Novel hamatrol derivative and use thereof

Abstract

The invention provides a novel Hammetrine derivative as well as a preparation method and application thereof. In the present invention, the anticancer effect thereof is confirmed using a novel Hammetrine derivative having improved stability.

Description

Technical Field

[0001] This invention provides a novel hemiasterlin derivative, its preparation method, and its uses. The novel hemiasterlin derivative synthesized in this invention exhibits a significant inhibitory effect on cancer cell lines, and therefore can be used as a safe anticancer agent. Background Technology

[0002] Hamitrin can be separated from marine sponge species of the genera *Cymbastela* sp., *Hemiasterella minor*, *Siphonochalina* sp., and *Aulettasp.* (Talpir et al., *Tetrahedron Letters*, vol. 35, no. 25, pp. 4453-4456, 1994).

[0003] Harmitrine is known to be a drug that inhibits the formation of microtubules required for cancer cell division. It is currently being actively studied for its use in the treatment of cancers such as ovarian cancer, but safety concerns remain.

[0004] Thus, the inventors confirmed the structure of the hammetrine derivative, which has improved safety as a therapeutic agent, and confirmed that it has anticancer effects similar to those of natural hammetrine, thereby completing the present invention. Summary of the Invention

[0005] The problem the invention aims to solve

[0006] To address the aforementioned problems, this invention identifies the structure of a novel hametrine derivative with improved safety and uses it in drugs for the prevention or treatment of cancer, and provides it in the form of drug-linker, drug-carrier conjugate (ADC), etc.

[0007] means for solving problems

[0008] To achieve the stated objectives, the present invention provides, as a novel derivative of hemiasterlin, a compound of the following chemical formula 1, its isomers, pharmaceutically acceptable salts thereof, or solvates thereof.

[0009] [Chemical Formula 1]

[0010]

[0011] In the chemical formula 1, R is selected from halogen, hydroxyl, carboxyl, C1-C6 alkyl and C1-C6 alkoxy.

[0012] In this invention, the derivatives or stereoisomers of the compound of chemical formula 1 include, but are not limited to, compounds represented by the following chemical formulas 2 to 7.

[0013] [Chemical Formula 2]

[0014]

[0015] [Chemical Formula 3]

[0016]

[0017] [Chemical Formula 4]

[0018]

[0019] [Chemical Formula 5]

[0020]

[0021] [Chemical Formula 6]

[0022]

[0023] [Chemical Formula 7]

[0024]

[0025] The present invention also provides a “carrier-drug conjugate” or “carrier-linker-drug conjugate” comprising: a compound of formula 1, its derivatives, its isomers, its pharmaceutically acceptable salts or solvates thereof; and a carrier connected to said compound.

[0026] In another embodiment of the invention, a "drug linker" is provided, comprising: a compound of formula 1, a derivative thereof, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvation thereof; and a linker connected to said compound.

[0027] In this invention, the connectors include, but are not limited to, GGFG or val-cit, etc. Any connector commonly used in this technical field can be used without restriction.

[0028] In this invention, "carrier" refers to a substance capable of selectively and specifically delivering the compounds of this invention to a target site (e.g., cancer cells), and may be an antibody, peptide, repeatbody, and / or aptamer, but is not limited thereto, with antibodies being preferred. For example, the carrier of this invention is selected from 4-1BB, 5T4, integrin, activin, amyloid beta, angiopoietin (angiopoietin 1 or 2), angiopoietin-like substance 3, B cell maturation antigen (BCMA), and B cell activating factor. factor, BAFF), B7-H3, complement 5 (complement5), CCR4, CCR5, CCL11, CD2, CD3, CD4, CD6, CD11a, CD16A, CD19, CD20, CD22, CD25, CD27, CD28, CD30, CD32B, CD33, CD38 , CD40, CD45, CD46, CD47, CD52, CD56, CD62, CD70, CD73, CD74, CD79b, CD80, CD105, CD123, CD154, CD166, CD262, CD278, CD319, CD326, Carcinoembryonic Antigen (Carcinoembryonic Antigen, CEA), CGRP, Claudin-18, c-Met, CSF-1, CSF-1 receptor, CTLA4, DLL3, EGF receptor, hemophilia factor, Fc receptor, FGF23, folate receptor, GD2, glucocorticoid-induced TNF receptor (GITR), phosphatidylinositol proteoglycan 3 (Glypican 3), GM-CSF, HER2, HER3, TROP2, hepatocyte growth factor (HGF) Factor (HGF), interferon receptor, interferon-γ, IgE, IGF-1 receptor, interleukin-1, interleukin-2 receptor, interleukin-4, interleukin-4 receptor, interleukin-5, interleukin-5 receptor, interleukin-6, interleukin-6 receptor, interleukin-8, interleukin-12 / 23, interleukin-13, interleukin-17A, interleukin-17 receptor A, interleukin-23, interleukin-31 receptor, interleukin-36 receptor, lymphocyte-activation gene 3,LAG3), Lysyl oxidase homolog 2 (LOXL2), Mesothelin, Mucin-1, Mucin-16, Netin-4, Nerve Growth Factor (NGF), OX40, Proprotein Convertase Subtilisin / Kexin Type 9 (PCSK9), PD-1, PD-L1, Phospholipase C, Receptor activator of nuclear factors kappa Bligand (RANKL), Tyrosine-protein kinase transmembrane receptor (ROR1), Sialic acid-binding ig-like lectin 15 An antibody, peptide, repeat, or aptamer that specifically binds to one or more of the following substances (antigens): Siglec-15, transforming growth factor beta (TGF-β), T-cell immunoglobulin (T-cell innunoreceptor with immunoglobulin and ITIM domain, TIGIT), T-cell immunoglobulin and mucin-domain-containing-3 (Tim-3), tissue factor, tissue factor pathway inhibitor (TFPI), TORP-2, tumor necrosis factor (TNF), thymic stromal lymphopoietin (TSLB), colony stimulating factor 1 receptor (CSF1R), vascular endothelial growth factor (VEGF), VEGF receptor, and von Willebrand factor (vWF). ,

[0029] For example, in this invention, the antibodies include, but are not limited to, urerumab, utomilumab, bebtelovimab, aducanumab, bapinezumab, crenezumab, donanemab, gantenerumab, lecanemab, solanezumab, nesvacumab, evinacumab, and enotozumab. oblituzumab, ocburtamab, belimumab, icariinumab, tabalumab, bertilimumab, mogamulizumab, leronlimab, siplizumab, foralumab, muromonab-CD3, otilixizumab, teplizumab, ibalizumab lizumab), tregalizumab, zanolimumab, itolizumab, efalizumab, inebilizumab, tafasitamab, tositumomab, ozerolizumab, offatumumab, rituximab, utuximab, veltuzumab, epathutuzumab tuzumab), basiliximab, daclizumab, varlilumab, lulizumab, itutumab, lintuzumab, daratumumab, felzartamab, isatuximab, mezagitamab, bleselumab, dacetuzumab, iscalimabLucarumumab, Mitazalimab, Sotigalimab, Dapirolizumab, Apamistamab, Ligufalimab, Magrolimab, Alemtuzumab, Crizanlizumab, Inclacumab, Cusatuzumab, Oleclumab, Milatuzumab, Gali Galiximab, Carotuximab, Adecatumumab, Eptinezumab, Erenumab, Fremanezumab, Galcanezumab, Zolbetuximab, Onartuzumab, Eculizumab, Pozelimab, Ravulizumab, Lacnotuzumab, and others. Axatilimab, Cabiralizumab, Emactuzumab, Ipilimumab, Quavonlimab, Tremelimumab, Zalifrelimab, Cetuximab, Depatuxizumab, Futuximab, Imgatuzumab, Matuzumab, Modotuximab, and Nexium Necitumumab, Nimotuzumab, Panitumumab, Tomuzotuximab, Zalutumumab, Batoclimab, Nipocalimab, Rozanolixizumab, Burosumab, Farletuzumab, Dinutuximab, Naxitamab, RagifilimabGimsilumab, Lenzilumab, Mavrilimumab, Namilumab, Otilimab, Plonmarlimab, Codrituzumab, Margetuximab, Pertuzumab, Trastuzumab, Datopotamab, Patritumab, Seribantumab, Dugo Duligotuzumab, Ficlatuzumab, Rilotumumab, Alomfilimab, Anifrolumab, Emapalumab, Ligelizumab, Omalizumab, Cixutumumab, Dalotuzumab, Figitumumab, Ganitumab, Teprotumumab Bermekimab, Canakinumab, Gevokizumab, Briakinumab, Ustekinumab, Anrukinzumab, Cendakimab, Lebrikizumab, Tralokinumab, Brodalumab, Bimekizumab, Ixekizumab, Secukinumab, etc. Brazikumab, Guselkumab, Mirikizumab, Risankizumab, Tildrakizumab, Nemolizumab, Imsidolimab, Spesolimab, Pascolizumab, Dupilumab, Depemokimab, Mepolizumab, ReslizumabBenralizumab, Clazakizumab, Olokizumab, Siltuximab, Sirukumab, Ziltivekimab, Levilimab, Sarilumab, Satralizumab, Tocilizumab, Abituzumab, Favezelimab, Fianlimab, Ellari Monoclonal antibodies (Ieramilimab), Relatlimab, Simtuzumab, Abagovomab, Oregovomab, Tanezumab, Ivuxolimab, Rocatinlimab, Tavolimab, Telazorlimab, Vonderolizumab, Alirocumab, Bococizumab, Inusizumab Ebronucimab, Evolocumab, Frovocimab, Ongericimab, Tafolecimab, Dostarlimab, Balstilimab, Camrelizumab, Cemiplimab, Geptanolimab, Nivolumab, Pembrolizumab, Penpulimab, Pidtilimab Pidilizumab, Prolgolimab, Retifanlimab, Sasanlimab, Serplulimab, Sintilimab, Spartalizumab, Tislelizumab, Toripalimab, Ezabenlimab, Zimberelimab, Atezolizumab, AvelumabCosibelimab, Sugemalimab, Durvalumab, Envafolimab, Suvratoxumab, Denosumab, Zilovertamab, Elotuzumab, Domvanalimab, Etigilimab, Ociperlimab, Tiragolumab, Vibostolimab Surzebiclimab, Cobolimab, Sabatolimab, Concizumab, Marstacimab, Adalimumab, Golimumab, Infliximab, Certolizumab, Conatumumab, Tigatuzumab, Tezepelumab, Gatipotuzumab, Carbi Cabiralizumab, Bevacizumab, Brolucizumab, Ranibizumab, Olinvacimab, Icrucumab, Ramucirumab, Caplacizumab, Abrilumab, Etrolizumab, Vedolizumab, Intetumumab, Natalizumab, Obrinda Monoclonal antibodies (Obrindatamab), Elranatamab, Linvoseltamab, Teclistamab, Epcoritamab, Glofitamab, Mosunetuzumab, Odronextamab, Flotetuzumab, Vibecotamab, Catuximab, Cibisatamab, TalquetamabUbamatamab, Emfizatamab, Blinatumomab, Amivantamab, Emicizumab, Zenocutuzumab, Zanidatamab, Tibulizumab, Naptumomab, Belantamab, Pivekimab, Protuzumab Praluzatamab, Coltuximab, Denintuzumab, Loncastuximab, Ibritumomab, Inotuzumab, Epratuzumab, Moxetumomab, Brentuximab, Gemtuzumab, Vadastuximab, Lovovir Lorvotuzumab, Polatuzumab, Tusamitamab, Telisotuzumab, Rovalpituzumab, Depatuxizumab, Farletuzumab, Mirvetuximab, Disitamab, Anetumab, Enfortumab Sacituzumab, Vobarilizumab, Cadonilimab, Vudalimab, Tebotelimab, Ivonescimab, Erfonrilimab, Ozoralizumab, Faricimab, Vanucizumab, and Navicixizumab.

