An HDAC inhibitor and its uses

Abstract

This invention discloses a class of HDAC inhibitors and their uses. Specifically, it relates to a compound of general formula (1) and its preparation method, and the use of the compound of general formula (1) and its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as HDAC inhibitors in the preparation of antitumor drugs.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and more specifically, relates to a class of HDAC inhibitors, their preparation methods, and the application of such compounds in the preparation of drugs for treating or preventing cancer. Background Technology

[0002] Histone deacetylases (HDACs) are a class of proteases that regulate gene expression and protein function by deacetyling histone and non-histone lysine residues. There are currently four main classes and 18 different subtypes of HDACs. Class I includes four subtypes: HDAC1, 2, 3, and 8; Class II includes six subtypes: HDAC4, 5, 6, 7, 9, and 10; and Class IV contains only one subtype: HDAC11. Classes I, II, and IV are structurally homologous; while Class III includes seven subtypes (SIRT1-7), which have no structural homology with the first three classes. HDAC inhibitors inhibit the growth and survival of various tumor cells in vitro. Several HDAC inhibitors, represented by chidamide, have been approved for clinical use as monotherapy or in combination for the treatment of relapsed or refractory peripheral T-cell lymphoma, multiple myeloma, large B-cell lymphoma, and breast cancer.

[0003] Recent studies have shown that, in addition to their functions in tumor cells, specific HDAC subtypes can regulate tumor immunity. For example, inhibiting HDAC1 and 2 upregulates NKG2D expression, enhancing the tumor-killing ability of NK cells (Molecules, 2021, 26(13):3952); inhibiting HDAC3 upregulates CXCL10-mediated immune cell infiltration (CancerImmunol Res, 2023, 11(5):657); inhibiting HDAC6 downregulates inflammasome-mediated IL1β release (Int J MolMed, 2024, 53(1):1-14); and HDAC10 regulates NK cell function by modulating CXCL10 expression (Proc NatlAcad Sci, 2021, 118(30):e2102718118). HDAC inhibitors can also regulate the tumor immune microenvironment and have anti-tumor effects by inhibiting angiogenesis. Different HDAC subtype inhibitors also have different regulatory effects on other important immune cells such as T cells. HDAC inhibitors targeting different subtypes can enhance the efficacy of tumor immunotherapy drugs, such as immune checkpoint inhibitors and anti-PD-1 monoclonal antibodies, and overcome drug resistance to these drugs. Therefore, developing drugs with selective inhibitory effects on specific HDAC subtypes can effectively improve the therapeutic efficacy of immune checkpoint inhibitors and has significant clinical value. Summary of the Invention

[0004] This invention provides a compound of general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0005]

[0006] In general formula (1):

[0007] X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 X 11 X 12 X 13 X 14 and X 15 Each is independently either hydrogen or deuterium, and X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 X 11 X 12 X 13 X 14 or X 15 At least one of them is selected from deuterium.

[0008] In another specific embodiment of the present invention, the compound of general formula (1) has one of the following structures:

[0009]

[0010]

[0011]

[0012] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, a diluent and / or an excipient, and a compound of general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

[0013] Another object of the present invention is to provide the use of the compound of general formula (1) of the present invention, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for treating, regulating or preventing diseases associated with HDAC inhibitors. The disease is preferably cancer, specifically hematologic malignancies and solid tumors. Preferred are breast cancer, colon cancer, uterine cancer, pancreatic cancer, lung cancer, gastric cancer, hematologic malignancies, lymphoma, prostate cancer, liver cancer, cervical cancer, neuroblastoma, melanoma, or intracranial tumors.

[0014] It should be understood that the foregoing general description of the invention and the following detailed description are exemplary and illustrative, and are intended to provide further explanation of the claimed invention.

[0015] Compound Synthesis

[0016] The preparation methods of the compounds of the present invention are described in detail below, but these specific methods do not constitute any limitation on the present invention.

[0017] The compounds described above can be synthesized using standard synthetic techniques or known techniques combined with the methods described herein. Furthermore, the solvents, temperatures, and other reaction conditions mentioned herein can be varied. Starting materials used for the synthesis of the compounds can be obtained synthetically or from commercial sources, such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.) or Sigma Chemical Co. (St. Louis, Mo.). The compounds described herein and other related compounds with different substituents can be synthesized using known techniques and starting materials, including those discovered in March, ADVANCED ORGANIC CHEMISTRY 4. th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd The method described in Ed. (Wiley 1999) can be used to prepare compounds by employing appropriate reagents and by introducing different groups into the molecular formulas provided herein.

[0018] On the one hand, the compounds described herein are prepared according to methods known in the art. However, the conditions of the method, such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to the explanations below. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art. On the other hand, the present invention also provides a method for preparing the compounds described herein, wherein compounds of general formula (1) can be prepared using the following general reaction procedure 1: General reaction procedure 1

[0019]

[0020] X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 X 11 X 12 X 13 X 14 and X 15As defined above. As shown in the general reaction flow 1, the raw materials S1 and S2 undergo an amino acid condensation reaction to obtain compound A3. A3 is deprotected under appropriate conditions to obtain compound A4. A4 then undergoes a condensation reaction with S3 to obtain compound A5. A5 is deprotected under acidic conditions to obtain the target compound (1).

