An HDAC8 inhibitor and its preparation method and application

Abstract

The present invention discloses an HDAC8 inhibitor, its preparation method, and application. The HDAC8 inhibitor is a diketopiperazine derivative that can be used to treat diseases or conditions related to HDAC8 activity and to prepare anti-tumor / tumor immunity-enhancing and / or anti-inflammatory drugs for treating and preventing tumors and / or inflammation.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a diketopiperazine derivative that can be used as an HDAC8 inhibitor, and a preparation method and application thereof. Background Art

[0002] Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysine residues on histone and non-histone proteins. HDACs have established roles in epigenetics and tumor biology, and new cellular roles for these enzymes are being revealed at an astonishing rate.

[0003] Despite initial progress in preclinical models, most known histone deacetylase inhibitors (HDACis) have failed to demonstrate clinical efficacy as single agents in virtually all solid tumor types. Therefore, the efficacy of HDACis in solid tumors remains uncertain.

[0004] HDACis can target not only tumor cells themselves, but also the tumor microenvironment and immune environment, making HDAC inhibitors a promising strategy for eradicating cancers that evade the immune system. Currently, most HDACis in clinical research are non-selective, which can lead to serious side effects, the most common of which are thrombocytopenia, neutropenia, anemia, fatigue, and diarrhea. Therefore, the development of selective HDAC inhibitors has become an important scientific issue. However, due to the sequence and structural similarity of the kinase domains of HDAC family members, selective and precise regulation of each subtype is a major challenge.

[0005] HDAC8 is highly expressed in a variety of cancers, such as colon cancer, breast cancer, lung cancer, and neuroblastoma. Therefore, HDAC8 has been identified as a potential cancer therapeutic target and is also considered a suitable cancer cell biomarker, being upregulated in aggressive colon cancer, lung cancer, and pancreatic cancer, acute lymphoblastic leukemia, acute myeloid leukemia, and childhood neuroblastoma.

[0006] HDAC8 affects genomic integrity and is a novel therapeutic target for multiple myeloma. Histone deacetylase inhibitors (HDACi), such as OJI-1, are emerging as a promising therapeutic strategy in combination with current anti-myeloma drugs.

[0007] Studies have shown that HDAC8 is a therapeutic target for hematological malignancies. In acute myeloid leukemia (AML), after AML cell lines were treated with PCI-34051 (a selective HDAC8 inhibitor), HDAC8 inhibition caused cytotoxic effects, cell cycle arrest, and subsequent apoptosis in THP-1 cells, while it had a cytostatic effect in HL60 cells lacking p53.

[0008] In tumor immunity, studies have shown that non-selective HDAC inhibitors can show immunosuppressive effects in patients by reducing the activation of natural killer cells and dendritic cells and the production of cytokines. Such non-selective HDAC inhibitors can also enhance the production and immunosuppressive function of regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), thereby promoting tumor growth.

[0009] HDAC8, a member of the class I HDAC family, has attracted the attention of cancer researchers due to its aberrant expression in various human cancers. Previous studies have reported that in hepatocellular carcinoma, epigenetic modifications mediated by HDAC8 overexpression activate the Wnt / β-catenin signaling pathway, which can promote immune evasion and resistance to immune checkpoint inhibitors. Summary of the Invention

[0010] In a first aspect, the present invention provides an HDAC8 inhibitor, which is a compound having a chemical structure shown in Formula I below and / or a pharmaceutically acceptable salt thereof:

[0011]

[0012] In formula I, R1 is H, C1-C6 alkyl or 2-propynyl;

[0013] And / or, a compound having the chemical structure shown in the following Formula II and / or a pharmaceutically acceptable salt thereof:

[0014]

[0015] In formula II, R1 is H, C1-C6 alkyl or 2-propynyl, and R2 is C1-C12 alkylene, phenyl or benzyl;

[0016] And / or, a compound having the chemical structure shown in the following formula III and / or a pharmaceutically acceptable salt thereof:

[0017]

[0018] In formula III, R1 is H, C1-C6 alkyl or 2-propynyl, R3 is O or imino, and R4 is empty or phenyl;

[0019] And / or, a compound having the chemical structure shown in the following formula IV and / or a pharmaceutically acceptable salt thereof:

[0020]

[0021] In formula IV, R1 is H, C1-C6 alkyl or 2-propynyl, and M is 2 or 3;

[0022] And / or, a compound having the chemical structure shown in the following formula V and / or a pharmaceutically acceptable salt thereof:

[0023]

[0024] In formula V, R1 is H, C1-C6 alkyl or 2-propynyl, and R5 is substituted or unsubstituted phenyl, thienyl, furyl, naphthyl or biphenyl, wherein the substituent on the phenyl is C1-C6 alkyl, C1-C6 alkoxy, halogen, halogen-substituted C1-C6 alkyl or dimethylamino.

[0025] The HDAC8 inhibitor can be specifically selected from at least one of the following compounds or pharmaceutically acceptable salts thereof:

[0026]

[0027]

[0028] In a second aspect, the present invention provides use of the HDAC8 inhibitor described in the first aspect in the preparation of a medicament for inhibiting HDAC8.

[0029] In a third aspect, the present invention provides use of the HDAC8 inhibitor described in the first aspect in the preparation of a medicament for treating and / or preventing diseases associated with abnormal HDAC8 activity.

[0030] The disease may be inflammation and / or cancer.

[0031] The cancer may be breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, urothelial cancer, urethral cancer, prostate cancer, testicular cancer, colorectal cancer, sarcoma, bone cancer, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyomas, fibromas, lipomas, teratomas, pharyngeal cancer, nasopharyngeal cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, small intestine cancer, gastric cancer, esophageal cancer, pancreatic cancer, liver cancer, bile duct cancer, neurofibromas, gliomas, neuroblastomas, neuroblastomas, melanomas, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, gastrointestinal stromal tumors.

[0032] The inflammation may be enteritis, psoriasis, dermatitis, encephalitis, keratitis, conjunctivitis, rhinitis, otitis media, gingivitis, pharyngitis, tonsillitis, pneumonia, hepatitis, dysentery, prostatitis, endometritis, cervicitis, pelvic inflammatory disease, paronychia, or myocarditis.

[0033] In a fourth aspect, the present invention provides a pharmaceutical composition comprising one or more of a pharmaceutically acceptable carrier, a diluent, and an excipient, and the HDAC8 inhibitor described in the first aspect.

[0034] In a fifth aspect, the present invention provides a method for preparing the HDAC8 inhibitor described in the first aspect.

