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WO2025160910A1 - Composé indazole et composition pharmaceutique, son procédé de préparation et son utilisation - Google Patents

Composé indazole et composition pharmaceutique, son procédé de préparation et son utilisation

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Publication number
WO2025160910A1
WO2025160910A1 PCT/CN2024/075342 CN2024075342W WO2025160910A1 WO 2025160910 A1 WO2025160910 A1 WO 2025160910A1 CN 2024075342 W CN2024075342 W CN 2024075342W WO 2025160910 A1 WO2025160910 A1 WO 2025160910A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
cancer
compound
optionally substituted
following groups
Prior art date
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Pending
Application number
PCT/CN2024/075342
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English (en)
Inventor
Halo. Q
Xf. WANG
Zj. SUN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
New Wish Biotechnology Wuxi Co Ltd
Original Assignee
New Wish Biotechnology Wuxi Co Ltd
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Priority to PCT/CN2024/075342 priority Critical patent/WO2025160910A1/fr
Priority to PCT/CN2025/075387 priority patent/WO2025162427A1/fr
Publication of WO2025160910A1 publication Critical patent/WO2025160910A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical

Definitions

  • the present disclosure belongs to the field of medicine, and particularly relates to an indazole compound, and pharmaceutical composition, preparation method and use thereof.
  • Non-communicable diseases are the leading cause of death in the world, and cancer is the disease with the highest fatality rate among the non-communicable diseases, which brings a heavy burden to the social health and medical system.
  • Traditional cancer treatment mainly includes surgery, radiotherapy, and chemotherapy, and chemotherapy is the main treatment for advanced cancer.
  • Traditional chemical anti-cancer drugs have serious side effects due to poor targeting.
  • targeted chemotherapeutic drugs typified by Gleevec
  • the pain caused by chemotherapy to patients has been alleviated.
  • These targeted drugs are designed based on the different growth characteristics and expressed molecules of cancer cells compared with normal cells. For example, Gleevec specifically targets the constitutively activated tyrosine kinase in chronic myelogenous leukemia, thereby achieving a good therapeutic effect (Flynn and Gerriets, 2020) .
  • Receptor tyrosine kinases are high-affinity cell surface receptors for many polypeptide growth factors, cytokines and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Mutations in the receptor tyrosine kinases activate a series of signaling cascade reactions that have many effects on protein expression.
  • Receptor tyrosine kinases are a large family of proteins among tyrosine kinases, which are characterized by a hydrophobic transmembrane domain, and tyrosine kinases without a transmembrane domain are non-receptor tyrosine kinases.
  • RTKs include: epidermal growth factor (EGF) receptor, platelet-derived growth factor (PDGF) receptor, macrophage colony stimulating factor (M-CSF) , insulin and insulin-like growth factor-1 (IGF-1) receptor, nerve growth factor (NGF) receptor, fibroblast growth factor (FGF) receptor, vascularendothelial growth factor (VEGF) receptor, hepatocyte growth factor (HGF) receptor, and the like.
  • EGF epidermal growth factor
  • PDGF platelet-derived growth factor
  • M-CSF macrophage colony stimulating factor
  • IGF-1 insulin and insulin-like growth factor-1
  • NGF nerve growth factor
  • FGF fibroblast growth factor
  • VEGF vascularendothelial growth factor
  • HGF hepatocyte growth factor
  • Drug resistance includes pharmacological drug resistance and biological drug resistance, wherein the pharmacological drug resistance is mostly caused by the interaction of drugs in the body that prevents the drugs from reaching effective concentrations around cancer cells, but the cancer cells themselves may still be sensitive to the drugs; biological resistance is caused by the cancer heterogeneity, the generation of drug resistance mutations due to drug selection pressure, and the activation of alternative bypass signaling pathways.
  • the present disclosure provides a compound represented by the following formula (I) , or a tautomer, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:
  • connected to a carbon atom represents that the carbon atom is fused with the phenyl ring, and connected to a nitrogen atom represents that the nitrogen atom is bonded to L;
  • Y is selected from O, S, S (O) , S (O) 2 , and CH 2 ;
  • R 1 is selected from H, and the following groups unsubstituted or optionally substituted with 1, 2 or more R 11 : C 1-10 alkyl, -OR 01 , C 2-10 alkenyl, C 3-10 cycloalkyl, and 3-to 10-membered heterocyclyl;
  • A is selected from H, and the following groups unsubstituted or optionally substituted with 1, 2 or more R a : C 1-10 alkyl, C 3-10 cycloalkyl, 3-to 10-membered heterocyclyl, C 6-14 aryl, and 5-to 14-membered heteroaryl;
  • B is selected from the following groups unsubstituted or optionally substituted with 1, 2 or more R b :C 3-10 cycloalkyl, 3-to 10-membered heterocyclyl, C 6-14 aryl, and 5-to 14-membered heteroaryl;
  • each R 01 , R 02 , R 03 , R 04 , R 05 , R 06 , R 07 , R 08 , R 09 and R 10 is identical or different, and is independently selected from H, C 1-10 alkyl, C 1-10 alkyloxy, C 2-10 alkenyl, C 3-10 cycloalkyl, 3-to 10-membered heterocyclyl, C 6-14 aryl, and 5-to 14-membered heteroaryl;
  • n is selected from 0, 1, 2, and 3.
  • R 1 is selected from the following groups unsubstituted or optionally substituted with 1, 2 or more R 11 : C 1-10 alkyl, C 3-10 cycloalkyl, and 3-to 10-membered heterocyclyl.
  • R 1 is selected from C 1-6 alkyl, such as methyl.
  • each R 21 , R 31 and R 41 is identical or different, and is independently selected from H, halogen, C 1-6 alkyl, and C 1-6 alkyloxy.
  • each R 01 and R 03 is identical or different, and is independently selected from H and C 1-6 alkyl.
  • R 5 is selected from C 1-6 alkyl and C 1-6 alkyloxy, for example, H.
  • R L is selected from the following groups unsubstituted or optionally substituted with 1, 2 or more R L1 : C 1-6 alkyl and C 3-6 cycloalkyl, for example, the following groups unsubstituted or optionally substituted with 1, 2 or more R L1 : methyl, ethyl, propyl, isopropyl, isobutyl, and cyclohexyl.
  • A is selected from the following groups unsubstituted or optionally substituted with 1, 2 or more R a : C 1-6 alkyl, C 3-8 cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 aryl, and 5-to 10-membered heteroaryl, for example, the following groups unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 R a : methyl, ethyl, propyl, butyl, phenyl, pyridyl, pyrazolyl, thienyl, pyrazinyl, pyrimidinyl, naphthyl, quinolyl, isoquinolyl, 2, 3- dihydrobenzofuranyl, dibenzothienyl, benzothienyl, benzofuranyl, 2, 3-dihydrobenzo [b] [1, 4] dioxinyl, cyclopropyl, cyclobutyl, cyclohe
  • each R a1 is identical or different, and is independently selected from H, halogen, OH, C 1-6 alkyl, C 1-6 alkyloxy, C 3-8 cycloalkyl, and 3-to 8-membered heterocyclyl, for example, H, F, OH, methyl, cyclobutyl, cyclopentyl, cyclohexyl, and morpholinyl.
