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WO2025140721A1 - Composé hydrazone, composition pharmaceutique associée et application associée - Google Patents

Composé hydrazone, composition pharmaceutique associée et application associée Download PDF

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Publication number
WO2025140721A1
WO2025140721A1 PCT/CN2024/143920 CN2024143920W WO2025140721A1 WO 2025140721 A1 WO2025140721 A1 WO 2025140721A1 CN 2024143920 W CN2024143920 W CN 2024143920W WO 2025140721 A1 WO2025140721 A1 WO 2025140721A1
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Prior art keywords
formula
compound
ring
iii
optionally substituted
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PCT/CN2024/143920
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English (en)
Chinese (zh)
Inventor
侯宪玉
邵黎明
王月桐
李宁
罗晨菲
段邵亮
李乔明
王漩
陈颖
黄志刚
李海森
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Greater Bay Area Institute Of Precision Medicine Guangzhou
Fudan University
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Greater Bay Area Institute Of Precision Medicine Guangzhou
Fudan University
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Publication of WO2025140721A1 publication Critical patent/WO2025140721A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to hydrazone compounds, pharmaceutical compositions and applications thereof.
  • Cancer is the leading cause of death worldwide, accounting for nearly 10 million deaths in 2021. Despite advances in treating some types of cancer through treatments such as surgery, radiation therapy, and chemotherapy, many types of cancer are essentially incurable. Even when effective treatments are available for a particular cancer, the side effects of that treatment can be severe, resulting in a significant decrease in quality of life.
  • Immunotherapy using immune checkpoint blockade (ICBs) and adoptive T cell therapy (ACT) has achieved landmark clinical efficacy in several advanced cancers, including melanoma, renal cell carcinoma, and lung cancer.
  • ICBs promote the proliferation of PD-1 + TCF1 + CD8 + tumor-infiltrating stem-like T cells (Im et al., 2016; Siddiqui et al., 2019) and act on different immune cell types within the tumor microenvironment (TME) to promote the anti-tumor effects of CD8 + T cells (Kurtulus et al., 2019).
  • TNBC triple-negative breast cancer
  • TME Tumor-derived mammal endothelial growth factor
  • stromal cells such as adipocytes and fibroblasts
  • immune cells and other cells.
  • a major effort is currently underway to improve immunotherapy by modifying the TME (Binnewies et al., 2018). Cancer cells are major players in regulating the TME (Wellenstein and de Visser, 2018). Tumors exhibit enormous intratumor heterogeneity.
  • CSCs cancer stem cells
  • TME is considered to be the niche of CSCs and regulates the phenotypic plasticity of CSCs.
  • the TME forms an interactive and immunosuppressive environment with tumor cells and immune cells such as tumor-associated macrophages (TAMs) (Hass et al., 2020). It has been found that stem cell-like subpopulations present in the tumor hemisphere of solid tumors are able to maintain tumor niches that are immunosuppressive and therapeutically evasive (Jain et al., 2021). In TNBC, quiescent cancer stem cells (QCSCs) have recently been found to constitute an immunosuppressive niche by orchestrating a local hypoxic immunosuppressive environment with dysfunctional dendritic cells (DCs), suppressive fibroblasts, reduced T cell infiltration, and enhanced T cell exhaustion (Baldominos et al., 2022).
  • DCs dysfunctional dendritic cells
  • suppressive fibroblasts reduced T cell infiltration
  • enhanced T cell exhaustion Baldominos et al., 2022).
  • the inventors have been committed to the study of stem cells and cancer stem cells.
  • a few years ago the inventors performed a genome-wide RNAi screen in Drosophila intestinal stem cells (ISCs) and discovered a group of genes (including genes in the arf1-mediated lipid metabolism pathway) whose knockdown can induce the release of cytokines, affect their microenvironment, and then lead to stem cell death.
  • ISCs Drosophila intestinal stem cells
  • tumor-associated CD4/CD8 double-positive T (DPT) cells have strong antitumor activity in hepatocellular carcinoma (HCC) and other tumors (Schad et al., 2022; Zheng et al., 2020). Since early DPTs are mainly present in the thymus, tumor-associated DPT cells may be derived from infiltrating CD4 + or CD8 + single-positive T cells, expressing both exhaustion and activation markers. DPT cells exhibit strong immune responses and are in an active antitumor state. In addition, HCC patients enriched in DPT cells are positively correlated with better treatment outcomes, indicating that DPT cells are superior antitumor T cells.