[0035] The HDAC8 inhibitor is a compound having a chemical structure as shown in Formula I, and its synthetic route A includes:

[0036]

[0037] In the synthetic route A, X is a halogen atom, compound a reacts with compound b and optionally added compound c (when compound c is not added, R1 in the subsequent product is H) in a Cs2CO3 N, N-dimethylformamide (DMF) solution to obtain compound d, and then under the action of acetic acid hydrazine (CH3COOH·NH2NH2), compound d is deprotected from the acetyl (Ac) protecting group in a methanol (CH3OH) solution of triethylamine (Et3N) to obtain compound e, which is then reacted under the action of trifluoroacetic acid (TFA) to obtain compound e. Compound e is subjected to deprotection of the tert-butyl protecting group in dichloromethane (DCM) to obtain compound f, compound f and compound g are subjected to amidation reaction in N,N-diisopropylethylamine (DIPEA) using a peptide condensation reagent HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) to obtain compound h, and compound h is reacted with p-toluenesulfonic acid monohydrate (pTsOH·H2O) in methanol (MeOH) to obtain a compound having the chemical structure shown in Formula I; or,

[0038] The HDAC8 inhibitor is a compound having a chemical structure as shown in Formula II, and its synthetic route B includes:

[0039]

[0040] In synthetic route B, compound f and compound i undergo an amidation reaction in N,N-diisopropylethylamine using a polypeptide condensation reagent HATU to obtain compound j, and then the tert-butyl protecting group of compound j is removed in dichloromethane under the action of trifluoroacetic acid to obtain compound k. Compound k and compound g undergo an amidation reaction in N,N-diisopropylethylamine using a polypeptide condensation reagent HATU to obtain compound m. Compound m is reacted with p-toluenesulfonic acid monohydrate in methanol to obtain a compound having a chemical structure shown in Formula II; or,

[0041] The HDAC8 inhibitor is a compound having a chemical structure as shown in Formula III, and its synthesis route is C1 or C2, wherein the synthesis route C1 includes:

[0042]

[0043] In synthetic route C1, X is a halogen atom, p-hydroxybenzaldehyde reacts with compound n in a K2CO3 N,N-dimethylformamide solution at 25-80°C to obtain compound o, compound o reacts with compound a and optionally added compound c in a Cs2CO3 N,N-dimethylformamide solution to obtain compound p, then the acetyl protecting group of compound p is removed in a methanol solution of triethylamine under the action of hydrazine acetate to obtain compound q, then the tert-butyl protecting group of compound q is removed in dichloromethane under the action of trifluoroacetic acid to obtain compound r, compound r and compound g undergo amidation reaction in N,N-diisopropylethylamine using a polypeptide condensation reagent HATU to obtain compound s, and compound s reacts with p-toluenesulfonic acid monohydrate in methanol to obtain a compound having the chemical structure shown in Formula III1;

[0044] Synthesis route C2 includes:

[0045]

[0046] In synthetic route C2, X is a halogen atom, compound a reacts with compound t and optionally added compound c in a Cs2CO3 N,N-dimethylformamide solution to obtain compound u, then, under the action of hydrazine acetate, compound u removes the acetyl protecting group in a methanol solution of triethylamine to obtain compound v, then, under the action of trifluoroacetic acid, compound v removes the tert-butyloxycarbonyl protecting group in dichloromethane to obtain compound w, compound w and compound b undergo an imine reduction reaction in an acetic acid / methanol mixture system under the action of sodium cyanoborohydride to obtain compound x, then, under the action of trifluoroacetic acid, compound x removes the tert-butyl protecting group in dichloromethane to obtain compound y, compound y and compound g undergo an amidation reaction in N,N-diisopropylethylamine using a polypeptide condensation reagent HATU to obtain compound z, and compound z reacts with p-toluenesulfonic acid monohydrate in methanol to obtain a compound having a chemical structure represented by formula III2; or,

[0047] The HDAC8 inhibitor is a compound having a chemical structure as shown in Formula IV, and its synthetic route D includes:

[0048]

[0049] In synthetic route D, compound f and compound a1 undergo an amidation reaction in N,N-diisopropylethylamine using a polypeptide condensation reagent HATU to obtain compound a2. Subsequently, the tert-butyloxycarbonyl (Boc) protecting group of compound a2 is removed in dichloromethane under the action of trifluoroacetic acid to obtain compound a3. Compound a3 and compound a4 undergo an amidation reaction in N,N-diisopropylethylamine using a polypeptide condensation reagent HATU to obtain compound a5. Subsequently, the tert-butyl protecting group of compound a5 is removed in dichloromethane under the action of trifluoroacetic acid to obtain compound a6. Compound a6 and compound g undergo an amidation reaction in N,N-diisopropylethylamine using a polypeptide condensation reagent HATU to obtain compound a7. Compound a7 is reacted with p-toluenesulfonic acid monohydrate in methanol to obtain a compound having the chemical structure shown in Formula IV; or,

[0050] The HDAC8 inhibitor is a compound having a chemical structure as shown in Formula V, and its synthetic route E includes:

[0051]

[0052] In synthetic route E, X is a halogen atom, compound b1 and compound b2 react in a 2-methylimidazole / N,N-dimethylformamide mixed system of PdCl2 and K2CO3 to obtain compound b3, compound b3 reacts with compound a and optionally added compound c in an N,N-dimethylformamide solution of Cs2CO3 to obtain compound b4, then the acetyl protecting group of compound b4 is removed in a methanol solution of triethylamine under the action of hydrazine acetate to obtain compound b5, then the tert-butyl protecting group of compound b5 is removed in dichloromethane under the action of trifluoroacetic acid to obtain compound b6, compound b6 and compound g undergo amidation reaction in N,N-diisopropylethylamine using a polypeptide condensation reagent HATU to obtain compound b7, and compound b7 reacts with p-toluenesulfonic acid monohydrate in methanol to obtain a compound having a chemical structure shown in Formula V.

[0053] Compared with the prior art, the present invention has the following beneficial effects: the HDAC8 inhibitor of the present invention has strong HDAC8 inhibitory activity, and the compound has the advantages of easy availability of reaction raw materials and easy preparation. In the field of preparing anti-tumor or anti-inflammatory drugs, it can be used as an anti-tumor or anti-inflammatory therapeutic agent. DETAILED DESCRIPTION

[0054] The present invention is further described below with reference to specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit its scope. The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and biological materials described are commercially available unless otherwise specified.