  • an example of A may be selected from H, and the following groups without further substitution or further substituted with 1, 2 or more R a : methyl,
  • B is selected from the following groups unsubstituted or optionally substituted with 1, 2 or more R b : C 6-10 aryl, 3-to 10-membered heterocyclyl, and 5-to 10-membered heteroaryl, for example, phenyl, thienyl and thiazolyl unsubstituted or optionally substituted with 1, 2 or 3 R b .
  • each R b is identical or different, and is independently selected from the following groups unsubstituted or optionally substituted with 1, 2 or more R b1 : C 1-6 alkyl, C 1-6 alkyloxy, C 3-6 cycloalkyl, 3-to 6-membered heterocyclyl, 3-to 6-membered heterocyclyloxy, C 6-10 aryl, 5-to 10-membered heteroaryl, and 3-to 10-membered heterocyclyl-C 1-6 alkyloxy, for example, the following groups unsubstituted or optionally substituted with 1, 2 or more R b1 : methyl, ethyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, phenyl, furanyl, and
  • B is selected from the following groups without further substitution or further substituted with 1, 2 or more R b1 :
  • n is selected from 0, 1, or 2, for example, 0 or 1.
  • the compound represented by formula (I) has a structure represented by the following formula (II) :
  • A, B, Y, R 1 , R 2 , R 3 , R 4 , R 5 , L, and n are independently defined as described above.
  • the compound represented by formula (I) has a structure represented by the following formula (I-1) , (I-2) , (I-3) , (I-4) , (I-5) , (I-6) , (I-7) or (I-8) :
  • A, B, Y, R 1 , R 2 , R 3 , R 4 , R 5 , L, and n are defined as described above;
  • p is selected from 0, 1, 2, 3, 4, or 5;
  • q is selected from 0, 1, 2, or 3.
  • the compound represented by formula (I) has one of the structures shown below:
  • A, B, Y, R 1 , R 2 , R 3 , R 4 , R 5 , L, and n are independently defined as described above;
  • p is selected from 0, 1, 2, 3, 4, or 5;
  • q is selected from 0, 1, 2, or 3.
  • the compound represented by formula (I) has a structure represented by the following formula (IA-1) or (IA-2) :
  • R 1 , R 5 , R a , R b , L, n, p, and q are independently defined as described above.
  • the compound represented by formula (I) has a structure represented by the following formula (IIA-1) or (IIA-2) :
  • R 1 , R 5 , R a , R b , L, n, p, and q are independently defined as described above.
  • the compound represented by formula (I) has a structure represented by the following formula (IB-1) :
  • R 1 , R 5 , R b , L, and n are defined as described above.
  • the compound represented by formula (I) has a structure represented by the following formula (IIB-1) :
  • R 1 , R 5 , R b , L, and n are defined as described above.
  • the compound represented by formula (I) may have a structure selected from the following:
  • the isotopically labeled compound may be a deuterate of the compound described above.
  • the present disclosure further provides a preparation method for the compound represented by formula (I) , or the tautomer, the stereoisomer, the isotopically labeled compound, the hydrate, the solvate, the pharmaceutically acceptable salt or the prodrug thereof, wherein the preparation method comprises the following scheme 1 or scheme 2:
  • the scheme 1 comprises reacting compound 1 with compound 2 as follows to give the compound represented by formula (I) :
  • A, B, Y, R 1 , R 2 , R 3 , R 4 , R 5 , L, and n are defined as described above;
  • X is selected from a leaving group, for example, halogen.
  • those skilled in the art may also protect a functional group (e.g., hydroxyl and/or amino) of compound 1 using an appropriate protecting group (e.g., a hydroxyl protecting group and/or amino protecting group known in the art) , and then react compound 1 with compound 2, followed by removal of the protecting group.
  • an appropriate protecting group e.g., a hydroxyl protecting group and/or amino protecting group known in the art
  • Appropriate protecting groups may be those known to those skilled in the art, for example, C 1-10 alkyl and C 6-14 aryl C 1-10 alkyl-, and examples thereof may be tert-butyl, isopropyl, benzyl, tert-butoxycarbonyl (Boc) , 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc) , trifluoroacetyl, and the like.
  • Conditions for removing the protecting group are known to those skilled in the art, for example, the protecting group is removed under a hydrolytic condition.
  • the preparation method may be carried out in the presence of a solvent such as an organic solvent.
  • the organic solvent may be selected from at least one of the following: alcohols such as methanol, ethanol, isopropanol and n-butanol; ethers such as ethyl propyl ether, n-butyl ether, anisole, phenetole, cyclohexylmethyl ether, dimethyl ether, diethyl ether, dimethyl glycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n- butyl ether, diisobutyl ether, diisoamyl ether, dimethoxyethane, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, dichlorodiethyl ether, and poly
  • the preparation method for compound 1 comprises the following steps:
  • B, Y, R 1 , R 2 , R 3 , R 4 , R 5 , and n are defined as described above;
  • Z is selected from halogen, such as Cl;
  • PG is an appropriate amino protecting group, such as p-toluenesulfonyl;
  • those skilled in the art may also protect a functional group (e.g., hydroxyl) of compound 1a using an appropriate protecting group (e.g., a hydroxyl protecting group known in the art) , and then react compound 1a with compound 1b, followed by removal of the protecting group.
  • an appropriate protecting group e.g., a hydroxyl protecting group known in the art
  • the scheme 2 comprises reacting compound 3 with compound 1d as follows to give the compound represented by formula (I) :
  • A, B, Y, Z, L, R 1 , R 2 , R 3 , R 4 , R 5 , and n are defined as described above;
  • those skilled in the art may also protect a functional group (e.g., hydroxyl and/or amino) of compound 3 using an appropriate protecting group (e.g., a hydroxyl protecting group and/or amino protecting group known in the art) , and then react compound 3 with compound 1d, followed by removal of the protecting group.
  • an appropriate protecting group e.g., a hydroxyl protecting group and/or amino protecting group known in the art
  • a preparation method for compound 3 comprises the following step: reacting compound 1a with compound 3a to give compound 3:
  • A, B, Y, Z, L, R 1 , R 2 , R 3 , R 4 , R 5 , and n are defined as described above.
  • the present disclosure further provides any one of compounds 1, 2, 3, 1a and 1c described above.
  • the present disclosure further provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the compound represented by formula (I) , or the tautomer, the stereoisomer, the isotopically labeled compound, the hydrate, the solvate, the pharmaceutically acceptable salt or the prodrug thereof.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable auxiliary material.
  • the present disclosure further provides use of the compound represented by formula (I) , or the tautomer, the stereoisomer, the isotopically labeled compound, the hydrate, the solvate, the pharmaceutically acceptable salt or the prodrug thereof for the manufacturing of a medicament.
  • the pharmaceutical composition or the medicament is used for the treatment of a tumor such as cancer.
  • the cancer comprises: gastric cancer, bladder cancer, leukemia, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, external genitalia cancer, genitourinary cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, muscular tissue cancer, neck cancer, oral or nasal mucosa cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, splenic cancer, small intestine cancer, colorectal cancer, testicular cancer, and/or thyroid cancer.
  • the present disclosure further provides the compound represented by formula (I) , or the tautomer, the stereoisomer, the isotopically labeled compound, the hydrate, the solvate, the pharmaceutically acceptable salt or the prodrug thereof, or the pharmaceutical composition for use in the prevention and/or treatment of a tumor such as cancer.