[0030] The present invention also provides a "pharmaceutical composition for the prevention or treatment of cancer" comprising a compound of formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, and "use for the prevention or treatment of cancer" of a compound represented by said formula 1.

[0031] The compound of chemical formula 1 may be provided in the form of being linked to a carrier via a linker.

[0032] In this invention, the cancers include, but are not limited to, pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampullary cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal cavity and sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, childhood leukemia, small intestine cancer, spinal meningioma, esophageal cancer, and neurological cancer. Glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastrointestinal stromal cancer, nephroblastoma, breast cancer, triple-negative breast cancer (TNBC), sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, leukemia, and thymic cancer.

[0033] Invention Effects

[0034] This invention provides a novel hammetrine derivative and its preparation method. The novel hammetrine derivative of this invention can be used as a safe and effective pharmaceutical composition. Attached Figure Description

[0035] Figure 1 The results show that the cell viability was determined by treating the lung cancer cell line (A549) with the compound of chemical formula 2, SC209 and MMAE, followed by isothermal incubation for 3 days, and then measuring the cell viability based on the treatment concentration.

[0036] Figure 2 The results show that the head and neck squamous cell carcinoma cell line (FaDu) was treated with compound of chemical formula 2, SC209 and MMAE, and then cultured at a constant temperature for 3 days, and the cell viability was determined according to the treatment concentration. Detailed Implementation

[0037] The following embodiments are provided to aid in understanding the present invention. These embodiments are provided solely to facilitate a clearer understanding of the invention, and the scope of protection of the invention is not limited to these embodiments.

[0038] This invention provides a compound of formula 1, its isomers, pharmaceutically acceptable salts thereof, or solvates thereof, as a derivative of hammetrine.

[0039] [Chemical Formula 1]

[0040]

[0041] In the chemical formula 1, R is selected from halogen, hydroxyl, carboxyl, C1-C6 alkyl and C1-C6 alkoxy.

[0042] In this specification, hemiasterlin is a substance with the molecular formula C 30 H 46 The compound N4O4 (molecular weight: 526.7 g / mol) has the following chemical structure.

[0043] [Hamitrin]

[0044]

[0045] In this specification, "isomer" refers to the relationship between compounds with the same chemical formula but different properties, and the types of isomers include structural isomers and stereoisomers. "Stereoisomers" refers to compounds with the same chemical composition but different spatial arrangements of atoms or groups. This includes not only optical isomers (e.g., essentially pure enantiomers, essentially pure diastereomers, or mixtures thereof), but also conformation isomers (i.e., isomers that differ only at the angle of one or more chemical bonds), position isomers (especially tautomers), or geometric isomers (e.g., cis-trans isomers). In this specification, isomers of compounds of formula 1 refer to stereoisomers, but are not limited to this.

[0046] The compounds of Formula 1 of the present invention are specifically selected from the following compounds, and may be in the form of individual isomers or mixtures thereof.

[0047]

[0048] In this specification, "salt" refers to a salt having preferred pharmacological activity of a parent compound according to one aspect of the invention, and can be a salt that does not cause severe irritation to the organism to which the compound is applicable and does not impair the biological activity and physical properties of the compound. Examples include: salts of inorganic ions (sodium, potassium, calcium, magnesium, lithium, copper, manganese, zinc, and iron, etc.); and salts of inorganic acids (hydrochloric acid, phosphoric acid, and sulfuric acid, etc.). In addition, it includes: salts of organic acids (ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, orotic acid, and acetylsalicylic acid, etc.); and salts of amino acids (lysine, arginine, and guanidine, etc.).

[0049] In particular, when the composition in this specification is a pharmaceutical composition, the term "salt" may be a "pharmaceutically acceptable salt." A "pharmaceutically acceptable salt" means a substance that, when used at a conventional medical dosage, avoids significant toxic effects and is therefore approved by a government or relevant regulatory agency or approved for use in animals (more specifically, humans), or is listed in a pharmacopoeia or recognized by other conventional pharmacopoeias.

[0050] In this specification, "salt" or "pharmaceutically acceptable salt" refers to an inorganic acid salt, organic acid salt, or metal salt addition salt of the compound. The inorganic acid salt may be a hydrochloride, bromate, phosphate, sulfate, or pyrosulfate. The organic acid salt may be a formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, benzenesulfonate, camphorsulfonate, ethanedisulfonate, trichloroacetate, trifluoroacetate, benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, pyrate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or aspartate. The metal salt may be a calcium salt, sodium salt, magnesium salt, strontium salt, or potassium salt.

[0051] In this specification, "solvate" refers to a compound that is solvated in an organic or inorganic solvent. For example, in this specification, the sovate may be a hydrate.

[0052] The compound of the present invention (Chemical Formula 1) can be provided in a form linked to a support.

[0053] In this invention, "carrier" refers to a substance capable of selectively and specifically delivering the compounds of this invention to a target site (e.g., cancer cells), and may be an antibody, peptide, repeatbody, and / or aptamer, but is not limited thereto, with antibodies being preferred.

[0054] For example, the vector of the present invention is selected from 4-1BB, 5T4, integrin, activin, β-amyloid beta, angiopoietin (angiopoietin 1 or 2), angiopoietin-like substance 3, B cell maturation antigen (BCMA), B-cell activating factor (BAFF), B7-H3, complement 5, etc. 5), CCR4, CCR5, CCL11, CD2, CD3, CD4, CD6, CD11a, CD16A, CD19, CD20, CD22, CD25, CD27, CD28, CD30, CD32B, CD33, CD38, CD40, CD45, CD46, C D47, CD52, CD56, CD62, CD70, CD73, CD74, CD79b, CD80, CD105, CD123, CD154, CD166, CD262, CD278, CD319, CD326, Carcinoembryonic Antigen (Carcinoembryonic Antigen, CEA, CGRP, Claudin-18, c-Met, CSF-1, CSF-1 receptor, CTLA4, DLL3, EGF receptor, hemophilia factor, Fc receptor, FGF23, folate receptor, GD2, glucocorticoid-induced TNF receptor (GITR), phosphatidylinositol proteoglycan 3, GM-CSF, HER2, HER3, TROP2, hepatocyte growth factor Factor (HGF), interferon receptor, interferon-γ, IgE, IGF-1 receptor, interleukin 1, interleukin 2 receptor, interleukin 4, interleukin 4 receptor, interleukin 5, interleukin 5 receptor, interleukin 6, interleukin 6 receptor, interleukin 8, interleukin 12 / 23, interleukin 13, interleukin 17A, interleukin 17 receptor A, interleukin 23, interleukin 31 receptor, interleukin 36 receptor, lymphocyte-activation gene 3 (LAG3), lysyl oxidase homolog 2,LOXL2), mesothelin, mucin-1, mucin-16, netin-4, nerve growth factor (NGF), OX40, proprotein convertase subtilisin / kexin type 9 (PCSK9), PD-1, PD-L1, phospholipase C, receptor activator of nuclear factor kappa B ligand (RANKL), tyrosine-protein kinase transmembrane receptor (ROR1), sialic acid-binding ig-like lectin 15 (Siglec-15), transforming growth factor beta (TGF-β), T-cell immunoglobulin. Antibodies, peptides, repeats, or aptamers that specifically bind to one or more of the following substances (antigens): immunoglobulin and ITIM domain (TIGIT), T cell immunoglobulin and mucin-domain containing-3 (Tim-3), tissue factor, tissue factor pathway inhibitor (TFPI), TORP-2, tumor necrosis factor (TNF), thymicstromal lymphopoietin (TSLB), colony-stimulating factor 1 receptor (CSF1R), vascular endothelial growth factor (VEGF), VEGF receptor, and von Willebrand factor (vWF).

[0055] In this invention, non-limiting examples may include urrelumab, utomilumab, bebtelovimab, aducanumab, bapinezumab, crenezumab, donanemab, gantenerumab, lecanemab, solanezumab, nesvacumab, evinacumab, and enotozumab. lituzumab, ocburtamab, belimumab, icariinumab, tabalumab, bertilimumab, mogamulizumab, leronlimab, siplizumab, foralumab, muromonab-CD3, otilixizumab, teplizumab, ibalizumab (Izumab), Tregalizumab, Zanomimab, Itolizumab, Efalizumab, Inebilizumab, Tafasitamab, Tositumomab, Ocrelizumab, Ofatumumab, Rituximab, Ublituximab, Veltuzumab, Epratuzumab Varilumab, Basiliximab, Daclizumab, Varlilumab, Lulizumab, Iratumumab, Lintuzumab, Daratumumab, Felzartamab, Isatuximab, Mezagitamab, Bleselumab, Dacetuzumab, IscalimabLucarumumab, Mitazalimab, Sotigalimab, Dapirolizumab, Apamistamab, Ligufalimab, Magrolimab, Alemtuzumab, Crizanlizumab, Inclacumab, Cusatuzumab, Oleclumab, Milatuzumab, Gali Galiximab, Carotuximab, Adecatumumab, Eptinezumab, Erenumab, Fremanezumab, Galcanezumab, Zolbetuximab, Onartuzumab, Eculizumab, Pozelimab, Ravulizumab, Lacnotuzumab, and others. Axatilimab, Cabiralizumab, Emactuzumab, Ipilimumab, Quavonlimab, Tremelimumab, Zalifrelimab, Cetuximab, Depatuxizumab, Futuximab, Imgatuzumab, Matuzumab, Modotuximab, and Nexium Necitumumab, Nimotuzumab, Panitumumab, Tomuzotuximab, Zalutumumab, Batoclimab, Nipocalimab, Rozanolixizumab, Burosumab, Farletuzumab, Dinutuximab, Naxitamab, RagifilimabGimsilumab, Lenzilumab, Mavrilimumab, Namilumab, Otilimab, Plonmarlimab, Codrituzumab, Margetuximab, Pertuzumab, Trastuzumab, Datopotamab, Patritumab, Seribantumab, Dugo Duligotuzumab, Ficlatuzumab, Rilotumumab, Alomfilimab, Anifrolumab, Emapalumab, Ligelizumab, Omalizumab, Cixutumumab, Dalotuzumab, Figitumumab, Ganitumab, Teprotumumab Bermekimab, Canakinumab, Gevokizumab, Briakinumab, Ustekinumab, Anrukinzumab, Cendakimab, Lebrikizumab, Tralokinumab, Brodalumab, Bimekizumab, Ixekizumab, Secukinumab, etc. Brazikumab, Guselkumab, Mirikizumab, Risankizumab, Tildrakizumab, Nemolizumab, Imsidolimab, Spesolimab, Pascolizumab, Dupilumab, Depemokimab, Mepolizumab, ReslizumabBenralizumab, Clazakizumab, Olokizumab, Siltuximab, Sirukumab, Ziltivekimab, Levilimab, Sarilumab, Satralizumab, Tocilizumab, Abituzumab, Favezelimab, Fianlimab, Ellari Monoclonal antibodies (Ieramilimab), Relatlimab, Simtuzumab, Abagovomab, Oregovomab, Tanezumab, Ivuxolimab, Rocatinlimab, Tavolimab, Telazorlimab, Vonderolizumab, Alirocumab, Bococizumab, Inusizumab Ebronucimab, Evolocumab, Frovocimab, Ongericimab, Tafolecimab, Dostarlimab, Balstilimab, Camrelizumab, Cemiplimab, Geptanolimab, Nivolumab, Pembrolizumab, Penpulimab, Pidtilimab Pidilizumab, Prolgolimab, Retifanlimab, Sasanlimab, Serplulimab, Sintilimab, Spartalizumab, Tislelizumab, Toripalimab, Ezabenlimab, Zimberelimab, Atezolizumab, AvelumabCosibelimab, Sugemalimab, Durvalumab, Envafolimab, Suvratoxumab, Denosumab, Zilovertamab, Elotuzumab, Domvanalimab, Etigilimab, Ociperlimab, Tiragolumab, Vibostolimab Surzebiclimab, Cobolimab, Sabatolimab, Concizumab, Marstacimab, Adalimumab, Golimumab, Infliximab, Certolizumab, Conatumumab, Tigatuzumab, Tezepelumab, Gatipotuzumab, Carbi Cabiralizumab, Bevacizumab, Brolucizumab, Ranibizumab, Olinvacimab, Icrucumab, Ramucirumab, Caplacizumab, Abrilumab, Etrolizumab, Vedolizumab, Intetumumab, Natalizumab, Obrinda Monoclonal antibodies (Obrindatamab), Elranatamab, Linvoseltamab, Teclistamab, Epcoritamab, Glofitamab, Mosunetuzumab, Odronextamab, Flotetuzumab, Vibecotamab, Catuximab, Cibisatamab, TalquetamabUbamatamab, Emfizatamab, Blinatumomab, Amivantamab, Emicizumab, Zenocutuzumab, Zanidatamab, Tibulizumab, Naptumomab, Belantamab, Pivekimab, Protuzumab Praluzatamab, Coltuximab, Denintuzumab, Loncastuximab, Ibritumomab, Inotuzumab, Epratuzumab, Moxetumomab, Brentuximab, Gemtuzumab, Vadastuximab, Lovotouzumab Lorvotuzumab, Polatuzumab, Tusamitamab, Telisotuzumab, Rovalpituzumab, Depatuxizumab, Farletuzumab, Mirvetuximab, Disitamab, Anetumab, Enfortumab, Gossautuzumab Sacituzumab, Vobarilizumab, Cadonilimab, Vudalimab, Tebotelimab, Ivonescimab, Erfonrilimab, Ozoralizumab, Faricimab, Vanucizumab, or Navicixizumab, etc., but not limited to these.