[0021] Further forms of the compound

[0022] "Pharmaceutical acceptable" here means that a substance, such as a carrier or diluent, will not destroy the biological activity or properties of a compound and is relatively non-toxic. For example, when given to an individual, a substance will not cause unwanted biological effects or interact with any of its components in a harmful manner.

[0023] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the administered organism and does not diminish the compound's biological activity and properties. In some specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of a general formula with an acid or base, wherein said acid or base includes, but is not limited to, those found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use 1. st Acids and bases in Ed. (Wiley, 2002).

[0024] It should be understood that references to pharmaceutically acceptable salts include solvent-added forms or crystalline forms, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. A hydrate is formed when the solvent is water, or an alcohol is formed when the solvent is ethanol. Solvates of compounds of general formula (1) are readily prepared or formed according to the methods described herein. For example, hydrates of compounds of general formula (1) are readily prepared by recrystallization from a mixture of water and organic solvents, including but not limited to tetrahydrofuran, acetone, ethanol, or methanol. Furthermore, the compounds mentioned herein can exist in both solvated and non-solvated forms. In summary, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solvated form.

[0025] In other specific embodiments, compounds of general formula (1) are prepared in various forms, including but not limited to amorphous, pulverized, and nano-particle forms. Furthermore, compounds of general formula (1) include crystalline forms and can also be polymorphic. Polymorphs comprise different lattice arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability, and solubility. Different factors such as recrystallization solvents, crystallization rates, and storage temperatures may cause a single crystal form to dominate.

[0026] In another aspect, compounds of general formula (1) may possess a chiral center and / or axial chirality, and thus appear as racemates, racemic mixtures, single enantiomers, diastereomers, and single diastereomers, and cis-trans isomers. Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds, are included within the scope of this invention. This invention means including all such isomeric forms of these compounds.

[0027] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 ( 125 I) and C-14 14 C). For example, deuterium can be used to replace hydrogen atoms to form deuterated compounds. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs generally have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug half-life in vivo. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0028] Unless otherwise specified, any atom in the compounds described in this invention refers to its stable-state isotope. Unless otherwise specified, when a site on the molecular structure is chosen as "H" or "hydrogen", that site should be understood as having a natural abundance of hydrogen isotopes. Similarly, unless otherwise specified, when a site is chosen as "D" or "deuterium", that site should be understood as having a deuterium isotope abundance of at least 3000 times its natural abundance (the natural abundance of deuterium isotopes is 0.015%).

[0029] In this invention, "isotope enrichment factor" means the ratio of the isotope to its natural isotope.

[0030] More preferably, the deuterium abundance at each deuteration site of the deuterated compound in this invention is at least 3500 times its natural abundance (52.2% deuterium enrichment). More preferably, at least 4500 times (67.5% deuterium enrichment). More preferably, at least 5000 times (75% deuterium enrichment). More preferably, at least 6000 times (90% deuterium enrichment). More preferably, at least 6333 times (95% deuterium enrichment). More preferably, at least 6466.7 times (97% deuterium enrichment). More preferably, at least 6600 times (99% deuterium enrichment). More preferably, at least 6633.3 times (99.5% deuterium enrichment).

[0031] the term

[0032] Unless otherwise specified, the terms used in this application, including the specification and claims, are defined as follows. It must be noted that in the specification and appended claims, unless otherwise clearly indicated, the singular form "a" includes the plural meaning. Unless otherwise specified, conventional methods such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used. In this application, unless otherwise specified, "or" or "and" refers to "and / or".

[0033] The term "isomer" means any tautomer, stereoisomer, isotopic isomer, enantiomer, or diastereomer of any compound of the present invention. The compounds of the present invention may have one or more chiral centers or double bonds, and thus exist in stereoisomeric form, such as double-bonded isomers (i.e., E / Z geometric isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). Therefore, the compounds of the present invention cover all corresponding stereoisomers, i.e., stereoisomerically pure (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) forms, as well as mixtures of enantiomers and stereoisomers, such as racemates. The enantiomers and stereoisomers of the compounds of this invention can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high-performance liquid chromatography, and by crystallizing the compounds as chiral salt complexes or by crystallizing the compounds in chiral solvents. The enantiomers and stereoisomers can also be obtained by well-known asymmetric synthetic methods using stereoisomerically pure or enantiomerically pure intermediates, reagents, and catalysts.

[0034] The term "isotope isomers" refers to different molecules that are identical in structure except for their isotopes.

[0035] Specific pharmaceutical and medical terminology

[0036] The term “acceptable,” as used herein, means that a prescription component or active ingredient does not have an excessively harmful effect on health for general therapeutic purposes.

[0037] The terms “treatment,” “treatment process,” or “therapy” as used herein include alleviating, suppressing, or improving symptoms or conditions of a disease; suppressing the development of complications; improving or preventing underlying metabolic syndromes; suppressing the development of a disease or symptom, such as controlling the progression of a disease or condition; reducing a disease or symptom; alleviating a disease or symptom; reducing complications arising from a disease or symptom; or preventing or treating signs arising from a disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, may improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. Whether administered regularly or intermittently, continuously or intermittently, it may be attributable to or related to the administration.

