A selective histone deacetylase inhibitor and its preparation method and application

Abstract

The present invention discloses a selective histone deacetylase inhibitor and a preparation method and application thereof. The histone deacetylase inhibitor is a compound with a six-membered cyclic ring as a parent core and a hydrazide as a zinc ion chelating group, and has a structure as shown in the general formula (I). The present invention also provides a preparation method of the compound. The compound of the present invention has a significant inhibitory effect on histone deacetylase 11 (HDAC11), and can be used to prepare drugs for treating diseases related to abnormal expression of histone deacetylase activity, such as tumors, liver diseases, hyperlipidemia, diabetes, cardiovascular diseases, obesity and atherosclerosis.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis drugs, and in particular to a hydrazide-containing histone deacetylase inhibitor, a preparation method and application thereof. Background Art

[0002] Histone deacetylase (HDAC) participates in a variety of physiological reactions through histone deacetylation and non-histone lysine post-translational modification. Targeting HDAC has shown significant clinical effects, especially for cancer treatment. The US and China Food and Drug Administration have approved five HDAC inhibitors (HDACIs) for the treatment of cutaneous T-cell lymphoma, peripheral T-cell lymphoma and multiple myeloma (Journal of Medicinal Chemistry, 2020, 63, 12460-12484). Among all zinc-dependent HDAC enzymes, HDAC11 was the latest to be discovered. HDAC11 is reported to be involved in immune function (Nature Immunology, 2009, 10, 92-100), myoblast differentiation (Molecules and Cells, 2017, 40, 667-676), metabolism (EBioMedicine 2018, 33, 157-168) and cancer (International Journal of Cancer, 2013, 132, 2200-2208; Blood, 2020, 135, 191-207; American Journal of Translational Research, 2019, 11, 983-990). In recent years, studies have shown that HDAC11 is highly expressed in hepatocellular carcinoma (HCC), and the loss of HDAC11 leads to the inhibition of cancer stemness and HCC progression, which is mediated by increasing the transcription of LKB1, activating the AMPK signaling pathway and inhibiting the glycolytic pathway (Cancer Research, 2021, 81, 2015-2028). Another study also showed that knocking out HDAC11 can inhibit the proliferation and sorafenib resistance of HCC (Frontiers in Cell and Developmental Biology, 2020, 8, 724). In addition, HDAC11 is closely related to abnormal glucose and lipid metabolism (EBioMedicine 2018, 33, 157-168; PNAS 2022, 119, e2119678119); researchers also found that the loss of HDAC11 can increase the number of oxidative muscle fibers in skeletal muscle (The FEBS Journal 2021, 288, 902–919); some studies have also found that HDAC11 induces vascular endothelial cell pyroptosis by activating the NLRP3 / caspase-1 / GSDMD and caspase-3 / GSDME pathways, ultimately leading to the occurrence of atherosclerosis (Cell Death Discovery 2022, 8, 112).Therefore, inhibiting HDAC11 may be a potential way to overcome kinase resistance in liver cancer treatment, and also a potential way to treat diseases related to glucose and lipid metabolism, such as obesity, fatty liver, diabetes, atherosclerosis, etc. Since inhibiting HDAC11 may help treat a variety of human diseases, the development of HDAC11 selective inhibitors is of great significance not only for in-depth research on the biological function of HDAC11, but also for the treatment of HDAC11-related indications.

[0003] Unlike the booming development of other HDAC subtype selective inhibitors, HDAC11 specific inhibitors are still in the initial stage of development, with only a few reports, such as: FT895 (Bioorganic & Medicinal Chemistry Letters, 2018, 28, 2143-2147), SIS17 (ACS Chemical Biology, 2019, 14, 1393-1397) and Garcinol (ACS Chemical Biology, 2020, 15, 2866-2871). Among them, FT895 inhibits HDAC11 with an IC 50 The value is 0.74 μM, and it also has micromolar inhibitory activity against HDAC4 and HDAC8. Garcinol is a natural product with an IC of 0. 50 The value is about 10μM. SIS17 is the most selective HDAC11 inhibitor currently. Its IC 50 The current HDAC11 inhibitors do not show ideal activity, so there is still a huge room for development of HDAC11 inhibitors. Summary of the invention

[0004] In view of the above problems, the first object of the present invention is to provide a class of histone deacetylase inhibitors having good anti-tumor and anti-metabolic disease activities and exhibiting excellent HDAC11 inhibition.

[0005] The second object of the present invention is to provide a method for preparing a histone deacetylase inhibitor compound, which can synthesize the desired compound with low-cost, readily available raw materials and high yield, and the prepared compound has stable properties.

[0006] The third object of the present invention is to provide the use of the above compounds in preparing HDAC11 inhibitors and drugs for anti-tumor and anti-metabolic diseases such as fatty liver, diabetes, obesity, atherosclerosis, etc.

[0007] The present invention designs and synthesizes a class of compounds with structures such as substituted or unsubstituted aromatic rings as the mother core and hydrazide groups with carbon chains of different lengths and heteroatom-containing carbon chains as zinc ion chelating groups, and verifies in vitro experiments that the compounds have significant therapeutic effects.

[0008] On the one hand, the present invention provides a histone deacetylase inhibitor, characterized in that it is a hydrazide compound with a substituted or unsubstituted aromatic ring structure as a parent core and a hydrazide as a zinc ion chelating group. The inhibitor is a compound having a structure as shown in general formula (I), a deuterated product thereof or a pharmaceutically acceptable salt thereof:

[0009]

[0010] in:

[0011] Ring A is selected from H,

[0012] or The R2 substituent is one or more and is not fixed in position on the ring, and is selected from H, halogen, C1-C2 alkane, C1-C2 haloalkyl, amino, nitro, hydroxyl or cyano; the amino group is optionally substituted by 1-2 C1-C2 alkyl, C2-C3 alkynyl; the hydroxyl group is optionally substituted by C1-C2 alkyl, C2-C3 alkynyl; X is selected from NH, O or S; Y is selected from CH or N; W is selected from CH2, O or NCH3; J1, J2, J3, J4 are independently selected from C, CH or N;

[0013] L is selected from a bond, or wherein the bond is a single bond or a double bond; R3 is selected from H, optionally substituted C1-C 12 alkyl;

[0014] Z is selected from a bond or a five-membered aromatic heterocycle;

[0015] R1 is selected from H, C1-C 20 Alkanes, C1-C 20 Alkyl-substituted C3-C6 cycloalkanes, C1-C 20 Alkyl substituted hydroxyl groups,

[0016]

[0017] m is selected from an integer between 1-10; n is selected from an integer between 1-10.

[0018] B, D, E, F, and G are independently selected from C, CR4 or N; wherein R4 is selected from one or more H, halogen, C1-C2 alkane, C1-C2 haloalkyl, amino, nitro, hydroxyl or cyano; the amino group is unsubstituted or optionally substituted with 1-2 C1-C2 alkyl, C1-C2 alkoxy, C2-C3 alkynyloxy groups; the hydroxyl group is unsubstituted or optionally substituted with C1-C2 alkyl, C1-C2 alkoxy or C2-C3 alkynyloxy groups.

[0019] The compound of general formula (I) further has a structure as shown in general formula (II) or general formula (III):

[0020] or

[0021] In the general formula (II) or (III), L is connected to B or G; in the general formula (II), B is a carbon atom; in the general formula (III), G is a carbon atom.

[0022] On the other hand, the present invention also provides a method for preparing the compound of the general formula (I) as described above, its deuterated product or pharmaceutically acceptable salt, comprising the following steps:

[0023]

[0024] Wherein X is NH, O or S, n is an integer between 1 and 18, and R5 is selected from H, C1-C18 alkyl or oxygen-containing alkyl.

[0025] First, compound 2 is used as a raw material to generate the corresponding potassium salt under the action of potassium hydroxide, which reacts with the corresponding compound 1 to obtain intermediate 3. Subsequently, dichloromethane or tetrahydrofuran or N,N-dimethylformamide or N,N-dimethylacetamide or dimethyl sulfoxide is used as a solvent to react with N,O-dimethylhydroxylamine hydrochloride under the action of 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole to obtain the corresponding amide intermediate 4. Finally, tetrahydrofuran is used as a solvent and lithium aluminum hydride is used to reduce to obtain the corresponding aldehyde intermediate 5. Using tetrahydrofuran or N,N-dimethylformamide or N,N-dimethylacetamide or dimethyl sulfoxide as solvent, tert-butyl acrylate and the corresponding intermediate 7 undergo Michael addition to obtain intermediate 8. Using dichloromethane or ethyl acetate or tetrahydrofuran as solvent, the tert-butyl group is removed by trifluoroacetic acid or saturated hydrogen chloride solution to obtain carboxylic acid intermediate 9. Subsequently, using dichloromethane or tetrahydrofuran or N,N-dimethylformamide or N,N-dimethylacetamide or dimethyl sulfoxide as solvent, 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole react with N,O-dimethylhydroxylamine hydrochloride to obtain the corresponding amide intermediate 10. Finally, using tetrahydrofuran as solvent, the corresponding aldehyde intermediate 11 is obtained by lithium aluminum hydride reduction. Subsequently, intermediate 12 is used as a raw material, and dichloromethane or tetrahydrofuran or N,N-dimethylformamide or N,N-dimethylacetamide or dimethyl sulfoxide is used as a solvent, in the presence of 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole or in the presence of triphosgene and triethylamine, it is reacted with substituted or unsubstituted 4-aminomethylbenzoic acid methyl ester hydrochloride, 4-aminobenzoic acid methyl ester or 3-aminomethylbenzoic acid methyl ester hydrochloride to obtain intermediate 13; intermediate 2 is reacted with hydrazine hydrate in methanol or ethanol as a solvent to obtain intermediate 14; intermediate 14 is further reacted with the corresponding aldehyde to obtain the final target compound.

[0026] In addition, the present invention also provides a pharmaceutical composition, which comprises a compound represented by the general formula (I), (II) or (III) as described above, a deuterated substance or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier; the content of the compound, the deuterated substance or the pharmaceutically acceptable salt thereof is 0.1-99.9wt%.

[0027] Finally, the present invention provides the use of the compound of the general formula (I), (II) or (III) as described above, or a deuterated product or a pharmaceutically acceptable salt thereof in the preparation of an HDAC11 inhibitor.

[0028] On the other hand, the present invention also provides the use of the compound of the general formula (I), (II) or (III) as described above, its deuterated product or pharmaceutically acceptable salt in the preparation of a drug for a disease associated with abnormal expression of HDAC11 activity, wherein the disease associated with abnormal expression of HDAC11 activity includes tumors, neurodegenerative diseases, metabolic diseases, inflammatory reactions, etc.

[0029] The tumors include liver cancer, thyroid cancer, various leukemias, lymphomas, myelomas, triple-negative breast cancer, lung cancer, melanoma, esophageal cancer, kidney cancer, oral cancer, tongue cancer, prostate cancer, breast cancer, cervical cancer, ovarian cancer, gastric cancer, pancreatic cancer, bladder cancer, colorectal cancer, nasopharyngeal cancer, brain tumors, gliomas, adult glioblastoma, bone cancer or soft tissue sarcoma.

[0030] The metabolic diseases include fatty liver, obesity, hyperlipidemia, hypertension, atherosclerosis and diabetes.

[0031] In particular, the compounds of the general formula (I), (II) or (III) of the present invention, their deuterated substances or pharmaceutically acceptable salts are used in the preparation of drugs for treating liver cancer or metabolic diseases.