  • HCC hepatocellular carcinoma
  • the present application is based on the inventor's unexpected discovery that ablating the COPI/Arf1-lipolysis ⁇ -oxidation pathway can eradicate cancer stem cells and induce DAMPs-mediated anti-tumor immune responses, and develops and identifies a new class of hydrazone compounds, their pharmaceutical compositions, and their applications.
  • the hydrazone compounds of the present application have good water solubility and induce strong anti-tumor immunity.
  • the hydrazone compounds of the present application are particularly suitable for treating and/or preventing diseases associated with Arf1 pathway activity; treating refractory, recurrent or metastatic cancers; selectively killing cancer cells with a specific dosing regimen; and targeting cancer stem cells (CSCs) to induce anti-tumor immune responses by inhibiting the Arf1 pathway, especially the COPI/Arf1-lipolysis ⁇ -oxidation pathway.
  • CSCs cancer stem cells
  • the present application provides a compound of formula (III) or a pharmaceutically acceptable salt thereof:
  • X 3 , X 4 , X 5 , X 6 and X 9 are each independently C(R x ) or N, and R x is independently H, D(deuterium), CN, OH, NH 2 , NHSO 2 C 1-6 alkyl , halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • X7 and X8 are each independently C( Rx ) or N, Rx is independently H, D(deuterium), CN, OH, NH2 , NHSO2, C1-6 alkyl, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy or C1-6 haloalkoxy ;
  • X7 is C( Rx )
  • X8 is C( Rx )
  • the ring D is a C5 - C6 cycloalkene, a 5-6 membered heterocycloalkene, a benzene ring or a 5-6 membered heteroaromatic ring
  • the heteroatoms in the 5-6 membered heterocycloalkene and the 5-6 membered heteroaromatic ring are independently selected from one or more of N, O and S, and the number of the heteroatoms is independently 1, 2 or 3;
  • Ring A is a C 5 -C 6 cycloalkene, a 5-6 membered heterocycloalkene, a benzene ring or a 5-6 membered heteroaromatic ring, wherein the heteroatoms in the 5-6 membered heterocycloalkene and the 5-6 membered heteroaromatic ring are independently selected from one or more of N, O and S, and the number of the heteroatoms is independently 1, 2 or 3;
  • n 1, 2 or 3;
  • Rx is independently H, OH, or NHSO2Me ; preferably H.
  • X 5 is C(R x ); for example, CH.
  • X 6 is C(R x ); for example, CH.
  • X 7 is C(R x ); for example,
  • X 8 is C(R x ); for example, CH.
  • X7 is C( Rx )
  • X8 is C( Rx )
  • the ring D is a 5-6 membered heteroaromatic ring; for example, Among them, 1 is connected to X6 , and 2 is connected to X9 .
  • X 9 is C(R x ); for example, CH.
  • Ring A is a 5-6 membered heterocycloalkene or a 5-6 membered heteroaryl ring.
  • n 1 or 2.