[0056] This invention provides a pharmaceutical composition for the prevention or treatment of cancer, the pharmaceutical composition comprising a compound (Chemical Formula 1) or a carrier-drug conjugate. The pharmaceutical composition of this invention can be administered to a subject in need at a therapeutically effective amount.

[0057] In this invention, cancers include, but are not limited to, pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, and ampullary cancer. Cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal cavity and sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, childhood leukemia, small intestine cancer, spinal meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastrointestinal cancer Interstitial lung cancer, nephroblastoma, breast cancer, triple-negative breast cancer (TNBC), sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, leukemia, and thymic cancer.

[0058] In this specification, the term "prevention" refers to all actions that inhibit the occurrence of cancer symptoms or delay the onset of the disease by administering the pharmaceutical composition described herein. The term "treatment" refers to all actions that improve or beneficially alter cancer symptoms by administering the pharmaceutical composition described herein.

[0059] In this specification, "patient," "subject," and "object" refer to animals, such as mammals. In a specific instance, the patient is a human being. In another specific instance, the patient is a non-human animal, such as a dog, cat, livestock (e.g., a horse, pig, or donkey), chimpanzee, or monkey.

[0060] The term "therapeutic effective amount" as used in this invention refers to the amount of a compound or carrier-drug conjugate that is effective in the treatment or prevention of cancer. Specifically, "therapeutic effective amount" refers to an amount sufficient to treat the disease with a reasonable benefit / risk ratio suitable for medical treatment, and the effective dosage level can be determined based on factors including individual type and severity, age, sex, disease type, drug activity, drug sensitivity, timing of administration, route of administration and excretion rate, duration of treatment, factors of concurrently used drugs, and other factors well known in the medical field. The pharmaceutical compositions of this invention can be administered as a single therapeutic agent or in combination with other therapeutic agents, or sequentially or simultaneously with commercially available therapeutic agents. Furthermore, single or multiple doses can be administered. It is important to consider all the aforementioned factors and administer the drug at the minimum dose to achieve the maximum effect without producing side effects. Since the compounds represented by Formula 1 of this invention, their derivatives, isomers, or pharmaceutically acceptable salts, or carrier-drug conjugates containing them exhibit dose-dependent effects, the dosage can be easily determined by those skilled in the art based on various factors such as the patient's condition, age, sex, and complications. Because the active ingredient in the pharmaceutical composition of the present invention has excellent safety, it can also be administered at a dose higher than a predetermined dosage.

[0061] The following examples specifically confirm the synthesis and effects of the compounds of the present invention.

[0062] [Example 1]

[0063] Synthesis of compounds of chemical formula 2 and chemical formula 3

[0064] 1-1. Synthesis of Fragment A

[0065]

[0066] In the chemical structure described, Boc2O refers to di-tert-butyl dicarbonate.

[0067] Step 1:

[0068]

[0069] Iodomethane (7.53 g, 3.30 mL, 2.4 eq, 53.1 mmol) was added to a 30 mL (dry) THF solution containing 2-(3-bromo-4-methoxyphenyl)acetonitrile (5.00 g, 1 eq, 22.1 mmol). The reaction mixture was cooled to 4 °C, and sodium hydride (60% dispersion in mineral oil) (2.12 g, 60% Wt, 2.4 eq, 53.1 mmol) was added dropwise. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. Iodomethane (628 mg, 277 μL, 0.2 eq, 4.42 mmol) and sodium hydride (60% dispersion in mineral oil) (177 mg, 60% Wt, 0.2 eq, 4.42 mmol) were added further, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (~100 mL) and extracted with EtOAc (3x). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated under reduced pressure to give a brown oil (6.47 g). After purification by rapid column chromatography (120 g SiO2, 0-20% EtOAc in heptane), the fraction was concentrated under reduced pressure to give a colorless oil.

[0070] Yield: 4.9g, 87%.

[0071] 1 H NMR (400MHz, CDCl3) δ7.62(d,J=2.6Hz,1H),7.40(dd,J=8.6,2.5Hz,1H),6.90(d,J=8.7Hz,1H),3.89(s,3H),1.70(s,6H).m / z 253.2 / 255.2[M+H] + ,Br isotope pattern.

[0072] Step 2:

[0073]

[0074] A 40 mL solution of dried DCM containing 4.68 g (1 eq, 18.4 mmol) of 2-(3-bromo-4-methoxyphenyl)-2-methylpropanenitril (dried) was cooled to -78 °C. Over 15 minutes, 3.40 g (23.9 mL, 1.0 mol, 1.3 eq, 23.9 mmol) of 1 M diisobutylaluminum hydride in hexane was added dropwise to the solution. The reaction mixture was stirred at -78 °C for 1.5 h. Further dropwise addition of 655 mg (4.60 mL, 1.0 mol, 0.25 eq, 4.60 mmol) of 1 M diisobutylaluminum hydride in hexane was made, and the reaction mixture was stirred at -78 °C for 30 minutes. The reaction mixture was heated to 0°C and slowly quenched with 2M HCl (60 mL). After stirring at 0°C for 30 minutes, the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water and extracted with DCM (3x). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated under reduced pressure to give a solid (4.39 g). The crude product was suspended in DCM and filtered. The filtrate was purified by column chromatography (120 g SiO2, 0–20% EtOAc in heptane). The fraction was concentrated under reduced pressure to give a light-yellow oil (2.77 g, 58%).

[0075] 1 H NMR (400MHz, CDCl3) δ9.44(s,1H),7.46(d,J=2.4Hz,1H),7.16(dd,J=8.6,2.4Hz,1H),6.90(d,J=8.6Hz,1H),3.89(s,3H),1.44(s,6H).m / z 257.2 / 259.2[M+H] + ,Br isotope pattern.

[0076] Step 3:

[0077]

[0078] Potassium cyanide (0.56 g, 1 eq, 8.6 mmol) and water (13 mL) were added to a 100 mL round-bottom flask. The solution was cooled to 0 °C, and methylamine hydrochloride (0.58 g, 1 eq, 8.6 mmol) was added. Then, a methanol solution (13 mL) containing 2-(3-bromo-4-methoxyphenyl)-2-methylpropanal (2.2 g, 1 eq, 8.6 mmol) was added. The resulting white suspension was stirred overnight at room temperature. The reaction mixture was diluted with H₂O (40 mL) and extracted with CH₂Cl₂ (3 × 50 mL). After combining the organic layers, the mixture was washed with brine (20 mL) and dried over Na₂SO₄. The solvent was removed under vacuum to obtain 3-(3-bromo-4-methoxyphenyl)-3-methyl-2-(methylamino)butanenitrile, which is a colorless oil.

[0079] Yield: 2.56g, 89%.

[0080] 1 H NMR (400MHz, CDCl3) δ7.57(d,J=2.4Hz,1H),7.36(dd,J=8.7,2.4Hz,1H),6.89(d,J=8.7Hz,1H ),3.89(s,3H),3.45-3.29(m,1H),2.48(s,3H),1.50(d,J=11.5Hz,6H).m / z297.0 / 299.0[M+H] + ,Br isotope pattern.

[0081] Step 4:

[0082]

[0083] In 45 mL of DMSO containing 2.53 g (1 eq, 8.51 mmol) of 3-(3-bromo-4-methoxyphenyl)-3-methyl-2-(methylamino)butanenitrile (1.71 g, 40.9 mL, 1.0 mol, 4.8 eq, 40.9 mmol) and hydrogen peroxide (4.63 g, 4.17 mL, 30% Wt, 4.8 eq, 40.9 mmol), water was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (385 mL) and extracted with ethyl acetate (2 × 385 mL). The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 2.8 g of a colorless, viscous solid. The product was purified by rapid column chromatography (80g SiO2, 0-5% methanol in dichloromethane) to obtain a white foam product.

[0084] Yield: 1.35g, 50%.

[0085] 1 H NMR (400MHz, DMSO) δ7.50 (d, J = 2.4Hz, 1H), 7.35-7.23 (m, 2H), 7.05-6.97 (m, 2H), 3.81 (s, 3H) ,2.99-2.90(m,1H),2.07(s,3H),1.44(bs,1H),1.25(d,J=7.8Hz,6H).m / z315.2 / 317.2[M+H] + ,Br isotope pattern.

[0086] Step 5:

[0087]

[0088] Dichloromethane (15 mL) was added to 3-(3-bromo-4-methoxyphenyl)-3-methyl-2-(methylamino)butanamide (1.31 g, 1 eq, 4.16 mmol). Next, Boc₂O (3.17 g, 3.5 eq, 14.5 mmol) was added. After a few minutes, a clear, colorless solution was obtained. The reaction mixture was stirred at room temperature for 3 days. DIPEA (591 mg, 787 μL, 1.1 eq, 4.57 mmol) and DMAP (50.8 mg, 0.1 eq, 416 μmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Water (45 mL) was added and the mixture was extracted with heptane (3 × 50 mL). The organic layer was washed with water (25 mL) and brine (25 mL). The organic layer was dried over sodium sulfate and concentrated to dryness. 2.8 g of a yellow oily substance was obtained and dissolved in THF (6.5 mL). 5 M sodium hydroxide (831 mg, 4.16 mL, 5.0 mol, 5 eq, 20.8 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. Then, water (25 mL) was added. The mixture was filtered, and the residue was washed with 0.5 M NaOH (25 mL). THF was removed under reduced pressure. The aqueous solution was washed with heptane, neutralized with solid citric acid, and extracted with ethyl acetate (3×). The organic layer was washed with brine and dried over sodium sulfate, then concentrated under reduced pressure to give 1.37 g of a colorless oily substance. After purification by column chromatography (40 g SiO2, 0–50% ethyl acetate in heptane), the fraction was concentrated under reduced pressure to give a white foamy product.

[0089] Yield: 1.02g, 59%.

[0090] 1 1H NMR indicates that the target compound is a mixture of rotamers.