[0032] Advantages of the present invention:

[0033] 1. Based on the prior art, the present invention aims at the deficiencies of the existing HDAC11 inhibitors and provides an HDAC inhibitor with a single ring, a double ring and a linked ring structure as the parent core, and a hydrazide group with carbon chains of different lengths and a heteroatom-containing carbon chain as the zinc ion chelating group, and verifies its significant therapeutic effect in in vitro experiments. This class of compounds has high subtype selectivity, HDAC targeting and excellent pharmacokinetic properties, and is a class of inhibitors with development potential.

[0034] 2. The synthesis method provided by the present invention has the following advantages: the described compound can be obtained in high yield by a simple and green synthesis method of 4-5 steps using cheap and readily available raw materials, which provides a new method for the synthesis of such compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 The IC of sorafenib combined with different concentrations of compound I-18 on the growth inhibition of liver cancer cell HUH7 50 value.

[0036] Figure 2 The IC of sorafenib combined with different concentrations of compound I-18 on the growth inhibition of liver cancer cell MHCC97H 50 value.

[0037] Figure 3The figure shows the body weight changes of the positive control group, the negative control group, and the group receiving 1 mg / kg and 2 mg / kg doses of compound I-18, respectively, in the mouse obesity model.

[0038] Figure 4 It is the triglyceride content in the blood of the positive control group, the negative control group and the group dosed with 1 mg / kg and 2 mg / kg of compound I-18, respectively, in the mouse obesity model.

[0039] Figure 5 This is a comparison of lipid droplets in liver tissue of the positive control group and the group dosed with 1 mg / kg of compound I-18 in a mouse obesity model.

[0040] Among them, A is the HFD group, and B is the HFD+I-18 1 mg / kg group. DETAILED DESCRIPTION

[0041] The present invention is further described in detail below through specific embodiments, the purpose of which is to help better understand the content of the present invention but not to limit the protection scope of the present invention.

[0042] I. Compounds of the present invention:

[0043] The compound represented by the general formula (I), its deuterated substance or its pharmaceutically acceptable salt:

[0044]

[0045] B, D, E, F and G are independently selected from C, CR4 or N; wherein R4 is selected from one or more H, halogen, C1-C2 alkane, C1-C2 haloalkyl, amino, nitro, hydroxyl or cyano; the amino or hydroxyl is unsubstituted or optionally substituted with 1-2 C1-C2 alkyl, C1-C2 alkoxy, C2-C3 alkynyloxy.

[0046] In some embodiments, 0-2 of B, D, E, F, and G are selected from N.

[0047] Ring A is selected from H,

[0048] or

[0049] The R2 substituent is one or more and is not fixed in position on the ring, and is selected from H, halogen, C1-C2 alkane, C1-C2 haloalkyl, amino, nitro, hydroxyl or cyano; the amino or hydroxyl is optionally substituted by 1-2 C1-C2 alkyl, C2-C3 alkynyl; X is selected from NH, O or S; Y is selected from CH or N; W is selected from CH2, O or NCH3; J1, J2, J3, J4 are independently selected from C, CH or N;

[0050] L is selected from a bond, or wherein R3 is selected from H, optionally substituted C1-C 12 alkyl;

[0051] Z is selected from a bond or a five-membered aromatic heterocycle;

[0052] R1 is selected from H, C1-C 20 Alkanes, C1-C 20 Alkyl-substituted C3-C6 cycloalkanes, C1-C 20 Alkyl substituted hydroxyl groups,

[0053]

[0054] m is selected from an integer between 1-10; n is selected from an integer between 1-10.

[0055] B, D, E, F and G are independently selected from C, CR4 or N; wherein R4 is selected from one or more H, halogen, C1-C2 alkane, C1-C2 haloalkyl, amino, nitro, hydroxyl or cyano; the amino or hydroxyl is unsubstituted or optionally substituted with 1-2 C1-C2 alkyl, C1-C2 alkoxy, C2-C3 alkynyloxy.

[0056] In some embodiments, R4 is H; in some embodiments, R4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0057] In some embodiments, R2 or R3 are independently selected from one or more halogen, haloalkyl, (C1-C2) alkoxy, phenolic hydroxyl, cyano. In some embodiments, R2 or R3 are selected from one or more halogen, haloalkyl, (C1-C2) alkoxy, phenolic hydroxyl. In some embodiments, R2 or R3 are selected from one or more halogen, haloalkyl, (C1-C2) alkoxy. In some embodiments, R2 or R3 are selected from one or more halogen, haloalkyl. In some embodiments, R2 or R3 are selected from one or more halogen. In some embodiments, R2 or R3 are selected from one or more halogen, haloalkyl. In some embodiments, R2 or R3 are selected from one or more halogen. In some embodiments, R2 or R3 are selected from one or more of F, Cl, Br or I. In some embodiments, R2 or R3 are selected from haloalkyl. In some embodiments, R2 or R3 are haloalkyl, wherein the halogen atom is selected from F, Cl, Br or I. In some embodiments, R2 or R3 are haloalkyl, wherein the halogen atom is F. In some embodiments, R2 or R3 are haloalkyl, wherein the halogen atom is Cl. In some embodiments, R2 or R3 are haloalkyl, wherein the halogen atom is Br. In some embodiments, R2 or R3 are haloalkyl, wherein the halogen atom is I. In some embodiments, R2 or R3 is -CH2Cl, CH2F, -CH2Br, CHF2, CF3, -CFClBr, CH2CH2F, -CH2CH2Cl, CH2CHF2, CH2CF3, -CH2CCl3, CH2CH2CH2F, CH2CH2CHF2 or CH2CH2CF3, etc.

[0058] Ring A is selected from H,

[0059] or

[0060] The R2 substituent is one or more and is not fixed in position on the ring, and is selected from H, halogen, C1-C2 alkane, C1-C2 haloalkyl, amino, nitro, hydroxyl or cyano; the amino or hydroxyl is optionally substituted by 1-2 C1-C2 alkyl, C2-C3 alkynyl; X is selected from NH, O or S; Y is selected from CH or N; W is selected from CH2, O or NCH3; J1, J2, J3, J4 are independently selected from C, CH or N;

[0061] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is H, L is Z is a bond, and the general formula (I) has the following structure:

[0062]

[0063] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is undecyl, L is Z is a bond, and the general formula (I) has the following structure:

[0064]

[0065] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is tetradecyl, L is Z is a bond, and the general formula (I) has the following structure:

[0066]

[0067] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is a decanyl hydroxyl group, L is Z is a bond, and the general formula (I) has the following structure:

[0068]

[0069] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is L is Z is a bond, and the general formula (I) has the following structure:

[0070]

[0071] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is L is Z is a bond, and the general formula (I) has the following structure:

[0072] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is L is Z is a bond, and the general formula (I) has the following structure:

[0073]

[0074] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is L is Z is a bond, and the general formula (I) has the following structure:

[0075]

[0076] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is tetradecyl, L is Z is a bond, and the general formula (I) has the following structure:

[0077]

[0078] In some embodiments, Ring A is H, B, E, F, and G are all CH, D is N, R1 is tetradecyl, L is a bond, and Z is The general formula (I) has the following structure:

[0079]

[0080] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is L is Z is a bond, and the general formula (I) has the following structure:

[0081]

[0082] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is L is Z is a bond, and the general formula (I) has the following structure:

[0083]

[0084] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is L is Z is a bond, and the general formula (I) has the following structure:

[0085]

[0086] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is L is Z is a bond, and the general formula (I) has the following structure:

[0087]

[0088] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is L is Z is a bond, and the general formula (I) has the following structure:

[0089]

[0090] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is L is Z is a bond, and the general formula (I) has the following structure:

[0091]

[0092] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is L is Z is a bond, and the general formula (I) has the following structure:

[0093]

[0094] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is L is Z is a bond, and the general formula (I) has the following structure:

[0095]

[0096] In some embodiments, Ring A is B, D, E, F and G are all CH, R1 is L is Z is a bond, and the general formula (I) has the following structure:

[0097]

[0098] The present invention also provides a compound of the general formula (I) as described above, a deuterated substance thereof or a pharmaceutically acceptable salt thereof for use as a medicament.

[0099] II. Preparation method:

[0100] The preparation method of the compound of general formula (I) comprises the following steps:

[0101] Route 1:

[0102]

[0103] In reaction 1, starting material 2 generates potassium alcohol under the action of KOH, and then reacts with raw material 1 to obtain intermediate 3, and the reaction conditions are: KOH, 90°C, 12h; in reaction 2, intermediate 3 is condensed with N,O-dimethylhydroxylamine hydrochloride under the action of EDCI and HOBt to obtain intermediate 4, and the reaction conditions are: EDCI, HOBt, DCM, rt, 6h; TEA, DCM, rt, 6h; in reaction 3, intermediate 4 is reduced with lithium aluminum hydride to obtain aldehyde intermediate 5, and the reaction conditions are: LiAlH4, THF, -20°C, 2h.

[0104] Route 2:

[0105]

[0106] In reaction 4, intermediates 6 and 7 undergo Michael addition reaction to obtain intermediate 8, and the reaction conditions are: NaH, rt, 24h; in reaction 5, intermediate 8 is hydrolyzed under alkaline conditions to obtain carboxylic acid compound 9, and the reaction conditions are: 3N KOH, rt, 2h; reactions 6 and 7 are consistent with route 1.

[0107] Route 3:

[0108]

[0109] In reaction 8, the starting material 12 reacts with substituted or unsubstituted 4-aminomethylbenzoic acid methyl ester hydrochloride or 4-aminobenzoic acid methyl ester under the action of EDCI and HOBt or triphosgene and triethylamine to obtain intermediate 13. The reaction conditions are: EDCI, HOBt, DCM, rt, 6h or TEA, DCM, rt, 6h.

[0110] In reaction 9, intermediate 13 reacts with hydrazine hydrate to obtain hydrazide key intermediate 14. The reaction conditions are: hydrazine hydrate, MeOH, 80° C., 24 h.

[0111] In reaction 10, intermediate 14 first reacts with aldehyde to form a Schiff base, and then is reduced with NaBH3CN to obtain a compound of formula (I). The reaction conditions are: aldehyde, MeOH, NaBH3CN, rt, 4h.

[0112] The above takes oxygen atom as an example, and the same applies to the corresponding N and S atoms.

[0113] III. Definitions

[0114] The prefix "C x -C y " means that the subsequent group has x (e.g. 1) to y (e.g. 12) carbon atoms, one or more of which may be replaced by one or more heteroatoms or heteroatom groups in some groups. For example, "(C1-C12 )alkyl" means that the alkyl group has 1 to 12 carbon atoms. Similarly, the term "xy-membered" ring, where x and y are numerical ranges, for example "5- to 6-membered heterocycle", refers to a ring containing xy atoms (e.g., 5-6), such as N, O, S, and the remaining atoms are carbon.

[0115] "Alkyl" refers to any group derived from a straight or branched saturated hydrocarbon. Alkyl includes, but is not limited to, methyl, ethyl, propyl such as prop-1-yl, prop-2-yl (isopropyl), butyl such as but-1-yl (n-butyl), but-2-yl (sec-butyl), 2-methyl-prop-1-yl (isobutyl), 2-methyl-prop-2-yl (tert-butyl), pentyl, hexyl, octyl, decyl, etc. Unless otherwise specified, alkyl has 1 to 12 carbon atoms, such as 1 to 8 carbon atoms, such as 1 to 6 carbon atoms, such as 1 to 4 carbon atoms, such as 1 to 2 carbon atoms.

[0116] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, "C1-C 12 "Alkenyl" refers to a straight or branched alkenyl group containing 1-12 carbon atoms, including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Unless otherwise specified, the alkenyl group has 1 to 12 carbon atoms, such as 1 to 8 carbon atoms, such as 1 to 6 carbon atoms, such as 1 to 4 carbon atoms, such as 1 to 2 carbon atoms. The alkenyl group can be substituted or unsubstituted.