[0038] "Active ingredient" refers to the compound represented by general formula (1), and pharmaceutically acceptable inorganic or organic salts of compounds of general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality), and thus appear as racemates, racemic mixtures, single enantiomers, diastereomers, and single diastereomers. The asymmetric centers that may exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention. The present invention means including all such isomeric forms of these compounds.

[0039] The terms “compound,” “composition,” “agent,” or “medicine or medicament” may be used interchangeably here, and all refer to a compound or composition that, when applied to an individual (human or animal), can induce a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0040] The term “administered, administering, or administration” here refers to the direct application of the compound or composition described herein, or the application of a prodrug, derivative, or analog of the active compound.

[0041] While the numerical ranges and parameters used to define the broader scope of this invention are approximate values, the relevant values ​​in the specific embodiments have been presented as precisely as possible. However, any value inevitably contains standard deviations due to individual test methods. Here, "approximately" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "approximately" may mean that the actual value falls within the acceptable standard error of the mean, as determined by those skilled in the art. Except for experimental examples, or unless explicitly stated otherwise, it is understood that all ranges, quantities, values, and percentages used herein (e.g., to describe material usage, duration, temperature, operating conditions, quantity ratios, and others similar) are modified with "approximately". Therefore, unless otherwise stated, the numerical parameters disclosed in this specification and the accompanying claims are approximate values ​​and are subject to change as needed. At a minimum, these numerical parameters should be understood as the indicated significant digits and values ​​obtained using general rounding.

[0042] Unless otherwise defined in this specification, scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art. Furthermore, unless conflicting with the context, singular nouns used herein include their plural forms, and vice versa.

[0043] Therapeutic uses

[0044] The present invention provides methods for treating diseases using compounds or pharmaceutical compositions of general formula (1) of the present invention, including but not limited to conditions involving HDAC enzymes (e.g., cancer).

[0045] In some embodiments, a method for treating cancer is provided, comprising administering to an individual in need an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of general formula (1). In some embodiments, the cancer is mediated by HDAC enzymes. In some embodiments, the compounds of the present invention are used in combination with immune checkpoint inhibitors; in some embodiments, the compounds of the present invention are used in combination with PD-1 or PD-L1 inhibitors; in some embodiments, the compounds of the present invention are used in combination with PD-1 antibodies; in some embodiments, the compounds of the present invention are used in combination with PD-L1 antibodies; in some embodiments, the compounds of the present invention are used in combination with VEGF / VEGFR inhibitors; in some embodiments, the compounds of the present invention are used in combination with immune checkpoint inhibitors and VEGF / VEGFR inhibitors; in some embodiments, the compounds of the present invention are used in combination with PD-1 inhibitors and VEGF / VEGFR inhibitors; in some embodiments, the compounds of the present invention are used in combination with PD-1 antibodies and VEGF / VEGFR inhibitors; wherein the PD-1 antibodies include, but are not limited to, nivolumab, pembrolizumab, toripalimab, sintilimab, camrelizumab, tislelizumab, penaprilimab, cepalimumab, slulimab, pectilimab, cimiprimab, spartazumab, and AMG404. RN888, mAbl5, MEDI-0680, BGB-108, spartazumab, IBI-308, mDX-400, SHR-1210, PF-06801591, PDR-001, GB-226, and STI-1110, as well as biosimilars, bioenhancers, and bioequivalents of these inhibitors; wherein the PD-L1 antibodies include, but are not limited to, durvalumab, atezolizumab, envorimab, sugemalimab, velumab, avilmab, and BMS-93. 6559, AMP-714, ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, and KY-1003, as well as biosimilars, bioenhancers, and bioequivalents of these inhibitors; wherein the VEGF / VEGFR inhibitors include, but are not limited to, bevacizumab, ranibizumab, ramucirumab, sorafenib, axitinib, apatinib, sunitinib, regorafenib, vandetanib, pazopanib, lenvatinib, cabozantinib, ponatinib, aflibercept, and fruquintinib. In other embodiments, the tumor range includes, but is not limited to: breast cancer, colon cancer, uterine cancer, pancreatic cancer, lung cancer, gastric cancer, hematological malignancies, lymphoma, prostate cancer, liver cancer, cervical cancer, neuroblastoma, melanoma, or intracranial tumors.

[0046] route of administration

[0047] The compounds of this invention and their pharmaceutically acceptable salts can be formulated into various preparations, comprising, within a safe and effective range, the compounds of this invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective range of the compound is determined based on the age, condition, and duration of treatment of the patient.

[0048] "Pharmaceutically acceptable excipients or carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0049] When applying the compounds of this invention, they can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), or topically.

[0050] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in the dosage forms of capsules, tablets, and pills.

[0051] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0052] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0053] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0054] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0055] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0056] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0057] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using the pharmaceutical composition, a safe and effective amount of the compound of this invention is applied to the mammal (e.g., human) requiring treatment, wherein the dose administered is a pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 20–1000 mg. Of course, the specific dosage should also consider factors such as the route of administration and the patient's health condition, which are within the scope of a skilled physician's expertise.

[0058] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features. Detailed Implementation

[0059] The following description will elaborate on the specific aspects, characteristics, and advantages of the aforementioned compounds, methods, and pharmaceutical compositions, making the content of this invention readily apparent. It should be understood that the detailed descriptions and examples described below are specific embodiments and are for reference only. After reading this description, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by this application.