  • the present disclosure further provides a method for preventing and/or treating a tumor such as cancer, comprising administering to a patient a therapeutically effective amount of at least one of the compound represented by formula (I) , or the tautomer, the stereoisomer, the isotopically labeled compound, the hydrate, the solvate, the pharmaceutically acceptable salt or the prodrug thereof, or the pharmaceutical composition.
  • the cancer comprises: gastric cancer, bladder cancer, leukemia, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, external genitalia cancer, genitourinary cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, muscular tissue cancer, neck cancer, oral or nasal mucosa cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, splenic cancer, small intestine cancer, colorectal cancer, testicular cancer, and/or thyroid cancer.
  • the treatment comprises inhibiting the proliferation of tumor cells and/or suppressing the volume of the tumor, for example, inhibiting the proliferation of cancer cells and/or suppressing the volume of a cancerous site.
  • the tumor or cancer may be a tumor or cancer that exhibits drug resistance to at least one known therapeutic agent.
  • the compound, or the tautomer, the stereoisomer, the isotopically labeled compound, the hydrate, the solvate, the pharmaceutically acceptable salt or the prodrug thereof disclosed herein may be used in combination with at least one additional therapeutic agent.
  • the pharmaceutical composition or medicament described above may comprise at least one additional therapeutic agent, or the compound, or the tautomer, the stereoisomer, the isotopically labeled compound, the hydrate, the solvate, the pharmaceutically acceptable salt or the prodrug thereof disclosed herein is used in combination with the compound of the present disclosure in the method for preventing and/or treating the tumor (e.g., cancer) .
  • the additional therapeutic agent is selected from a drug known for use in the tumor or cancer.
  • an example of the therapeutic agent may be apatinib.
  • the compound, or the tautomer, the stereoisomer, the isotopically labeled compound, the hydrate, the solvate, the pharmaceutically acceptable salt or the prodrug thereof disclosed herein may be combined or formulated with a suitable and pharmaceutically acceptable auxiliary material (such as a carrier, a diluent, or an excipient) , and may be formulated into a preparation in the form of a solid, a semisolid, a liquid or a gas, such as a tablet, a capsule, a powder, a granule, an ointment, a solution formulation, a suppository, an injection, an inhalant, a gel, a microsphere, and an aerosol.
  • a suitable and pharmaceutically acceptable auxiliary material such as a carrier, a diluent, or an excipient
  • the routes of administration include oral administration, intraperitoneal administration, transdermal administration, subcutaneous administration, intravenous or intramuscular injection, inhalation, topical administration, intralesional administration, infusion; liposome-mediated delivery; topical, intrathecal, gingival pocket, rectal, intrabronchial, nasal, transmucosal, intestinal, ocular or otic delivery, or any other methods known in the art, which can achieve the treatment of tumors.
  • the therapeutically effective amount or dose described herein will vary depending on several factors, including the chosen route of administration, the formula of the composition, the patient's response, the severity of the condition, the subject's body weight, and the judgment of the prescribing physician.
  • the therapeutically effective amount or dose is 1-200 mg/kg or 40-150 mg/kg, such as 50 mg/kg.
  • the dose may be increased or decreased over time, as needed for individual patients. In some cases, patients are initially given a low dose, which is then increased to an effective dose that the patients can tolerate. In addition, the patients may be given multiple doses over a defined period of time, particularly in time increments (e.g., daily, weekly, biweekly, monthly, quarterly, biyearly, or the like) .
  • a numerical range set forth in the description and claims shall be construed as at least including each specific integer value within the range.
  • the numerical range of “1-10” shall be construed as including each integer value in the numerical range “1-10” , i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
  • C 1-10 alkyl represents a linear or branched saturated hydrocarbyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.
  • the C 1-10 alkyl includes C 1-3 alkyl, C 1-6 alkyl, C 3-6 alkyl, and the like.
  • “C 1-10 alkyl” represents linear and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms
  • “C 1-8 alkyl” represents linear and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms
  • C 1-6 alkyl represents linear and branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms.
  • the alkyl is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3, 3-dimethylbutyl, 2, 2-dimethylbutyl, 1, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, 1, 2-dimethylbutyl, etc., or isomers thereof.
  • alkylidene means a divalent group formed from an alkane by removal of two hydrogen atoms.
  • C 2-10 alkenyl should be understood to preferably represent a linear or branched monovalent hydrocarbyl group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, more preferably “C 2-8 alkenyl” .
  • C 2-8 alkenyl should be understood to preferably represent a linear or branched monovalent hydrocarbyl group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, or 8 carbon atoms, for another example, having 2, 3, 4, 5, or 6 carbon atoms (i.e., C 2-6 alkenyl) or having 2 or 3 carbon atoms (i.e., C 2-3 alkenyl) .
  • alkenyl contains more than one double bond
  • the double bonds may be separated from one another or conjugated.
  • the alkenyl is, for example, ethenyl, allyl, (E) -2-methylethenyl, (Z) -2-methylethenyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-enyl, hex-5-enyl, (E) -hex-4-enyl, (Z) -hex-4-enyl, (E) - -enyl,
  • C 3-10 cycloalkyl represents a saturated monovalent monocyclic or bicyclic (such as fused, bridged or spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.
  • the C 3-10 cycloalkyl includes C 3-8 cycloalkyl, C 3-5 cycloalkyl, C 6-8 cycloalkyl, C 3-4 cycloalkyl, C 5-6 cycloalkyl, C 6 cycloalkyl, and the like.
  • the C 3-10 cycloalkyl may be monocyclic hydrocarbyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic hydrocarbyl such as bornyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, 6, 6-dimethylbicyclo [3.1.1] heptyl, 2, 6, 6-trimethylbicyclo [3.1.1] heptyl, bicyclo [2.2.2] octyl, 2, 7-diazaspiro [3, 5] nonyl, 2, 6-diazaspiro [
  • 3-to 10-membered heterocyclyl refers to a saturated or unsaturated non-aromatic ring or ring system and contains at least one heteroatom selected from O, S, and N.
  • the heterocyclyl may be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present) .
  • the heterocyclyl may include fused or bridged rings as well as spiro rings.
  • the heterocyclyl may include, but is not limited to: 4-membered rings such as azetidinyl and oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, and pyrrolinyl; 6-membered rings such as tetrahydropyranyl, piperidyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, and trithianyl; or 7-membered rings such as diazepanyl.
  • the heterocyclyl may be benzo-fused.
  • the heterocyclyl may be bicyclic, for example, but not limited to, a 5, 5-membered ring such as a hexahydrocyclopenta [c] pyrrol-2 (1H) -yl ring, or a 5, 6-membered bicyclic ring such as a hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl ring.
  • the heterocyclyl may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, dihydrofuranyl, dihydropyranyl, 2, 5-dihydro-1H-pyrrolyl, 4H- [1, 3, 4] thiadiazinyl, 1, 2, 3, 5-tetrahydrooxazolyl, or 4H- [1, 4] thiazinyl, or it may be benzo-fused, for example, but not limited to, dihydroisoquinolyl.
  • the group may be connected to the carbon atom on the 3-to 10- membered heterocyclyl, or may be connected to the heteroatom (e.g., N atom) on the 3-to 10-membered heterocyclyl.