[0055] Example 1

[0056] The synthetic route is as follows:

[0057]

[0058] Step 1: Synthesis of tert-butyl (Z)-4-((4-acetyl-3,6-dioxo-1-(propynyl)piperazin-2-ylidene)methyl)benzoate

[0059]

[0060] 198.18 mg (1.0 mmol) of diacetyl diketopiperazine and 515.2 mg (2.5 mmol) of tert-butyl 4-formylbenzoate were accurately weighed and dissolved in 10 mL of DMF. 814.6 mg (2.5 mmol) of cesium carbonate was added. After the reaction flask was purged with nitrogen three times, 295 mg (2.5 mmol) of propargyl bromide was added to the reaction mixture. Under N2 protection, the mixture was stirred at room temperature for 5 hours. After the reaction was completed, 100 mL of water was added to dilute the mixture, followed by extraction with dichloromethane three times. The organic phases were collected and combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain tert-butyl (Z)-4-((4-acetyl-3,6-dioxo-1-(propynyl)piperazin-2-ylene)methyl)benzoate (yield 48.0%).

[0061] The structural confirmation data are as follows:

[0062] 1 H NMR(600MHz, CDCl3-d1)δ:8.03(d,J=8.4,2H),7.47(s,1H),7.41(d,J=7.8,2H),4.5 8(s,2H),4.27(d,J=2.6,2H),2.66(s,3H),2.15(t,J=2.6,1H),1.62(s,3H).ESI-MS m / z: 383.1602[M+H] + .

[0063] Step 2: Synthesis of tert-butyl (Z)-4-((3,6-dioxo-1-(propynyl)piperazin-2-ylidene)methyl)benzoate

[0064]

[0065] Accurately weigh 25.0 mg (0.077 mmol) of (Z)-4-((4-acetyl-3,6-dioxo-1-(propynyl)piperazine-2-ylidene)methyl)benzoic acid tert-butyl ester and dissolve it in 2 mL of methanol. Weigh 21.2 mg (0.23 mmol) of hydrazine acetate and 23.3 mg (0.23 mmol) of triethylamine, and stir at room temperature for 5 hours. After the reaction is completed, concentrate under reduced pressure to obtain a crude product, which is separated by silica gel column chromatography to obtain (Z)-4-((3,6-dioxo-1-(propynyl)piperazine-2-ylidene)methyl)benzoic acid tert-butyl ester (yield 84.5%).

[0066] The structural confirmation data are as follows:

[0067] 1H NMR(600MHz, CDCl3-d1)δ:8.01(d,J=8.4,2H),7.39(d,J=7.8,2H),7.38(s,1 H),4.27(d,J=2.6,2H),4.18(s,2H),2.13(t,J=2.6,1H),1.61(s,3H).ESI-MS m / z: 341.1496[M+H] + .

[0068] Step 3: Synthesis of (Z)-4-((3,6-dioxo-1-(propynyl)piperazin-2-ylidene)methyl)benzoic acid

[0069]

[0070] Accurately weigh 137.9 mg (0.41 mmol) of tert-butyl (Z)-4-((3,6-dioxo-1-(propynyl)piperazine-2-ylidene)methyl)benzoate and dissolve it in 3 mL of dichloromethane (CH2Cl2). Add an equal volume of trifluoroacetic acid (TFA), stir at room temperature for 3 h, and concentrate under reduced pressure to obtain (Z)-4-((3,6-dioxo-1-(propynyl)piperazine-2-ylidene)methyl)benzoic acid (yield 100%).

[0071] The structural confirmation data are as follows:

[0072] 1 H NMR(600MHz, DMSO-d6)δ:8.02(d,J=8.4,2H),7.60(d,J=7.8,2H),6.84(s,1H),4.73(d,J=2.3,2H),3.84(s,2H),2.66(t,J=2.4,1H).ESI-MS m / z:285.0870[M+H] + .

[0073] Step 4: Synthesis of (Z)-4-((3-6-dioxo-1-(propynyl)piperazin-2-ylidene)methyl)-N-benzamide ((tetrahydro-2H-pyran)-2-oxy)

[0074]

[0075] 30.0 mg (0.078 mmol) of (Z)4-((3,6-dioxo-1-(propynyl)piperazine-2-ylidene)methyl)benzoic acid was accurately weighed and dissolved in 2 mL of DMF. 60.6 mg (0.16 mmol) of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and 54.6 mg (0.42 mmol) of N,N-diisopropylethylamine (DIPEA) were weighed and stirred at room temperature for 6 h. The crude product obtained after concentration under reduced pressure was separated by silica gel column chromatography to obtain (Z)-4-((3-6-dioxo-1-(propynyl)piperazine-2-ylidene)methyl)-N-benzamide ((tetrahydro-2H-pyran)-2-oxygen) (yield 52.1%).

[0076] The structural confirmation data are as follows:

[0077] 1 H NMR(600MHz,DMSO-d6)δ:7.96(d,J=8.4,2H),7.61(d,J=7.8,2H),6.76(s,1H),4.99(t,J=6.7,1 H), 4.69(d,J=2.3,2H),3.75(m,2H),2.66(t,J=2.4,1H),1.80(m,2H),1.61-1.65(m,4H).ESI-MS m / z: 406.1374[M+Na] + .

[0078] Step 5: Synthesis of Compound 1

[0079]

[0080] 30.0 mg (0.078 mmol) of (Z)-4-((3-6-dioxo-1-(propynyl)piperazine-2-ylidene)methyl)-N-benzamide ((tetrahydro-2H-pyran)-2-oxy) was accurately weighed and dissolved in 2 mL of methanol. 3.0 mg (0.016 mmol) of p-toluenesulfonic acid monohydrate (pTsOH·H2O) was added and the mixture was allowed to react overnight at room temperature. After completion of the reaction, the crude product was concentrated under reduced pressure and purified by HPLC (20-100% methanol + 0.1% trifluoroacetic acid / water + 0.1% trifluoroacetic acid for 40 min) to give Compound 1 (yield 81.6%).

[0081] The structural confirmation data of compound 1 are as follows:

[0082] 1H NMR(600MHz,DMSO-d6)δ:11.29(s,1H),9.10(s,1H),8.47(s,1H),7.77(d,J=8.4,2H),7.4 8(d,J=7.8,2H),7.11(s,1H),4.13(d,J=2.1,1H), 4.02(d,J=2.1,2H),3.12(t,J=2.7,2H). 13 C NMR(151MHz,DMSO-d6)δ:165.56,163.57,163.03,136.16,132.45,130.79,129.33,126.97,119.57,77.99,74.71,44.47,33.11.ESI-MS m / z: 300.0972[M+H] + .

[0083] Example 2

[0084] With reference to Example 1, methyl iodide was used in place of propyne bromide in Step 1 to obtain Compound 2.