[0060] In all embodiments, 1 H-NMR was recorded using a Vian Mercury 400 NMR spectrometer, and chemical shifts are expressed as δ (ppm). Unless otherwise specified, the silica gel used for separation was 200-300 mesh, and all eluent ratios were by volume.

[0061] The following abbreviations are used in this invention: ACN represents acetonitrile; AcOH represents glacial acetic acid; AIBN represents azobisisobutyronitrile; Boc2O represents ditert-butyl dicarbonate; CDCl3 represents deuterated chloroform; (COCl)2 represents oxaloyl chloride; D2 represents deuterium; D2O represents heavy water; DBU represents 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM represents dichloromethane; Dioxane represents 1,4-dioxane; DIPEA represents diisopropylethylamine; DMSO represents dimethyl sulfoxide; DMAP represents 4-dimethylaminopyridine; DMF represents N,N-dimethylformamide; EA represents ethyl acetate; EtOH represents ethanol; EDCI represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Flash represents rapid medium-pressure preparative chromatography; h represents hours; H2 represents hydrogen; HOB represents... t represents 1-hydroxybenzotriazole; K2CO3 represents anhydrous potassium carbonate; KOH represents potassium hydroxide; LC-MS represents liquid chromatography-mass spectrometry; LiOH represents lithium hydroxide; LiOH.H2O represents lithium hydroxide monohydrate; MeOH represents anhydrous methanol; MeOD represents deuterated methanol; min represents minutes; mL represents milliliters; MS represents mass spectrometry; NaBD4 represents sodium tetradeuterated borohydride; NaOAc represents anhydrous sodium acetate; n-BuLi represents n-butylaluminum; NaBH(OAc)3 represents sodium triacetoxyborohydride; NBS represents N-succinimide bromide; NH4Cl represents ammonium chloride; NMR represents nuclear magnetic resonance; Pd / C represents palladium on carbon; PE represents petroleum ether; PPTS represents pyridine 4-methylbenzenesulfonic acid; TFA represents trifluoroacetic acid; TFAA represents trifluoroacetic anhydride; THF represents tetrahydrofuran; Zn represents zinc powder.

[0062] Preparation Example 1: Synthesis of 4-((2,2,2-trifluoroacetamido)methyl)benzoic acid-2-d acid (S1-1)

[0063]

[0064] Synthesis of S1-1a:

[0065] 2.0 g (8.2 mmol) of methyl 2-bromo-4-(aminomethyl)benzoate, 1 g of sodium acetate, 200 mg of 10% Pd / C, and 40 mL of MeOH were added to a 100 mL single-necked flask. The system was purged with deuterium three times, and then stirred at room temperature for 6 h using a deuterium gas bag. After the reaction was completed as detected by LC-MS, the mixture was filtered, and the filtrate was concentrated under reduced pressure to a small amount. The residue was added to EA (100 mL) and saturated sodium bicarbonate solution (50 mL), stirred, and separated. The organic phase was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a colorless oily product (1.82 g, >100%).

[0066] ESI-MS m / z: 167.1 [M+H] + .

[0067] Synthesis of S1-1b:

[0068] Compound S1-1a (1.82 g, crude product, 8.2 mmol), THF (20 mL), MeOH (10 mL), and NaOH (1.6 g, 40.0 mmol) were added to a 100 mL single-necked flask. The mixture was stirred at room temperature for 5 h. After the reaction was completed as detected by LC-MS, the mixture was concentrated, the residue was flash purified, and lyophilized to give a white solid product (840 mg, 67.4%).

[0069] ESI-MS m / z: 153.0 [M+H] + .

[0070] Synthesis of S1-1:

[0071] Compound S1-1b (840 mg, 5.52 mmol), DCM (84 mL), and DIPEA (1.78 g, 13.8 mmol) were added to a 250 mL single-necked flask. A solution of TFAA (1.74 g, 8.28 mmol) in DCM (10 mL) was added dropwise under ice bath conditions. After addition, the mixture was stirred at room temperature for 6 h. After the reaction was complete as detected by LC-MS, 30 mL of 2N HCl solution was added to the mixture, and the mixture was stirred for 20 min. The mixture was then separated, and the organic phase was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was slurried with EA (5 mL) / PE (30 mL) at room temperature for 30 min, filtered, and dried to obtain a white solid product (1.21 g, 88.4%).

[0072] ESI-MS m / z: 249.0 [M+H] + .

[0073] Using different raw materials, the target intermediates S1-2 to S1-6 were obtained by the synthesis method of intermediate S1-1.

[0074] Table 1. Structural Formulas of Intermediates S1-2 to S1-6

[0075]

[0076]

[0077] Preparation Example 2: Synthesis of 4-((2,2,2-trifluoroacetamido-d)methyl-d2)benzoic acid (S1-7)

[0078]

[0079] Synthesis of S1-7a:

[0080] 4-Cyanobenzic acid (2.94 g, 20.0 mmol), 4M HCl / MeOH (5 mL, 20.0 mmol), and 10% Pd / C (300 mg) were added to MeOH (100 mL) in a 500 mL single-necked flask. The system was purged with deuterium three times, and then the mixture was stirred at room temperature for 20 h using a deuterium gas bag. After the reaction was completed, the mixture was filtered by LC-MS, and the filtrate was concentrated to dryness under reduced pressure to give a white solid product (4.1 g, >100%).