  • R c is independently halogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, or C 1-6 alkoxy; for example, methyl, methoxy, ethyl, trifluoromethyl, tert-butyl, fluoro, isopropyl, n-propyl, or
  • R d is independently C 1-6 alkyl, -C(O)-5-14 membered heteroaryl, -C(O)-C 1-6 alkyl, -C(O)-OC 1-6 alkyl, -C(O)-C 3-6 cycloalkyl, or -C(O)-C 6-14 aryl optionally substituted with 1, 2, or 3 Ra -1 ; for example, methyl, ethyl, n-propyl,
  • each R 1 is independently H, biphenyl, -C(O)-OC 1-6 alkyl, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl optionally substituted by 1, 2 or 3 R c , or 5-14 membered heteroaryl optionally substituted by 1, 2 or 3 R c ; for example, H, methyl, Propyl, butyl, pentyl, Ethyl,
  • R 1 on two adjacent carbon atoms together with the carbon atom to which they are attached form a C 5-8 cycloalkene optionally substituted with 1, 2 or 3 R d or a 5-8 membered heterocycloalkene optionally substituted with 1, 2 or 3 R d ; for example, a C 5-8 cycloalkene optionally substituted with 1, 2 or 3 R d
  • a C 5-8 cycloalkene optionally substituted with 1, 2 or 3 R d For example,
  • it is a 5-8 membered heterocyclic olefin optionally substituted by 1, 2 or 3 R d ; for example, Further example,
  • R 1 for in for R 1 is defined as described in any embodiment of the present invention, for when , R 1 on two adjacent carbon atoms and the atoms to which they are attached do not form a ring; for example,
  • R 1 is defined as described in any embodiment of the present invention, and R 1 on two adjacent carbon atoms forms a ring with the atoms to which they are connected; for example,
  • X 3 , X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are each independently selected from C(R x ) or N, and R x is independently selected from the group consisting of H, D(deuterium), CN, OH, NH 2 , NHSO 2 Me, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;
  • R 1 , R 2 , and R 3 are each independently absent or selected from the group consisting of H, D, CN, OH, halogen, biphenyl, -C(O)-OC 1-6 alkyl, C 1-6 alkyl optionally substituted with 1-3 R a , C 1-6 alkoxy optionally substituted with 1-3 R b , C 3-6 cycloalkyl optionally substituted with 1-3 R a , C 3-6 heterocycloalkyl optionally substituted with 1-3 R a , C 6-14 aryl optionally substituted with 1-3 R c , C 6-14 heteroaryl optionally substituted with 1-3 R c , or R 1 and R 2 together with the carbon atom to which they are attached form a C 5-8 carbocyclic ring optionally substituted with 1-3 R d or a 5- to 8-membered heterocyclic ring, wherein the 5- to 8-membered heterocyclic ring optionally contains 1 or more heteroatoms selected from N, O
  • Ring D is absent or is a C 5-6 carbocyclic ring or a 5- to 6-membered heterocyclic ring optionally substituted with 1-3 Re ;
  • Ring A is selected from the following ring structures:
  • R 1 , R 2 , and R 3 are each independently absent or selected from H, D, CN, OH, halogen, biphenyl, -C(O)-OC 1-6 alkyl, C 1-6 alkyl optionally substituted with 1-3 R a , C 1-6 alkoxy optionally substituted with 1-3 R b , C 3-10 cycloalkyl optionally substituted with 1-3 R a , C 3-6 heterocycloalkyl optionally substituted with 1-3 R a , C 6-14 aryl optionally substituted with 1-3 R c , and C 6-14 aryl optionally substituted with 1-3 R c .
  • the group consisting of 6-14 heteroaryl groups for example, H, D, CN, OH, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, adamantyl, cyclohexyl, tetrahydrofuranyl, methoxy, ethoxy, propoxy, butoxy, methoxycarbonyl, ethoxycarbonyl, phenyl, tolyl, ethylphenyl, methoxyphenyl, trifluoromethylphenyl, fluorophenyl, dimethylphenyl, isopropylphenyl, isobutenylphenyl, epoxybutylphenyl, cyclohexylphenyl, biphenyl or naphthyl.
  • 6-14 heteroaryl groups for example, H, D, CN, OH, F, Cl, Br, I,
  • Ring A is selected from the following ring structures:
  • R 1 and R 2 together with the carbon atom to which they are attached form a C 5-8 carbocyclic ring or a 5- to 8-membered heterocyclic ring, for example, selected from the following ring structures:
  • the C 5-8 carbocyclic ring or 5- to 8-membered heterocyclic ring is optionally substituted with 1 to 3 R d .
  • the condensed ring structure formed together with Ring A is selected from the following structures:
  • the condensed ring structure formed together with Ring A is selected from the following structures:
  • Ring B is selected from the following structures:
  • X 5 , X 6 , X 7 , X 8 , and X 9 are each independently selected from C(R x ).
  • ring C when ring D is present, ring C is optionally substituted with 1-2 R x ; ring C is, for example, a pyridine ring substituted with 1 or 2 R x .
  • the cancer or tumor is selected from the group consisting of breast cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, renal cell carcinoma, melanoma, hepatocellular carcinoma, cervical cancer, sarcoma, brain tumor, gastric cancer, multiple myeloma, and leukemia and lymphoma.