[0091] 1 ¹H NMR (400MHz, CDCl₃) δ 7.60–7.51 (m, 1H), 7.38–7.27 (m, 1H), 6.83 (d, J = 8.7 Hz, 1H), 5.07–4.84 (m, 1H), 3.88 (s, 3H), 2.85–2.62 (m, 3H), 1.58–1.39 (m, 15H). m / z 414.2 / 416.2 [MH]-, Br isotope mode.

[0092] Step 6:

[0093]

[0094] In a microwave-safe vial containing a mixture (20 mL) of 3-(3-bromo-4-methoxyphenyl)-2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanoic acid (350 mg, 1 eq, 841 μmol) and toluene (5.0 mL), a 32% (9.21 g, 10.2 mL, 32% Wt, 100 eq, 84.1 mmol) ammonium hydroxide solution was added, followed by the addition of copper powder (160 mg, 3 eq, 2.52 mmol). The vial was tightly capped and stirred at 100 °C for 6 hours. The reaction mixture was filtered, and the filtrate was evaporated to dryness. The residue was simultaneously evaporated with ethanol (3×) to remove moisture. The crude product was coated onto a hydromatrix matrix and purified by rapid column chromatography (12 g SiO2, 0–10% methanol in dichloromethane). The fraction was concentrated under reduced pressure to give 232 mg of a green oil / foam product. The product will be used directly in the next step.

[0095] Yield: 67%.

[0096] 1 H NMR (400MHz, CDCl3) δ7.23-5.96(m,3H),5.20-4.70(m,1H),4.05-3.55(m,3H),3.01-2.41(m,4H),1.93-1.09(m,17H).m / z 705.2[2M+H] + .

[0097] Step 7:

[0098]

[0099] Alloc-OSu (232 mg, 2 eq, 1.16 mmol) was added to a solution of 3-(3-amino-4-methoxyphenyl)-2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanoic acid (205 mg, 1 eq, 582 μmol) in 1.5 mL of tetrahydrofuran, followed by the addition of triethylamine (177 mg, 243 μL, 3 eq, 1.75 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by rapid column chromatography (12 g SiO2, 0–10% methanol in dichloromethane). The fraction was concentrated to give 143 mg (42%) of a light brown oil. NMR showed the rotational isomer.

[0100] 1 H NMR (400MHz, CDCl3) δ8.20(s,1H),7.24(s,1H),7.11-6.97(m,1H),6.79(d,J=8.6Hz,1H),6.05-5.92(m,1H),5.41-5.33( m,1H),5.28-5.23(m,1H),4.94(s,1H),4.70-4.64(m,2H),3.84(s,3H),2.77(s,1H),2.65(s,2H),1.56-1.40(m,16H).m / z 459.2[M+Na] + .

[0101]

[0102] Step 1:

[0103]

[0104] HBTU (9.0 g, 1.1 eq, 22 mmol) was added dropwise to a stirred solution of N-(tert-butoxycarbonyl)-N-methyl-L-valine (5.0 g, 1 eq, 22 mmol), N,O-dimethylhydroxylamine hydrochloride (2.3 g, 1.1 eq, 24 mmol), and DIPEA (5.6 g, 7.5 mL, 2 eq, 43 mmol) in 50 mL of dichloromethane. The reaction mixture was stirred overnight at room temperature. The reaction mixture was washed with water. The organic layer was separated and dried over Na₂SO₄. The organic layer was then evaporated to dryness and purified by column chromatography (120 g SiO₂, 0–40% ethyl acetate in heptane). A clear, colorless oily product was given.

[0105] Yield: 3.15g, 53%.

[0106] 1 ¹H NMR (400MHz, DMSO-d6) δ 4.94–4.44 (m, 1H), 3.64 (d, J = 10.0 Hz, 3H), 3.19–3.01 (m, 3H), 2.74–2.60 (m, 3H), 2.21–2.04 (m, 1H), 1.48–1.33 (m, 9H), 0.89–0.73 (m, 6H).

[0107] Step 2:

[0108]

[0109] At -78°C, 69.2 mg (759 μL, 2.4 mol, 1 eq, 1.82 mmol) of THF containing 2.4 M lithium aluminum hydride was added to a solution of 2.5 mL of THF containing 500 mg (1 eq, 1.82 mmol) of (S)-(1-(methoxy(methyl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate. The reaction mixture was then heated to 0°C and stirred for 15 minutes. The reaction mixture was then transferred to a stirred 0.25 M ice-cold aqueous solution of potassium hydrogen sulfate (496 mg, 14.6 mL, 0.25 mol, 2 eq, 3.64 mmol) and allowed to separate into layers. The aqueous layer was extracted with diethyl ether (3x). The combined organic layers were washed with 1M HCl (2x), saturated aqueous sodium bicarbonate (2x), and brine, and then dried with sodium sulfate before concentration (bath temperature below 20°C). The crude aldehyde, without purification, could be used directly in the next step.

[0110] Step 3:

[0111]

[0112] To a solution of (S)-methyl (3-methyl-1-oxobutan-2-yl)carbamate (392 mg, 1 eq, 1.82 mmol) in dichloromethane (2.5 mL), ethyl 2-(triphenyl-λ5-phosphaneylidene)propanoate (857 mg, 1.3 eq, 2.37 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with diethyl ether (3x). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give 1.0 g of a yellow oil. Purification by rapid column chromatography (40 g SiO2, 0–10% ethyl acetate in heptane) gave 237 mg of a colorless oil.

[0113] 1H NMR (400MHz, CDCl3) δ6.70-6.60(m,1H),4.64-4.25(m,1H),4.21(q,J=7.1Hz,2H),2.80-2 .62(m,3H),1.96-1.81(m,4H),1.45(s,9H),1.31(t,J=7.0Hz,3H),0.96-0.79(m,6H).m / z 322.2[M+Na] + .

[0114] Step 4:

[0115]

[0116] Trifluoroacetic acid (2.5 mL) was added to a solution of dichloromethane containing ethyl(S,E)-4-((tert-butoxycarbonyl)(methyl)amino)-2,5-dimethylhex-2-enoate (235 mg, 1 eq, 785 μmol). The reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, and the residue was evaporated simultaneously with dichloromethane (6x) to give 325 mg of a light yellow, turbid oil. The product was used directly in the next reaction step.

[0117] 1 H NMR (400MHz, CDCl3) δ8.86 (d, J = 174.6Hz, 1H), 6.63-6.56 (m, 1H), 4.33-4.17 (m, 2H, coinsides with H2O peak),3.82-3.69(m,1H),2.62(s,3H),2.25-2.13(m,1H),1.95(s,3H),1.33(t,J=7.1Hz,3H),1.02(dd,J=12.2,6.8Hz,6H).m / z 200.0[M+H] + .

[0118] Step 5:

[0119]

[0120] DIPEA (101 mg, 137 μL, 1 eq, 785 μmol) was added to a solution of N,N-dimethylformamide (3.0 mL) containing N-Boc-L-tert-leucine (272 mg, 1.5 eq, 1.18 mmol) and HATU (448 mg, 1.5 eq, 1.18 mmol). After stirring the mixture for 5 minutes, 1.5 mL of a peptide-grade solution of ethyl(S,E)-2,5-dimethyl-4-(methylamino)hex-2-enoate 2,2,2-trifluoroacetate (246 mg, 1 eq, 785 μmol) and DIPEA (507 mg, 684 μL, 5 eq, 3.93 mmol) was added dropwise. The mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted with ethyl acetate, washed with water (2x) and brine (2x), dried over sodium sulfate, and concentrated to give 478 mg of a yellow oil. After purification by rapid column chromatography (24g SiO2, 0-50% ethyl acetate in heptane), the fraction was concentrated to obtain 272mg (76%) of a colorless oil.

[0121] 1 H NMR (400MHz, CDCl3) δ6.68-6.60(m,1H),5.22(d,J=10.1Hz,1H),5.15-5.06(m,1H),4.43(d,J=10.1Hz,1H),4.20(q,J=7 .1Hz,2H),2.99(s,3H),1.90(m,4H),1.42(s,9H),1.31(t,J=7.1Hz,3H),0.96(s,9H),0.86(dd,J=18.3,6.6Hz,6H).m / z 413.2[M+H] + .

[0122] Step 6:

[0123]

[0124] Trifluoroacetic acid (4.0 mL) was added to a solution of (S,E)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoate (260 mg, 90.7% Wt, 1 eq, 572 μmol) in dichloromethane (4.0 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, and the residue was evaporated simultaneously with dichloromethane (6x) to give 329 mg of a colorless oil.

[0125] 1 H NMR (400MHz, CDCl3) δ7.92(bs,2H),6.69-6.62(m,1H),5.70(bs,3H),5.00(t,J=10.1Hz,1H),4.27(s,1H),4.22(q,J=7.1H z,2H),2.98(s,3H),2.03-1.93(m,1H),1.91(s,3H),1.31(t,J=7.1Hz,3H),1.08(s,9H),0.87(dd,J=11.3,6.5Hz,6H).m / z 313.4[M+H] + .

[0126] 1-3. Synthesis of compounds with chemical formulas 2 and 3

[0127]

[0128] Step 1:

[0129]

[0130] In the presence of 3-(3-(((allyloxy)carbonyl)amino)-4-methoxyphenyl)-2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanoic acid (3-(((allyloxy)carbonyl)amino)-4-methoxyphenyl)-2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanoic acid To a solution of N,N-dimethylformamide (1.8 mL) (128 mg, 85% Wt, 1 eq, 249 μmol) [fragment A], add ethyl(S,E)-4-((S)-2-amino-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoate 2,2,2-trifluoroacetate (142 mg, 75% Wt, 1 eq, 249 μmol), followed by PyBOP (143 mg, 1.1 eq, 274 μmol). The reaction mixture was cooled to 0°C, and DIPEA (129 mg, 174 μL, 4 eq, 997 μmol) was added. The resulting clear solution was stirred overnight at room temperature. The reaction mixture was then used directly for purification using acid-based preparative MPLC (Luna 40-80). After combining the fractions, they were lyophilized and then evaporated together with DCM. An orange oil was obtained.

[0131] Yield: 98 mg, 54%. The product was obtained as a mixture of diastereomers.

[0132] 11H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.25 - 7.17 (m, 1H), 7.15 - 6.99 (m, 1H), 6.78 (d, J = 8.6 Hz, 1H), 6.65 - 6.57 (m, 1H), 6.38 - 6.06 (m, 1H), 6.06 - 5.91 (m, 1H), 5.41 - 5.33 (m, 1H), 5.29 - 5.23 (m, 1H), 5.12 - 4.81 (m, 2H), 4.75 - 4.59 (m, 3H), 4.23 - 4.15 (m, 2H), 3.82 (s, 3H), 2.97 - 2.79 (m, 6H), 1.91 - 1.80 (m, 4H), 1.54 - 1.37 (m, 14H), 1.33 - 1.22 (m, 4H), 0.90 - 0.72 (m, 16H). m / z 731.6 [M+H] + 。

[0133] Step 2:

[0134]

[0135] Through the presence of (9S,12S,E)-6-(2-(3-(((allyloxy)carbonyl)amino)-4-methoxyphenyl)prop-2-yl)-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-13-en-15-oic acid ethyl ester (ethyl(9S,12S,E)-6-(2-(3-(((allyloxy)carbonyl)amino)-4 A solution of tetrahydrofuran (6.0 mL) containing 90.5 mg (1 eq, 124 μmol) of (-methoxyphenyl)propan-2-yl)-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadec-13-en-15-oate) was bubbled under nitrogen. Pd(PPh3)4 (7.1 mg, 0.05 eq, 6.19 μmol) was added, followed by tri-n-butyltin hydride (72.1 mg, 66.1 μL, 2 eq, 248 μmol). The mixture was stirred for 2 hours under nitrogen and at room temperature. The solvent was removed under reduced pressure, and the crude product was purified by rapid column chromatography (12 g SiO2, dichloromethane, 0–10% methanol). The fractions were combined and concentrated to give 79 mg of an orange oil. Purification by rapid column chromatography (4 g SiO2, 0–40% ethyl acetate in heptane) yielded a white solid product.