[0085] Compound 2: 1 H NMR (600MHz, DMSO-d6): δ11.27(s,1H),10.09(s,1H),9.05(s,1H),8.36(s,1H), 7.77(d,J=8.5Hz,2H),7.55(d,J=8.0Hz,2H),6.69(s,1H),4.01(d,J=2.1Hz,2H). 13 C NMR (151MHz, DMSO-d6) δ164.7,159.7,136.3,131.5,129.1,127.0,112.8,48.6,44.8.ESI-MS m / z: 262.0813[M+H] + .

[0086] Example 3 to Example 10

[0087] The synthetic route is as follows:

[0088]

[0089] First, compound f was synthesized with reference to Example 1, and then each reaction step was completed by replacing the corresponding substrate with reference to the corresponding reaction conditions of Example 1 to obtain the corresponding compound.

[0090] Compound 3: 11H NMR (600 MHz, DMSO-d6): δ 10.33 (s, 1H), 8.49 (t, J = 5.6 Hz, 1H), 8.43 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.00 (s, 1H), 4.00 (d, J = 2.1 Hz, 2H), 3.96 (s, 2H), 3.24 (q, J = 7.1 Hz, 2H), 2.71 (s, 3H), 1.94 (t, J = 7.3 Hz, 2H), 1.46 - 1.51 (m, 4H), 1.24 - 1.30 (m, 4H). 13 1H NMR (151 MHz, CD3OD-d4) δ 169.1, 165.7, 165.6, 162.5, 136.6, 133.9, 133.5, 129.3, 127.0, 117.2, 55.0, 48.6, 44.6, 34.7, 32.2, 29.0, 28.3, 26.2, 25.1. ESI-MS m / z: 403.1976 [M+H] + .

[0091] Compound 4: 1 1H NMR (600 MHz, DMSO-d6): δ 11.14 (s, 1H), 10.51 (s, 1H), 8.97 (s, 1H), 8.50 (s, 1H), 7.99 (d, J = 8.9 Hz, 2H), 7.85 (d, J = 8.9 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.17 (s, 1H), 4.18 (d, J = 2.1 Hz, 2H), 4.05 (d, J = 1.8 Hz, 2H), 3.17 (d, J = 5.1 Hz, 2H), 3.16 (d, J = 2.4 Hz, 2H). 13 1H NMR (151 MHz, DMSO-d6) δ 165.5, 165.2, 162.9, 134.3, 131.0, 129.6, 129.3, 127.9, 127.6, 127.0, 119.6, 119.4, 77.9, 74.9, 74.8, 44.5, 33.1. ESI-MS m / z: 419.1350 [M+H]<0OO0020>.

[0092] Compound 5:<000002l>¹H NMR (600 MHz, DMSO-d₆): δ 11.14 (s, 1H), 10.49 (s, 1H), 8.46 (s, 1H), 7.98 (d, J = 8.9 Hz, 2H), 7.86 (d, J = 8.9 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.04 (s, 1H), 4.03 (d, J = 1.8 Hz, 2H), 2.75 (s, 3H). 13 ¹³C NMR (151 MHz, DMSO-d₆) δ 165.7, 162.4, 137.5, 133.8, 133.2, 129.4, 127.6, 125.8, 119.6, 117.5, 117.0, 54.9, 53.6, 48.58, 44.6, 34.8, 18.1, 16.7. ESI-MS m / z: 395.1350 [M+H] + 。

[0093] Compound 6:<了 1 ¹H NMR (600 MHz, DMSO-d₆): δ 11.17 (s, 1H), 9.17 (t, J = 6.0 Hz, 1H), 8.99 (s, 1H), 7.92 (d, J = 7.9 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 7.9 Hz, 2H), 7.13 (s, 1H), 4.51 (d, J = 6.8 Hz, 2H), 4.14 (d, J = 1.8 Hz, 2H), 4.03 (d, J = 2.9 Hz, 2H), 3.12 (t, J = 2.4 Hz, 1H). 13 ¹³C NMR (151 MHz, DMSO-d₆) δ 170.₃, 165.7, 165.5, 163.0, 136.4, 129.3, 127.4, 127.1, 126.9, 119.5, 78.0, 74.7, 59.7, 54.9, 44.5, 42.4, 33.1. ESI-MS m / z: 433.1507 [M+H] + 。

[0094] Compound 7: 1 It should be noted that there seems to be an incorrect character "了" in the tag . Please check and correct it if necessary.1H NMR (600 MHz, DMSO-d6): δ 11.18 (brs, 1H), 9.16 (t, J = 6.0 Hz, 1H), 8.99 (s, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.01 (s, 1H), 4.51 (d, J = 5.8 Hz, 2H), 4.14 (d, J = 1.8 Hz, 2H), 4.01 (d, J = 2.0 Hz, 2H), 2.72 (s, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 165.8, 165.7, 162.5, 142.9, 137.0, 133.6, 133.3, 131.3, 129.4, 127.1, 127.1, 126.9, 117.1, 48.6, 44.6, 42.4, 34.8. ESI-MS m / z: 409.1507 [M + H]<......> 。

[0095] Compound 8: 1 1H NMR (600 MHz, DMSO-d6): δ 11.17 (brs, 1H), 10.10 (s, 1H), 9.14 (s, 1H), 9.00 (s, 1H), 8.37 (s, 1H), 7.92 (d, J = 6.6 Hz, 2H), 7.71 (d, J = 6.6 Hz, 2H), 7.58 (d, J = 6.6 Hz, 2H), 7.38 (d, J = 6.6 Hz, 2H), 6.71 (s, 1H), 4.53 (d, J = 3.3 Hz, 2H), 4.01 (s, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 165.23, 161.87, 160.27, 157.58, 130.09, 129.62, 128.55, 128.01, 127.54, 127.47, 125.05, 117.83, 113.38, ....... + 。

[0096] Compound 9: 1H NMR (600MHz, DMSO-d6): δ11.21 (s, 1H), 10.46 (s, 1H), 9.06 (s, 1H), 8.50 (s, 1H), 8.19 (td, J = 6.2Hz; J = 2.8Hz, 1H), 8.01 (d, J = 8. 5Hz,2H),7.56(d,J=8.5Hz,2H),7.43(m,2H),7.17(s,1H),4.18(d,J=2.2Hz,2H),4.05(d,J=2.2Hz,2H),3.14(t,J=2.4Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ165.6,165.0,164.2,163.0,139.2,136.8,134.3,133.4, 131.0,129.3,128.6,127.8,122.9,121.7,120.0,78.0,74.8,44.5,33.1.ESI-MS m / z: 419.1350[M+H] + .