[0081] ESI-MS m / z: 156.1 [M+H] + .

[0082] Synthesis of S1-7:

[0083] Compound S1-1b (4.1 g, 20.0 mmol), DCM (160 mL), and DIPEA (12.9 g, 0.1 mol) were added to a 500 mL single-necked flask. A solution of TFAA (6.3 g, 30 mmol) in DCM (20 mL) was added dropwise under ice bath conditions. After addition, the mixture was stirred at room temperature for 6 h. After the reaction was complete as detected by LC-MS, 30 mL of 2N HCl solution was added to the mixture, and the mixture was stirred for 20 min. The mixture was then separated, and the organic phase was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was slurried with EA (20 mL) / PE (100 mL) at room temperature for 30 min, filtered, and dried to obtain a white solid product (2.65 g, 53%).

[0084] ESI-MS m / z: 251.0 [M+H] + .

[0085] Preparation Example 3: Synthesis of tert-butyl (2-amino-4-d-phenyl)carbamate (S2-1)

[0086]

[0087] Synthesis of S2-1a:

[0088] 4-Bromo-2-nitroaniline (2.17 g, 10.0 mmol) was dissolved in DCM (30 mL), and DMAP (610 mg, 5.0 mmol), DIPEA (2.58 g, 20.0 mmol), and Boc₂O (2.62 g, 12.0 mmol) were added. The mixture was heated to reflux for 20 h under argon protection. After the reaction was completed as detected by LC-MS, water (50 mL) and DCM (50 mL) were added to the mixture, which was stirred, separated, and the organic phase was washed with 1N HCl (50 mL), saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a yellow-brown solid product (3.3 g, yield: >100%).

[0089] ESI-MS m / z: 317.0 [M+H] + .

[0090] Synthesis of S2-1b:

[0091] The crude product S2-1a was added to THF (50 mL), followed by zinc powder (6.5 g, 0.1 mol). Then, a THF (10 mL) solution of AcOH (6 g, 0.1 mol) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 4 h. After the reaction was complete as detected by LC-MS, the mixture was filtered, the filter cake was washed with THF, the filtrate was concentrated, and the residue was purified by column chromatography to obtain a brown solid product (2.0 g, 69.7%).

[0092] ESI-MS m / z: 287.0 [M+H] + .

[0093] Synthesis of S2-1:

[0094] Compound S2-1b (2.0 g, 6.97 mmol), 10% Pd / C (100 mg), and sodium acetate (500 mg) were added to MeOH (30 mL). The system was purged with deuterium three times, and then stirred at room temperature for 20 h using a deuterium gas bag. After the reaction was completed, the mixture was filtered by LC-MS. The filtrate was concentrated under reduced pressure to a small amount. The residue was added to EA (50 mL) and saturated sodium bicarbonate solution (50 mL), stirred, and separated. The organic phase was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a brown solid product (1.65 g, 88%).

[0095] ESI-MS m / z: 210.1 [M+H] + .

[0096] Using different raw materials, the target intermediates S2-2 to S2-5 were obtained by the synthesis method of intermediate S2-1.

[0097] Table 2. Structural Formulas of Intermediates S2-2 to S2-5

[0098]

[0099] Preparation Example 4: Synthesis of (E)-3-(pyridin-3-yl-4-d)acrylic acid (S3-1)

[0100]

[0101] Synthesis of S3-1a:

[0102] 4-Bromopyridine-3-carboxaldehyde (1.86 g, 10.0 mmol), 10% Pd / C (200 mg), and sodium acetate (1 g) were added to MeOH (30 mL). The system was purged with deuterium three times, and then stirred at room temperature for 20 h using a deuterium gas bag. After the reaction was completed, the mixture was filtered by LC-MS. The filtrate was concentrated under reduced pressure to a small amount. The residue was added to EA (50 mL) and saturated sodium bicarbonate solution (50 mL), stirred, and separated. The organic phase was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a white solid product (1.1 g, >100%).

[0103] ESI-MS m / z: 109.1 [M+H] + .

[0104] Synthesis of S3-1:

[0105] Compound S3-1a (1.1 g, 10.0 mmol), malonic acid (2.08 g, 20 mmol), piperidine (2.55 g, 30 mmol), and pyridine (10 mL) were added to a 100 mL single-necked flask. After purging the mixture with argon, the mixture was heated to reflux and stirred for 20 h. After the reaction was completed, the mixture was concentrated by LC-MS, the residue was flash purified, and lyophilized to obtain a white solid product (853 mg, 56.9%).

[0106] ESI-MS m / z: 151.0 [M+H] + .

[0107] Using different raw materials, the target intermediates S3-2 to S3-7 were obtained by the synthesis method of intermediate S3-1.

[0108] Table 3. Structural Formulas of Intermediates S3-2 to S3-7

[0109]

[0110] Preparation Example 5: Synthesis of (E)-3-(pyridin-3-yl)acrylic acid-2,3-d2 acid (S3-8)

[0111]

[0112] Synthesis of S3-8a:

[0113] Methyl 3-(pyridin-3-yl)propynate (1.61 g, 10.0 mmol) and 10% Pd / C (200 mg) were added to MeOH (30 mL). The system was purged with deuterium three times, and then stirred at room temperature for 20 h using a deuterium gas bag. After the reaction was completed, the mixture was filtered by LC-MS, and the filtrate was concentrated to dryness under reduced pressure to obtain anhydrous oily product (1.8 g, >100%).