  • the present application provides a kit for treating or preventing a disease associated with Arf1 pathway activity in a subject, the kit comprising a compound of formula (I) or formula (III) as described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above; a container; and optionally a package insert or label indicating treatment or prevention.
  • the subject is a mammal, such as a human.
  • the kit further comprises at least one immune checkpoint inhibitor, such as an anti-PD-1 antibody.
  • the kit detects at least one biomarker indicative of the presence of a disease associated with Arf1 pathway activity.
  • the cancer or tumor is selected from the group consisting of breast cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, renal cell carcinoma, melanoma, hepatocellular carcinoma, cervical cancer, sarcoma, brain tumor, gastric cancer, multiple myeloma, leukemia and lymphoma.
  • the present application provides the use of the compounds of formula (I) or formula (III) described herein, their pharmaceutically acceptable salts, or the pharmaceutical compositions described above in the preparation of therapeutic vaccines for blocking tumor development.
  • the tumor is selected from the group consisting of breast cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, renal cell carcinoma, melanoma, hepatocellular carcinoma, cervical cancer, sarcoma, brain tumor, gastric cancer, multiple myeloma, leukemia and lymphoma.
  • the cell is a progenitor cell, a stem cell, a cancer stem cell, or a cancer cell.
  • the small molecule Arf1 inhibitor is a compound of formula (I) or formula (III) described herein or a pharmaceutically acceptable salt thereof.
  • Figures 1-3 show the inhibition of Arf1 activation by the compounds of the present application
  • Figures 4-8 show the inhibitory effects of the compounds of the present application on tumor growth in Drosophila.
  • any variable occurs more than one time in any constituent, e.g., in formula (I), formula (III), or in any other formula depicting and describing the compounds of the present application, its definition on each occurrence is independent of its definition at every other occurrence. Furthermore, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • cancer stem cell and “CSC” are interchangeable.
  • the CSC is of mammalian origin, and in some embodiments, the CSC is of human origin, but is not limited thereto.
  • the definition and functional characteristics of cancer stem cells are: 1) a population of tumor cells with extensive proliferation capacity; 2) capable of asymmetric cell division to produce one or more differentiated offspring with reduced proliferation or developmental potential; 3) capable of self-renewal or self-maintaining symmetric cell division.
  • Other common methods for characterizing CSCs include examining morphology, cell surface markers, transcriptional profiles, and drug responses.
  • CSCs are also referred to as tumor/cancer initiating cells, cancer stem-like cells, stem-like cancer cells, highly tumorigenic cells, tumor stem cells, solid tumor stem cells, drug survival cells (DSCs), drug-resistant cells (DRCs), or super malignant cells.
  • DSCs drug survival cells
  • DRCs drug-resistant cells
  • the term “subject” refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, rodents, etc., that is to be the recipient of a particular treatment.
  • the terms “subject” and “patient” are used interchangeably herein to refer to human subjects.
  • the group may be deuterated.
  • the group may be deuterated, one, two, three or even more hydrogen atoms thereon may be replaced by deuterium, until all hydrogen atoms on the group are replaced by deuterium, and at this time it may be referred to as a "perdeuterated group".
  • Heterocycloalkyl includes, but is not limited to, azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like; for example,
  • cycloalkyl refers to non-aromatic, saturated monocyclic and polycyclic ring systems, wherein all ring atoms are carbon. Unless otherwise indicated, cycloalkyl groups can contain 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl). In certain embodiments, cycloalkyl groups can include 3 to 9, 3 to 8, 3 to 7, 3 to 6, 4 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 10, 5 to 9, 5 to 8, 5 to 7, 5 to 6 ring carbon atoms, etc. In particular, cycloalkyl can be monocyclic or bicyclic. Alternatively, bicyclic cycloalkyl groups can include fused, spirocyclic and bridged cycloalkyl structures.