[0136] Yield: 56 mg, 70%.

[0137] 1 H NMR (400MHz, CDCl3) δ7.01-6.55(m,4H),6.28-5.98(m,1H),5.11-5.00(m,1H),4.60(dd,J=39.1,9.2Hz,1H),4.24-4. 14(m,2H),3.86-3.71(m,5H),2.98-2.81(m,6H),1.86(d,J=10.1Hz,4H),1.51-1.18(m,19H),0.91-0.68(m,16H).m / z 647.2[M+H] + .

[0138] Step 3:

[0139]

[0140] In the presence of (9S,12S,E)-6-[2-(3-amino-4-methoxyphenyl)propan-2-yl]-9-tert-butyl-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-13-en-15-oic acid ethyl ester (ethyl(9S,12S,E)-6-(2-(3-amino-4-methoxyphenyl)propan-2-yl)-9-(tert- A solution of lithium hydroxide monohydrate (16.4 mg, 5 eq, 390 μmol) in 1.0 mL of water was added to a methanol (2.0 mL) solution of butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadec-13-en-15-oate (50.5 mg, 1 eq, 78.1 μmol). The solution turned yellow. The reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralized with acetic acid and extracted with ethyl acetate (3x). The organic layer was washed with brine, dried over sodium sulfate, concentrated, and co-evaporated with dichloromethane (2x) to give a beige solid.

[0141] Yield: 47 mg, 97%.

[0142] m / z 619.2 [M+H] + .

[0143] Step 4:

[0144]

[0145] In the presence of (9S,12S,E)-6-[2-(3-amino-4-methoxyphenyl)propan-2-yl]-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadec-13-en-15-oic acid ((9S,12S,E)-6-(2-(3-amino-4-methoxyphenyl)propan-2-yl)-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadec-13-en-15-oic To a solution of 46 mg (1 eq, 74 μmol) of acid in dichloromethane (1.0 mL), add 1.0 mL of dichloromethane containing 10% TFA and stir the reaction mixture at room temperature for 1 hour. Cool the mixture to 0 °C and add TFA dropwise (740 mg, 500 μL, 87 eq, 6.49 mmol). Stir the reaction mixture at room temperature for 1 hour. Remove the solvent under reduced pressure and purify the residue by acidic preparative MPLC (Luna 5-40). After combining the fractions, lyophilize.

[0146] Yield: 19 mg, 50%.

[0147] The product was obtained as a mixture of diastereomers. The diastereomers were separated by RP-HPLC to yield S,S,S (5 mg) and R,S,S (7 mg) isomers.

[0148] 1 H NMR (400MHz, DMSO-d6) δ7.76 (s, 1H), 6.76-6.54 (m, 4H), 5.31-4.01 (m, 4H), 3.73 (d, J = 2.9Hz, 3H), 3.30 (s, 2H), 3.16-2 .89(m,4H),2.12-1.89(m,4H),1.78(d,J=1.4Hz,3H),1.28-1.10(m,6H),0.90(d,J=24.6Hz,9H),0.83-0.67(m,6H).m / z 519.4[M+H] + .

[0149] [Example 2]

[0150] Synthesis of compounds with chemical formulas 4 and 5

[0151]

[0152] 2-1. Synthesis of Fragment A

[0153]

[0154] Step 1:

[0155]

[0156] Iodomethane (7.53 g, 3.30 mL, 2.4 eq, 53.1 mmol) was added to a 30 mL (dry) THF solution containing 4.64 g (4.64 g, 1 eq, 22.1 mmol) of 2-(3-bromo-4-methylphenyl)acetonitrile (dried). The reaction mixture was cooled to 4 °C, and sodium hydride (60% dispersion in mineral oil) (2.12 g, 60% Wt, 2.4 eq, 53.1 mmol) was added dropwise. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. Iodomethane (628 mg, 277 μL, 0.2 eq, 4.42 mmol) and sodium hydride (60% dispersion in mineral oil) (177 mg, 60% Wt, 0.2 eq, 4.42 mmol) were added further, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (~100 mL) and extracted with EtOAc (3x). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated under reduced pressure to give a brown oil (6.47 g). After purification by rapid column chromatography (120 g SiO2, 0–20% EtOAc in heptane), the fraction was concentrated under reduced pressure to give a colorless oil.

[0157] Yield: 4.47g, 85%.

[0158] 1 H NMR (400MHz, CDCl3) δ7.60(d,J=2.6Hz,1H),7.37(dd,J=8.6,2.5Hz,1H),6.89(d,J=8.7Hz,1H),2.34(s,3H),1.71(s,6H).m / z 238.2 / 240.2[M+H] + ,Br isotope pattern.

[0159] Step 2:

[0160]

[0161] A 40 mL solution of dried DCM containing 4.38 g (1 eq, 18.4 mmol) of 2-(3-bromo-4-methylphenyl)-2-methylpropanenitrile was cooled to -78 °C. 3.40 g (23.9 mL, 1.0 mol, 1.3 eq, 23.9 mmol) of 1 M diisobutylaluminum hydride in hexane was added dropwise to the solution over 15 minutes. The reaction mixture was stirred at -78 °C for 1.5 hours. Further dropwise addition of 655 mg (4.60 mL, 1.0 mol, 0.25 eq, 4.60 mmol) of 1 M diisobutylaluminum hydride in hexane was performed, and the reaction mixture was stirred at -78 °C for 30 minutes. The reaction mixture was heated to 0°C and slowly quenched with 2M HCl (60 mL). After stirring at 0°C for 30 minutes, the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water and extracted with DCM (3x). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated under reduced pressure to give a solid (4.39 g). The crude product was suspended in DCM and filtered. The filtrate was purified by column chromatography (120 g SiO2, 0–20% EtOAc in heptane). The fraction was concentrated under reduced pressure to give a light-yellow oil (2.68 g, 60%).

[0162] 1 H NMR (400MHz, CDCl3) δ9.42(s,1H),7.41(d,J=2.4Hz,1H),7.13(dd,J=8.6,2.4Hz,1H),6.85(d,J=8.6Hz,1H),2.33(s,3H),1.43(s,6H).m / z 241.2 / 243.2[M+H] + ,Br isotope pattern.

[0163] Step 3:

[0164]

[0165] Potassium cyanide (0.56 g, 1 eq, 8.6 mmol) and water (13 mL) were added to a 100 mL round-bottom flask. The solution was cooled to 0 °C, and methylamine hydrochloride (0.58 g, 1 eq, 8.6 mmol) was added. Then, a methanol solution (13 mL) containing 2-(3-bromo-4-methylphenyl)-2-methylpropanal (2.25 g, 1 eq, 8.6 mmol) was added. The resulting white suspension was stirred overnight at room temperature. The reaction mixture was diluted with H₂O (40 mL) and extracted with CH₂Cl₂ (3 × 50 mL). After combining the organic layers, the mixture was washed with brine (20 mL) and dried over Na₂SO₄. The solvent was removed under vacuum to obtain 3-(3-bromo-4-chlorophenyl)-3-methyl-2-(methylamino)butanenitrile, which is a colorless oil.

[0166] Yield: 2.2g, 86%.

[0167] 1 H NMR (400MHz, CDCl3) δ7.52(d,J=2.4Hz,1H),7.31(dd,J=8.7,2.4Hz,1H),6.84(d,J=8.7Hz,1H ),3.43-3.31(m,1H),2.46(s,3H),2.33(s,3H),1.50(d,J=11.5Hz,6H).m / z281.0 / 283.0[M+H] + ,Br isotope pattern.

[0168] Step 4:

[0169]

[0170] In 45 mL of DMSO containing 2.39 g (1 eq, 8.51 mmol) of 3-(3-bromo-4-methylphenyl)-3-methyl-2-(methylamino)butanenitrile, water containing 1 M (1.71 g, 40.9 mL, 1.0 mol, 4.8 eq, 40.9 mmol) of lithium hydroxide monohydrate and hydrogen peroxide (4.63 g, 4.17 mL, 30% Wt, 4.8 eq, 40.9 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (385 mL) and extracted with ethyl acetate (2 × 385 mL). The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 2.5 g of a colorless, viscous solid. Purification was performed using a rapid chromatographic column (80g SiO2, 0-5% methanol in dichloromethane) to obtain a white foam product.

[0171] Yield: 1.23g, 48%.

[0172] 1 H NMR (400MHz, DMSO) δ7.46 (d, J = 2.4Hz, 1H), 7.33-7.21 (m, 2H), 7.02-6.95 (m, 2H), 2.97-2.87 ( m,1H),2.30(s,3H),2.07(s,3H),1.44(bs,1H),1.23(d,J=7.8Hz,6H).m / z299.2 / 301.2[M+H] + ,Br isotope pattern.

[0173] Step 5:

[0174]

[0175] Dichloromethane (15 mL) was added to 3-(3-bromo-4-methylphenyl)-3-methyl-2-(methylamino)butanamide (1.24 g, 1 eq, 4.16 mmol). Next, Boc₂O (3.17 g, 3.5 eq, 14.5 mmol) was added. After a few minutes, a clear, colorless solution was obtained. The reaction mixture was stirred at room temperature for 3 days. DIPEA (591 mg, 787 μL, 1.1 eq, 4.57 mmol) and DMAP (50.8 mg, 0.1 eq, 416 μmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Water (45 mL) was added and the mixture was extracted with heptane (3 × 50 mL). The organic layer was washed with water (25 mL) and brine (25 mL). The organic layer was dried over sodium sulfate and concentrated to dryness. 2.8 g of a yellow oily substance was obtained and dissolved in THF (6.5 mL). 5 M sodium hydroxide (831 mg, 4.16 mL, 5.0 mol, 5 eq, 20.8 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. Then, water (25 mL) was added. The mixture was filtered, and the residue was washed with 0.5 M NaOH (25 mL). THF was removed under reduced pressure. The aqueous solution was washed with heptane, neutralized with solid citric acid, and extracted with ethyl acetate (3×). The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 1.35 g of a colorless oily substance. After purification by column chromatography (40 g SiO2, 0–50% ethyl acetate in heptane), the fraction was concentrated under reduced pressure to give a white foamy product.

[0176] Yield: 1.04g, 62%.

[0177] 1 ¹H NMR (400MHz, CDCl₃) δ 7.55–7.46 (m, 1H), 7.33–7.22 (m, 1H), 6.78 (d, J = 8.7 Hz, 1H), 5.03–4.80 (m, 1H), 2.82–2.60 (m, 3H), 2.33 (s, 3H), 1.53–1.35 (m, 15H). m / z 398.2 / 400.2 [MH]-, Br isotope mode.

[0178] Step 6:

[0179]

[0180] In a microwave-safe vial containing a mixture (20 mL) of 3-(3-bromo-4-methylphenyl)-2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanoic acid (354 mg, 1 eq, 841 μmol) and toluene (5.0 mL), a 32% (9.21 g, 10.2 mL, 32% Wt, 100 eq, 84.1 mmol) ammonium hydroxide solution was added, followed by the addition of copper powder (160 mg, 3 eq, 2.52 mmol). The vial was tightly capped and stirred at 100 °C for 6 hours. The reaction mixture was filtered, and the filtrate was evaporated to dryness. The residue was simultaneously evaporated with ethanol (3×) to remove moisture. The crude product was coated onto an aqueous matrix and purified by rapid column chromatography (12 g SiO2, 0–10% methanol in dichloromethane). The fraction was concentrated under reduced pressure to give 232 mg of a green oil / foam product. The product will be used directly in the next step.

[0181] Yield: 70%.