[0117] "Haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are each replaced by a halogen. Examples include, but are not limited to, -CH2Cl, CH2F, -CH2Br, CHF2, CF3, -CFClBr, CH2CH2F, -CH2CH2Cl, CH2CHF2, CH2CF3, -CH2CCl3, CH2CH2CH2F, CH2CH2CHF2, CH2CH2CF3, etc., and alkyl groups such as perfluoroalkyl groups in which all hydrogen atoms are replaced by fluorine atoms.

[0118] "Alkoxy" refers to a moiety of the formula -O-alkyl, wherein the alkyl portion is as defined above. For example, C1-C2 alkoxy refers to an alkyl portion having 1-2 carbon atoms attached to an oxygen. "Haloalkoxy" refers to a moiety of the formula -O-haloalkyl, wherein the haloalkyl portion is as defined above. For example, (C1-C2)alkoxy refers to a moiety having 1-2 carbon haloalkyl attached to an oxygen.

[0119] "Multiple" independently refers to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0120] "Optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted with one or more substituents" means that the substituents may but need not be present, and the description includes instances where the heterocyclic group is substituted with substituents and instances where the heterocyclic group is not substituted with substituents.

[0121] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example: amino or hydroxyl groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated (such as olefinic) bonds.

[0122] It will be appreciated by those skilled in the art that salts of compounds of formula (I) (I) may be prepared, including pharmaceutically acceptable salts. These salts may be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.

[0123] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, stearate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluenesulfonate or trifluoroacetate.

[0124] Inorganic acids which can form salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.

[0125] Organic acids which can form salts include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc. Pharmaceutically acceptable base addition salts can be formed with inorganic or organic bases.

[0126] Inorganic bases from which salts can be formed include, for example, ammonium salts and metals from Groups I to XII of the periodic table. In certain embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc or copper; particularly suitable salts include ammonium, potassium, sodium, calcium or magnesium salts.

[0127] Organic bases from which salts can be formed include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

[0128] The pharmaceutically acceptable salts of the present invention can be synthesized from alkaline or acidic parts by conventional chemical methods. Generally, these salts can be prepared by reacting the free acid forms of these compounds with a chemical amount of a suitable base (hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K), or by reacting the free base forms of these compounds with a chemical amount of a suitable acid. These reactions are usually carried out in water or in an organic solvent, or in a mixture of the two. Generally, when appropriate, it is necessary to use a non-aqueous medium, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Lists of other suitable salts can be found in "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0129] Solvates of compounds of formula (I) (I) can also be prepared, including pharmaceutically acceptable solvates. "Solvate" refers to a complex of variable chemical amounts formed by a solute and a solvent. Such solvents for the purposes of the present invention do not affect the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH or AcOH. Solvates in which water is a solvent molecule generally refer to hydrates. Hydrates include components comprising a stoichiometric amount of water, as well as components comprising a variable amount of water.

[0130] As used herein, the term "pharmaceutically acceptable" means a compound suitable for pharmaceutical use. Salts and solvates (e.g., hydrates and hydrates of salts) of the compounds of the invention suitable for pharmaceutical use are those in which the counter ion or associated solvent is pharmaceutically acceptable. However, salts and solvates with non-pharmaceutically acceptable counter ions or associated solvents are also included within the scope of the present invention, for example, as intermediates for preparing other compounds of the present invention and pharmaceutically acceptable salts and solvates thereof.

[0131] The compound of general formula (I) (including its salt and solvate) can exist in crystalline form, non-crystalline form or its mixture. The compound, its deuterated substance or its salt or solvate can also show polymorphism, i.e. the ability to appear in different crystalline forms. These different crystalline forms are generally known as "polymorph". Polymorphs have the same chemical composition, but the stacking, geometric arrangement and other descriptive characteristics of the crystalline solid state are different. Therefore, polymorphs can have different physical properties, such as shape, density, hardness, deformability, stability and solubility properties. Polymorphs usually show different melting points, IR spectra and X-ray powder diffraction patterns, all of which can be used for identification. It will be appreciated by those skilled in the art that, for example, different polymorphs may be produced by changing or adjusting the conditions used in the crystallization / recrystallization of the compound of formula (I).

[0132] The present invention also includes different isomers of compounds of general formula (I). "Isomer" refers to compounds with the same composition and molecular weight, but different physical and / or chemical properties. The difference in structure can be in the structure (geometric isomer) or in the ability to rotate plane polarized light (stereoisomer). Regarding stereoisomers, the compound of formula (I) can have one or more asymmetric carbon atoms and can appear as a racemate, a racemic mixture, and as a single enantiomer or diastereomer. All such isomeric forms are included within the scope of the present invention, including mixtures thereof. If the compound contains a double bond, the substituent can be an E or Z configuration. If the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl can have a cis- or trans-configuration. It is also desirable to include all tautomeric forms.

[0133] Any asymmetric atom (e.g., carbon, etc.) of the compounds of general formula (I) can exist in racemic or enantiomerically enriched form, such as (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in (R)- or (S)-configuration. Substituents on atoms with unsaturated double bonds are present in cis-(Z)- or trans-(E)-form, if possible.

[0134] Thus, as used herein, the compounds of general formula (I) can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example as substantially pure geometric isomers (cis or trans), diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0135] Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0136] Any resulting racemate of the final product or intermediate can be resolved into the optical enantiomers by known methods (e.g., by separation of its diastereomeric salts), which are obtained with optically active acids or bases and release optically active acidic or basic compounds. In particular, the basic moiety can therefore be used to resolve the compounds of the invention into their optical enantiomers, for example, by fractional crystallization of salts formed with optically active acids (e.g., tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid). The racemic product can also be resolved by chiral chromatography, for example, high performance liquid chromatography (HPLC) using a chiral adsorbent.

[0137] The present invention includes unlabeled forms and isotopically labeled forms of compounds of formula (I). Isotopically labeled compounds have structures described by the chemical formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 18 F. 31P. 32 P. 35 S. 36 Cl, 125 I. The present invention includes various isotopically labeled compounds as defined herein, for example, those in which a radioactive isotope (e.g. 3 H and 14 C) or those in which non-radioactive isotopes (e.g. 2 H and 13 C). These isotope-labeled compounds can be used for metabolic studies (e.g., using 14 C) reaction kinetics studies (e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including tissue distribution analysis of drug substrates, or radiation therapy for patients. In particular, PET or SPECT studies may be particularly needed 18 Isotope-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples and preparations, using an appropriate isotope-labeled reagent in place of the unlabeled reagent previously used.

[0138] In addition, the use of heavier isotopes, especially deuterium (i.e. 2 The substitution of H or D)) may bring certain therapeutic advantages caused by stronger metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improvement of therapeutic index. It is understood that deuterium is considered as a substituent of the compound of formula (I) in this article. The concentration of the heavier isotope, especially deuterium, may be determined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. If substituents in a compound of the invention are labeled as deuterium, then for each deuterium atom labeled, the compound has an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation at each deuterium atom labeled), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0139] Those skilled in the art will be able to identify whether a stereocenter is present in a compound of formula (I). Therefore, the present invention includes possible stereoisomers, and includes both racemic compounds and single enantiomers. When the desired compound is a single enantiomer, it can be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate or starting material can be achieved by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Elliel, SH Wilen and LN Mander (Wiley-interscience, 1994).

[0140] IV. Pharmaceutical Compositions:

[0141] The present invention provides a pharmaceutical composition comprising the compound of the general formula (I) as described above, its deuterated substance or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

[0142] The pharmaceutical composition can be formulated for a specific route of administration, such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical composition of the present invention can be prepared in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including, but not limited to, solutions, suspensions, or emulsions). The pharmaceutical composition can undergo conventional pharmaceutical operations (such as sterilization) and / or can contain conventional inert diluents, lubricants or buffers and adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers, etc.

[0143] Typically, the pharmaceutical composition is a tablet or capsule, which contains the active ingredient and

[0144] a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, etc.;

[0145] b) Lubricants, such as silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets also

[0146] c) binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired,

[0147] d) disintegrants, for example starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or

[0148] e) absorbents, colorants, flavorings and sweeteners.

[0149] Tablets may be film coated or enteric coated according to methods known in the art.

[0150] Suitable compositions for oral administration include an effective amount of a compound of formula (I), a deuterated substance thereof, or a pharmaceutically acceptable salt thereof, in the form of tablets, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions for oral use are prepared according to any method known in the art for preparing pharmaceutical compositions, and in order to provide a refined and palatable preparation, the composition can contain one or more agents selected from sweeteners, flavoring agents, coloring agents, and preservatives. Tablets can contain active ingredients mixed with nontoxic pharmaceutically acceptable excipients suitable for preparing tablets. These excipients are, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate); granulating agents and disintegrants (e.g., corn starch, or alginic acid); adhesives (e.g., starch, gelatin, or gum arabic); and lubricants (e.g., magnesium stearate, stearic acid, or talc). Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a lasting effect over a long period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral administration can be presented in hard gelatin capsules, where the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or in soft gelatin capsules, where the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).

[0151] Some injectable compositions are isotonic aqueous solutions or suspensions, and suppositories are advantageously prepared from fat emulsions or suspensions. The compositions may be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting or emulsifiers, dissolution promoters, salts for regulating osmotic pressure and / or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulation or coating methods, respectively, and contain about 0.1-75% or about 1-50% of active ingredients.

[0152] The present invention also provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may facilitate the degradation of certain compounds.

[0153] The anhydrous pharmaceutical composition and dosage form of the present invention can be prepared using anhydrous or low-water content ingredients and low-water content or low humidity conditions. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous properties. Therefore, the anhydrous composition is packaged using known materials that prevent contact with water so that it can be included in a suitable formula kit. Examples of suitable packaging include, but are not limited to, airtight foil, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0154] The present invention further provides pharmaceutical compositions and dosage forms, which contain one or more agents that reduce the decomposition rate of the compounds of the present invention as active ingredients. Such agents (referred to herein as "stabilizers") include, but are not limited to, antioxidants (e.g., ascorbic acid), pH buffers or salt buffers, etc.

[0155] For an individual of about 50-70 kg, the pharmaceutical composition or combination product of the present invention can be a unit dose of about 1-1000 mg of active ingredient, or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredient. The therapeutically effective dose of the compound, pharmaceutical composition or combination product thereof depends on the species, body weight, age and individual condition of the individual, the disorder or disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill can easily determine the effective amount of each active ingredient required for preventing, treating or inhibiting the development of a disorder or disease.

[0156] V. Therapeutic Uses

[0157] In some embodiments, provided is the use of the compound of formula (I) as described above, its deuterated substance or a pharmaceutically acceptable salt thereof in the preparation of an HDACs inhibitor.

[0158] In some embodiments, provided is the use of the compound of formula (I) as described above, its deuterated product or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease associated with abnormal expression of HDAC activity.

[0159] In some embodiments, the diseases associated with abnormal expression of HDAC activity include developmental abnormalities, tumors, neurodegenerative diseases, metabolic diseases, inflammatory responses or heart diseases, etc., wherein the tumors include liver cancer, various leukemias, lymphomas, myeloma, triple-negative breast cancer, lung cancer, melanoma, esophageal cancer, prostate cancer, breast cancer, etc. The metabolic diseases include fatty liver, obesity, hyperlipidemia, hypertension, atherosclerosis and diabetes.