[0097] Compound 10: 1 H NMR (600MHz, CD3OD-d4): δ7.91(d,J=7.4Hz,2H),7.76(s,1H),7.64(d,J=7.4Hz,1H),7.55(d,J=7.4Hz,1H), 7.44(d,J=7.7Hz,1H),7.28(s,1H),4.63(s,2H),4.25(d,J=2.2Hz,2H),4.10(s,2H),2.55(t,J=2.4Hz,1H). 13 C NMR(151MHz,CD3OD-d4)δ169.4,168.1,167.3,166.0,140.9,138.3,135.6,133.9, 131.9,131.7,130.7,129.9,128.7,127.3,126.9,122.7,45.8,44.3,34.7.ESI-MS m / z: 433.1507[M+H] + .

[0098] Example 11 to Example 23

[0099] The synthetic route is as follows:

[0100]

[0101] According to the above synthetic route, the same reaction process as in Example 1 adopts the same reaction conditions. The other reaction processes are described as follows:

[0102] 1) p-Hydroxybenzaldehyde reacts with compound n in a K2CO3 N,N-dimethylformamide solution at 25-80°C to obtain compound o. Depending on the product, the corresponding R4 group in compound n is selected.

[0103] 2) Compound w and compound b undergo imine reduction reaction in an acetic acid / methanol mixture system under the action of sodium cyanoborohydride to obtain compound x.

[0104] Compound 11: 1 H NMR (600MHz, DMSO-d6): δ11.17(s,1H),8.17(s,1H),7.70(d,J=8.6Hz,2H),7.41(d,J=8.6Hz,2H),7.07 (d,J=8.6Hz,2H),6.80(s,1H),6.59(d,J=8.6Hz,2H),3.96(s,2H),3.89(d,J=2.2Hz,2H),2.79(s,3H). 13 C NMR(151MHz,DMSO-d6)δ165.89,159.02,157.27,149.13,148.69,135.17,131.0 3,129.45,128.68,127.05,126.94,120.45,111.76,48.56,44.68,34.00.ESI-MS m / z: 381.1558[M+H] + .

[0105] Compound 12: 1 H NMR (600MHz, DMSO-d6): δ11.23(s,1H),9.06(t,J=6.0Hz,1H),8.31(s,1H),7.90(d,J=7.9Hz,2H),7.53(d,J=7.9H z,2H),7.30(d,J=7.9Hz,2H),7.06(d,J=7.9Hz,2H),6.92(s,1H),5.19(s,2H),3.96(d,J=1.8Hz,2H),2.75(s,3H). 13 C NMR (151MHz, DMSO-d6) δ165.8,164.0,163.2,158.1,140.0,132.3,131.3,131.1,127.5,127.1,126.2,118.5,114.6,68.7,44.7,34.3.ESI-MS m / z: 382.1398[M+H] + .

[0106] Compound 13:1 H NMR (600MHz, DMSO-d6): δ10.86(s,1H),8.31(s,1H),7.30(d,J=9.0Hz,2H),6.99 (d,J=7.9Hz,2H),6.92(s,1H),4.49(s,2H),3.96(d,J=2.2Hz,2H),2.74(s,3H). 13 C NMR (151MHz, DMSO-d6) δ165.8,164.1,163.2,157.6,131.4,131.0,126.6,118.4,114.5,65.8,48.6,44.7,34.3.ESI-MS m / z: 328.0904[M+Na] + .

[0107] Example 14 to Example 17

[0108] The synthetic route is as follows:

[0109]

[0110] First, compound f was synthesized with reference to Example 1, and then each reaction step was completed by replacing the corresponding substrate with reference to the corresponding reaction conditions of Example 1 to obtain the corresponding compound.

[0111] Compound 14: 1 H NMR (600MHz, CD3OD-d4): δ7.90(d,J=8.3Hz,2H),7.86(d,J=8.3Hz,2H),7.82(d,J=8.2Hz,1H),7.50(d,J=8. 2Hz,1H),7.27(s,1H),4.63(s,2H),4.23(d,J=2.2Hz,2H),4.10(s,2H),3.64(s,4H),2.55(d,J=2.2Hz,1H). 13 C NMR(151MHz,CD3OD-d4)δ171.94,169.92,169.74,167.34,166.02,138.53,138.16,136.40,135.81, 131.72,130.89,130.64,128.65,128.61,128.33,122.71,78.11,73.98,45.83,40.93,34.68.ESI-MS m / z: 490.1722[M+H] + .

[0112] Compound 15: 11H NMR (600 MHz, DMSO-d6): δ 11.33 (s, 1H), 9.13 (d, J = 1.8 Hz, 1H), 8.72 (t, J = 5.2 Hz, 1H), 8.67 (t, J = 5.2 Hz, 1H), 8.43 (t, J = 2.0 Hz, 1H), 7.90 (dd, J = 8.4 Hz; J = 1.6 Hz, 2H), 7.86 (dd, J = 8.4 Hz; J = 1.6 Hz, 2H), 7.82 (dd, J = 8.4 Hz; J = 1.6 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.00 (s, 1H), 4.00 (d, J = 2.0 Hz, 2H), 3.45 (t, J = 2.5 Hz, 4H), 2.71 (s, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 166.0, 165.6, 163.5, 162.5, 136.8, 135.0, 133.7, 133.5, 129.3, 127.1, 126.8, 117.2, 44.6, 34.7. ESI-MS m / z: 466.1722 [M+H] + .

[0113] Compound 16: 1 1H NMR (600 MHz, CD3OD-d4): δ 7.92 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 4.25 (d, J = 2.0 Hz, 2H), 4.10 (s, 2H), 3.98 (s, 1H), 3.50 (t, J = 2.0 Hz, 2H), 2.55 (t, J = 2.0 Hz, 1H), 1.93 (q, J = 6.0 Hz, 1H). 13 13C NMR (151 MHz, CD3OD-d4) δ 169.6, 169.4, 167.4, 166.0, 138.5, 138.1, 136.4, 135.9, 131.7, 130.7, 128.6, 128.6, 128.4, 122.7, 78.1, 74.0, 55.1, 45.8, 38.4, 34.7, 30.3. ESI-MS m / z: 466.1722 [M+H] + .