  • cycloolefin refers to a cycloolefin having at least one unsaturated site, ie, a carbon-carbon sp2 double bond (eg, a C5 - C8 cycloolefin); for example,
  • heterocyclic olefin refers to a cyclic olefin having at least one unsaturated site, i.e., a carbon-carbon sp2 double bond, wherein at least one carbon atom is replaced by a heteroatom selected from N, O and S (e.g., 5-8 membered heterocyclic olefin, 5-6 membered heterocyclic olefin), for example,
  • aryl refers to a monocyclic, bicyclic or polycyclic carbocyclic ring system having at least one aromatic ring. Unless otherwise indicated, an aryl group can be 6 to 10 members. In certain embodiments, an aryl group can contain 6 ring-forming carbon atoms. All atoms within a carbocyclic aryl group are carbon atoms. Non-limiting examples of aryl groups include phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, etc. In the context of the present invention, the terms “aryl” and “aromatic ring” can be used interchangeably.
  • heteroaryl or “heteroaromatic ring” refers to a monocyclic system, or a fused or bridged bicyclic system, wherein the ring system contains one, two, three or four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; and at least one ring is an aromatic ring.
  • the heteroaryl group can be 5 to 10 members. In certain embodiments, the heteroaryl group can be 5 or 6 members. In certain embodiments, the heteroaryl group can contain one, two or three heteroatoms. In certain embodiments, the heteroaryl group can contain one or two heteroatoms.
  • heteroaryl groups include benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indolyl, isoindazolyl, isoquinolyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl, quinolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, tetrazolyl, indolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl etc.
  • Heteroaryl groups include at least one heteroatomic ring and at least one aromatic ring with at least one as mentioned above.For example, the ring with at least one heteroatomic can benzo
  • Non-limiting examples of fused heteroaryl groups include 1,2,3,5,8,8a-hexahydroindolizine, 2,3-dihydrobenzofuran, 2,3-dihydroindole, 2,3-dihydrobenzothiophene, etc.
  • heteroaryl and “heteroaromatic ring” are used interchangeably.
  • aryl may also refer to a cyclic group consisting of only carbon atoms, having a specified number of carbon atoms (e.g., C 6 -C 14 ), which is monocyclic or polycyclic, and at least one ring is aromatic (in accordance with Huckel's rule).
  • Aromatic rings include, but are not limited to, phenyl, naphthyl, or wait.
  • heteroaryl may also refer to a cyclic group having a specified number of ring atoms (e.g., 5-14 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified heteroatom species (one, two, or three of N, O, and S), which is monocyclic or polycyclic, and at least one ring is aromatic (in accordance with Huckel's rule).
  • the heteroaryl group is connected to the rest of the molecule through a carbon atom or a heteroatom; the heteroaryl group is connected to the rest of the molecule through a ring having heteroatoms or a ring without heteroatoms.
  • Heteroaryl includes, but is not limited to, furan ring, pyrrole ring, thiophene ring, pyrazole ring, imidazole ring, oxazole ring, thiazole ring, pyridine ring, pyrimidine ring, indole ring, benzopyrrole ring, or wait.
  • the term "pharmaceutically acceptable salt” includes a salt that maintains the biological effectiveness of the free acid/base form of a particular compound and is not undesirable in biology or other aspects.
  • Pharmaceutically acceptable salts may include salts formed with inorganic bases or acids and organic bases or acids.
  • the present invention also includes their corresponding pharmaceutically acceptable salts. Therefore, the compound of the present application containing an acidic group (such as a carboxyl group) can exist in salt form and can be used according to the present invention, for example, alkali metal salts, alkaline earth metal salts, aluminum salts or ammonium salts.
  • salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts or salts with ammonia or organic amines (such as ethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, N-methylglutamine or amino acids).
  • a compound with an acidic group with a suitable base (such as lithium hydroxide, sodium hydroxide, sodium propoxide, potassium hydroxide, potassium ethoxide, magnesium hydroxide, calcium hydroxide or barium hydroxide), these salts are easily obtained.
  • the compound of formula (I), the compound of formula (III) and pharmaceutically acceptable salts thereof may exist in unsolvated and solvated forms.
  • the compound of formula (I) or the compound of formula (III) may have one or more chiral (asymmetric) centers.
  • the present invention encompasses all stereoisomeric forms of the compound of formula (I) or the compound of formula (III).
  • the asymmetric centers present in the compound of formula (I) or the compound of formula (III) may have (R) or (S) configuration independently of each other.
  • the present invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, such as mixtures of enantiomers and/or diastereomers of all ratios. Therefore, enantiomers are enantiomerically pure forms (as left-handed and right-handed enantiomers), racemic forms and mixtures of two enantiomers in all ratios of the subject matter of the present invention. In the case of cis/trans isomers, the present invention includes mixtures of all ratios of cis-form and trans-form and these forms.