[0160] In some embodiments, a method for treating or preventing a disease associated with abnormal expression of HDACs activity is provided, comprising administering a therapeutically effective amount of a compound of formula (I), a deuterated substance thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0161] In some embodiments, the method comprises administering a compound of Formula (I), a deuterated form thereof, or a pharmaceutically acceptable salt thereof in combination with one, two, three, or four other therapeutic agents.

[0162] Herein, if the term "combination" is used to describe combined administration, it should be understood that this can mean simultaneous administration, independent administration or sequential administration. In one aspect of the invention, "combination administration" refers to simultaneous administration. In another aspect of the invention, "combination administration" refers to independent administration. In another aspect of the invention, "combination administration" refers to sequential administration. When administered sequentially or independently, the delay in administering the second component should not, for example, lose the benefit of the effect produced by the use of the combination.

[0163] The present invention is further illustrated below by means of specific preparation examples and application examples.

[0164] The numbers, names and structures of the compounds in the examples are shown in the following table.

[0165]

[0166]

[0167]

[0168]

[0169]

[0170] Route 1:

[0171]

[0172]

[0173] Intermediate 5a: 9-methoxynonanal (5a)

[0174] The specific synthesis steps are as follows:

[0175] a. Synthesis of compound [9-methoxynonanoic acid] (3a)

[0176] Place KOH (700 mg, 12.6 mmol) in a 100 mL single-mouth bottle, add 30 mL of dry MeOH to dissolve, and heat the solution to 90 ° C for 1 hour. Add 9-bromononanoic acid (1 g, 4.2 mmol) to the above reaction solution and react overnight. TLC detected that the raw material reacted completely, evaporated the solvent and adjusted the pH to 4 with 1M HCl. Extract with ethyl acetate (20 mL × 3), combine the organic phases and dry with anhydrous MgSO4, filter and evaporate to obtain 654 mg of white solid, with a yield of 83%. ESI-MS m / z: 187.92 [MH] - .

[0177] b. Synthesis of compound [N,9-dimethoxy-N-methylnonanamide] (4a)

[0178] Compound 3a (500 mg, 2.66 mmol) was placed in a 50 mL single-mouth bottle, 15 mL of dry dichloromethane was added to dissolve, EDCI (612 mg, 3.2 mmol), HOBt (432 mg, 3.2 mmol) and triethylamine (807 mg, 8 mmol) were added under an ice bath, and the reaction was continued for 30 min. N, O-dimethylhydroxylamine hydrochloride (312 mg, 3.2 mmol) was added to the reaction solution and the reaction was continued overnight at room temperature. TLC detected that the reaction of the raw material was complete, the reaction solution was washed with 1M HCl (20 mL × 3), and the organic phase was dried with anhydrous MgSO4. After column chromatography, 342 mg of colorless oil was obtained, with a yield of 56%. 1 H NMR (400MHz, Chloroform-d) δ3.66(s,3H),3.34(t,J=6.6Hz,2H),3.31(s,3H),3.16(s,3H),2.39(t,J=7.6Hz,2H),1.66-1.49(m,6H),1.31-1.28(m,6H).

[0179] c. Synthesis of compound [9-methoxynonanal] (5a)

[0180] Compound 4a (231 mg, 1 mmol) was placed in a 50 mL two-necked bottle and dissolved in dry tetrahydrofuran under N2 protection. Lithium aluminum hydride (76 mg, 2 mmol) was added at -20°C and reacted for 2 h. TLC showed that the reaction of the raw material was complete. 5 mL of 1 M HCl was added to quench the reaction. The solvent was evaporated and extracted with dichloromethane (20 mL × 3). The organic phases were combined and dried over anhydrous MgSO4. The solvent was evaporated to obtain 123 mg of colorless oil with a yield of 71%. ESI-MS m / z: 172.92 [M+H] + .

[0181] Intermediate 5b: 8-ethoxyoctanal (5b)

[0182] The specific synthesis steps are as follows:

[0183] The methanol in the intermediate 5a was replaced by ethanol, and the 9-bromononanoic acid was replaced by 8-bromooctanoic acid. The rest was the same as the preparation method in 5a, and the total yield was 35%.

[0184] Intermediate 5c: 7-Propoxyheptanal (5c)

[0185] The methanol in the intermediate 5a was replaced by n-propanol, and the 9-bromononanoic acid was replaced by 7-bromonoheptanoic acid, and the rest was the same as the preparation method in 5a. The total yield was 32%.

[0186] Intermediate 5d: 6-Butoxyhexanal (5d)

[0187] The methanol in the intermediate 5a was replaced by n-butanol, and the 9-bromononanoic acid was replaced by 6-bromohexanoic acid, and the rest was the same as the preparation method in 5a. The total yield was 32%.

[0188] Intermediate 5e: 5-(pentyloxy)pentanal (5e)

[0189] The methanol in the intermediate 5a was replaced by n-pentanol, and the 9-bromononanoic acid was replaced by 5-bromovaleric acid, and the rest was the same as the preparation method in 5a. The total yield was 37%.

[0190] Intermediate 5f: 12-Methoxydodecanal (5f)

[0191] The 9-bromononanoic acid in the intermediate 5a was replaced by 12-bromodedecanoic acid, and the rest was the same as the preparation method in 5a. The total yield was 36%.

[0192] Intermediate 5g: 6-(2-methoxyethoxy)hexanal (5f)

[0193] The methanol in the intermediate 5a was replaced by ethylene glycol monomethyl ether, and the 9-bromononanoic acid was replaced by 6-bromohexanoic acid, and the rest was the same as the preparation method in 5a. The total yield was 36%.

[0194] Intermediate 5h: 6-(2-methoxyethoxy)hexanal (5f)

[0195] The methanol in the intermediate 5a was replaced by ethylene glycol monoethyl ether, and the 9-bromononanoic acid was replaced by 5-bromovaleric acid. The rest was the same as the preparation method in 5a. The total yield was 39%.

[0196] Intermediate 5i: 6-(2-methoxyethoxy)hexanal (5f)

[0197] The 9-methoxynonanoic acid in the intermediate 5a was replaced by 10-hydroxydecanoic acid, and the rest was the same as the preparation method in 5a. The total yield was 25%.

[0198] Route 2:

[0199]

[0200] Intermediate 11:

[0201] a. Synthesis of compound [2,5,8,11-tetraoxy tert-butyl propionate methyl ether] (8)

[0202] Tert-butyl acrylate (2g, 15.6mmol), triethylene glycol monomethyl ether (2.6g, 15.6mmol) and catalytic amount of NaH were placed in a 100mL two-necked bottle, and dry tetrahydrofuran was added under N2 protection to dissolve and react for 24h. TLC detected that the raw material reacted completely, and column chromatography separated 3.2g of colorless oil, with a yield of 70%. ESI-MS m / z: 292.96 [M+H] + .

[0203] b. Synthesis of compound [2,5,8,11-tetraoxypropionic acid methyl ether] (9)

[0204] Compound 8 (2.9 g, 10 mmol) was placed in a 100 mL single-mouth bottle, and 20 mL of methanol and 10 mL of 3N KOH were added. The reaction was allowed to proceed at room temperature for 2 h. TLC showed that the reaction was complete. After evaporating the solvent, the pH was adjusted to 4 with 1 M HCl. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and dried with anhydrous MgSO4. The mixture was filtered and evaporated to obtain 2.1 g of a colorless oil with a yield of 89%. ESI-MS m / z: 235.91 [MH] - .

[0205] c. Synthesis of the compound [N-methoxy-N-methyl-2,5,8,11-tetraoxypropionic acid-14-amide] (10)

[0206] The preparation method is the same as compound 4a.

[0207] 1 H NMR (400MHz, Chloroform-d) δ3.76(t,J=6.7Hz,2H),3.67(s,3H),3.63-3.60(m,12H),3.35(d,J=13.4Hz,3H),3.15(s,3H),2.72(t,J=6.8Hz,2H).ESI-MS m / z:279.94[M+H] +

[0208] d. Synthesis of compound [2,5,8,11-tetraoxypropionic acid-14-aldehyde] (11)

[0209] The preparation method is the same as compound 5a.

[0210] Intermediate 12: N-(4-(hydrazinecarbonyl)benzyl)benzamide (12)

[0211] The specific synthesis steps are as follows:

[0212] a. Synthesis of compound [methyl 4-(benzamidomethyl)benzoate]

[0213] Benzoic acid (244 mg, 2 mmol) was placed in a 100 mL eggplant-shaped bottle at room temperature, and 30 mL of dichloromethane was added to dissolve. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) (460 mg, 2.4 mmol), 1-hydroxybenzotriazole (HOBt) (325 mg, 2.4 mmol) and triethylamine (506 mg, 5 mmol) were added under ice bath and reacted for 0.5 h. After adding 4-aminomethylbenzoic acid methyl ester hydrochloride (483 mg, 2.4 mmol), the reaction was allowed to proceed overnight at room temperature. TLC detected that the raw material had reacted completely, and then the reactant was washed with water (20 mL×3), and the organic phase was dried over anhydrous Na2SO4. After column chromatography, the compound 4-(benzamidomethyl)benzoic acid methyl ester (379 mg, yield 70%) was obtained as a white solid, which was directly used in the next step of synthesis. ESI-MSm / z: 269.92[M+H] +

[0214] b. Synthesis of the intermediate [N-(4-(hydrazinecarbonyl)benzyl)benzamide]

[0215] At room temperature, methyl 4-(benzamidomethyl)benzoate (269 mg, 1 mmol) was placed in a 100 mL eggplant-shaped bottle and dissolved in 30 mL methanol. Hydrazine hydrate (840 mg, 15 mmol) was added and refluxed for 24 hours. TLC detected that the raw material had reacted completely. After methanol was evaporated, 12 (261 mg, yield 97%) was obtained and used directly in the next step. ESI-MS m / z: 269.94 [M+H] + .

[0216] Example 1: N-(4-(2-Undecylhydrazine-1-carbonyl)benzyl)benzamide (I-12)

[0217] The specific synthesis steps are as follows:

[0218] At room temperature, intermediate 12 (269 mg, 1 mmol) was placed in a 100 mL eggplant-shaped bottle, 30 mL of methanol was added to dissolve, and then undecyl aldehyde (170 mg, 1 mmol) was added. After 2 h of reaction, NaBH3CN (250 mg, 4 mmol) was added and adjusted to acidity with HCl methanol solution, and the reaction was continued for 6 h. TLC detected that the raw material reaction was complete, 20 mL of saturated sodium bicarbonate solution was added, and after 0.5 h of reaction, methanol was evaporated and extracted with dichloromethane (20 mL × 3), and the organic phases were combined and dried over anhydrous Na2SO4. After column chromatography, compound I-12 (262 mg, yield 62%) was obtained. 1H NMR (500MHz, DMSO-d6) δ9.96 (s, 1H), 9.08 (t, J = 6.0Hz, 1H), 7.91-7.86 (m, 2H), 7.79-7.73 (m, 2H), 7.57-7.50 (m, 1H), 7.50-7.44 (m, 2H), 7 .37(d,J=8.3Hz,2H),5.08(s,1H),4.51(d,J=6.0Hz,2H),2.75(t,J=7.1Hz,2H),1.48-1.38(m,2H),1.34-1.15(m,16H),0.87-0.81(m,3H). 13 C NMR(126MHz,DMSO-d6)δ166.76,165.58,143.48,134.66,132.17,131.78,128.81,127.69,127.5 3,127.43,51.65,42.85,31.74,29.46,29.41,29.15,28.04,27.10,22.54,14.40.HRMS(ESI)for C 26 H 36 N3O2[MH] - calcd422.28130,found 422.28137.