[0114] Compound 17: 1H NMR (600MHz, DMSO-d6): δ11.32(s,1H),9.12(s,1H),8.60(t,J=5.5Hz,1H),8.55(t,J =5.5Hz, 1H), 8.42 (s, 1H), 7.90 (dd, J = 8.4Hz; J = 1.9Hz, 2H), 7.86 (dd, J = 8.4Hz; J = 1.9 Hz, 2H), 7.82 (dd, J = 8.4Hz; J = 1.9Hz, 2H), 7.43 (dd, J = 8.4Hz; J = 1.9Hz, 2H), 7.00 (s, 1 H), 4.00 (d, J = 2.0Hz, 2H), 3.44 (q, J = 6.6Hz, 4H), 2.72 (s, 3H), 1.79 (q, J = 6.0Hz, 1H). 13 C NMR(151MHz,DMSO-d6)δ165.7,165.6,165.6,163.5,162.5,136.8,136.7,135.0,133.7 ,133.5,129.3,127.2,127.0,126.9,117.2,48.6,44.6,37.2,37.1,34.7,29.2.ESI-MS m / z: 480.1878[M+H] + .

[0115] Example 18 to Example 31

[0116] The synthetic route is as follows:

[0117]

[0118] Following the above synthetic route, the same reaction process and conditions as in Example 1 were employed. The remaining reaction processes are described below: Compound b1 reacted with Compound b2 in a mixture of PdCl2 and K2CO3 in 2-methylimidazole / N,N-dimethylformamide to yield Compound b3. The corresponding R5 group in Compound b1 was selected based on the product.

[0119] Compound 18: 1 H NMR (600MHz, DMSO-d6): δ10.79(s,1H),8.40(s,1H),7.60(d,J=8.1Hz,1H),7.45(d,J=15.7Hz,1H),7.38 (d,J=8.1Hz,2H),6.97(s,1H),6.50(d,J=15.7Hz,1H),4.00(d,J=2.0Hz,2H),3.17(s,1H),2.75(s,3H). 13C NMR (151MHz, DMSO-d6) δ165.7,162.7,162.6,137.6,134.9,134.4,133.1,130.0,127.3,119.6,117.6,44.6,34.7.ESI-MS m / z: 302.1136[M+H] + .

[0120] Compound 19: 1 H NMR (600MHz, DMSO-d6): δ10.76(s,1H),9.06(s,1H),8.44(s,1H),7.44(s,1H),7.42(d,J=15.6Hz,1H),7.40(d,J=3.3 Hz,2H),7.22(d,J=8.6Hz,1H),6.97(s,1H),6.48(d,J=15.7Hz,1H),4.02(d,J=2.0Hz,2H),2.60(s,3H),2.28(s,3H). 13 C NMR (151MHz, DMSO-d6) δ165.3,162.7,162.2,137.8,137.2,134.5,133.6,129.9,128.9,124.6,119.4,116.4,44.6,34.2,19.7.ESI-MS m / z: 316.1292[M+H] + .

[0121] Compound 20: 1 H NMR (600MHz, DMSO-d6): δ10.80(s,1H),9.07(s,1H),8.40(s,1H),7.64(d,J=15.6Hz,1H),7.20(d,J =8.0Hz,1H),6.93(s,1H),6.41(d,J=15.7Hz,1H),4.00(d,J=2.0Hz,2H),2.75(s,3H),2.38(s,3H). 13 C NMR (151MHz, DMSO-d6) δ165.6,162.6,136.6,135.0,134.7,133.3,132.9,131.7,127.5,125.7,120.8,117.6,44.6,34.7,19.3.ESI-MS m / z: 316.1292[M+H] + .

[0122] Compound 21: 1H NMR (600MHz, DMSO-d6): δ10.78(s,1H),8.41(s,1H),7.64(d,J=15.6Hz,1H),7.53(d,J=8.1Hz,1H),7.05(s,1H),6.97(s,1H),6 .94(d,J=8.0Hz,1H),6.55(d,J=15.7Hz,1H),4.11(q,J=6.9Hz,2H),4.01(d,J=2.0Hz,2H),2.77(s,3H),1.40(t,J=6.9Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ165.65,162.56,156.41,136.35,133.11,127.86,1 21.91,119.89,117.74,113.46,63.80,48.57,44.63,34.66,14.61.ESI-MS m / z: 346.1398[M+H] + .

[0123] Compound 22: 1 H NMR (600MHz, DMSO-d6): δ10.75(s,1H),8.41(s,1H),7.65(d,J=15.6Hz,1H),7.54(d,J=8.0Hz,1H),7.08(s,1H ),6.98(s,1H),6.95(d,J=8.0Hz,1H),6.53(d,J=15.7Hz,1H),4.01(d,J=2.0Hz,2H),3.87(s,3H),2.78(s,3H). 13 C NMR (151MHz, DMSO-d6) δ165.7,162.6,157.1,136.4,133.1,132.7,127.6,122.9,122.0,119.9,117.7,112.7,55.7,44.6,34.7.ESI-MS m / z: 332.1241[M+H] + .

[0124] Compound 23: 11H NMR (600 MHz, DMSO-d6): δ 10.82 (brs, 1H), 8.49 (s, 1H), 7.49 (d, J = 15.6 Hz, 1H), 7.47 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 6.90 (s, 1H), 6.55 (d, J = 15.7 Hz, 1H), 4.01 (d, J = 2.0 Hz, 2H), 2.74 (s, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 165.3, 161.9, 160.5, 158.9, 134.9, 131.6, 123.1, 121.1, 114.2, 114.0, 109.7, 44.6, 34.1. ESI-MS m / z: 320.1042 [M+H] + 。

[0125] Compound 24: 1 1H NMR (600 MHz, DMSO-d6): δ 10.82 (brs, 1H), 8.55 (s, 1H), 7.97 (s, 1H), 7.90 (d, J = 8.0, 1H), 7.56 (d, J = 15.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 1.8 Hz, 1H), 6.63 (d, J = 15.7 Hz, 1H), 4.04 (d, J = 2.0 Hz, 2H), 2.60 (s, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 165.3, 161.4, 136.2, 135.1, 135.0, 133.5, 132.2, 130.6, 124.9, 123.0, 121.5, 112.4, 44.6, 34.5. ESI-MS m / z: 370.1010 [M+H] + 。

[0126] Compound 25: 1 1H NMR (600 MHz, DMSO-d6): δ 10.79 (brs, 1H), 9.01 (s, 1H), 8.34 (s, 1H), 7.63 (d, J = 16.0 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.35 (dd, J = 8. Hz; J = 1.8 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.94 (s, 1H), 6.54 (d, J = 16.0 Hz, 1H), 3.98 (d, J = 2.0 Hz, 2H), 3.34 (brs, 2H), 2.75 (s, 3H). 1313C NMR (151 MHz, DMSO-d6) δ 165.7, 163.0, 157.3, 133.1, 132.0, 131.7, 129.4, 126.1, 123.0, 120.3, 117.9, 111.6, 55.8, 44.7, 34.3. ESI-MS m / z: 332.1241 [M+H] + 。