[0182] 1 H NMR (400MHz, CDCl3) δ7.18-5.90(m,3H),5.15-4.65(m,1H),2.89-2.39(m,4H),2.33-2.28(m,3H)1.90-1.05(m,17H).m / z 673.2[2M+H] + .

[0183] Step 7:

[0184]

[0185] Alloc-OSu (232 mg, 2 eq, 1.16 mmol) was added to a solution of 3-(3-amino-4-methylphenyl)-2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanoic acid (196 mg, 1 eq, 582 μmol) in 1.5 mL of tetrahydrofuran, followed by the addition of triethylamine (177 mg, 243 μL, 3 eq, 1.75 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by rapid column chromatography (12 g SiO2, 0–10% methanol in dichloromethane). The fraction was concentrated to give 110 mg (45%) of a light brown oil. NMR showed the rotational isomer.

[0186] 1 H NMR (400MHz, CDCl3) δ8.18(s,1H),7.21(s,1H),7.08-6.95(m,1H),6.75(d,J=8.6Hz,1H),6.02-5.90(m,1H),5.39-5.31( m,1H),5.25-5.20(m,1H),4.91(s,1H),4.68-4.62(m,2H),2.75(s,1H),2.63(s,2H),2.31(s,3H),1.52-1.38(m,16H).m / z 443.2[M+Na] + .

[0187] 2-2. Synthesis of compounds with chemical formulas 4 and 5

[0188]

[0189] Step 1:

[0190]

[0191] In the presence of 3-(3-(((allyloxy)carbonyl)amino)-4-methylphenyl)-2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanoic acid (3-(((allyloxy)carbonyl)amino)-4-methylphenyl)-2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanoic acid Add (S,E)-4-((S)-2-amino-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoate 2,2,2-trifluoroacetate (BCD fragment) (142 mg, 75% Wt, 1 eq, 249 μmol) [fragment A] (123 mg, 85% Wt, 1 eq, 249 μmol) to a solution of N,N-dimethylformamide (Fragment A) (1.8 mL), followed by (S,E)-4-((S)-2-amino-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoate 2,2,2-trifluoroacetate (Fragment BCD) (142 mg, 75% Wt, 1 eq, 249 μmol), and then add PyBOP (143 mg, 1.1 eq, 274 μmol). The reaction mixture was cooled to 0°C, and DIPEA (129 mg, 174 μL, 4 eq, 997 μmol) was added. The resulting clear solution was stirred overnight at room temperature. The reaction mixture was then used directly for purification using acid-based preparative MPLC (Luna 40-80). After combining the fractions, they were lyophilized and then evaporated together with DCM. An orange oil was obtained.

[0192] Yield: 108 mg, 60%. The product was obtained as a mixture of diastereomers.

[0193] 11H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.23 - 7.12 (m, 1H), 7.12 - 6.96 (m, 1H), 6.75 (d, J = 8.6 Hz, 1H), 6.63 - 6.54 (m, 1H), 6.35 - 6.03 (m, 1H), 6.03 - 5.88 (m, 1H), 5.38 - 5.30 (m, 1H), 5.25 - 5.20 (m, 1H), 5.10 - 4.78 (m, 2H), 4.72 - 4.55 (m, 3H), 4.20 - 4.12 (m, 2H), 2.95 - 2.75 (m, 6H), 2.31 (s, 3H), 1.89 - 1.78 (m, 4H), 1.52 - 1.32 (m, 14H), 1.31 - 1.20 (m, 4H), 0.89 - 0.70 (m, 16H). m / z 715.6 [M+H] + .

[0194] Step 2:

[0195]

[0196] Through the presence of (9S,12S,E)-6-[2-(3-((allyloxy)carbonyl)amino)-4-methylphenyl)prop-2-yl]-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-13-en-15-oic acid ethyl ester (ethyl(9S,12S,E)-6-(2-(3-(((allyloxy)carbonyl)amino)-4- A solution of tetrahydrofuran (6.0 mL) containing methylphenyl)propan-2-yl)-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadec-13-en-15-oate (88.6 mg, 1 eq, 124 μmol) was bubbled under nitrogen. Pd(PPh3)4 (7.1 mg, 0.05 eq, 6.19 μmol) was added, followed by tri-n-butyltin hydride (72.1 mg, 66.1 μL, 2 eq, 248 μmol). The mixture was stirred for 2 hours under nitrogen and at room temperature. The solvent was removed under reduced pressure, and the crude product was purified by rapid column chromatography (12 g SiO2, 0–10% methanol in dichloromethane). The fractions were combined and concentrated to give 79 mg of an orange oil. Purification by rapid column chromatography (4 g SiO2, 0–40% ethyl acetate in heptane) yielded a white solid product.

[0197] Yield: 53 mg, 68%.

[0198] 1 H NMR (400MHz, CDCl3) δ6.98-6.52(m,4H),6.25-5.95(m,1H),5.06-4.95(m,1H),4.55(dd,J=39.1,9.2Hz,1H),4.20-4.10(m, 2H),3.83-3.68(m,2H),2.95-2.78(m,6H),2.22(s,3H),1.86(d,J=10.1Hz,4H),1.51-1.18(m,19H),0.91-0.68(m,16H).m / z 631.2[M+H] + .

[0199] Step 3:

[0200]

[0201] In the presence of (9S,12S,E)-6-[2-(3-amino-4-methylphenyl)propan-2-yl]-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-13-en-15-oic acid ethyl ester (ethyl(9S,12S,E)-6-(2-(3-amino-4-methylphenyl)propan-2-yl)-9-(tert-butyl) A solution of lithium hydroxide monohydrate (16.4 mg, 5 eq, 390 μmol) in 2.0 mL of methanol (49 mg, 1 eq, 78.1 μmol) was dissolved in 1.0 mL of water (1.0 mL) containing lithium hydroxide monohydrate (16.4 mg, 5 eq, 390 μmol). The solution turned yellow. The reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralized with acetic acid and extracted with ethyl acetate (3x). The organic layer was washed with brine, dried over sodium sulfate, concentrated, and co-evaporated with dichloromethane (2x) to give a beige solid.

[0202] Yield: 46 mg, 98%.

[0203] m / z 603.2 [M+H] + .

[0204] Step 4:

[0205]

[0206] In the presence of (9S,12S,E)-6-(2-(3-amino-4-methylphenyl)propan-2-yl)-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadec-13-en-15-oic acid ((9S,12S,E)-6-(2-(3-amino-4-methylphenyl)propan-2-yl)-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadec-13-en-15-oic To a solution of 46 mg (1 eq, 74 μmol) of acid in dichloromethane (1.0 mL), add 1.0 mL of dichloromethane containing 10% TFA and stir the reaction mixture at room temperature for 1 hour. Cool the mixture to 0 °C and add TFA dropwise (740 mg, 500 μL, 87 eq, 6.49 mmol). Stir the reaction mixture at room temperature for 1 hour. Remove the solvent under reduced pressure and purify the residue by acidic preparative MPLC (Luna 5-40). After combining the fractions, lyophilize.

[0207] Yield: 19 mg, 50%.

[0208] The product was obtained as a mixture of diastereomers. The diastereomers were separated by RP-HPLC to yield S,S,S (5 mg) and R,S,S (7 mg) isomers.

[0209] 1 H NMR (400MHz, DMSO-d6) δ7.72(s,1H),6.73-6.51(m,4H),5.30-4.00(m,4H),3.28(s,2H),3.14-2.86(m,4H),2.18(d,J= 2.9Hz,3H),2.10-1.84(m,4H),1.74(d,J=1.4Hz,3H),1.24-1.08(m,6H),0.89(d,J=24.6Hz,9H),0.82-0.65(m,6H).m / z 503.4[M+H] + .

[0210] [Example 3]

[0211] Synthesis of compounds with chemical formulas 6 and 7

[0212]

[0213] 3-1. Synthesis of Fragment A

[0214]

[0215] Step 1:

[0216]

[0217] Iodomethane (7.53 g, 3.30 mL, 2.4 eq, 53.1 mmol) was added to a 30 mL (dry) THF solution containing 2-(3-bromo-4-chlorophenyl)acetonitrile (5.00 g, 1 eq, 22.1 mmol). The reaction mixture was cooled to 4 °C, and sodium hydride (60% dispersion in mineral oil) (2.12 g, 60% Wt, 2.4 eq, 53.1 mmol) was added dropwise. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. Iodomethane (628 mg, 277 μL, 0.2 eq, 4.42 mmol) and sodium hydride (60% dispersion in mineral oil) (177 mg, 60% Wt, 0.2 eq, 4.42 mmol) were added further, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (~100 mL) and extracted with EtOAc (3x). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated under reduced pressure to give a brown oil (6.47 g). After purification by rapid column chromatography (120 g SiO2, 0-20% EtOAc in heptane), the fraction was concentrated under reduced pressure to give a colorless oil.

[0218] Yield: 4.7g, 82%.

[0219] 1 H NMR (400MHz, CDCl3) δ7.52(d,J=2.6Hz,1H),7.34(dd,J=8.6,2.5Hz,1H),7.15(d,J=8.7Hz,1H),1.70(s,6H).m / z 257.2 / 259.2[M+H] + ,Br isotope pattern.

[0220] Step 2:

[0221]

[0222] A 40 mL solution of dried DCM containing 4.76 g (1 eq, 18.4 mmol) of 2-(3-bromo-4-chlorophenyl)-2-methylpropanenitrile was cooled to -78 °C. 3.40 g (23.9 mL, 1.0 mol, 1.3 eq, 23.9 mmol) of 1 M diisobutylaluminum hydride in hexane was added dropwise to the solution over 15 minutes. The reaction mixture was stirred at -78 °C for 1.5 hours. Further dropwise addition of 655 mg (4.60 mL, 1.0 mol, 0.25 eq, 4.60 mmol) of 1 M diisobutylaluminum hydride in hexane was performed, and the reaction mixture was stirred at -78 °C for 30 minutes. The reaction mixture was heated to 0°C and slowly quenched with 2M HCl (60 mL). After stirring at 0°C for 30 minutes, the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water and extracted with DCM (3x). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated under reduced pressure to give a solid (4.39 g). The crude product was suspended in DCM and filtered. The filtrate was purified by column chromatography (120 g SiO2, 0-20% EtOAc in heptane). The fraction was concentrated under reduced pressure to give a light-yellow oil (2.49 g, 52%).

[0223] 1 H NMR (400MHz, CDCl3) δ9.45(s,1H),7.51(d,J=2.3Hz,1H),7.35(dd,J=8.5,2.3Hz,1H),7.18(d,J=8.5Hz,1H),1.45(s,6H).m / z 260.2 / 262.2[M+H] + ,Br isotope pattern.

[0224] Step 3:

[0225]

[0226] Potassium cyanide (0.56 g, 1 eq, 8.6 mmol) and water (13 mL) were added to a 100 mL round-bottom flask. The solution was cooled to 0 °C, and methylamine hydrochloride (0.58 g, 1 eq, 8.6 mmol) was added. Then, a methanol solution (13 mL) containing 2-(3-bromo-4-chlorophenyl)-2-methylpropanal (2.25 g, 1 eq, 8.6 mmol) was added. The resulting white suspension was stirred overnight at room temperature. The reaction mixture was diluted with H₂O (40 mL) and extracted with CH₂Cl₂ (3 × 50 mL). After combining the organic layers, the mixture was washed with brine (20 mL) and dried over Na₂SO₄. The solvent was removed under vacuum to obtain 3-(3-bromo-4-chlorophenyl)-3-methyl-2-(methylamino)butanenitrile, which is a colorless oil.

[0227] Yield: 2.08g, 80%.

[0228] 1 H NMR (400MHz, CDCl3) δ7.58 (d, J=2.4Hz, 1H), 7.33 (dd, J=8.7, 2.4Hz, 1H), 7.09 (d,J=8.7Hz,1H),3.45-3.35(m,1H),2.48(s,3H),1.52(d,J=11.5Hz,6H).m / z 300.4 / 302.4[M+H] + ,Br isotope pattern.