  • the group may be connected to the nitrogen atom or carbon atom on the piperazinyl.
  • the group may be connected to the nitrogen atom on the piperidyl ring or the carbon atom at the ortho-, meta-or para-position.
  • C 6-14 aryl should be understood to preferably represent an aromatic or partially aromatic monovalent monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ( “C 6-14 aryl” ) , in particular a ring having 6 carbon atoms ( “C 6 aryl” ) , such as phenyl or biphenyl, a ring having 9 carbon atoms ( “C 9 aryl” ) , such as indanyl or indenyl, a ring having 10 carbon atoms ( “C 10 aryl” ) , such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, a ring having 13 carbon atoms ( “C 13 aryl” ) , such as fluorenyl, or a ring having 14 carbon atoms ( “C 14 aryl” ) , such as anthryl.
  • C 6-20 a
  • 5-to 14-membered heteroaryl represents a monovalent or polyvalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, wherein the ring atoms comprise 1-5 heteroatoms independently selected from N, O and S, and the bicyclic and tricyclic aromatic ring systems may be fused, spiro, or bridged rings.
  • the number of heteroatoms in the 5-to 14-membered heteroaryl is 1-5, preferably 1-3.
  • the 5-to 14-membered heteroaryl in each case may be benzo-fused.
  • the 5-to 14-membered heteroaryl includes 5-to 8-membered heteroaryl, 5-to 9-membered heteroaryl, 5-to 10-membered heteroaryl, 5-to 6-membered heteroaryl, 8-to 10-membered heteroaryl, 6-membered heteroaryl, and the like.
  • the heteroaryl include, but are not limited to: 5-membered rings such as oxazolyl, pyrazolyl, thienyl, thiazolyl, triazole, imidazolyl and the like; and 6-membered rings such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and the like.
  • the heterocyclyl may be bicyclic, including but not limited to: 5, 5-membered rings such as tetrahydrocyclopentapyrazole; 5, 6-membered rings such as tetrahydroindole, tetrahydropyrazolopyridine, tetrahydroimidazopyridine, tetrahydrobenzisoxazole, tetrahydrobenzoxazole, tetrahydrobenzothiazole, tetrahydrobenzisothiazole, dihydrofuropyrazole, tetrahydrobenzofuran, dihydrobenzofuran and tetrahydrobenzothiophene; 6, 6-membered rings such as tetrahydroquinoline; and 5, 7-membered rings such as tetrahydrocycloheptathiazole and tetrahydrocycloheptafuran.
  • 5-membered rings such as tetrahydrocyclopentapyrazole
  • the heterocyclyl may be tricyclic, including but not limited to: 6, 7-dihydrospiro [cyclopropane-1, 5-pyrrolo [1, 2-c] imidazole] .
  • the 5-to 14-membered heteroaryl When the 5-to 14-membered heteroaryl is substituted, it may be monosubstituted or polysubstituted.
  • the substitution site is not limited. For example, hydrogen connected to the carbon atom on the heteroaryl ring may be substituted, or hydrogen connected to the heteroatom on the heteroaryl ring may be substituted.
  • spiro rings refers to a ring system in which two rings share 1 ring-forming atom.
  • fused rings refers to a ring system in which two rings share 2 ring-forming atoms.
  • bridged rings refers to a ring system in which two rings share more than 3 ring-forming atoms.
  • halogen represents fluorine, chlorine, bromine, or iodine.
  • Halo refers to substitution with one or more halogens.
  • C 1-10 haloalkyl refers to an alkyl group as defined above which is substituted with one or more halogens as defined above.
  • the haloalkyl includes, but is not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 2, 2-difluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
  • C 1-10 alkyl also applies to the definitions of C 1-10 alkyloxy, C 1-10 alkylthio, C 1-10 alkylamino, C 1-10 alkylcarbonyl, and other groups containing C 1-10 alkyl.
  • solvate refers to an association of one or more molecules of the compound of the present disclosure with one or more molecules of a solvent.
  • the solvent may be water, in which case the solvate is a hydrate.
  • the solvent may also be an organic solvent.
  • the compound of the present disclosure may exist as a hydrate, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like, as well as corresponding solvated forms.
  • the compound of the present disclosure may be a true solvate, but in other cases, the compound of the present disclosure may only occasionally retain water or mixtures of water with some other solvents.
  • the compound of the present disclosure may be reacted in one solvent or precipitated or crystallized in one solvent. Solvates of the compound of the present disclosure are also included within the scope of the present disclosure.
  • pharmaceutically acceptable refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compound of the present disclosure and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an undesirable manner with any of the components contained in the composition.
  • the compounds disclosed herein may be present in the form of various pharmaceutically acceptable salts. If such compounds have basic centers, they can form acid addition salts; if such compounds have acidic centers, they can form base addition salts; if these compounds comprise both acidic centers (e.g., carboxyl) and basic centers (e.g., amino) , they can also form internal salts.
  • tautomer refers to functional isomers resulting from the rapid movement of an atom in a molecule between two positions.
  • the compounds disclosed herein may exhibit the tautomerism.
  • Tautomeric compounds may be present in two or more interconvertible forms.
  • Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
  • Tautomers are generally present in an equilibrium form. Efforts to separate a single tautomer usually lead to a mixture, the physicochemical properties of which are consistent with the mixture of the compound. The position of the equilibrium depends on the chemical properties of the molecule.
  • keto form predominates
  • enol form predominates
  • all tautomeric forms of the compounds are included.
  • the compounds of the present disclosure may be chiral and may therefore be present in various enantiomeric forms. These compounds may therefore be present in a racemic or optically active form.
  • the compounds of the present disclosure encompass isomers with each chiral carbon in R or S configuration, or mixtures and racemates thereof.
  • the compounds of the present disclosure or intermediates thereof may be separated into enantiomers by chemical or physical methods well known to those skilled in the art, or used in such form for synthesis. In the case of racemic amines, diastereoisomers are prepared from mixtures by reaction with optically active resolving agents.
  • suitable resolving agents are optically active acids such as R-or S-tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline) , or various optically active camphorsulfonic acids.
  • optically active resolving agents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel.
  • Suitable eluents for this purpose are mixtures of solvents containing water or alcohol, for example, hexane/isopropanol/acetonitrile.
  • “pharmaceutical composition” refers to a preparation of the compound disclosed herein with a medium generally accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human) .
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and exert biological activity.
  • auxiliary material includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is approved by the relevant governmental regulatory agency for human or livestock use.
  • solvate means that the compound disclosed herein or a salt thereof comprises a stoichiometric or non-stoichiometric amount of a solvent bonded by non-covalent intermolecular forces, and when the solvent is water, the solvate is a hydrate.
  • prodrug can be converted to the compound disclosed herein with biological activity under physiological conditions or by solvolysis.
  • the prodrug disclosed herein is prepared by modifying a functional group in the compound, wherein the modification may be removed by conventional operation or be removed in vivo to give the parent compound.
  • the prodrug includes a compound formed by connecting a hydroxyl or amino group of the compound disclosed herein to any group. When the prodrug of the compound disclosed herein is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group.
  • isotope means all isotopes of atoms occurring in the compounds of the present disclosure. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of the isotopes suitable for incorporation into the compound of the present disclosure are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 31 P, 32 P, 35 S, 18 F and 36 C1, respectively.