[0127] Compound 26: 1 1H NMR (600 MHz, DMSO-d6): δ 10.82 (brs, 1H), 9.00 (s, 1H), 8.34 (s, 1H), 7.63 (d, J = 16.0 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 8.0 Hz; J = 1.8 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 6.56 (d, J = 16.0 Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.98 (d, J = 2.0 Hz, 2H), 3.34 (brs, 2H), 2.75 (s, 3H), 1.41 (t, J = 7.0 Hz, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 165.7, 163.1, 163.0, 156.7, 133.4, 132.0, 131.6, 126.0, 123.0, 120.4, 117.9, 112.3, 63.9, 44.7, 34.4, 14.6. ESI-MS m / z: 346.1398 [M+H] + 。

[0128] Compound 27: 1 1H NMR (600 MHz, DMSO-d6): δ 10.80 (brs, 1H), 8.34 (s, 1H), 7.64 (d, J = 16.0 Hz, 1H), 7.39 (d, J = 1.8 Hz, 1H), 7.29 (dd, J = 8.0 Hz; J = 1.8 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.94 (s, 1H), 6.39 (d, J = 1,6.0 Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.98 (d, J = 2.0 Hz, 2H), 2.78 (s, 3H), 2.72 (s, 3H). 13C NMR (151MHz, DMSO-d6) δ165.7,163.0,158.1,131.4,131.2,128.9,127.3,118.8,118.1,118.0,114.6,44.6,44.2,34.4.ESI-MS m / z: 345.1558[M+H] + .

[0129] Compound 28: 1 H NMR (600MHz, DMSO-d6): δ10.71(brs,1H),9.08(brs,1H),8.42(s,1H),7.59(d,J=16.0Hz,1H),7.38(d,J=3 .9Hz,1H),7.17(d,J=3.9Hz,1H),7.01(s,1H),6.23(d,J=16.0Hz,1H),3.96(d,J=2.0Hz,2H),2.97(s,3H). 13 C NMR (151MHz, DMSO-d6) δ166.0,162.7,162.2,141.76,136.6,132.6,131.5,131.1,130.9,118.7,111.3,48.6,44.6,34.8.ESI-MS m / z: 308.0700[M+H] + .

[0130] Compound 29: 1 H NMR (600MHz, DMSO-d6): δ10.93(brs,1H),9.06(brs,1H),8.43(s,1H),7.28(d,J=16.0Hz,1H),6.91(d,J=3 .9Hz,1H),6.90(d,J=3.9Hz,1H),6.83(s,1H),6.24(d,J=16.0Hz,1H),3.99(d,J=2.0Hz,2H),3.13(s,3H). 13 C NMR (151MHz, DMSO-d6) δ165.5,162.5,152.4,149.4,130.3,125.1,117.8,117.5,116.4,105.3,48.6,44.5,35.2.ESI-MS m / z: 292.0928[M+H] + .

[0131] Compound 30: 1H NMR (600MHz, DMSO-d6): δ10.83(brs,1H),9.09(brs,1H),8.44(s,1H),8.07(s,1H),7.95(dd,J=8.4Hz; J=3.9Hz,2H),7.89(s,1H),7 .74(d,J=8.4Hz,1H),7.62(d,J=16.0Hz,1H),7.51(d,J=3.9Hz,1H),7.13(s,1H),6.61(d,J=16.0Hz,1H),4.04(s,2H),3.75(s,3H). 13 C NMR(151MHz,DMSO-d6)δ166.26,163.27,163.22,138.71,133.76,133.60,133.42,132.97,13 2.88,129.30,129.14,128.87,128.67,128.29,124.79,120.33,118.55,45.25,35.33.ESI-MS m / z: 352.1292[M+H] + .

[0132] Compound 31: 1 H NMR (600MHz, DMSO-d6): δ10.78(brs,1H),8.40(s,1H),7.79(d,J=8.4Hz,2H),7.77(d,J=8.4Hz,2H),7.68(d,J=8.4Hz,2H ),7.50(d,J=16.0Hz,1H),7.46(d,J=8.0Hz,1H),7.02(s,1H),6.52(d,J=16.0Hz,1H),4.01(d,J=2.0Hz,2H),2.70(s,3H). 13 C NMR (151MHz, DMSO-d6) δ165.7,162.8,140.1,138.7,134.2,133.4,132.8,130.2,128.1,127.0,126.3,119.2,117.8,44.7,34.7.ESI-MS m / z: 378.1449[M+H] + .

[0133] Evaluation of HDAC inhibitory activity

[0134] (1) Set up the experimental group, control group and 100% group, see Table 1.

[0135] Table 1 HDAC8 fluorescence analysis grouping

[0136] Group HDAC8 enzyme dilution solution solvent Compound Fluorescent substrates 100% group 25 μL 5μL 20 μL Blank group 30 μL 20 μL Experimental group 25 μL 5μL 20 μL

[0137] (2) Experimental Procedure: In the 100% and experimental groups, 5 μL of solvent or different concentrations of compound and HDAC8 enzyme dilution were added to a black 96-well plate and incubated at 37°C for 5 min. In the blank group, 30 μL of solvent was added to each well. Then, 20 μL of fluorescent substrate was added to all wells and incubated at 37°C for 30-60 min. Subsequently, 50 μL of pancreatic enzyme solution was added to each well, and the incubation continued for 30 min before the fluorescence value was measured on a microplate reader. Each group was measured in triplicate.

[0138] The inhibition rate of the compound was calculated according to the following formula, and the IC of the compound was calculated using Graphicpad Prism 9. 50 value.

[0139] The determination method of HDAC1 and HDAC6 is the same as that of HDAC8, and the relevant substrates are shown in Table 2 below.

[0140] Table 2 Substrates for fluorescence analysis of different HDAC isoforms

[0141] HDAC isoforms HDAC substrates HDAC1 Ac-Leu-Gly-Lys(Ac)-AMC HDAC6 Ac-Leu-Gly-Lys(Ac)-AMC HDAC8 Ac-Leu-Gly-Lys(tfa)-AMC

[0142] (3) The experimental results are shown in Table 3.

[0143] Table 3 Inhibitory effects of compounds 1 to 38 on HDAC1, 6, and 8

[0144]

[0145]

[0146] Note: The positive drug (TSA) is Trichostatin A (Synonyms: Trichostatin A).

[0147] The results of HDAC inhibitory activity screening showed that most of the compounds of the present invention had good inhibitory activity against HDAC1, 6, and 8, among which three compounds were screened out with IC 50 The concentration was below 1 nM and the selectivity was high, as shown in Table 4.