[0229] Step 4:

[0230]

[0231] In 45 mL of DMSO containing 2.57 g (1 eq, 8.51 mmol) of 3-(3-bromo-4-chlorophenyl)-3-methyl-2-(methylamino)butanenitrile (3-(3-bromo-4-chlorophenyl)-3-methyl-2-(methylamino)butanenitrile), water containing 1 M (1.71 g, 40.9 mL, 1.0 mol, 4.8 eq, 40.9 mmol) of lithium hydroxide monohydrate and hydrogen peroxide (4.63 g, 4.17 mL, 30% Wt, 4.8 eq, 40.9 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (385 mL) and extracted with ethyl acetate (2 × 385 mL). The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 2.5 g of a colorless, viscous solid. The product was purified by rapid column chromatography (80g SiO2, 0-5% methanol in dichloromethane) to obtain a white foam product.

[0232] Yield: 1.23g, 45%.

[0233] 1 H NMR (400MHz, DMSO) δ7.52 (d, J = 2.4Hz, 1H), 7.38-7.28 (m, 2H), 7.18-7.13 (m, 2H),3.00-2.95(m,1H),2.10(s,3H),1.48(bs,1H),1.25(d,J=7.8Hz,6H).m / z 318.4 / 320.4[M+H] + ,Br isotope pattern.

[0234] Step 5:

[0235]

[0236] Dichloromethane (15 mL) was added to 3-(3-bromo-4-chlorophenyl)-3-methyl-2-(methylamino)butanamide (1.33 g, 1 eq, 4.16 mmol). Next, Boc₂O (3.17 g, 3.5 eq, 14.5 mmol) was added. After a few minutes, a clear, colorless solution was obtained. The reaction mixture was stirred at room temperature for 3 days. DIPEA (591 mg, 787 μL, 1.1 eq, 4.57 mmol) and DMAP (50.8 mg, 0.1 eq, 416 μmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Water (45 mL) was added and the mixture was extracted with heptane (3 × 50 mL). The organic layer was washed with water (25 mL) and brine (25 mL). The organic layer was dried over sodium sulfate and concentrated to dryness. 2.8 g of a yellow oily substance was obtained and dissolved in THF (6.5 mL). 5 M sodium hydroxide (831 mg, 4.16 mL, 5.0 mol, 5 eq, 20.8 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. Then, water (25 mL) was added. The mixture was filtered, and the residue was washed with 0.5 M NaOH (25 mL). THF was removed under reduced pressure. The aqueous solution was washed with heptane, neutralized with solid citric acid, and extracted with ethyl acetate (3×). The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 1.37 g of a colorless oily substance. After purification by column chromatography (40 g SiO2, 0-50% ethyl acetate in heptane), the fraction was concentrated under reduced pressure to give a white foamy product.

[0237] Yield: 1.13g, 65%.

[0238] 1 ¹H NMR (400MHz, CDCl₃) δ 7.58–7.48 (m, 1H), 7.39–7.32 (m, 1H), 7.18 (d, J = 8.7 Hz, 1H), 5.13–4.90 (m, 1H), 2.92–2.70 (m, 3H), 1.58–1.45 (m, 15H). m / z 419.2 / 421.2 [MH]-, Br isotope mode.

[0239] Step 6:

[0240]

[0241] In a microwave-safe vial containing a mixture (354 mg, 1 eq, 841 μmol) of 3-(3-bromo-4-chlorophenyl)-2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanoic acid (354 mg, 1 eq, 841 μmol) and toluene (5.0 mL) (20 mL), a 32% (9.21 g, 10.2 mL, 32% Wt, 100 eq, 84.1 mmol) ammonium hydroxide solution was added, followed by the addition of copper powder (160 mg, 3 eq, 2.52 mmol). The vial was tightly capped and stirred at 100 °C for 6 hours. The reaction mixture was filtered, and the filtrate was evaporated to dryness. The residue was simultaneously evaporated with ethanol (3×) to remove moisture. The crude product was coated onto an aqueous matrix and purified by rapid column chromatography (12 g SiO2, 0–10% methanol in dichloromethane). The fraction was concentrated under reduced pressure to give 232 mg of a green oil / foam product. The product will be used directly in the next step.

[0242] Yield: 60%.

[0243] 1 H NMR (400MHz, CDCl3) δ7.28-6.90(m,2H),6.85-6.30(m,1H),5.25-4.85(m,1H),2.95-2.59(m,4H),1.92-1.10(m,17H).m / z 713.4[2M+H] + .

[0244] Step 7:

[0245]

[0246] Alloc-OSu (232 mg, 2 eq, 1.16 mmol) was added to a solution of 3-(3-amino-4-chlorophenyl)-2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanoic acid (205 mg, 1 eq, 582 μmol) in 1.5 mL of tetrahydrofuran, followed by the addition of triethylamine (177 mg, 243 μL, 3 eq, 1.75 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by rapid column chromatography (12 g SiO2, 0–10% methanol in dichloromethane). The fraction was concentrated to give 120 mg (47%) of a light brown oil. NMR indicates the rotational isomer.

[0247] 1 H NMR (400MHz, CDCl3) δ8.28(s,1H),7.31(s,1H),7.25-7.10(m,1H),6.95(d,J=8.6Hz,1H),6.12-6.05(m,1H),5.45- 5.36(m,1H),5.28-5.23(m,1H),4.96(s,1H),4.72-4.68(m,2H),2.85(s,1H),2.73(s,2H),1.55-1.42(m,16H).m / z 463.2[M+Na] + .

[0248] 3-2. Synthesis of compounds with chemical formulas 6 and 7

[0249]

[0250] Step 1:

[0251]

[0252] Fragment A of 3-(3-(((allyloxy)carbonyl)amino)-4-chlorophenyl)-2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanoic acid (125 mg, 88%) To a solution of N,N-dimethylformamide (1.8 mL, Wt, 1 eq, 249 μmol) (S,E)-4-((S)-2-amino-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoate 2,2,2-trifluoroacetate (ethyl(S,E)-4-((S)-2-amino-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoate 2,2,2-trifluoroacetate) (142 mg, 75% Wt, 1 eq, 249 μmol) [BCD fragment], PyBOP (143 mg, 1.1 eq, 274 μmol) was added. The reaction mixture was cooled to 0°C, and DIPEA (129 mg, 174 μL, 4 eq, 997 μmol) was added. The resulting clear solution was stirred overnight at room temperature. The reaction mixture was then used directly for purification using acid-based preparative MPLC (Luna 40-80). After combining the fractions, they were lyophilized and then evaporated together with DCM. An orange oil was obtained.

[0253] Yield: 120 mg, 65%. The product was obtained as a mixture of diastereomers.

[0254] 1H NMR (400MHz, CDCl3) δ8.30 (s, 1H), 7.33-7.22 (m, 1H), 7.22-7.06 (m, 1H), 6.85 (d, J = 8.6Hz ,1H),6.73-6.64(m,1H),6.45-6.13(m,1H),6.13-5.98(m,1H),5.48-5.40(m,1H),5.35-5. 30(m,1H),5.20-4.88(m,2H),4.82-4.65(m,3H),4.30-4.22(m,2H),3.05-2.85(m,6H),1.9 5-1.85(m,4H),1.55-1.38(m,14H),1.35-1.25(m,4H),0.92-0.75(m,16H).m / z735.2[M+H] + .

[0255] Step 2:

[0256]

[0257] Through the presence of (9S,12S,E)-6-[2-(3-((allyloxy)carbonyl)amino)-4-chlorophenyl)prop-2-yl]-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-13-en-15-oic acid ethyl ester (ethyl(9S,12S,E)-6-(2-(3-(((allyloxy)carbonyl)amino)-4 A solution of tetrahydrofuran (6.0 mL) containing 91 mg (1 eq, 124 μmol) of (-chlorophenyl)propan-2-yl)-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadec-13-en-15-oate) was bubbled under nitrogen. Pd(PPh3)4 (7.1 mg, 0.05 eq, 6.19 μmol) was added, followed by tri-n-butyltin hydride (72.1 mg, 66.1 μL, 2 eq, 248 μmol). The mixture was stirred for 2 hours under nitrogen and at room temperature. The solvent was removed under reduced pressure, and the crude product was purified by rapid column chromatography (12 g SiO2, dichloromethane, 0–10% methanol). The fractions were combined and concentrated to give 79 mg of an orange oil. Purification by rapid column chromatography (4 g SiO2, 0–40% ethyl acetate in heptane) yielded a white solid product.

[0258] Yield: 53.2 mg, 66%.

[0259] 1 H NMR (400MHz, CDCl3) δ7.08-6.62(m,4H),6.35-6.05(m,1H),5.16-5.05(m,1H),4.65(dd,J=39.1,9.2Hz,1H),4.30-4. 20(m,2H),3.93-3.78(m,2H),3.05-2.88(m,6H),1.96(d,J=10.1Hz,4H),1.61-1.28(m,19H),0.95-0.72(m,16H).m / z 651.2[M+H] + .

[0260] Step 3:

[0261]

[0262] In the presence of (9S,12S,E)-6-[2-(3-amino-4-chlorophenyl)propan-2-yl]-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-13-en-15-oic acid ethyl ester (ethyl(9S,12S,E)-6-(2-(3-amino-4-chlorophenyl)propan-2-yl)-9-(tert-butyl) A solution of lithium hydroxide monohydrate (16.4 mg, 5 eq, 390 μmol) in 2.0 mL of methanol (51 mg, 1 eq, 78.1 μmol) was dissolved in 1.0 mL of water (1.0 mL) containing lithium hydroxide monohydrate (16.4 mg, 5 eq, 390 μmol). The solution turned yellow. The reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralized with acetic acid and extracted with ethyl acetate (3x). The organic layer was washed with brine, dried over sodium sulfate, concentrated, and co-evaporated with dichloromethane (2x) to give a beige solid.

[0263] Yield: 46 mg, 95%.

[0264] m / z 623.2 [M+H] + .

[0265] Step 4:

[0266]

[0267] In the presence of (9S,12S,E)-6-[2-(3-amino-4-chlorophenyl)propan-2-yl]-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadec-13-en-15-oic acid ((9S,12S,E)-6-(2-(3-amino-4-chlorophenyl)propan-2-yl)-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadec-13-en-15-oic To a solution of 44 mg (1 eq, 74 μmol) of acid in dichloromethane (1.0 mL), add 1.0 mL of dichloromethane containing 10% TFA and stir the reaction mixture at room temperature for 1 hour. Cool the mixture to 0 °C and add TFA dropwise (740 mg, 500 μL, 87 eq, 6.49 mmol). Stir the reaction mixture at room temperature for 1 hour. Remove the solvent under reduced pressure and purify the residue by acidic preparative MPLC (Luna 5-40). After combining the fractions, lyophilize.

[0268] Yield: 17.8 mg, 48%.

[0269] The product was obtained as a mixture of diastereomers. The diastereomers were separated by RP-HPLC to yield S,S,S (5.5 mg) and R,S,S (7.5 mg) isomers.

[0270] 1 H NMR(400MHz,DMSO-d6)δ7.82(s,1H),6.83-6.61(m,4H),5.40-4.10(m,4H),3.38(s,2H),3.24-2.96(m,4H), 2.20-1.94(m,4H),1.84(d,J=1.4Hz,3H),1.28-1.13(m,6H),0.92(d,J=24.6Hz,9H),0.85-0.68(m,6H).m / z 523.4[M+H] + .