  • the isotopically-labeled compound of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described in the accompanying examples using an appropriate isotopically labeled reagent in place of a non-isotopically labeled reagent.
  • Such a compound has a variety of potential uses, for example, as a standard sample and reagent in the determination of biological activity. In the case of a stable isotope, this compound has the potential to favorably modify biological, pharmacological or pharmacokinetic properties.
  • tumor includes both benign tumors and malignant tumors (e.g., cancers) .
  • treatment and other similar synonyms as used herein include the following meanings:
  • patient refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans.
  • terapéuticaally effective amount refers to the amount of the active compound or drug that causes a biological or medical response that researchers, veterinarians, physicians or other clinicians are looking for in tissues, systems, animals, individuals or humans, including one or more of the following effects: (1) disease prevention: for example, the prevention of a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or exhibited the pathology or symptoms of the disease; (2) disease inhibition: for example, the inhibition of a disease, disorder or condition in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, disorder or condition (i.e., the prevention of the further development of the pathology and/or symptoms) ; and (3) disease alleviation: for example, the alleviation of a disease, disorder or condition in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, disorder or condition (i.e., the reverse of the pathology and/or symptoms) .
  • disease prevention for example, the prevention of a disease, disorder or condition in an individual who is
  • the compound, or the tautomer, the stereoisomer, the hydrate, the solvate, the pharmaceutically acceptable salt or the prodrug thereof disclosed herein has an excellent tumor inhibitory effect and can be used for preventing and/or treating a cancer.
  • the compound disclosed herein not only has a novel structure and excellent tumor inhibitory activity different from those of known anti-cancer drugs, but also can achieve excellent synergistic effects when used in combination with a known anti-cancer drug.
  • the preparation method for the compound disclosed herein is simple and convenient, thus being suitable for large-scale production.
  • Step 1 Into a solution of compound 1 (33 g) in CH 3 CN (350 mL) was added Ac 2 O (58.35 mL, 621.26 mmol, 8 eq) , pyridine (49.99 mL) and DMAP (0.95 g) . The reaction mixture was then stirred for 16 h at 25 °C under N 2 . LCMS showed the reaction was complete. The solution was concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with PE/EtOAc (5/1) to give compound 2 (36 g) as a white solid.
  • Step 2 Into a solution of the compound 2 (36 g) in DCM (1000 mL) , 1, 4-dioxane (500 mL) and H 2 O (125 mL) was added DDQ (148.30 g) in portions at 0 °C. The reaction mixture is then stirred at 25 °C for 16 h under N 2 . LCMS showed the reaction was complete. Then DMAP (128.50 g) was added into the solution to quench the excessive DDQ at 0 °C. The solution was stirred at 0 °C for 1 h. The mixture was filtered through a Celite pad, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with PE/EtOAc (3/1) to give compound 3 (28 g) as a white solid.
  • Step 3 Into a solution of the compound 3 (28 g) in EtOH (500 mL) and H 2 O (50 mL) was added 4-methylbenzenesulfonohydrazide (27.69 g) and H 2 SO 4 (1.34 mL) . The reaction mixture was then heated at 80 °C for 24 h under N 2 . LCMS showed the reaction was complete. The precipitate was filtered and dried in vacuo to give crude compound 4 (38 g) as yellow oil, which was used for next step without further purification.
  • Step 4 Into a solution of the compound 4 (14 g) in MeOH (120 mL) was added a solution of LiOH (8.01 g) in H 2 O (30 mL) . The reaction mixture was then heated at 30 °C for 2 h. LCMS showed the reaction was complete. The mixture was adjusted to pH 7 with HCl (4 mol/L) , then CH 3 OH was removed. The aqueous layer was extracted with ethyl acetate (100 mL ⁇ 3) and the organic layer was washed with saline. The organic layer was evaporated to afford the crude product, which was purified by column chromatography on silica gel eluted with PE/EtOAc (1: 4) to give compound 2A (8 g) as a white solid..
  • Step 2 To a solution of compound 2 (4.76 g) in refresh distilled THF (30.0 mL) and dry toluene (15.0 mL) was added 1.6 M butyllithium (11.63 mL) at -65 °C over 20 mins. The mixture was stirred at this temperature for 1h. Then a solution of compound 3 (7.22 g) in THF (15.0 mL) was added dropwise. The resulted solution was stirred for another 2 h. The reaction was successful and confirmed by LCMS. The mixture was quenched by sat. NH 4 Cl (150 mL) , extracted with EtOAc (150 mL x 3) . The organic layer was washed with sat.
  • Step 3 To a mixture solution of compound 3 (5 g) in MeOH (75 mL) was added CeCl 3 ⁇ 7H 2 O (2.45 g) and NaBH 4 (1.51 g) at -0°C. The reaction reacted at 25 °C for 30 min. Target product was detected by LCMS. The reaction mixture was diluted with ice water (150 mL) . MeOH was concentrated under reduced pressure. The resulting mixture was partitioned between EA (150 mL) and water (100 mL) . The aqueous layer was extracted again with EA (150 mL*3) .
  • Step 5 To a solution of compound 5 (7.18 g) in ACN (100 mL) was added Ac 2 O (20.28 mL) , pyridine (17.36 mL) and DMAP (0.33 g) . The reaction mixture was then stirred for 16 h at 25 °C. The mixture was quenched by H 2 O (200 mL) , extracted with EtOAc (150 mL x 3) , the organic layer was washed with sat.
  • Step 8 To a mixture solution of compound 7 (1.6 g) in DMF (16 mL) was added NIS (1.28 g) . Under N 2 atmosphere, the reaction mixture was then stirred for 3 h at 25°C. Target product was detected by LCMS. The mixture was quenched by sat. Na 2 S 2 O 3 (100 mL) , extracted with EtOAc (100 mL x 3) . The organic layer was washed with sat.
  • INT9 900 mg
  • iodobenzene 529.65 mg
  • CuI 20.7 mg
  • K 2 CO 3 597.11 mg
  • N 1 , N 2 -dimethylcyclohexane-1, 2-diamine 61.60 mg
  • DMF 8.0 mL
  • the resulting solution was stirred for 3 h at 110°C.
  • LCMS showed INT9 was consumed and target product was observed.
  • the resulting solution was diluted with 60 mL of water, then extracted with 2 x 60 mL of ethyl acetate.
  • Step 1 The solution of 1 (300 mg) , 2 (138 mg) in H 2 SO 4 (1 mL) and EtOH (3 mL) was stirred at 100 °C for 48 hours under N 2 . LCMS showed 1 was consumed and 21%of target mass was observed. Concentrated under vacuum to give the crude product (270 mg) .
  • Step 2 To a solution of 3 (270 mg) in MeOH (5 mL) and H 2 O (1 mL) was added LiOH (0.19 g) at room temperature. The mixture was reacted at room temperature for 2 hours. The mixture was purified by Prep-HPLC to afford the desired product (180 mg, 80%yield) as a white solid.
  • Step 3 To a solution of 4 (180 mg) in DMA (2 mL) was added dimethylglycine (43.3 mg) , CuI (23.9 mg) and Cs 2 CO 3 (292.5 mg) at room temperature. The mixture was reacted at 130 °C under N 2 for 2 hours. The mixture was purified by Prep-HPLC to afford the desired product (10.14 mg) as a white solid.