  • single stereoisomers can be prepared by conventional methods (such as by chromatography or crystallization, by using stereochemically uniform synthetic starting materials or by stereoselective synthesis) separation mixture.
  • derivatization can be carried out before stereoisomer separation.
  • the separation of stereoisomer mixtures can be carried out in an intermediate step during the synthesis of formula (I) compound or formula (III) compound, or can be carried out on the final racemic product.
  • Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with reagents containing stereocenters of known configuration.
  • absolute stereochemistry may be determined by vibrational circular dichroism (VCD) spectroscopy.
  • the compounds of the present application are particularly suitable as Arf1 inhibitors for treating diseases and conditions associated with the Arf1 pathway, especially the COPI/Arf1-lipolysis ⁇ -oxidation pathway, such as cancer, including but not limited to the following: breast cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, renal cell carcinoma, melanoma, hepatocellular carcinoma, cervical cancer, sarcoma, brain tumor, gastric cancer, multiple myeloma, leukemia and lymphoma, etc.
  • cancer including but not limited to the following: breast cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, renal cell carcinoma, melanoma, hepatocellular carcinoma, cervical cancer, sarcoma, brain tumor, gastric cancer, multiple myeloma, leukemia and lymphoma, etc.
  • the compound of the present application can be used in an amount effective to treat a disease or condition described herein.
  • the compound of the present application can be used as the compound itself, or alternatively, as a pharmaceutically acceptable salt.
  • the compound of the present application itself (compound of formula (I) or compound of formula (III)) or its pharmaceutically acceptable salt is referred to as the compound of the present application or the compound of the present disclosure.
  • the dosage regimen of the compound of the present application and/or the composition comprising the compound is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the specific compound used. Therefore, the dosage regimen can be very different.
  • the dosage level of the compound of the present application can be about 0.001 to about 100 mg/kg (i.e., mg/kg body weight) per day.
  • the total daily dose of the compound of the present application administered in a single or divided dose can be about 0.001 to about 10 mg/kg. It is not uncommon that the administration of the compound of the present application can be repeated multiple times in one day.
  • the compounds of the present disclosure may be used in combination with one or more other therapeutic agents.
  • the other therapeutic agents include immune checkpoint inhibitors, such as anti-PD-1 antibodies, etc. These therapeutic agents may be administered before, after, or simultaneously with the administration of the compounds of the present disclosure.
  • an immune checkpoint inhibitor refers to any compound that inhibits the function of an immune checkpoint protein. Inhibition includes reduced function and complete blocking.
  • an immune checkpoint inhibitor can be an antibody, synthetic or natural sequence peptide, small molecule, or aptamer that binds to an immune checkpoint protein and its ligand.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a compound of formula (III) as provided herein, a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • the term "pharmaceutically acceptable carrier and/or excipient” refers to a carrier or excipient that can be used to prepare a pharmaceutical composition, which is generally safe, non-toxic and not biologically or otherwise undesirable, and includes carriers or excipients that are acceptable for veterinary use as well as human pharmaceutical use.
  • Pharmaceutically acceptable carriers or excipients as used herein include one and more than one such carrier or excipient. The specific carrier or excipient used will depend on the manner and purpose of applying the compound of the present application. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems.
  • the present disclosure relates to a method for treating diseases and conditions associated with Arf1 pathway activity in a subject in need thereof, such as a method for treating cancer. Since the compounds of the present application have Arf1 inhibitory activity, the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (III) as provided herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.
  • the present disclosure relates to the use of a compound of formula (I) or formula (III), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above as provided herein in the preparation of a medicament for treating diseases and conditions associated with Arf1 pathway activity, such as cancer or tumors.
  • the present disclosure relates to a compound of formula (I) or (III), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for use as a test reagent for diagnosing a disease associated with Arf1 pathway activity in a subject.
  • protecting groups for example those described in T. W. Greene and P. G. M. Wutts, Protecting Groups in Organic Synthesis, 4th ed., John Wiley and Sons.
  • the protecting groups are optionally removed at a convenient subsequent stage using methods well known in the art.
