity model was used to fit the corresponding KD value, as shown in Table 1.
  • the compounds of the embodiments of the present disclosure have a strong affinity with the WDR5 protein at the molecular level.
  • N.D. indicates that the compound has no significant binding to WDR5; N.T. indicates that the affinity of the compound has not been tested
  • Test Example 2 Anti-proliferation activity test of compounds on neuroblastoma cells
  • the antiproliferative activity of the compounds of the present disclosure on neuroblastoma cells was tested by the following method:
  • Compound preparation Weigh the compound accurately and dissolve it in DMSO to 10 mM stock solution for later use. Use DMEM or IMDM medium to dilute the compound to a final test concentration of 10 ⁇ M and a final DMSO concentration of 0.1%, and transfer the compound to a 96-well plate for subsequent experiments.
  • Cell Counting Kit-8 Test (CCK-8): 293T, SK-N-AS, IMR32 and LAN5 cells were inoculated into 96-well cell culture plates at a seeding volume of 2x10 4 cells/well. The corresponding compounds and DMSO control were added to each well and cultured for 72 hours. Then 10 ⁇ L of CCK-8 reagent was added to each well and incubated at 37 degrees for 2 hours. The absorbance of the cells at 450 nm was measured using a microplate reader.
  • Detection and analysis Collect the absorbance data corresponding to the cells in each well, and calculate the corresponding cell survival rate and inhibition rate, see Table 2 for details.
  • Test Example 3 Structural analysis of the complex of some compounds disclosed herein and WDR5
  • Protein crystal preparation The expression vector Rosetta2 competent cells of WDR5 were placed in a 37°C constant temperature shaking incubator and cultured until the OD value was 0.6-0.8. IPTG with a final concentration of 0.1 mM was added and cultured at 16°C for 20 hours before the cells were collected. The cells were crushed using a high-pressure cell disruptor and the supernatant was collected after high-speed centrifugation for 30 minutes.
  • Ni-NTA affinity chromatography gel resin 10 mL was added, stirred and bound at 4°C for 1 hour, and the supernatant was collected by centrifugation and then purified using a decontamination buffer (50 mM Tris pH 7.5, 150 mM NaCl, 50 mM imidazole, The resin was treated with 50 mM Tris pH 7.5, 1 mM TCEP) and elution buffer (50 mM Tris pH 7.5, 150 mM NaCl, 300 mM imidazole, 1 mM TCEP) to obtain the preliminary target protein. After that, an anion exchange chromatography column and a molecular exclusion chromatography column were used to obtain high-purity WDR5 protein, and the sample was collected and the protein purity was identified by SDS-polyacrylamide gel electrophoresis.
  • a decontamination buffer 50 mM Tris pH 7.5, 150 mM NaCl, 50 mM imidazole
  • the obtained high-purity WDR5 protein was concentrated to 11 mg/mL using an ultrafiltration tube and centrifuged at 12000 rpm for 30 minutes.
  • Crystallization buffer was prepared: 0.1 M Bis-Tris, pH 5.8, 0.2 M ammonium acetate, 30% (w/v) pEG3350. Crystallization conditions were optimized using a 24-well hanging drop plate. 1 mL of buffer per well. The two solutions were mixed in a ratio of 1.5 ⁇ L crystallization buffer + 1.5 ⁇ L protein solution, and crystals were grown in a constant temperature incubator at 18°C for 2-3 days. The crystals were in the form of flakes.
  • the complex crystals of WDR5 and active compounds were obtained by immersion method.
  • Detection and analysis The diffraction data of the crystals were collected at the microcrystal complex beamline BL18U1 of the Shanghai Synchrotron Radiation Source (SSRF). The collected data were processed using HKL3000, including data point selection, indexing, correction, integration, data merging and normalization, to generate MTZ files.
  • the WDR5 empty protein crystal structure resolved by this laboratory was used as a template, and the Phaser module in CCP4 was used for molecular replacement to generate the initial structural coordinates.
  • COOT was used for model construction and optimization, and then Phenix was used to further optimize the model, and the R factor in the structural parameters was repeatedly made less than 0.25. The results are shown in Figure 1.
  • Test Example 4 In vitro efficacy test of some compounds disclosed herein on acute myeloid leukemia, hepatoma cell lines and pancreatic cancer cell lines
  • Compound preparation Weigh the compound accurately and dissolve it in DMSO to 10mM stock solution for later use. Use MEM or RPMI 1640 medium to dilute the compound to a final test concentration of 10 ⁇ M and a final DMSO concentration of 0.1%, and transfer the compound to a 96-well plate for subsequent experiments.
  • Cell Counting Kit-8 Test (CCK-8): Hep3B, Huh-7, MV4-11 and Mia-Paca2 cells were inoculated into 96-well cell culture plates at a seeding volume of 2x10 4 cells/well. The corresponding compounds and DMSO control were added to each well and cultured for 72 hours. Then 10 ⁇ L of CCK-8 reagent was added to each well and incubated at 37 degrees for 2 hours. The absorbance of the cells at 450 nm was measured using a microplate reader.
  • Detection and analysis Collect the absorbance data corresponding to the cells in each well and calculate the corresponding inhibition rate, see Table 3 for details.
  • Test Example 5 Pharmacokinetic test of some compounds disclosed in the present invention on normal mice