  • Step 2 Into a 25-mL round-bottom flask was placed INT9 (120 mg) , the compound 2 (85.5 mg) obtained in Step 1, Cs 2 CO 3 (188 mg) and DMF (2 mL) . The resulting solution was stirred for 5 h at 30 °C. The reaction was successful and confirmed by LCMS. The mixture was filtered to give crude product, which was purified by Prep-HPLC to afford the mixture of diastereoisomers (100 mg) . The diastereoisomers was purified by SFC to afford a single unknown stereoisomer peak 1 (454, 25.81 mg, 100%de) and peak 2 (455, 22.53 mg, 98.6%de) both as white solid.
  • Step 1 Into a 50-mL microwave tube purged and maintained with an inert atmosphere of nitrogen was placed compound 1 (2 g) and THF (10 mL) , EtMgBr (29 mL) was added at 0 °C. The resulting solution was stirred for 4 h at room temperature. Target product generation was detected by NMR detection. The reaction mixture was quenched by the H 2 O. Then mixture was extracted with ethyl acetate (20 mL ⁇ 3) . The Organic layer was evaporated to afford compound 2 (1.8 g) .
  • Step 2 Into a 50-mL microwave tube purged and maintained with an inert atmosphere of nitrogen was placed the compound 2 (1.6 g) and DCM (10 mL) . PBr 3 (2.9 g) was added at 0 °C. The resulting solution was stirred for 16 h at room temperature. Target product was detected by NMR detection. The reaction mixture was quenched by the H 2 O, extracted with ethyl acetate (20 mL ⁇ 3) . The Organic layer was evaporated to afford Compound 3 (1.6 g) .
  • Step 3 Into a 10-mL microwave tube purged and maintained with an inert atmosphere of nitrogen was placed INT9 (100 mg) , the compound 3 (61 mg) , Cs 2 CO 3 (164 mg) and DMF (1 mL) . The resulting solution was stirred for 30 °C for 3 h. LCMS showed INT9 was consumed and target product was observed. The mixture was filtered to give crude product, which was purified by Prep-HPLC to afford the mixture of diastereoisomers (42 mg) , which was further purified by SFC to give to afford unknown stereoisomer peak 1 (466) (13.33 mg, 100%de) and peak 2 (467) (9.09 mg, 100%de) both as white solid.
  • Step 1 Into a 25-Ml round-bottom flask was placed 3-iodoaniline (1000 mg) in DMF (3 Ml) being cooled to 0 °C was added the NaH (913 mg, 60%dispersion in mineral oil) . The above mixture was stirred for 0.5 hour at 0 °C. CH 3 CH 2 I (3560.63 mg) was added via microsyringe to the above mixture. The temperature was increased to room temperature naturally. The reaction mixture for 0.5 h at 25°C. The reaction was successful and confirmed by LCMS. The reaction was quenched by saturated NH 4 Cl in water and was taken up in EtOAc (30 Ml) and washed with water (20 Ml x 3) and brine (25 Ml x 2) .
  • Step 2 Into a 10-Ml microwave tube purged and maintained with an inert atmosphere of nitrogen was placed INT9 (50 mg) , N, N-diethyl-3-iodoaniline (39.67 mg) , CuI (1.15 mg) , K 2 CO 3 (34.85 mg) , N 1 , N 2 -dimethylcyclohexane-1, 2-diamine (3.375 mg) and DMF (1.0 Ml) . The resulting solution was stirred for 3 h at 110 °C. LCMS showed INT9 was consumed and target mass was observed. The mixture was filtered to give crude product, which was purified by Prep-HPLC to afford the desired product (23.21 mg) as a white solid.
  • Step 2 Into a 10-Ml microwave tube purged and maintained with an inert atmosphere of nitrogen was placed INT9 (100 mg) , 1- (1-bromoethyl) -4-methylbenzene (57.4 mg) , and Cs 2 CO 3 (164.21 mg) in DMF (0.5 Ml) . The resulting solution was stirred for 3 h at 30 °C. LCMS showed INT9 was consumed and target mass was observed. The mixture was filtered to give crude product, which was purified by Prep-HPLC to afford the mixture of diastereoisomers (about 50 mg) .
  • Step 1 Into a 25-mL round-bottom flask were placed 1- (3, 5-difluorophenyl) ethan-1-one (1 g) , EtOH (10 mL) and NaBH 4 (606 mg) . The resulting solution was stirred for 12 h at 25 °C. A new point was detected in TLC. The reaction was then quenched by the addition of 50 mL of saturated aqueous NH 4 Cl, extracted with 3x40 mL of ethyl acetate. The organic layers were combined, washed with brine, dried and concentrated under vacuum to give crude product (1 g) as a colorless oil, which was used for next step directly.
  • Step 2 Into a 25-mL round-bottom flask were placed 1- (3, 5-difluorophenyl) ethan-1-ol (0.7 g) , DCM (5 mL) and PBr 3 (1.34 g) . The resulting solution was stirred for 12 h at 25 °C. A new point was detected in TLC. The reaction was then quenched by the addition of 50 mL of H 2 O, extracted with 2x40 mL of DCM. The organic layers were combined, washed with brine, dried and concentrated under vacuum to give crude product (0.6 g) as a colorless oil, which was used for next step directly.
  • Step 3 Into a 25-mL round-bottom flask were placed INT9 (140 mg) , 1- (1-bromoethyl) -3, 5-difluorobenzene (148 mg) , Cs 2 CO 3 (220 mg) and DMF (3mL) . The resulting solution was stirred for 3 h at 30 °C. The reaction was successful and confirmed by LCMS. The mixture was filtered to give crude product, which was purified by Prep-HPLC to afford the mixture of diastereoisomers (60 mg) .
  • Step 4 The mixture was purified by SFC to afford unknown stereoisomer peak 1 (479, 10.71 mg, 100%de) and peak 2 (478, 1.49 mg, 99.2 de) both as white solid.
  • Step 1 Into a 25-mL round-bottom flask was placed 1-phenylbutan-1-one (1 g) , EtOH (10 mL) and NaBH 4 (642 mg) . The resulting solution was stirred for 12 h at 25 °C. A new point was detected in TLC. The reaction was then quenched by the addition of 50 mL of saturated aqueous NH 4 Cl, extracted with 3x40 mL of ethyl acetate. The organic layers were combined, washed with brine, dried and concentrated under vacuum to give crude product (1 g) as a colorless oil, which was used for next step directly.
  • Step 2 Into a 25-mL round-bottom flask were placed 1-phenylbutan-1-ol (1 g) , DCM (5 mL) and PBr 3 (2.68 g) . The resulting solution was stirred for 12 h at 25 °C. A new point was detected in TLC. The reaction was then quenched by the addition of 50 mL of H 2 O, extracted with 2x40 mL of DCM. The organic layers were combined, washed with brine, dried and concentrated under vacuum to give crude product (1 g) as a colorless oil, which was used for next step directly.
  • Step 3 Into a 25-mL round-bottom flask was placed INT9 (100 mg) , (1-bromobutyl) benzene (102 mg) , Cs 2 CO 3 (156.7 mg) and DMF (3 mL) . The resulting solution was stirred for 3 h at 30 °C. The reaction was successful and confirmed by LCMS. The mixture was filtered to give crude product, which was purified by Prep-HPLC to afford the desired compound 480 (21.21 mg) as a white solid.