[0271] [Example 4]

[0272] Cell viability analysis

[0273] 3000 FaDu or A549 cell lines were seeded into each well of a 96-well plate and incubated at a constant temperature (37°C and 5% CO2). After 24 hours, the cell lines were treated with 100 μL of nine different concentrations of drug (serial dilutions of 1 / 5 each, starting from 1000 nM). The drugs used were the compound of Formula 2 prepared according to Example 1, SC209 (MedChemExpress), and MMAE. A control group (drug concentration of 0) without drug treatment was also prepared. After 3 days of incubation at a constant temperature (37°C and 5% CO2), 100 μL of CellTiter-Glo reagent (using...) was added to each well of the plate. After using the Luminescent Cell Viability Assay Kit (Promega, G7571), the cells were pipetted. After 10 minutes of incubation at room temperature (RT), the luminescence value was measured. The luminescence value at which the drug concentration was 0 was considered 100%, and the concentration exhibiting 50% luminescence was defined as the IC50 value. 50 value.

[0274] Table 1

[0275]

[0276] The results are as follows Figure 1 , Figure 2 As shown in Table 1, these results confirm that when lung cancer cell line (A529) and head and neck squamous cell carcinoma cell line (FaDu) were treated with the compounds of the present invention, cell viability decreased to a level similar to that achieved with treatment using SC209 and MMAE. That is, the compounds of the present invention (chemical formula 2 in this embodiment) have an apoptotic effect on cancer cells. As confirmed in the described embodiments, the compounds of the present invention exhibit an apoptotic effect on cancer cells and can therefore be used as components comprising these compounds for the prevention or treatment of cancer.

[0277] While this specification does not impose any particular limitation, the invention may be provided in the form of pharmaceuticals commonly used in the art, in addition to compositions containing the compounds alone. For example, it may be provided as a drug-linker in which the compounds of the invention are combined with a linker, a drug-carrier in which the compounds are combined with a carrier, or a drug-linker-carrier (wherein the carrier includes antibodies, aptamers, repebosomes, etc.). More specifically, a drug in the form of an antibody-drug conjugate containing the compounds as a payload may be provided, and compositions that can be used in various ways for co-administration may also be provided. It will be apparent to those skilled in the art that the drug-linker, drug-carrier, or drug-linker-carrier forms may have apoptosis-like effects equivalent to or similar to those of the compounds of the invention alone, and known peptide-based linkers (GGFG, val-cit, etc.), acid-sensitive linkers (such as CL2A), and conjugates combining the compounds of the invention are also within the scope of this invention.

[0278] The present invention has been described above with reference to preferred embodiments. It will be understood by those skilled in the art that the invention can be implemented in modified forms without departing from its essential characteristics. Therefore, the disclosed embodiments should not be considered restrictively, but rather illustratively. The scope of the invention is defined by the claims rather than the foregoing description, and all differences within the scope of the claims should be interpreted as included within the present invention.

Claims

1. A compound, its derivatives, its isomers, its pharmaceutically acceptable salts, or its solvates, characterized in that, The compound is represented by chemical formula 1. [Chemical Formula 1] In the chemical formula 1, R is selected from halogen, hydroxyl, carboxyl, C1-C6 alkyl and C1-C6 alkoxy.

2. The compound, its isomer, its pharmaceutically acceptable salt, or its solvate according to claim 1, characterized in that, The derivatives of chemical formula 1 are compounds represented by chemical formula 2 or chemical formula 3: [Chemical Formula 2] [Chemical Formula 3] 3. The compound, its isomer, its pharmaceutically acceptable salt, or its solvate according to claim 1, characterized in that, The derivatives of chemical formula 1 are compounds represented by chemical formula 4 or chemical formula 5: [Chemical Formula 4] [Chemical Formula 5] 4. The compound, its isomer, its pharmaceutically acceptable salt, or its solvate according to claim 1, characterized in that, The derivatives of chemical formula 1 are compounds represented by chemical formula 6 or chemical formula 7: [Chemical Formula 6] [Chemical Formula 7] 5. A carrier-drug conjugate, characterized in that, The carrier-drug conjugate includes: Compounds of Formula 1, their derivatives, their isomers, their pharmaceutically acceptable salts or solvates thereof; and The carrier attached to the compound, [Chemical Formula 1] In the chemical formula 1, R is selected from halogen, hydroxyl, carboxyl, C1-C6 alkyl and C1-C6 alkoxy.

6. The carrier-drug conjugate according to claim 5, characterized in that, The derivatives of chemical formula 1 are compounds represented by chemical formula 2 or chemical formula 3: [Chemical Formula 2] [Chemical Formula 3] 7. The carrier-drug conjugate according to claim 5, characterized in that, The derivatives of chemical formula 1 are compounds represented by chemical formula 4 or chemical formula 5: [Chemical Formula 4] [Chemical Formula 5] 8. The carrier-drug conjugate according to claim 5, characterized in that, The derivatives of chemical formula 1 are compounds represented by chemical formula 6 or chemical formula 7: [Chemical Formula 6] [Chemical Formula 7] 9. The carrier-drug conjugate according to claim 5, characterized in that, The carrier-drug conjugate is a form in which a carrier is conjugated to a drug via a linker.

10. The carrier-drug conjugate according to claim 5, characterized in that, The connector includes GGFG or val-cit.

11. The carrier-drug conjugate according to claim 8, characterized in that, The vector is an antibody, peptide, repeat, or aptamer.

12. The carrier-drug conjugate according to claim 8, characterized in that, The antibodies selected are urerucumab, utorumab, betelumab, aducanumab, bavizumab, kleinezumab, donepemab, gantrub, lencanemab, sorazumab, nevasumab, ivexumab, enoxazumab, octotuzumab, belimumab, iricumab, tabecucizumab, bertilimab, moglizumab, lelizumab, cilizumab, francirumab, morozumab-CD3, oxizumab, tabecucizumab, trelizumab, zamumab, iricumab, efalizumab, enoxazumab, tancituzumab, tosimo, ozenatuzumab, oxalizumab, oxalizumab, rituximab, utorumab, vetozumab, and ipatuzumab. Antibiotics, baliximab, daliximab, variluximab, ruliximab, itotuzumab, lintoximab, daratumumab, finzartuzumab, esatatumumab, mizartuzumab, buluruximab, dasiximab, icaliximab, rucamumab, micoxalimab, sotilimab, dapirizumab, etanerizumab, lifarizumab, moloturiximab Alendumab, Crizotinib, Inlazotinib, Gutozumab, Oleruzanib, Milazizumab, Galiliximab, Caltuximab, Ademumab, Eprazole, Erenelumab, Remanuumab, Garcaneizumab, Zoltozumab, Onatuxizumab, Ikuzumab, Pazelizanib, Riflizumab, Latozumab, Ekleyzanib Carbelizumab, Erenexumab, Ipilimumab, Zivorimumab, Tesimemab, Zeflizumab, Cetuximab, Ditoxumab, Votoxumab, Imatrozumab, Matoxumab, Zartuxumab, Nexitoxumab, Nitoxumab, Panitumab, Toltuxumab, Zartuxumab, Butolizumab, Nicalizumab, Lolixizumab Antibiotics, ibuprofen, favuzumab, dartuximab, nacitabine, lagovilimab, ginsruzilimab, lenzruzilimab, malvastatin, namexilam, otelimab, punaglimab, cotrastuzumab, magruzilimab, pertuzumab, trastuzumab, dababutuzumab, pertrastuzumab, seretuzumab, dugautozumab, felatinumab Monoclonal antibodies, rituximab, elolimab, arunizumab, imalitum, ligolizumab, omalizumab, cetuximab, darotox, fentuximab, ganituximab, teltolimab, bemaciz, cannabidiol, givitazine, brenumab, ustekinumab, anitoxin, sendazine, levofloxacin, troroluruzine Brolimumab, Bechzizumab, Isebemab, Secukinumab, Brekumab, Gusekumab, Migizumab, Risazalizumab, Titragizumab, Nemolizumab, Emisolizumab, Septosolizumab, Pacozumab, Duprelimumab, Democtomycin, Meplerizumab, Relizumab, Benalizumab, KrazazumabOlogizumab, Stochasticumab, Sirukumab, Zervec, Leveli, Salirulumab, Saturizumab, Tocilizumab, Arbitril, Maiziram, Furanli, Ellari, Rilaril, Sintrol, Abavo, Ogovo, Tadazoli, Evoril, Nocatetil, Taliximab, Trazoli, Pergalizumab, Alijumab, Bercosizumab, Inusizumab, Elevulil, Frosi, Ongoreci, Tolecithin, Dotali, Batitil, Camrelizumab, Cimiprizumab, Jerolizumab, Nivolumab, Pembrolizumab, Pembrolizumab, Pembrolizumab Pidilelimumab, Palolilimumab, Refulimab, Sassalimumab, Slulilimumab, Sintilimumab, Spartazumab, Tislelilimumab, Toripalimab, Ebenlimumab, Sepapalimab, Atezolilimumab, Averumumab, Kochialimumab, Sugelimumab, Duvalilumab, Envorimab, Sutosulimumab, Dinolimumab, Zelotuzumab, Elotuzumab, Dovanarimab, Etelimumab, Osperidone, Tirelimumab, Vembolilimumab, Suzelimumab, Cobbolilimumab, Sabatolimumab, Constezilumab, Matasimsimab, Adalimumab, Golimumab, Infliximab, Sertolilimumab, Canamumab, Tigalimumab Tezolizumab, gatizumab, carbizumab, bevacizumab, broluzumab, ranibizumab, olivazumab, ikumab, ramoxizumab, caprilzumab, abulizumab, etatozumab, vedozumab, intertozumab, natalzumab, obrindazumab, ellanazumab, linwosaizumab, teratozumab, etaolizumab, glofoemumab, motuzumab, odorazumab, fredozumab, vebetozumab, caputoxumab, sibitozumab, taquitozumab, ubatuzumab, enthalpyzumab, belintozumab, ervatozumab, emecoxumab, zetuzumab, zenidatuzumab, tibolizumab, napotomomumab, belan The group consisting of at least one of the following: taurumab, pivevizimab, protaurumab, cotoxicumab, dinetaurumab, rontoxicumab, teimozumab, ozoguzumab, ipataurumab, mosetaurumab, vebutaurumab, getoxicumab, varadaurumab, lovotoxicumab, vebutaurumab, tsazotoxicumab, terlisotaurumab, lovatoxicumab, ditoxicumab, falutuzumab, mitutaurumab, dicetoxicumab, anetoxicumab, enrofloxacin, gossazotoxicumab, vobalizumab, candunizumab, vodalizumab, terpolizumab, edoxicillin, ilexizumab, orlistatumab, falexizumab, vanucizumab, and nalexizumab.

13. A drug-linker, characterized in that, The drug-linker includes: Compounds of Formula 1, their derivatives, their isomers, their pharmaceutically acceptable salts or solvates thereof; and The carrier attached to the compound, [Chemical Formula 1] In the chemical formula 1, R is selected from halogen, hydroxyl, carboxyl, C1-C6 alkyl and C1-C6 alkoxy.

14. The drug-linker according to claim 13, characterized in that, The connectors include GGFG or val-cit, etc.

15. A pharmaceutical composition for the prevention or treatment of cancer, characterized in that, The pharmaceutical composition comprises a compound of formula 1, its derivatives, its isomers, its pharmaceutically acceptable salts, or its solvates: [Chemical Formula 1] In the chemical formula 1, R is selected from halogen, hydroxyl, carboxyl, C1-C6 alkyl and C1-C6 alkoxy.

16. The pharmaceutical composition according to claim 15, characterized in that, The compound of chemical formula 1 is connected to the carrier via a linker.

17. The pharmaceutical composition according to claim 15, characterized in that, The cancers selected include pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampullary cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal cavity and sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, and renal pelvis cancer. The cancer is defined as at least one of the following: kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastrointestinal stromal cancer, nephroblastoma, breast cancer, triple-negative breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, leukemia, and thymic cancer.

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