[0114] ESI-MS m / z: 170.1 [M+H] + .

[0115] Synthesis of S3-8b:

[0116] Compound S3-8a (1.8 g, 10.0 mmol), AIBN (164 mg, 1.0 mmol), and acetonitrile (40 mL) were added to a 100 mL single-necked flask, followed by the addition of NBS (1.96 g, 11.0 mmol) in portions. The mixture was heated to reflux and reacted for 6 h. After the reaction was confirmed to be complete by LC-MS, the mixture was cooled, concentrated, and the residue was directly added to the next step.

[0117] Synthesis of S3-8c:

[0118] Compound S3-8b (5.2 g, crude product, 10.0 mmol), DBU (3.04 g, 20.0 mmol), and acetonitrile (40 mL) were added to a 100 mL single-necked flask, and the mixture was heated to 50 °C and reacted for 4 h. After the reaction was confirmed to be complete by LC-MS, the mixture was cooled, concentrated, and the residue was Flash purified to give a colorless oily product (930 mg, 56.4%).

[0119] ESI-MS m / z: 166.1 [M+H] + .

[0120] Synthesis of S3-8:

[0121] Compound S3-8c (930 mg, 5.64 mmol), THF (5 mL), MeOH (5 mL), and LiOH·H2O (474 ​​mg, 11.3 mmol) were added to a 100 mL single-necked flask. The mixture was stirred at room temperature for 5 h. After the reaction was completed as detected by LC-MS, the mixture was concentrated, the residue was flash purified, and lyophilized to give a white solid product (716 mg, 83.5%).

[0122] ESI-MS m / z: 152.0 [M+H] + .

[0123] Using different raw materials, the target intermediates S3-9 to S3-15 were obtained by the synthesis method of intermediate S3-8.

[0124] Table 4. Structural Formulas of Intermediates S3-9 to S3-15

[0125]

[0126] Preparation Example 6: Synthesis of (E)-3-(pyridin-3-yl)acrylic acid-3-d acid (S3-16)

[0127]

[0128] Synthesis of S3-16a:

[0129] 3-O-3-(pyridin-3-yl)propionic acid (2 g, 12.12 mmol), THF (30 mL), and MeOD (2 g) were added to a 100 mL single-necked flask. NaBD4 (509 mg, 12.12 mmol) was added in portions at room temperature. After the addition was complete, the mixture was stirred at room temperature for 2 h. After the reaction was confirmed to be complete by LC-MS, the mixture was quenched dropwise with D2O (5 mL), concentrated, and purified by Flash to give a colorless solid product (1.66 g, 81%).

[0130] ESI-MS m / z: 170.0 [M+H] + .

[0131] Synthesis of S3-16:

[0132] Compound S3-16a (1.66 g, 9.82 mmol), toluene (20 mL), PPTS (250 mg, 1.0 mmol), and 4A molecular sieve (5 g) were added to a 100 mL single-necked flask. The mixture was heated to 100 °C and stirred for 16 h. After the reaction was confirmed to be complete by LC-MS, the mixture was filtered, the filter cake was washed with THF, the filtrate was concentrated to dryness, and the residue was flash purified to give a white solid product (1.03 g, 69.9%).

[0133] ESI-MS m / z: 151.0 [M+H] + .

[0134] Using different raw materials, the target intermediate S3-17 was obtained by synthesizing intermediate S3-16.

[0135] Table 5. Structural Formula of Intermediate S3-17

[0136]

[0137] Example 1: Synthesis of (E)-N-(2-aminophenyl-5-d)-4-((3-(pyridin-3-yl)acrylamido)methyl)benzamide (compound 1)

[0138]

[0139]

[0140] Step 1: Synthesis of compound 1-1:

[0141] In a 100 mL single-necked flask, 4-((2,2,2-trifluoroacetamido)methyl)benzoic acid (S1-0, 446 mg, 1.8 mmol), DMF (20 mg), and DCM (10 mL) were added. Under argon protection, a 2 mL solution of DCM containing 343 mg (2.7 mmol) of COCl2 was added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 2 h. After the reaction was confirmed to be complete by LC-MS, the mixture was concentrated to dryness under pressure. 10 mL of DCM was added to the residue, followed by the sequential addition of a 5 mL solution of DIPEA (700 mg, 5.43 mmol) and S2-1 (378 mg, 1.81 mmol) of DCM at room temperature. After the addition was complete, the mixture was stirred at room temperature for 1 h. After the reaction was confirmed to be complete by LC-MS, DCM (30 mL) and water (30 mL) were added to the mixture, and the mixture was stirred, separated, and the organic phase was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then slurried with EA (2 mL) / PE (8 mL) at room temperature, filtered, dried, and a light brown solid product (564 mg, 71.0%) was obtained.

[0142] ESI-MS m / z: 439.1 [M+H] + .