  • Step 1 Into a 25-mL round-bottom flask was placed 2-methyl-1-phenylpropan-1-one (1000 mg) , EtOH (10 mL) and NaBH 4 (641.7 mg) . The resulting solution was stirred for 12 h at 25 °C. A new point was detected in TLC. The reaction was then quenched by the addition of 80 mL of saturated aqueous NH 4 Cl. The resulting solution was extracted with 2x80 mL of ethyl acetate. The organic layers were combined, washed with brine, dried and concentrated under vacuum. The residue was applied on a silica gel column and eluted with PE/EA (10/1) to give the desired product (860 mg) as a colorless oil.
  • PE/EA PE/EA
  • Step 2 Into a 25-mL round-bottom flask was placed 2-methyl-1-phenylpropan-1-ol (860 mg) , DCM (5 mL) and PBr 3 (3.87 g) . The resulting solution was stirred for 2 h at 25 °C. A new point was detected in TLC. The reaction was concentrated under vacuum to give crude product (800 mg) as a colorless oil, which was used for next step directly.
  • Step 3 Into a 25-mL round-bottom flask was placed INT9 (50 mg) , (1-bromo-2-methylpropyl) benzene (30.6 mg) , Cs 2 CO 3 (78.3 mg) and DMF (2 mL) . The resulting solution was stirred for 3 h at 80 °C. The reaction was successful and confirmed by LCMS. The mixture was filtered to give crude product, which was purified by Prep-HPLC to afford the desired compound 483 (17.66 mg) as a green solid.
  • Step 1 Into a 10-mL microwave tube purged and maintained with an inert atmosphere of nitrogen was placed INT11 (720 mg) , 2- (5- (4-fluorophenyl) thiophen-2-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (1.2 g) , Pd (PPh 3 ) 2 Cl 2 (93 mg) , Na 2 CO 3 (279 mg) , THF (12 mL) and H 2 O (2.4 mL) . The resulting solution was stirred for 3 h at 100 °C. LCMS showed INT11 was consumed and target product was observed.
  • Step 2 Into a 10-mL microwave tube purged and maintained with an inert atmosphere of nitrogen was placed 1 (50 mg) , 1-iodo-4- (trifluoromethoxy) benzene (28 mg) , CuI (0.79 mg) , K 2 CO 3 (23 mg) , N 1 , N 2 -dimethylcyclohexane-1, 2-diamine (2.3 mg) and DMF (2 mL) . The resulting solution was stirred for 3 h at 110 °C. LCMS showed 1 was consumed and target product was observed. The reaction mixture was quenched by the H 2 O. Then mixture was extracted with ethyl acetate (20 mL ⁇ 3) . The Organic layer was evaporated to afford compound 2 (63 mg, crude) as a yellow solid.
  • Step 3 Into a 10-mL microwave tube purged was placed 2 (63 mg) , LiOH (35 mg) , CH 3 OH (4 mL) and H 2 O (0.8 mL) . The resulting solution was stirred for 1 h at 30 °C. LCMS showed 2 was consumed and target product was observed. The mixture was filtered to give crude product, which was purified by Prep-HPLC to afford the desired product (12.01 mg) as a white solid.
  • Step 1 Into a 10-mL microwave tube purged and maintained with an inert atmosphere of nitrogen was placed 1 (40 mg) , 1-chloro-4-iodobenzene (19.1 mg) , CuI (0.64 mg) , K 2 CO 3 (18.46 mg) , N 1 , N 2 -dimethylcyclohexane-1, 2-diamine (2 mg) and DMF (1 mL) . The resulting solution was stirred for 3 h at 110 °C. LCMS showed 1 was consumed and target product was observed. The resulting solution was diluted with 30 mL of water, then extracted with 2x30 mL of ethyl acetate. The organic layers were combined, washed with brine, dried and concentrated under vacuum to give the crude compound 2 (40 mg) as a brown oil.
  • Step 2 Into a 10-mL microwave tube was placed the crude compound 2 (40 mg) , LiOH (23.5 mg) , CH 3 OH (4 mL) and H 2 O (0.8 mL) . The resulting solution was stirred for 1 h at 30 °C. LCMS showed 2 was consumed and target product was observed. The mixture was filtered to give crude product, which was purified by Prep-HPLC to afford the desired compound 502 (2.38 mg) as a white solid.
  • Step 1 Into a 100-mL microwave tube purged and maintained with an inert atmosphere of nitrogen was placed compound 1 (8.8 g) , furan-2-ylboronic acid (8.25 g) , Pd (PPh 3 ) 2 Cl 2 (3.44 g) , Na 2 CO 3 (10.42 g) , THF (40 mL) and H 2 O (8 mL) . The resulting solution was stirred for 3 h at 100 °C. LCMS showed the compound 1 was consumed and target product was observed. The resulting solution was extracted with ethyl acetate (100 mL ⁇ 3) and the organic layer was washed with saline. The organic layer was evaporated to afford the crude product, which was purified by reverse column chromatography eluted with CH 3 CN/H 2 O (10: 90) to give compound 2 (700 mg) as a yellow solid.
  • Step 2 Into a 25-mL microwave tube purged and maintained with an inert atmosphere of nitrogen was placed the compound 2 (200 mg) , t-BuONO (199 mg) , CuBr 2 (135 mg) and CH 3 CN (5 mL) . The resulting solution was stirred for 3 h at 0 °C. LCMS showed the compound 2 was consumed and target product was observed. The resulting solution was extracted with ethyl acetate (100 mL ⁇ 3) and the organic layer was washed with saline. The organic layer was evaporated to afford the crude product, which was purified by column chromatography on silica gel eluted with PE/EA (50: 1) to give compound 3 (100 mg) as a yellow solid.
  • Step 3 The reaction mixture of Zn (92 mg) and I 2 (9 mg) in DMA (1 mL) was stirred at 25 °C for 5 mins, then the compound 3 (80 mg) was added. The reaction mixture was then stirred at 25 °C for 30 mins to give compound 4. The product had no further operation and was used into next step directly.
  • Step 4 Into a 10-mL microwave tube purged and maintained with an inert atmosphere of nitrogen was placed INT9 (96 mg) , the compound 4 (3 eq) , Pd (dppf) 2 Cl 2 (13 mg) , CuI (3.3 mg) and DMA (1 mL) . The resulting solution was stirred for 3 h at 110 °C. LCMS showed INT11 was consumed and target product was observed. The resulting solution was extracted with ethyl acetate (10 mL ⁇ 3) and the organic layer was washed with saline. The organic layer was evaporated to afford the crude product, which was purified by Prep-HPLC to afford the desired product 5 (27 mg) as a white solid.
  • Step 5 Into a 10-mL microwave tube purged and maintained with an inert atmosphere of nitrogen was placed 5 (25 mg) , iodobenzene (11 mg) , CuI (0.41 mg) , K 2 CO 3 (12 mg) , N 1 , N 2 -dimethylcyclohexane-1, 2-diamine (1.24 mg) and DMF (1 mL) . The resulting solution was stirred for 3 h at 110 °C. LCMS showed 5 was consumed and target product was observed. The reaction mixture was quenched by the H 2 O. Then mixture was extracted with ethyl acetate (20 mL ⁇ 3) . The Organic layer was evaporated to afford compound 6 (28 mg, crude) as a yellow solid.