[0219] Example 2: N-(4-(2-(9-methoxynonyl)hydrazine-1-carbonyl)benzyl)benzamide (I-13)

[0220] The specific synthesis steps are as follows:

[0221] The undecanal in Example 1 was replaced by intermediate 5a, and the rest was the same as Example 1. The total yield was 34%. 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H),9.07(t,J=6.0Hz,1H),7.88-7.82(m,2H),7.74(d,J=8.3Hz,2H),7.55-7.48(m,1H),7.44(dd,J=8.2,6.5Hz, 2H),7.36-7.30(m,2H),5.04(s,1H),4.48(d,J=6.0Hz,2H),3.24(t,J=6 .5Hz,2H),2.72(t,J=7.1Hz,2H),1.46-1.36(m,4H),1.28-1.18(m,10H). 13C NMR(101MHz,DMSO-d6)δ166.79,165.65,143.57,134.72,132.26,131.87,128.90,127.79,127.62,1 27.50,72.42,58.31,51.72,42.90,29.56,29.53,29.47,29.37,28.14,27.18,26.20.HRMS(ESI)for C 25 H 34 N3O3[MH] - calcd424.26057, found 424.26059.

[0222] Example 3: N-(4-(2-(8-ethoxyoctyl)hydrazine-1-carbonyl)benzyl)benzamide (I-14)

[0223] The specific synthesis steps are as follows:

[0224] The undecanal in Example 1 was replaced by intermediate 5b, and the rest was the same as Example 1. The total yield was 34%. 1 H NMR (400MHz, DMSO-d6) δ9.94 (s, 1H), 9.07 (t, J = 5.9Hz, 1H), 7.89-7.82 (m, 2H), 7. 77-7.69(m,2H),7.51(t,J=7.2Hz,1H),7.47-7.41(m,2H),7.34(d,J=8.1Hz,2H),5 .03(s,1H),4.48(d,J=5.9Hz,2H),3.34(d,J=6.9Hz,2H),3.27(t,J=6.6Hz,2H),2 .72(t,J=7.1Hz,2H),1.45-1.37(m,4H),1.26-1.19(m,8H),1.04(t,J=6.9Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ166.79,165.66,143.57,134.72,132.25,131.87,128.90,127.78,127.62,1 27.50,70.26,65.70,51.73,42.90,29.81,29.50,29.41,28.13,27.16,26.25,15.69.HRMS(ESI)forC 25 H 34 N3O3[MH] - calcd 424.26057,found424.26065.

[0225] Example 4: N-(4-(2-(7-propoxyheptyl)hydrazine-1-carbonyl)benzyl)benzamide (I-15)

[0226] The specific synthesis steps are as follows:

[0227] The undecanal in Example 1 was replaced by intermediate 5c, and the rest was the same as Example 1. The total yield was 34%. 1 H NMR(400MHz,DMSO-d6)δ9.94(d,J=5.4Hz,1H),9.07(t,J=6.0Hz,1H),7.91-7.81(m,2 H),7.74(d,J=8.3Hz,2H),7.56-7.48(m,1H),7.48-7.41(m,2H),7.34(d,J=8.2Hz,2H) ,5.01(d,J=6.5Hz,1H),4.48(d,J=6.0Hz,2H),3.28(t,J=6.5Hz,2H),3.24(t,J=6.6Hz ,2H),2.76-2.68(m,2H),1.47-1.36(m,6H),1.30-1.21(m,6H),0.80(t,J=7.4Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ166.80,165.66,143.57,134.72,132.27,131.87,128.90,127.79,127.62,1 27.50,72.08,70.43,51.72,42.90,29.76,29.36,28.12,27.19,26.25,23.01,11.13.HRMS(ESI)for C 25 H 34 N3O3[MH] - calcd 424.26057, found 424.26065.

[0228] Example 5: N-(4-(2-(6-butoxyhexyl)hydrazine-1-carbonyl)benzyl)benzamide (I-16)

[0229] The specific synthesis steps are as follows:

[0230] The undecanal in Example 1 was replaced by the intermediate 5d, and the rest was the same as Example 1. The total yield was 34%. 1H NMR(400MHz,DMSO-d6)δ9.94(d,J=5.8Hz,1H),9.07(t,J=6.0Hz,1H),7.89-7.83 (m,2H),7.74(d,J=8.3Hz,2H),7.54-7.48(m,1H),7.48-7.41(m,2H),7.34(d,J= 8.3Hz,2H),5.02(d,J=5.9Hz,1H),4.48(d,J=6.0Hz,2H),3.28(t,J=6.5Hz,4H), 2.76-2.68(m,2H),1.48-1.35(m,6H),1.34-1.22(m,6H),0.82(t,J=7.3Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ166.80,165.66,143.57,134.73,132.27,131.87,128.90,127.79,127.62,1 27.51,70.44,70.14,51.70,42.91,31.88,29.76,28.15,27.05,26.22,19.44,14.32.HRMS(ESI)for C 26 H 40 N3O3[MH] - calcd 466.30752, found 466.30746.

[0231] Example 6: N-(4-(2-(10-hydroxydecyl)hydrazine-1-carbonyl)benzyl)benzamide (I-17)

[0232] The specific synthesis steps are as follows:

[0233] The undecanal in Example 1 was replaced by the intermediate 5i, and the rest was the same as Example 1. The total yield was 34%. 1 H NMR (400MHz, DMSO-d6) δ9.95(s,1H),9.09(t,J=6.0Hz,1H),7.86(d,J=7.2Hz,2H),7.74(d,J=8.0Hz,2H),7.51(t,J=7.2Hz,1H),7.44(t,J=7.4Hz,2 H),7.34(d,J=8.0Hz,2H),5.06(s,1H),4.48(d,J=6.0Hz,2H),4.30(t,J= 5.2Hz,1H),2.72(t,J=7.1Hz,2H),1.46-1.32(m,4H),1.30-1.19(m,12H). 13C NMR(101MHz,DMSO-d6)δ166.80,165.66,143.58,134.71,132.24,131.88,128.91,127.79,127.6 2,127.51,61.24,51.73,42.90,33.08,29.62,29.54,29.51,28.15,27.21,26.04.HRMS(ESI)for C 25 H 34 N3O3[MH] - calcd 424.26057, found 424.26059.

[0234] Example 7: N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide (I-18)

[0235] The specific synthesis steps are as follows:

[0236] The undecanal in Example 1 was replaced by the intermediate 5e, and the rest was the same as Example 1. The total yield was 34%. 1 H NMR (400MHz, DMSO-d6) δ9.94 (s, 1H), 9.07 (t, J = 6.0Hz, 1H), 7.91-7.82 (m, 2H), 7.74(d,J=8.3Hz,2H),7.54-7.48(m,1H),7.47-7.41(m,2H),7.34(d,J=8.1Hz, 2H),5.04(s,1H),4.48(d,J=6.0Hz,2H),3.31-3.22(m,4H),2.72(t,J=7.0Hz,2 H),1.51-1.36(m,6H),1.36-1.27(m,2H),1.25-1.16(m,4H),0.85-0.76(m,3H). 13 C NMR (101MHz, DMSO-d6) δ166.83,165.69,143.57,134.73,132.26,131.86,129.95,128.89,127.79,127. 63,127.51,70.48,70.42,51.71,42.92,29.69,29.45,28.46,27.97,23.94,22.49,14.47.HRMS(ESI)for C 25 H 34 N3O3[MH] - calcd 424.26057, found 424.26047.

[0237] Example 8: 4-Fluoro-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide (I-19)

[0238] The specific synthesis steps are as follows:

[0239] The benzoic acid in the synthesis method of intermediate 12 was replaced by 4-fluorobenzoic acid, and the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 34%. 1 H NMR (400MHz, DMSO-d6) δ9.94 (s, 1H), 9.09 (t, J = 6.0Hz, 1H), 7.96-7.89 (m, 2H), 7.76-7.7 1(m,2H),7.34(d,J=8.3Hz,2H),7.30-7.25(m,2H),5.16-4.96(m,1H),4.47(d,J=6.0Hz, 2H),4.29(t,J=5.2Hz,1H),3.34(t,J=5.6Hz,2H),3.28-3.26(m,2H),2.72(t,J=7.0Hz,2 H),1.47-1.38(m,6H),1.34-1.27(m,2H),1.25-1.20(m,4H),0.81(t,J=6.9Hz,3H).(M+H + ) / z=444.03.

[0240] Example 9: 4-Chloro-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide (I-20)

[0241] The specific synthesis steps are as follows:

[0242] The benzoic acid in the synthesis method of intermediate 12 was replaced by 4-chlorobenzoic acid, and the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 35%. 1 H NMR (400MHz, DMSO-d6) δ9.98(s,1H),9.22-9.18(m,1H),7.89(d,J=8.3Hz,2H),7.74(d,J=7.9Hz,2H),7.52(d,J=8.3Hz,2H),7.34( d,J=8.0Hz,2H),4.47(d,J=6.0Hz,2H),3.29-3.28(m,2H),3.27(s,2H),2.76-2.69(m,2H),1.44-1.20(m,12H),0.82-0.79(m,3H). 13C NMR (101MHz, DMSO-d6) δ165.77,165.65,143.39,136.69,133.44,132.25,129.76,128.98,127. 65,127.57,70.47,70.41,51.66,42.97,29.68,29.45,28.46,27.92,23.93,22.49,14.47.(M+H + ) / z=459.98.

[0243] Example 10: 4-Bromo-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide (I-21)

[0244] The specific synthesis steps are as follows:

[0245] The benzoic acid in the synthesis method of intermediate 12 was replaced by 4-bromobenzoic acid, and the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 31%. 1 H NMR (400MHz, DMSO-d6) δ10.02(s,1H),9.28-9.20(m,1H),7.82(d,J=8.7Hz,2H),7.74(d,J=8.2Hz,2H),7.66(d,J=8.4Hz,2H) ,7.34(d,J=8.1Hz,2H),4.50-4.43(m,2H),3.31-3.26(m,4H),2.79-2.66(m,2H),1.45-1.21(m,12H),0.84-0.77(m,3H).(M+H + ) / z=503.94.

[0246] Example 11: 4-iodo-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide (I-22)

[0247] The specific synthesis steps are as follows:

[0248] The benzoic acid in the synthesis method of intermediate 12 was replaced by 4-iodobenzoic acid, and the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 33%. 1H NMR (400MHz, DMSO-d6) δ9.96(s,1H),9.13(t,J=5.9Hz,1H),7.83(d,J=8.4Hz,2H),7.73(d,J=8.1Hz,2H),7.64(d,J=8.4Hz,2H),7. 33(d,J=8.1Hz,2H),4.46(d,J=5.8Hz,2H),3.28(d,J=4.1Hz,4H),2.72(d,J=6.9Hz,2H),1.43-1.20(m,12H),0.80(d,J=7.0Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ166.17,165.66,143.37,137.79,134.12,132.27,129.78,127.64,127 .55,99.56,70.47,70.41,51.67,42.95,29.68,29.45,28.46,27.93,23.93,22.49,14.49.(M+H + ) / z=551.96.

[0249] Example 12: 4-methoxy-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide (I-23)

[0250] The specific synthesis steps are as follows:

[0251] The benzoic acid in the synthesis method of intermediate 12 was replaced by 4-methoxybenzoic acid, and the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 36%. 1 H NMR (400MHz, DMSO-d6) δ9.84(d,J=15.0Hz,2H),8.76(t,J=6.0Hz,1H),7.53(d,J=8.5Hz,4H),7.24(d,J=8.1Hz,2H),6.81-6.72(m,2H),4.44(d,J=6 .0Hz,2H),3.81(s,1H),3.33-3.23(m,4H),2.72(t,J=7.0Hz,2H),1.52-1 .34(m,7H),1.38-1.25(m,3H),1.27-1.16(m,6H),0.86-0.75(m,4H).(M+H + ) / z=456.05.