[0143] Step 2: Synthesis of compounds 1-2:

[0144] Compound 1-1 (556 mg, 1.27 mmol), MeOH (10 mL), and anhydrous potassium carbonate (351 mg, 2.54 mmol) were added to a 100 mL single-necked flask. After purging the mixture with argon, the temperature was raised to 60 °C and the mixture was stirred for 6 h. After the reaction was confirmed to be complete by LC-MS, the mixture was concentrated. The residue was added to DCM (30 mL) and saturated sodium chloride solution (20 mL), stirred, separated, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give an off-white solid product (471 mg, 106%).

[0145] ESI-MS m / z: 343.1 [M+H] + .

[0146] Step 3: Synthesis of compounds 1-3:

[0147] (E)-3-(pyridin-3-yl)acrylic acid (S3-0, 42 mg, 0.278 mmol), DIPEA (72 mg, 0.556 mmol), HOBt (56 mg, 0.417 mmol), EDCI (80 mg, 0.417 mmol), and DMF (5 mL) were added to a 100 mL single-necked flask. The mixture was stirred at room temperature for 15 min, and then compounds 1-2 (95 mg, 0.278 mmol) were added. The reaction was continued with stirring for 16 h. After the reaction was confirmed to be complete by LC-MS, the mixture was flash purified to give a pale yellow solid product (118 mg, 90%).

[0148] ESI-MS m / z: 474.1 [M+H] + .

[0149] Step 4: Synthesis of Compound 1:

[0150] Compounds 1-3 (118 mg, 0.25 mmol), DCM (5 mL), and TFA (0.5 mL) were added to a 100 mL single-necked flask, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated, and the residue was purified by liquid chromatography to give a white solid product (48 mg, 51.7%).

[0151] ESI-MS m / z: 374.1 [M+H] + .

[0152] Similar to the synthesis of compound 1, using different intermediates as raw materials, target compounds 2-91 in Table 6 can be obtained.

[0153] Table 6

[0154]

[0155]

[0156]

[0157]

[0158] The NMR data for some of the compounds in this patent are listed in Table 7 below:

[0159] Table 7

[0160]

[0161]

[0162] Biological Example 1: Inhibition of Jurkat and 293T cell proliferation by the compounds of the present invention

[0163] 3000 Jurkat or 293T cells per well were seeded in 96-well plates. After overnight adhesion, serially diluted compounds were added. Intracellular ATP levels were measured using CTG after 72 hours. The IC50 of the compounds was calculated compared to DMSO to inhibit cell proliferation. 50 .

[0164] Table 8. Inhibitory activity of the compounds of the present invention against the proliferation of Jukat / 293T cells (IC50) 50 (μM)

[0165] compound Jukat cells 293T cells 1 0.16 5.41 4 0.19 3.69 5 0.12 0.80 Chidamide 1.62 6.71

[0166] Biological Example 2: Determination of Intracellular Acetyl Lysine / H3K27 Acetyl Lysine Levels by Compounds of the Present Invention

[0167] 20,000 HeLa cells per well were seeded in 96-well plates and allowed to adhere overnight. Then, serially diluted compounds were added and the cells were treated for 24 hours. The levels of Acetyl lysine and H3K27Acetyl lysine in the cells were detected by ELISA.

[0168] Table 9. Effects of the compounds of this invention on Acetyl lysine and H3K27Acetyl lysine levels.

[0169]

[0170] Biological Example 3: Assay on the inhibitory activity of the compounds of the present invention against HDAC1, 2, 3 and 10 enzymes.

[0171] The inhibitory activities of the compounds of this invention against HDAC1, HDAC2, HDAC3, and HDAC10 were determined using a fluidometric method. HDAC1, HDAC2, HDAC3, and HDAC10 were obtained by purification or by purchasing reagents directly.

[0172] Specific method: Add serially diluted DMSO sample solution to the reaction wells, add enzyme to the 384-well plate, and add reaction buffer to the control wells. Incubate at room temperature for 15 min, then add fluorescent substrate solution to start the reaction. Use a Paradigm multi-label microplate reader to detect the fluorescence intensity readings per minute over 60 min (excitation: 355 nM, emission: 460 nM), and calculate the slope value. Inhibition rate (%) = (maximum value - sample value) / (maximum value - minimum value) × 100%. Use Y = Bottom + (Top - Bottom) / (1 + (IC)50 The formula / X)^HillSlope) is fitted to a curve to obtain IC. 50 Value, Y is the inhibition rate, and X is the compound concentration.

[0173] Table 10 Inhibitory activity of the compounds of the present invention against HDAC1, 2, 3, and 10 enzymes (IC50) 50 ,nM)

[0174] compound HDAC1 HDAC2 HDAC3 HDAC10 4 70 148 735 110

[0175] Biological Example 4: Metabolic kinetics of the compounds of the present invention in mice.

[0176] Female CD-1 mice aged 7 to 10 weeks were selected, and the intravenous and oral doses were 1 mg / kg and 10 mg / kg, respectively. Mice were fasted for at least 12 hours before administration, and were given food 4 hours after administration. They had free access to water throughout the experiment.

[0177] On the day of the experiment, animals in the intravenous group were administered the corresponding compound via a single tail vein injection at a volume of 10 mL / kg; animals in the oral group were administered the corresponding compound via a single gavage injection at a volume of 10 mL / kg. Animal weight was measured before administration, and the volume of administration was calculated based on body weight. Samples were collected at 0.083, 0.167, 0.5, 1, 2, 4, 8, and 24 hours. At each time point, approximately 200 μL of whole blood and plasma were collected via the orbital venous plexus for concentration determination using high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). The non-compartmental model of Winnolin pharmacokinetic software was used to process plasma concentrations, and the linear logarithmic trapezoidal method was used to calculate pharmacokinetic parameters.