  • the compounds of the present application can be easily prepared using readily available starting materials, reagents and conventional synthesis procedures according to the reaction schemes familiar to those skilled in the art or their modifications. In these reactions, variants known to those skilled in the art but not mentioned in more detail can also be used. In addition, according to the reaction schemes and embodiments described herein, other methods for preparing the compounds of the present application will be apparent to those skilled in the art. Unless otherwise indicated, all variables are defined as above. In general, in chemical procedures, all reagents and starting materials can be purchased from commercial suppliers or can be easily prepared by those skilled in the art.
  • Step 1 General method for the preparation of compound 59-2 series
  • ND Indicates not tested.
  • the CCK8-method was used to detect the cytotoxicity IC 50 .
  • the amount of cells per well was determined according to the cell size and proliferation rate.
  • 100 ⁇ L of CT-26 cell suspension (cell number was 1 ⁇ 10 3 / well) was added to each well and cultured for 24 h at 37°C and 5% CO 2. The next day, the culture medium was discarded, and 100 ⁇ L of culture medium containing different concentrations (0.01, 0.1, 1.0, 10.0, 100.0 ⁇ M) of the drug to be tested was added to the well plate. Incubate in a 37°C incubator for 24 h, 48 h, and 96 h. 10 ⁇ L of CCK-8 solution (Cat. No.
  • N/A means not tested.
  • test results are shown in Figures 9-10 (wherein, T-test statistics are used, * represents statistically significant differences, i.e., P ⁇ 0.05; the number of “ ⁇ ” represents the number of samples), indicating that compound 55 of the present application can effectively inhibit CT26 colon cancer in BALB/c mice.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé hydrazone, une composition pharmaceutique de celui-ci, et une application de celui-ci. Plus particulièrement, l'invention concerne un composé représenté par la formule (III) ou un sel pharmaceutiquement acceptable de celui-ci. Le composé présente un ou plusieurs des avantages suivants : une bonne solubilité dans l'eau ; une cytotoxicité relativement faible ; une bonne activité inhibitrice sur l'activation de Arf1 ; et le fait qu'il possède ou induit une immunité antitumorale relativement forte.
PCT/CN2024/143920 2023-12-28 2024-12-30 Composé hydrazone, composition pharmaceutique associée et application associée Pending WO2025140721A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002057271A2 (fr) * 2000-10-23 2002-07-25 Board Of Regents, The University Of Texas System Inhibiteurs de la famille src a base de thienopyrimidine
WO2022028429A1 (fr) * 2020-08-04 2022-02-10 复旦大学 Nouvel inhibiteur de la voie copi/arf1-lipolyse et composé pour éradiquer des cellules souches cancéreuses et induire une réponse immunitaire antitumorale à médiation par l'humidité
WO2025026209A1 (fr) * 2023-07-28 2025-02-06 双翼原创（上海）医药有限公司 Inhibiteur d'arf1 et son utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002057271A2 (fr) * 2000-10-23 2002-07-25 Board Of Regents, The University Of Texas System Inhibiteurs de la famille src a base de thienopyrimidine
WO2022028429A1 (fr) * 2020-08-04 2022-02-10 复旦大学 Nouvel inhibiteur de la voie copi/arf1-lipolyse et composé pour éradiquer des cellules souches cancéreuses et induire une réponse immunitaire antitumorale à médiation par l'humidité
WO2025026209A1 (fr) * 2023-07-28 2025-02-06 双翼原创（上海）医药有限公司 Inhibiteur d'arf1 et son utilisation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE Registry 15 December 2010 (2010-12-15), ANONYMOUS: "Benzaldehyde, 4-hydroxy-, 2-thieno[2,3-d]pyrimidin-4-ylhydrazone (CA INDEX NAME) OTHER CA INDEX NAMES: 4-Hydroxybenzaldehyde 2-thieno[2,3-d]pyrimidin-4-ylhydrazone", XP093329903, Database accession no. 1256561-38-2 *
LANG LIWEI, SHAY CHLOE, ZHAO XIANGDONG, TENG YONG: "Combined targeting of Arf1 and Ras potentiates anticancer activity for prostate cancer therapeutics", JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, vol. 36, no. 1, 1 December 2017 (2017-12-01), XP055893361, DOI: 10.1186/s13046-017-0583-4 *

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