[0252] Example 13: 4-Hydroxy-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide (I-24)

[0253] The specific synthesis steps are as follows:

[0254] The benzoic acid in the synthesis method of intermediate 12 was replaced by 4-hydroxybenzoic acid, and the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 39%. 1 H NMR (400MHz, DMSO-d6) δ9.94(d,J=15.0Hz,2H),8.80(t,J=6.0Hz,1H),7.73(d,J=8.5Hz,4H),7.32(d,J=8.1Hz,2H),6.81-6.72(m,2H),4.44 (d,J=6.0Hz,2H),3.33-3.23(m,4H),2.72(t,J=7.0Hz,2H),1.52-1.34(m,7H),1.38-1.25(m,3H),1.27-1.16(m,6H),0.86-0.75(m,4H).(M+H + ) / z=441.95.

[0255] Example 14: 4-nitro-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide (I-25)

[0256] The specific synthesis steps are as follows:

[0257] The benzoic acid in the synthesis method of intermediate 12 was replaced by 4-nitrobenzoic acid, and the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 29%. 1 H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.47-9.34(m,1H),8.36-8.25(m,2H),8.14-8.05(m,2H),7.80-7.71(m,2H),7.42-7.28(m,2H),5.02(s,1 H),4.59-4.44(m,2H),3.28(t,J=3.3Hz,2H),2.73(s,2H),1.58-1.37(m ,6H),1.37-1.28(m,2H),1.26-1.17(m,4H),0.81(t,J=3.9Hz,3H).(M+H + ) / z=470.96.

[0258] Example 15: 4-amino-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide (I-26)

[0259] The specific synthesis steps are as follows:

[0260] I-25 (100 mg, 0.21 mmol) was placed in a 25 mL single-mouth bottle, 50 mL of methanol was added to dissolve, 10% Pd / C was added, and the mixture was reacted for 2 h under a hydrogen atmosphere. TLC detected that the reaction of the raw material was complete, and after filtering off the palladium carbon, column chromatography was performed to obtain 83 mg of a white solid with a yield of 89%. 1 H NMR (400MHz, DMSO-d6) δ9.93 (s, 1H), 8.58 (t, J = 6.0Hz, 1H), 7.87-7.68 (m ,2H),7.63-7.53(m,2H),7.37-7.26(m,2H),6.53-6.48(m,2H),5.60(s,2H ),4.51-4.37(m,2H),3.28(t,J=3.3Hz,2H),2.72(t,J=7.0Hz,1H),1.52-1 .36(m,6H),1.36-1.27(m,2H),1.26-1.19(m,4H),0.85-0.78(m,3H).(M+H + ) / z=441.02.

[0261] Example 16: N-(4-(2-(6-(2-methoxyethoxy)hexyl)hydrazine-1-carbonyl)benzyl)benzamide (I-27)

[0262] The specific synthesis steps are as follows:

[0263] The undecanal in Example 1 was replaced by 5 g of the intermediate, and the rest was the same as Example 1. The total yield was 34%. 1 H NMR (400MHz, DMSO-d6) δ9.96 (s, 1H), 9.09 (t, J = 6.0Hz, 1H), 7.90-7.84 (m, 2H) ,7.75(d,J=8.3Hz,2H),7.54-7.47(m,1H),7.47-7.41(m,2H),7.35(d,J=8.1Hz ,2H),5.04(s,1H),4.49(d,J=6.0Hz,2H),3.46-3.36(m,5H),3.31(t,J=6.6Hz, 2H),3.19(s,3H),2.73(t,J=7.1Hz,2H),1.49-1.35(m,4H),1.34-1.21(m,4H). 13C NMR(101MHz,DMSO-d6)δ166.83,165.69,143.58,134.73,132.27,131.86,128.89,127.79,127.6 3,127.53,71.83,70.82,69.81,58.59,51.72,42.93,29.72,28.14,27.05,26.14.HRMS(ESI)for C 24 H 32 N3O4[MH] - calcd 426.23963, found 426.23962.

[0264] Example 17: N-(4-(2-(5-(2-ethoxyethoxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide (I-28)

[0265] The specific synthesis steps are as follows:

[0266] The undecanal in Example 1 was replaced by the intermediate 5h, and the rest was the same as Example 1. The total yield was 34%. 1 H NMR (400MHz, DMSO-d6) δ10.00(d,J=7.5Hz,1H),9.20-9.07(m,1H),7.90(d,J=7.7Hz,2H),7.78(d,J=8.0Hz,2H),7.59-7.44(m,3H),7.38( d,J=8.0Hz,2H),4.52(d,J=6.2Hz,2H),3.48-3.37(m,8H),2.84-2.69(m,2H),1.58-1.40(m,4H),1.39-1.25(m,2H),1.08(t,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ166.82,165.68,143.58,134.72,132.26,131.87,128.91,127.80,127.6 4,127.52,70.81,70.06,69.76,66.08,51.69,42.92,29.65,27.98,23.88,15.66.HRMS(ESI)for C 24 H 32 N3O4[MH] - calcd 426.23963, found 426.24023.

[0267] Example 18: N-(4-(2-dodecylhydrazine-1-carbonyl)benzyl)benzamide (I-29)

[0268] The specific synthesis steps are as follows:

[0269] The undecanal in Example 1 was replaced by dodecanal, and the rest was the same as Example 1. The total yield was 34%. 1 H NMR(400MHz, DMSO-d6)δ9.93(s,1H),9.06(t,J=6.0Hz,1H),7.89-7.82(m,2H),7.74(d,J=8.3Hz,2H),7.55-7.48(m,1H),7.46–7.4 0(m,2H),7.34(d,J=8.1Hz,2H),4.48(d,J=6.0Hz,2H),2.72(t,J=7.1Hz,2H),1.47-1.35(m,2H),1.20(s,18H),0.83-0.78(m,3H). 13 CNMR(101MHz,DMSO-d6)δ166.80,165.65,143.56,134.74,132.27,131.86,128.89,127.78,127.61, 127.50,51.74,42.92,31.83,29.60,29.55,29.52,29.25,28.15,27.20,22.63,14.49.HRMS(ESI)for C 27 H 38 N3O2[MH] - calcd436.29695, found 436.29691.

[0270] Example 19: N-(4-(2-Tridecylhydrazine-1-carbonyl)benzyl)benzamide (I-30)

[0271] The specific synthesis steps are as follows:

[0272] The undecanal in Example 1 was replaced by tridecanal, and the rest was the same as Example 1. The total yield was 34%. 1 H NMR(500MHz, DMSO-d6)δ9.96(s,1H),9.08(t,J=6.0Hz,1H),7.92-7.86(m,2H),7.76(d,J=8.2Hz,2H),7.57-7.50(m,1H),7.50-7.44(m,2H),7 .37(d,J=8.3Hz,2H),5.10(s,1H),4.51(d,J=5.9Hz,2H),2.75(t,J=7.1Hz,2H),1.51-1.38(m,2H),1.35-1.19(m,20H),0.84(t,J=6.9Hz,3H). 13C NMR(126MHz,DMSO-d6)δ166.75,165.58,143.49,134.66,132.17,131.78,128.81,127.69,127.53,1 27.43,51.65,42.85,31.74,29.49,29.45,29.41,29.14,28.04,27.10,22.54,14.40.HRMS(ESI)for C 28 H 40 N3O2[MH] - calcd 450.31260, found 450.31253.

[0273] Example 20: N-(4-(2-Tetradecylhydrazine-1-carbonyl)benzyl)benzamide (I-31)

[0274] The specific synthesis steps are as follows:

[0275] The undecanal in Example 1 was replaced by tetradecanal, and the rest was the same as Example 1. The total yield was 34%. 1 H NMR(400MHz, DMSO-d6)δ9.94(s,1H),9.06(t,J=6.0Hz,1H),7.89-7.84(m,2H),7.74(d,J=8.2Hz,2H),7.53-7.48(m,1H),7.47-7.4 1(m,2H),7.34(d,J=8.1Hz,2H),4.48(d,J=6.0Hz,2H),2.72(t,J=7.1Hz,2H),1.46-1.32(m,2H),1.19(s,22H),0.86-0.75(m,3H). 13 CNMR(101MHz,DMSO-d6)δ166.80,165.65,143.56,134.74,132.27,131.84,128.88,127.78,127.61, 127.50,51.76,42.92,31.84,29.60,29.56,29.53,29.26,28.17,27.21,22.64,14.48.HRMS(ESI)for C 29 H 42 N3O2[MH] - calcd464.32825,found 464.32819.

[0276] Example 21: N-(4-(2-(12-methoxydodecyl)hydrazine-1-carbonyl)benzyl)benzamide (I-32)

[0277] The specific synthesis steps are as follows:

[0278] The undecanal in Example 1 was replaced by the intermediate 5f, and the rest was the same as Example 1. The total yield was 34%. 1 H NMR (500MHz, DMSO-d6) δ9.95 (s, 1H), 9.08 (t, J = 6.0Hz, 1H), 7.92-7.86 (m, 2H),7.77(d,J=8.4Hz,2H),7.57-7.50(m,1H),7.51-7.44(m,2H),7.37(d, J=8.2Hz,2H),5.03(s,1H),4.51(d,J=6.0Hz,2H),3.27(t,J=6.6Hz,2H),3 .19(s,3H),2.75(t,J=7.1Hz,2H),1.50-1.37(m,4H),1.27-1.20(m,16H). 13 C NMR(126MHz,DMSO-d6)δ166.72,165.57,143.47,134.68,132.21,131.76,128.80,127.70,127.53,1 27.43,72.35,58.22,51.67,42.85,29.47,29.44,29.42,29.31,28.08,27.12,26.11.HRMS(ESI)for C 28 H 40 N3O3[MH] - calcd466.30752, found 466.30746.

[0279] Example 22: N-(4-(7,10,13,16-tetraoxo-2,3-diazoheptadecanyl)benzyl)benzamide (I-33)

[0280] The specific synthesis steps are as follows:

[0281] The undecanal in Example 1 was replaced by the intermediate 11, and the rest was the same as Example 1. The total yield was 34%. 1H NMR (400MHz, DMSO-d6) δ10.09(s,1H),9.09(t,J=6.0Hz,1H),7.87(d,J=6.8Hz,2H),7.75(d,J=7.9Hz,2H),7.51(t,J=7.2Hz,1H),7.44(t, J=7.5Hz,2H),7.35(d,J=7.9Hz,2H),4.48(d,J=5.9Hz,2H),3.50-3.38(m,14H),3.18(s,3H),2.83(t,J=7.0Hz,2H),1.66(p,J=6.6Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ166.83,165.74,143.77,134.72,132.00,131.87,128.90,127.79,127.7 0,127.55,71.79,70.34,70.30,70.10,70.07,68.97,58.56,48.91,42.92,28.17.HRMS(ESI)for C 25 H 34 N3O6[MH] - calcd 472.24531, found 472.24521.