  • mice Balb/c female mice, 6-8 weeks old, were selected and injected with compound 2 by gavage or tail vein. Whole blood was collected at 5min, 15min, 30min, 1h, 2h, 4h, 8h, and 24h after administration. After centrifugation at 8000rpm for 5min, the upper plasma was collected. The plasma exposure of the drug at different time points was tested by HPLC-MS/MS method, and the pharmacokinetic parameters were calculated.
  • the specific experimental results are as follows:
  • the compound of the embodiment of the present disclosure is rapidly absorbed orally, has extremely high bioavailability, and has a plasma half-life T 1/2 of up to 15.9 h, making it an ideal potential oral drug candidate molecule.
  • Test Example 6 Efficacy test of some compounds disclosed herein on the IMR32 CDX mouse neuroblastoma model
  • This test example studies the efficacy of compound 1 and compound 2 in a neuroblastoma model.
  • Human neuroblastoma IMR32 cells were selected for in vitro monolayer culture and routine digestion and passage with trypsin-EDTA twice a week. When the cell saturation was 80%-90%, the cells were collected, counted, and the inoculation concentration was adjusted to 10,000,000 cells/mouse. The cells were inoculated subcutaneously on the upper right back of the animal. When the tumor grew to about 120 mm 3 , the animals were randomly grouped and dosed according to their weight and tumor volume. The animal weight and tumor volume were measured twice a week. The efficacy data are expressed in terms of tumor volume (TV), tumor inhibition rate (TGI), and relative volume (T/C). The specific experimental data are as follows:
  • Test Example 7 Efficacy test of some compounds disclosed herein on Hep3B CDX mouse hepatoma model
  • This test example studies the efficacy of compound 2 in a liver cancer model.
  • Human liver cancer Hep3B cells were selected for in vitro monolayer culture and routine digestion and passage with trypsin-EDTA twice a week. When the cell saturation was 80%-90%, the cells were collected, counted, and the inoculation concentration was adjusted to 10,000,000 cells/mouse. The cells were inoculated subcutaneously on the upper right back of the animal. When the tumor grew to about 110 mm 3 , the animals were randomly grouped and dosed according to their weight and tumor volume. The animal weight and tumor volume were measured twice a week.
  • the efficacy data are expressed in terms of tumor volume (TV), tumor inhibition rate (TGI), and relative volume (T/C).
  • TGI tumor inhibition rate
  • T/C relative volume
  • the experimental results showed that there was no obvious abnormality in the health status of the animals during the administration period; compared with the solvent control (Vehicle) group, the low-dose and high-dose groups of the disclosed embodiment compounds showed obvious anti-tumor efficacy and good dose-effect relationship, with TGI reaching 40% and 106.8% respectively, and the tumors of some animals in the high-dose 90 mg/kg group completely disappeared in the late stage of administration. It can be seen that the disclosed embodiment compounds have significant efficacy in the Hep3B liver cancer xenograft tumor model.
  • Test Example 8 Safety test of some compounds disclosed in the present invention on normal mice
  • This test example studied the safety of compound 1 and compound 2, using female, 6-8 week old ICR mice as the research subjects.
  • the animals were randomly divided into groups according to their weight and orally administered with 100 mg/kg, 300 mg/kg, 400 mg/kg, and 500 mg/kg, respectively.
  • the weight changes, morbidity, and mortality of the animals were observed.
  • the specific results are as follows:
  • the experimental results show that, in ICR mice, oral administration of the embodiment compound 1 of the present disclosure at doses of 100 mg/kg and 300 mg/kg did not cause illness or death in all animals, and oral administration of the embodiment compound 2 of the present disclosure at doses of 100 mg/kg, 300 mg/kg and 400 mg/kg did not cause illness or death in all animals, and only one animal in the 500 mg/kg group died on the third day of the experiment. It can be seen that the expected tolerable dose of the embodiment compound of the present disclosure is as high as 400 mg/kg, and the safety is good.
  • the plasma protein binding rate of compound 1 and compound 2 in human plasma was determined by equilibrium dialysis.
  • the left and right chambers were separated by a semipermeable membrane.
  • the drug-containing protein solution was added to the left side, and the blank buffer was added to the right side.
  • the unbound free drug can freely pass through the semipermeable membrane. After a certain period of incubation, the two sides reached equilibrium, and the free drug concentration was equal.
  • the plasma protein binding rate can be calculated by measuring the drug concentration on both sides. The results are shown in Table 8:

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Abstract

L'invention concerne l'utilisation d'un composé sulfonamide tel que représenté dans la formule (I) ou d'un sel pharmaceutiquement acceptable de celui-ci, d'un tautomère de celui-ci, ou d'un stéréoisomère de celui-ci en tant qu'inhibiteur de WDR5. Le composé a un effet significatif en tant que bloqueur d'interaction WDR5 et Myc, et est propice au traitement du cancer. A1 et A2 sont des structures cycliques, et R1 et R2 sont des substituants.
PCT/CN2024/110126 2023-08-09 2024-08-06 Utilisation d'un composé sulfonamide dans la préparation d'un médicament pour le traitement de cancers Pending WO2025031361A1 (fr)

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