[0178] Table 11. In vivo pharmacokinetic evaluation results of the compounds

[0179]

[0180]

[0181] Biological Example 5: Liver microsomal stability test of the compounds of the present invention

[0182] After incubating 1 μM of the compound with 500 mg / ml liver microsomes from humans, monkeys, beagle dogs, rats, or mice, as well as an NADPH regeneration system at 37°C for different times, the remaining amount of the compound was analyzed by LC-MS-MS, and T was calculated. 1 / 2 .

[0183] Table 12 Results of stability evaluation of compounds in human and mouse liver microparticles

[0184]

[0185] Biological Example 6: In vivo efficacy experiment of the compounds of the present invention

[0186] Female C57BL6N mice (6 weeks old, 18-22g) were provided by Vital River Pharmaceuticals Ltd. in China and used after one week of quarantine and acclimatization. All animals were housed in a room at 23±2℃ and 50±5% relative humidity, with artificial lighting from 08:00 to 20:00 daily and ventilation 13-18 times per hour.

[0187] Mouse colon cancer MC38 cells were routinely cultured in a 37°C, 5% CO2 incubator using 1640 containing 10% fetal bovine serum. After passage, cells were harvested when the desired cell count was reached. 2 × 10⁻⁶ cells were subcutaneously injected into the right side of C57BL6N mice. 6 MC38 cells formed a tumor, and the tumor grew to 100 mm. 3 After administration, animals were randomly divided into groups and administered the drug. Tumor volume was measured using calipers on days 3, 7, 10, 14, 17, and 21 post-administration. The tumor growth inhibition capacity of the compound was evaluated using the tumor growth inhibition rate (TGI) formula: 1 - (tumor volume on day 28 of the administered group - tumor volume on day 1 of the administered group) / (tumor volume on day 28 of the control group - tumor volume on day 1 of the control group). The toxicity of the compound was evaluated based on mouse body weight and condition.

[0188] The groups are as follows:

[0189] 1) Solvent control group; 2) PD-1 group; 3) BDO group; 4) Chidamide group; 5) Compound 4 group; 6) Compound 5 group; 7) PD-1 + BDO group; 8) Compound 4 + PD-1 + BDO combination group; 9) Compound 5 + PD-1 + BDO combination group; 10) Chidamide + PD-1 + BDO combination group, 6 mice in each group. The results are shown in Table 13 below.

[0190] Table 13. In vivo efficacy of some compounds of the present invention in the MC-38 model.

[0191]

[0192] Notes: BDO indicates anti-VEGF antibody; PD-1 indicates anti-PD-1 antibody; IV indicates intravenous administration; IP indicates intraperitoneal administration; PO indicates oral administration; QD indicates once-daily administration; QW indicates once-weekly administration; PR indicates partial remission (tumor volume shrinks by more than 30% relative to the initial volume after the completion of the dosing cycle); CR indicates complete tumor regression.

[0193] The in vivo experimental results above show that the compounds of this invention, in combination with PD-1 and BDO, have a good inhibitory effect on the MC-38 in vivo tumor model. Compounds 4 and 5 alone can slow or eliminate tumor growth in tumor-bearing mice. Particularly in the triple combination group, compound 4 + PD-1 + BDO (group 8) caused complete tumor regression in 83.3% (5 / 6) of mice, and compound 5 + PD-1 + BDO (group 9) caused complete tumor regression in 66.7% (4 / 6) of mice, significantly better than Chidamide + PD-1 + BDO (group 10, 1 / 6, only one mouse achieved partial remission).

[0194] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of formula (1) or a pharmaceutically acceptable salt thereof: In general formula (1): X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 X 11 X 12 X 13 X 14 and X 15 Each is independently either hydrogen or deuterium, and X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 X 11 X 12 X 13 X 14 or X 15 At least one of them is selected from deuterium.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures:

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures:

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures:

5. A pharmaceutical composition, characterized in that, It contains a pharmaceutically acceptable excipient or carrier, and a compound or a pharmaceutically acceptable salt thereof as any one of claims 1-4 as an active ingredient.

6. A pharmaceutical composition, characterized in that, It contains a pharmaceutically acceptable excipient or carrier, and a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-4, and a therapeutically effective amount of an immune checkpoint inhibitor as the active ingredient.

7. A pharmaceutical composition, characterized in that, It contains a pharmaceutically acceptable excipient or carrier, and a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-4, as well as a therapeutically effective amount of an immune checkpoint inhibitor and a therapeutically effective amount of a VEGFR inhibitor as active ingredients.

8. Use of a compound as described in any one of claims 1-4 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in any one of claims 5-7, in the preparation of a medicament for treating, modulating, and / or preventing diseases associated with HDAC inhibitors.

9. The use as claimed in claim 8, wherein the disease is cancer, and the cancer is a hematologic malignancy or a solid tumor.

10. The use as claimed in claim 9, wherein the cancer includes breast cancer, colon cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, leukemia, lymphoma, prostate cancer, liver cancer, cervical cancer, neuroblastoma, melanoma, or intracranial tumor.

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