  • Step 6 Into a 10-mL microwave tube purged was placed 6 (28 mg) , LiOH (19 mg) , CH 3 OH (4 mL) and H 2 O (0.8 mL) . The resulting solution was stirred for 1 h at 30 °C. LCMS showed 6 was consumed and target product was observed. The mixture was filtered to give crude product, which was purified by Prep-HPLC to afford the desired compound 497 (1.12 mg) as a white solid.
  • test compounds with different concentrations were separately used to act on the tumor cells described above for 48 h, and the tumor growth inhibition rate was detected by the MTT method, so that the degree of inhibition of the compounds on different tumor cells was detected.
  • a and the compounds disclosed herein were each dissolved in a certain volume of DMSO to prepare a mother liquor with a concentration of 20 mmol/L.
  • the mother liquor was stored at -20 °C, and when in use, the mother liquor was taken and diluted into a solution with a certain dilution factor.
  • the tumor cells described above in the logarithmic growth phase were taken, centrifuged, and resuspended, and the cell suspension density was adjusted to 4 ⁇ 10 4 cells/mL.
  • the cell suspension was then added into a 96-well culture plate at 100 ⁇ L/well, and the cells were incubated in a cell incubator at 37 °C with 5%CO 2 for conventional culture.
  • Monotherapy 071 preparation A DMEM complete medium (containing 10%FBS and 1%anti-anti) was added into five 1.5 mL centrifuge tubes at 1 mL/tube, and 2.5 ⁇ L, 2 ⁇ L, 1.5 ⁇ L, 1 ⁇ L and 0.5 ⁇ L of 071 at a concentration of 20 mmol/L were added to the five tubes, respectively.
  • the drug mixtures at different concentrations were separately added into the wells of experimental groups at 160 ⁇ L/well.
  • the final concentrations of 071 were 0.625 ⁇ mol/L, 1.25 ⁇ mol/L, 2.5 ⁇ mol/L, 5 ⁇ mol/L, 10 ⁇ mol/L, 20 ⁇ mol/L, 30 ⁇ mol/L, 40 ⁇ mol/L and 50 ⁇ mol/L, with 4 replicate wells set for each concentration.
  • 071 + A preparation All the samples were prepared according to the monotherapy 071 preparation, with each tube only containing 1 mL of drug mixture. 0.5 ⁇ L of A at a concentration of 20 mmol/L was added into each tube, and the final concentration of A was 10 ⁇ mol/L. Meanwhile, a blank group (only containing the culture medium without the addition of the cell suspension) and a negative control group (only containing the cell suspension) were set.
  • Inhibition rate (%) (OD value of cell control well -OD value of administration well) / (OD value of cell control well -OD value of blank well) ⁇ 100%
  • IC 50 half maximal inhibitory concentration
  • A represents apatinib.
  • the compound number represents the compound having the number disclosed above.
  • “351” represents compound 351 disclosed herein.

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Abstract

La présente invention concerne un composé représenté par la formule suivante (I), ou un tautomère, un stéréoisomère, un composé marqué isotopiquement, un hydrate, un solvate, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci. Le composé selon l'invention présente non seulement une nouvelle structure et une excellente activité inhibitrice de tumeur différentes de celles des médicaments anticancéreux connus, mais peut également assurer d'excellents effets synergiques lorsqu'il est utilisé en combinaison avec un médicament anticancéreux connu.
PCT/CN2024/075342 2024-02-01 2024-02-01 Composé indazole et composition pharmaceutique, son procédé de préparation et son utilisation Pending WO2025160910A1 (fr)

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PCT/CN2025/075387 WO2025162427A1 (fr) 2024-02-01 2025-01-27 Composé indazole et composition pharmaceutique, son procédé de préparation et son utilisation

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WO2003099836A1 (fr) * 2002-05-20 2003-12-04 Bristol-Myers Squibb Company C-aryl glucosides en tant qu'inhibiteurs de sglt-2 et methode correspondante
WO2008042688A2 (fr) * 2006-09-29 2008-04-10 Lexicon Pharmaceuticals, Inc. Inhibiteurs de co-transporteur 2 de sodium glucose et procédés d'utilisation de ceux-ci
WO2008109591A1 (fr) * 2007-03-08 2008-09-12 Lexicon Pharmaceuticals, Inc. Analogues de phlorizine utilisés comme inhibiteurs du co-transporteur 2 du sodium-glucose
WO2009014970A1 (fr) * 2007-07-26 2009-01-29 Lexicon Pharmaceuticals, Inc. Procédés et composés utiles pour la préparation d'inhibiteurs de co-transporteur 2 de sodium-glucose
WO2012078777A1 (fr) * 2010-12-09 2012-06-14 Amgen Inc. Composés bicycliques en tant qu'inhibiteurs de pim
WO2022007134A1 (fr) * 2020-07-06 2022-01-13 诺未科技（北京）有限公司 Utilisation d'un composé ou d'un sel pharmaceutiquement acceptable, dimère ou trimère de celui-ci dans la préparation d'un médicament pour le traitement du cancer

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EP2514756B1 (fr) * 2003-08-01 2014-12-17 Mitsubishi Tanabe Pharma Corporation Nouveaux composés présentant une activité inhibitrice contre le transporteur dépendant du sodium
DE102008017590A1 (de) * 2008-04-07 2009-10-08 Merck Patent Gmbh Glucopyranosidderivate
WO2011107494A1 (fr) * 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
CN115677662A (zh) * 2021-07-28 2023-02-03 江苏恒瑞医药股份有限公司 吲唑类化合物、其制备方法及其在医药上的应用
CN115613060B (zh) * 2022-11-11 2025-06-27 浙江工业大学 一种直接电化学氧化合成c-3磷酸化2h-吲唑类化合物的方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003099836A1 (fr) * 2002-05-20 2003-12-04 Bristol-Myers Squibb Company C-aryl glucosides en tant qu'inhibiteurs de sglt-2 et methode correspondante
WO2008042688A2 (fr) * 2006-09-29 2008-04-10 Lexicon Pharmaceuticals, Inc. Inhibiteurs de co-transporteur 2 de sodium glucose et procédés d'utilisation de ceux-ci
WO2008109591A1 (fr) * 2007-03-08 2008-09-12 Lexicon Pharmaceuticals, Inc. Analogues de phlorizine utilisés comme inhibiteurs du co-transporteur 2 du sodium-glucose
WO2009014970A1 (fr) * 2007-07-26 2009-01-29 Lexicon Pharmaceuticals, Inc. Procédés et composés utiles pour la préparation d'inhibiteurs de co-transporteur 2 de sodium-glucose
WO2012078777A1 (fr) * 2010-12-09 2012-06-14 Amgen Inc. Composés bicycliques en tant qu'inhibiteurs de pim
WO2022007134A1 (fr) * 2020-07-06 2022-01-13 诺未科技（北京）有限公司 Utilisation d'un composé ou d'un sel pharmaceutiquement acceptable, dimère ou trimère de celui-ci dans la préparation d'un médicament pour le traitement du cancer

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