[0282] Example 23: N-(4-(2-Tetradecylhydrazine-1-carbonyl)benzyl)benzofuran-2-carboxamide (I-34)

[0283] The specific synthesis steps are as follows:

[0284] The benzoic acid in the synthesis method of intermediate 12 was replaced by benzofuran-2-carboxylic acid, the undecanal in Example 1 was replaced by tetradecanal, and the rest was the same as Example 1. The total yield was 34%. 1 H NMR (500MHz, DMSO-d6) δ9.96(s,1H),9.33(t,J=6.2Hz,1H),7.77(dd,J=8.4,2.3Hz,3H),7.65(d,J=8.3Hz,1H),7.57(s,1H),7.46(t,J=7.7Hz,1H),7. 39(d,J=8.0Hz,2H),7.33(t,J=7.5Hz,1H),4.51(d,J=6.2Hz,2H),2.75(t,J =7.1Hz,2H),1.49-1.37(m,2H),1.31-1.11(m,24H),0.83(t,J=6.7Hz,3H). 13C NMR (126MHz, DMSO-d6) δ165.54,158.68,154.72,149.44,142.97,132.31,129.88,127.76,127.60,127.56,127.33,124. 17,123.24,112.24,110.10,51.66,42.39,31.74,29.49,29.46,29.42,29.15,28.06,27.11,22.54,14.39.HRMS(ESI)for C 31 H 42 N3O3[MH] - calcd 504.32317, found 504.32324.

[0285] Example 24: N-(4-(2-Tetradecylhydrazine-1-carbonyl)benzyl)benzo[b]thiophene-2-carboxamide (I-35)

[0286] The specific synthesis steps are as follows:

[0287] The benzoic acid in the synthesis method of intermediate 12 was replaced by benzothiophene-2-carboxylic acid, the undecanal in Example 1 was replaced by tetradecanal, and the rest was the same as Example 1. The total yield was 34%. 1 H NMR(500MHz, DMSO-d6)δ9.97(s,1H),9.36(t,J=6.1Hz,1H),8.13(s,1H),8.01(d,J=7.4Hz,1H),7.96-7.89(m,1H),7.81-7.76(m,2H),7.49-7 .41(m,3H),7.40(d,J=8.2Hz,3H),4.52(d,J=6.0Hz,2H),2.75(t,J=7.1Hz,2H),1.48-1.36(m,2H),1.30-1.19(m,24H),0.83(t,J=6.9Hz,3H). 13 C NMR(126MHz,DMSO-d6)δ165.55,162.09,143.00,140.69,140.09,139.60,132.33,129.92,127.76,127.59,127.57,126.71,1 25.66,125.42,125.39,123.25,51.66,42.92,31.73,29.48,29.45,29.41,29.14,28.05,27.10,22.53,14.38.HRMS(ESI)for C 31 H 42 N3O2S[MH]- calcd520.30032, found 520.30054.

[0288] Example 25: 2-(Pyridin-3-yl)-N'-tetradecylthiazole-4-carbohydrazide (I-36)

[0289] The specific synthesis steps are as follows:

[0290] The intermediate 12 in Example 1 was replaced by 2-(pyridin-3-yl)thiazole-4-carbohydrazide, and the undecanal was replaced by tetradecanal. The rest was the same as in Example 1. The total yield was 34%. (M+H + ) / z=416.93.

[0291] Example 26: N-(4-(2-pentadecylhydrazine-1-carbonyl)benzyl)benzamide (I-37)

[0292] The specific synthesis steps are as follows:

[0293] The undecanal in Example 1 was replaced by pentadecanal, and the rest was the same as Example 1. The total yield was 34%. 1 H NMR (500MHz, DMSO-d6) δ10.00(s,1H),9.08(t,J=6.1Hz,1H),7.91-7.86(m,2H),7.77(d,J=8.0Hz,2H),7.53(t,J=7.3Hz,1H),7.47(t,J=7. 5Hz,2H),7.37(d,J=8.0Hz,2H),4.51(d,J=6.0Hz,2H),2.76(t,J=7.1Hz,2H),1.48-1.37(m,2H),1.25-1.17(m,24H),0.84(t,J=6.8Hz,3H). 13 CNMR(126MHz,DMSO-d6)δ166.74,165.58,143.54,134.66,131.76,129.85,128.80,127.69,127. 55,127.44,51.63,42.85,31.74,29.49,29.45,29.15,27.95,27.09,22.54,14.40.HRMS(ESI)for C 30 H 44 N3O2[MH] - calcd 478.34390, found 478.34372.

[0294] Example 27: N-(4-(2-hexadecylhydrazine-1-carbonyl)benzyl)benzamide (I-38)

[0295] The specific synthesis steps are as follows:

[0296] The undecanal in Example 1 was replaced by hexadecanal, and the rest was the same as Example 1. The total yield was 34%. 1 H NMR(500MHz, DMSO-d6)δ9.96(s,1H),9.08(t,J=6.0Hz,1H),7.92-7.86(m,2H),7.76(d,J=8.3Hz,2H),7.57-7.50(m,1H),7.50-7.44(m,2H), 7.37(d,J=8.3Hz,2H),5.08(s,1H),4.51(d,J=6.0Hz,2H),2.75(t,J=7.1Hz,2H),1.47-1.37(m,2H),1.33-1.19(m,26H),0.88–0.80(m,3H). 13 C NMR(126MHz,DMSO-d6)δ166.76,165.58,143.48,134.65,132.17,131.78,128.81,127.69,127.53,1 27.44,51.65,42.85,31.73,29.47,29.44,29.41,29.14,28.03,27.10,22.54,14.40.HRMS(ESI)for C 31 H 46 N3O2[MH] - calcd 492.35955, found 492.35962.

[0297] Example 28: N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)nicotinamide (I-39)

[0298] The specific synthesis steps are as follows:

[0299] The benzoic acid in the synthesis method of intermediate 12 was replaced by nicotinic acid, the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 31%. 1H NMR (400MHz, DMSO-d6) δ9.94 (s, 1H), 9.26 (t, J = 6.0Hz, 1H), 9.02 (dd, J = 2.4, 0.9H z,1H),8.68(dd,J=4.8,1.7Hz,1H),8.23-8.16(m,1H),7.78-7.69(m,2H),7.52-7 .44(m,1H),7.39-7.32(m,2H),5.02(s,1H),4.50(d,J=5.9Hz,2H),3.30-3.25(m, 4H),2.72(t,J=7.1Hz,2H),1.47-1.21(m,12H),0.86-0.76(m,3H).HRMS(ESI)for C 25 H 35 N4O3[MH] - calcd 425.21586, found 425.21372.

[0300] Example 29: N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)pyrazine-2-carboxamide (I-40)

[0301] The specific synthesis steps are as follows:

[0302] The benzoic acid in the synthesis method of intermediate 12 was replaced by 2-pyrazine carboxylate, and the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 30%. 1 H NMR(400MHz,Chloroform-d)δ9.96(s,1H),9.08(s,1H),8.87(s,1H),8.28-7.71(m,1H),7.70-7.48(m,2H),7.41-7.04 (m,3H),4.51-4.20(m,2H),3.43-3.31(m,4H),2.92-2.84(m,2H),1.67-1.17(m,14H),0.92-0.80(m,3H).HRMS(ESI)for C 23 H 32 N5O3[MH] - calcd 426.13646, found 426.13578.

[0303] Example 30: N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)cyclohexanecarboxamide (I-41)

[0304] The specific synthesis steps are as follows:

[0305] The benzoic acid in the synthesis method of intermediate 12 was replaced by cyclohexanecarboxylic acid, and the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 31%. 1 H NMR(400MHz, DMSO-d6)δ9.93(s,1H),8.24(t,J=6.0Hz,1H),7.75-7.68(m,2H),7.28-7.20(m,2H),4.24(d,J=6.0Hz,2H),3.30-3.22(m,4 H),2.72(t,J=7.0Hz,2H),2.20-2.06(m,1H),1.74-1.64(m,4H),1.62-1.52(m,1H),1.51-1.18(m,16H),0.88-0.75(m,3H).HRMS(ESI)for C 25 H 42 N3O3[M+H] + calcd 432.08534, found 432.07957.

[0306] Example 31: N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)thiophene-2-carboxamide N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)thiophene-2-carboxamide (I-42)

[0307] The specific synthesis steps are as follows:

[0308] The benzoic acid in the synthesis method of intermediate 12 was replaced by thiophene 2-carboxylic acid, the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 38%. 1 H NMR(400MHz, DMSO-d6)δ9.94(s,1H),9.07(t,J=6.0Hz,1H),7.80-7.70(m,4H),7.36-7.30(m,2H),7.12(dd,J=5.0,3.7Hz, 1H),4.45(d,J=6.0Hz,2H),3.30-3.24(m,4H),2.72(t,J=7.0Hz,2H),1.52-1.19(m,12H),0.85-0.77(m,3H).HRMS(ESI)for C 23 H 34 N3O3S[M+H] + calcd 432.18247, found 432.18153.

[0309] Example 32: N-(3-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide (I-43)

[0310] The specific synthesis steps are as follows:

[0311] The 4-aminomethylbenzoic acid hydrochloride in the synthesis method of intermediate 12 was replaced by 3-aminomethylbenzoic acid hydrochloride, and the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 34%. 1 H NMR (400MHz, DMSO-d6) δ9.98 (s, 1H), 9.05 (t, J = 6.0Hz, 1H), 7.90-7.83 (m, 2H),7.75(d,J=1.8Hz,1H),7.67-7.62(m,1H),7.55-7.48(m,1H),7.46-7.4 2(m,2H),7.36(t,J=7.6Hz,1H),4.48(d,J=6.0Hz,2H),3.30-3.25(m,4H),2 .72(t,J=7.0Hz,2H),1.46-1.20(m,12H),0.87-0.76(m,3H).HRMS(ESI)for C 25 H 34 N3O3[MH] - calcd 424.26057, found 424.26047.

[0312] Example 33: 5-Chloro-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)nicotinamide (I-44)

[0313] The specific synthesis steps are as follows:

[0314] The benzoic acid in the synthesis method of intermediate 12 was replaced by 3-chloronicotinic acid, and the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 37%. 1 H NMR (400MHz, DMSO-d6) δ9.95(s,1H),9.35(t,J=5.9Hz,1H),8.96(d,J=1.8Hz,1H),8.77(d,J=2.4Hz,1H),8.31(t,J=2.1Hz,1H),7.78-7.71(m,2H),7. 41-7.33(m,2H),5.05(s,1H),4.50(d,J=5.9Hz,2H),3.30-3.26(m,4H),2. 73(t,J=7.0Hz,2H),1.45-1.21(m,12H),0.85-0.80(m,3H).HRMS(ESI)forC 24 H 32 N4O3Cl[MH] -calcd459.34196,found 459.35047.

[0315] Example 34: N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)oxazole-4-carboxamide (I-45)

[0316] The specific synthesis steps are as follows:

[0317] The benzoic acid in the synthesis method of intermediate 12 was replaced by oxazole-4-carboxylic acid, and the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 28%. 1 H NMR (400MHz, DMSO-d6) δ9.93(s,1H),8.91(t,J=6.3Hz,1H),8.62(d,J=1.0Hz,1H),8.50(d,J=1.0Hz,1H),7.75-7.69(m,2H),7.35- 7.27(m,2H),4.42(d,J=6.3Hz,2H),3.30-3.26(m,4H),2.72(t,J=7.0Hz,2H),1.46-1.21(m,12H),0.84-0.79(m,3H).HRMS(ESI)for C 22 H 31 N4O4[MH] - calcd415.18244,found415.18368.

[0318] Example 35: N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)pyrimidine-5-carboxamide (I-46)

[0319] The specific synthesis steps are as follows:

[0320] The benzoic acid in the synthesis method of intermediate 12 was replaced by pyrimidine-5-carboxylic acid, and the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 24%. 1 H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.63(t,J=6.1Hz,1H),8.10(s,2H),7.74(d,J=8.1Hz,2H),7.32(d,J=8.0Hz,2H),4 .42(d,J=6.0Hz,2H),3.28-3.24(m,4H),2.77(t,J=7.1Hz,2H),1.44-1.19(m,12H),0.81(t,J=6.8Hz,3H).HRMS(ESI)for C 23 H 32 N5O3[MH]- calcd 426.27851, found 426.27936.

[0321] Example 36: N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)isoxazole-3-carboxamide (I-47)

[0322] The specific synthesis steps are as follows:

[0323] The benzoic acid in the synthesis method of intermediate 12 was replaced by 3-isoxazolecarboxylic acid, and the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 27%. 1 H NMR(400MHz, DMSO-d6)δ9.94(s,1H),9.38(t,J=6.2Hz,1H),9.06(d,J=1.7Hz,1H),7.76-7.71(m,2H),7.36-7.30(m, 2H),6.88(d,J=1.7Hz,1H),4.45(d,J=6.2Hz,3H),3.30-3.26(m,4H),2.72(t,J=7.0Hz,2H),1.45-1.21(m,12H),0.83 -0.79(m,3H).HRMS(ESI)for C 22 H 31 N4O4[MH] - calcd415.18354,found415.18378.

[0324] Example 37: N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)furan-3-carboxamide (I-48)

[0325] The specific synthesis steps are as follows:

[0326] The benzoic acid in the synthesis method of intermediate 12 was replaced by 3-furancarboxylic acid, and the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 34%. 1H NMR (400MHz, DMSO-d6) δ9.94(s,1H),8.75(t,J=6.1Hz,1H),8.18(dd,J=1.6,0.8Hz,1H),7.80-7.72(m,2H),7.70(t,J=1.7Hz,1H),7.35-7.28(m,2H) ,6.84(dd,J=1.9,0.8Hz,1H),4.42(d,J=6.0Hz,2H),3.30-3.25(m,4H),2.72(t,J=7.0Hz,2H),1.45-1.22(m,12H),0.84-0.79(m,3H).HRMS(ESI)for C 23 H 32 N3O4[MH] - calcd414.19624, found 414.19732.

[0327] Example 38: N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)tetrahydro-2H-pyran-4-carboxamide (I-49)

[0328] The specific synthesis steps are as follows:

[0329] The benzoic acid in the intermediate 12 was replaced by 4-pyrancarboxylic acid, the undecanal in Example 1 was replaced by the intermediate 5e, and the rest was the same as Example 1. The total yield was 29%. 1 H NMR(400MHz,Chloroform-d)δ9.94(s,1H),9.38(t,J=6.2Hz,1H),7.76-7.71(m,2H),7.36-7.30(m,2H),4.49-4.32(m,2H),4.09-3.90(m,2H), 3.40-3.34(m,4H),3.04-2.78(m,2H),2.54-2.33(m,2H),1.90-1.69(m,4H),1.66-1.51(m,6H),1.28(m,6H),0.90-0.83(m,3H).HRMS(ESI)for C 24 H 38 N3O4[MH] - calcd 432.34871, found 432.34914.

[0330] Example 39: 1-(2,6-dimethylphenyl)-3-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)urea (I-50)

[0331] The specific synthesis steps are as follows:

[0332] The benzoic acid in the synthesis method of intermediate 12 was replaced by 2,6-dimethylphenyl isocyanate, and the undecanal in Example 1 was replaced by intermediate 5e, and the rest was the same as Example 1. The total yield was 45%. 1 H NMR (400MHz, DMSO-d6) δ9.93(s,1H),7.78-7.71(m,2H),7.57(s,1H),7.31(d,J=8.2Hz,2H),7.04-6.95(m,3H),6.57(s,1H),5.04(s,1 H),4.27(d,J=6.1Hz,2H),3.30-3.23(m,4H),2.73(t,J=7.0Hz,2H),2.13(s,6H),1.46-1.21(m,12H),0.85-0.77(m,3H).HRMS(ESI)for C 27 H 39 N4O3[MH] - calcd 467.53571,found467.53764.

[0333] Example 12: In vitro and in vivo activity testing

[0334] 1. In vitro inhibitory activity test of HDAC1, 4, 6, 11

[0335] 1. Experimental methods:

[0336] 50 μL of HDAC buffer containing drugs was mixed with 10 μL of enzyme solution and pre-incubated for 5 min. After adding 40 μL of substrate, the reaction was carried out at 37°C for 30 min. Then, 100 μL of trypsin stop solution was added to terminate the reaction. The reaction was carried out at 37°C for 20 min, and the fluorescence intensity was measured at 390 nm / 460 nm.

[0337]

[0338] Finally, the inhibition rate (%) of the compound and its corresponding concentration were fitted with an S curve to calculate the IC 50 value.

[0339] 2. Cell proliferation inhibitory activity assay method:

[0340] The target compound was tested for its in vitro synergistic cell proliferation inhibition activity with sorafenib using the resazurin colorimetric assay. The experiment used human hepatoma cell lines HUH7 and MHCC97H, both of which were cultured in DMEM medium containing 10% fetal bovine serum. The experiment used cells in the logarithmic growth phase, which were digested with 0.5% trypsin, centrifuged at 1000r / min for 5min, and the supernatant was discarded. The cell pellet was mixed with culture medium to prepare a cell suspension. The cell suspension of the above cells was counted under an inverted microscope, and the culture medium was added to adjust the cell concentration to 5×10 4 / mL. Take a 96-well cell culture plate, set up a blank control group, sorafenib group, compound group and sorafenib combined with compound group, set up two parallel duplicate wells for each group, add 100 μL of cell suspension to each well, and fill the surrounding wells with sterile PBS. After 6 hours of cell attachment, add drugs, in which 100 μL of cell culture fluid is added to each well of the blank control group, 100 μL of cell culture fluid containing gradient dilution of sorafenib at different concentrations is added to each well of the sorafenib group, 100 μL of cell culture fluid containing gradient dilution of different concentrations of compound is added to each well of the compound group, and 100 μL of cell culture fluid containing fixed concentration of compound and gradient dilution of different concentrations of sorafenib is added to each well of the sorafenib combined with compound group. After the addition of drugs, the 96-well cell culture plate was cultured in an incubator at 37°C and 5% CO2 for 72 hours. After 72 h, 15 μL of resazurin (1 mg / mL) was added to each well and incubated for another 2 h. The fluorescence intensity was then measured using an ELISA reader at Ex / Em=560 nm / 590 nm. Graphpad prism 8.0 software was used for data analysis, antiproliferation curves were drawn, and IC 50 .

[0341] 3. Experimental results:

[0342] The results of the inhibitory activity are shown in Table 1 below. The experimental results show that the compounds have low nanomolar inhibitory activity against HDAC11, and most of the compounds have significantly higher activity than the positive control SIS17 and have no significant inhibitory activity against other HDAC subtypes, indicating that the compounds involved in the present invention have strong subtype selectivity. Among them, <100nM = A, 100-500nM = B, 500-1000nM = C, >1000nM = D.

[0343] Table 1 IC values ​​of compounds against HDAC1, 4, 6 and 11 50 value

[0344]

[0345]

[0346] In sorafenib-resistant hepatoma cells HUH7 and MHCC97H, compound I-18 showed significant synergistic effects with sorafenib in a dose-dependent manner, with an IC 50 Between 3-10 μM (such as Figure 1 and 2 As shown), compound I-18 has no anti-liver cancer activity. Therefore, the compounds involved in the present invention have a significant effect of reversing liver cancer drug resistance and do not have significant cytotoxicity.

[0347] 2. In vivo activity test

[0348] 1. Experimental methods:

[0349] Eight-week-old male C57 / BL6 mice were randomly divided into four groups (n=10), with the negative control group fed with a 10% fat diet, the positive control group and the drug-treated group fed with a high-fat diet, and their body weights were recorded weekly. After 12 weeks of feeding, the mice were killed and three mice from each group were taken to measure blood lipid content ( Figure 3 ). Three mice from the positive control group and the drug-treated group were selected for liver sectioning, fixed with formaldehyde solution, stained with oil red, and imaged using a fluorescence microscope.

[0350] 2. Experimental results

[0351] In a high-fat diet-induced mouse obesity model, at a dosage of 1 mg / kg and 2 mg / kg, Example I-18 was able to significantly reduce the body weight and blood lipid content of mice (eg Figure 3 and Figure 4 ), and significantly reduced the number and size of lipid droplets in tissues (as shown Figure 5 Therefore, the compound involved in the present invention has significant functions of reducing weight and regulating lipid metabolism.

[0352] It should be noted that the above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this field, several improvements and modifications can be made without departing from the principles of the invention. These improvements and modifications should not be excluded from the scope of protection of the present invention.

Claims

1. A compound represented by the general formula (II) as a histone deacetylase 11 inhibitor, a deuterated substance thereof or a pharmaceutically acceptable salt thereof: in: Ring A is selected from R2 substituent is selected from H, halogen, amino, nitro, hydroxyl or cyano; X is selected from O or S; L is selected from B, D, E, F, and G are carbon atoms; Z is selected from a bond; R1 is selected from C1-C 20 alkyl, m is selected from an integer between 1-10; n is selected from an integer between 1-10.

2. The compound according to claim 1, its deuterated substance or pharmaceutically acceptable salt, characterized in that: The compound of general formula (II) is one of the following: N-(4-(2-(9-methoxynonyl)hydrazine-1-carbonyl)benzyl)benzamide; N-(4-(2-(8-ethoxyoctyl)hydrazine-1-carbonyl)benzyl)benzamide; N-(4-(2-(7-propoxyheptyl)hydrazine-1-carbonyl)benzyl)benzamide; N-(4-(2-(6-butoxyhexyl)hydrazine-1-carbonyl)benzyl)benzamide; N-(4-(2-(10-hydroxydecyl)hydrazine-1-carbonyl)benzyl)benzamide; N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide; 4-Fluoro-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide; 4-Chloro-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide; 4-Bromo-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide; 4-iodo-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide; 4-methoxy-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide; 4-Hydroxy-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide; 4-nitro-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide; 4-amino-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide; N-(4-(2-(6-(2-methoxyethoxy)hexyl)hydrazine-1-carbonyl)benzyl)benzamide; N-(4-(2-(5-(2-ethoxyethoxy)pentyl)hydrazine-1-carbonyl)benzyl)benzamide; N-(4-(2-(12-methoxydodecyl)hydrazine-1-carbonyl)benzyl)benzamide; N-(4-(7,10,13,16-tetraoxo-2,3-diazoheptadecanyl)benzyl)benzamide; N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)nicotinamide; N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)pyrazine-2-carboxamide; N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)cyclohexanecarboxamide; N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)thiophene-2-carboxamide; 5-Chloro-N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)nicotinamide; N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)oxazole-4-carboxamide; N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)pyrimidine-5-carboxamide; N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)isoxazole-3-carboxamide; N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)furan-3-carboxamide; N-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)tetrahydro-2H-pyran-4-carboxamide; 1-(2,6-dimethylphenyl)-3-(4-(2-(5-(pentyloxy)pentyl)hydrazine-1-carbonyl)benzyl)urea.

3. A pharmaceutical composition, characterized in that The invention comprises the compound according to claim 1 or 2, its deuterated product or pharmaceutically acceptable salt as the main active ingredient and a pharmaceutically acceptable diluent or carrier, wherein the content of the compound, its deuterated product or pharmaceutically acceptable salt is 0.1-99.9wt%.

4. Use of the compound according to claim 1 or 2, its deuterated product or pharmaceutically acceptable salt in the preparation of histone deacetylase 11 inhibitors.

5. Use of the compound according to claim 1 or 2, its deuterated substance or pharmaceutically acceptable salt in the preparation of drugs for weight loss or regulating lipid metabolism.

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