[0148] Table 4 Selectivity of diketopiperazine derivatives for HDAC1, 6, and 8

[0149]

[0150] As shown in Table 4, there are three compounds with IC values ​​of 50The concentration has reached below 1 nM, and the selectivity is high, ranging from 100-11,000 times for HDAC1 and HDAC6. This class of drugs provides a theoretical basis for the discovery of new highly selective HDAC8 inhibitors and provides a lead compound for the development of anti-tumor / tumor immunity-enhancing / anti-inflammatory drugs.

[0151] In addition, it should be understood that after reading the above description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. An HDAC8 inhibitor, characterized in that A compound having the chemical structure shown in the following formula I and / or a pharmaceutically acceptable salt thereof: In formula I, R1 is H, C1-C6 alkyl or 2-propynyl; And / or, a compound having the chemical structure shown in the following Formula II and / or a pharmaceutically acceptable salt thereof: In formula II, R1 is H, C1-C6 alkyl or 2-propynyl, and R2 is C1-C12 alkylene, phenyl or benzyl; And / or, a compound having the chemical structure shown in the following formula III and / or a pharmaceutically acceptable salt thereof: In formula III, R1 is H, C1-C6 alkyl or 2-propynyl, R3 is O or imino, and R4 is empty or phenyl; And / or, a compound having the chemical structure shown in the following formula IV and / or a pharmaceutically acceptable salt thereof: In formula IV, R1 is H, C1-C6 alkyl or 2-propynyl, and M is 2 or 3; And / or, a compound having the chemical structure shown in the following formula V and / or a pharmaceutically acceptable salt thereof: In formula V, R1 is H, C1-C6 alkyl or 2-propynyl, and R5 is thienyl, furyl, naphthyl, biphenyl or substituted or unsubstituted phenyl, wherein the substituent on the phenyl is C1-C6 alkyl, C1-C6 alkoxy, halogen, halogen-substituted C1-C6 alkyl or dimethylamino.

2. An HDAC8 inhibitor, characterized in that At least one compound selected from the following compounds or pharmaceutically acceptable salts thereof:

3. Use of the HDAC8 inhibitor according to claim 1 or 2 in the preparation of a medicament for inhibiting HDAC8.

4. Use of the HDAC8 inhibitor according to claim 1 or 2 in the preparation of a medicament for treating and / or preventing diseases associated with abnormal HDAC8 activity.

5. The use according to claim 4, characterized in that The disease is inflammation and / or cancer; The cancer is selected from breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, urothelial cancer, urethral cancer, prostate cancer, testicular cancer, colorectal cancer, sarcoma, bone cancer, multiple myeloma, leukemia, myxoma, rhabdomyomas, leiomyomas, fibromas, lipomas, teratomas, pharyngeal cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, small intestine cancer, gastric cancer, esophageal cancer, pancreatic cancer, liver cancer, bile duct cancer, neurofibromas, gliomas, neuroblastomas, neuroblastomas, melanomas, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, and gastrointestinal stromal tumors. The inflammation is enteritis, dermatitis, encephalitis, keratitis, conjunctivitis, rhinitis, otitis media, gingivitis, pharyngitis, tonsillitis, pneumonia, hepatitis, prostatitis, endometritis, cervicitis, pelvic inflammatory disease, paronychia, and myocarditis.

6. The use according to claim 5, characterized in that The head and neck cancer is nasopharyngeal carcinoma.

7. A pharmaceutical composition, characterized in that The composition comprises one or more pharmaceutically acceptable carriers and excipients, and the HDAC8 inhibitor according to claim 1 or 2.

8. A pharmaceutical composition, characterized in that The invention comprises one or more pharmaceutically acceptable carriers and diluents, and the HDAC8 inhibitor according to claim 1 or 2.

9. The method for preparing the HDAC8 inhibitor according to claim 1, characterized in that: The HDAC8 inhibitor is a compound having a chemical structure as shown in Formula I, and its synthetic route A includes: In synthetic route A, X is a halogen atom, compound a reacts with compound b and compound c in a Cs2CO3 N,N-dimethylformamide solution to obtain compound d, then the acetyl protecting group of compound d is removed in a methanol solution of triethylamine under the action of hydrazine acetate to obtain compound e, then the tert-butyl protecting group of compound e is removed in dichloromethane under the action of trifluoroacetic acid to obtain compound f, compound f and compound g undergo amidation reaction in N,N-diisopropylethylamine using a polypeptide condensation reagent HATU to obtain compound h, and compound h reacts with p-toluenesulfonic acid monohydrate in methanol to obtain a compound having a chemical structure shown in Formula I; or, The HDAC8 inhibitor is a compound having a chemical structure as shown in Formula II, and its synthetic route B includes: In synthetic route B, compound f and compound i undergo an amidation reaction in N,N-diisopropylethylamine using a polypeptide condensation reagent HATU to obtain compound j, and then the tert-butyl protecting group of compound j is removed in dichloromethane under the action of trifluoroacetic acid to obtain compound k. Compound k and compound g undergo an amidation reaction in N,N-diisopropylethylamine using a polypeptide condensation reagent HATU to obtain compound m. Compound m is reacted with p-toluenesulfonic acid monohydrate in methanol to obtain a compound having a chemical structure shown in Formula II; or, The HDAC8 inhibitor is a compound having a chemical structure as shown in Formula III, and its synthesis route is C1 or C2, wherein the synthesis route C1 includes: In synthetic route C1, X is a halogen atom, p-hydroxybenzaldehyde reacts with compound n in a K2CO3 N,N-dimethylformamide solution at 25-80°C to obtain compound o, compound o reacts with compound a and compound c in a Cs2CO3 N,N-dimethylformamide solution to obtain compound p, then the acetyl protecting group of compound p is removed in a methanol solution of triethylamine under the action of hydrazine acetate to obtain compound q, then the tert-butyl protecting group of compound q is removed in dichloromethane under the action of trifluoroacetic acid to obtain compound r, compound r and compound g undergo amidation reaction in N,N-diisopropylethylamine using a polypeptide condensation reagent HATU to obtain compound s, and compound s reacts with p-toluenesulfonic acid monohydrate in methanol to obtain a compound having a chemical structure represented by formula III1; Synthesis route C2 includes: In synthetic route C2, X is a halogen atom, compound a reacts with compound t and compound c in a Cs2CO3 N,N-dimethylformamide solution to obtain compound u, then, under the action of hydrazine acetate, compound u removes the acetyl protecting group in a methanol solution of triethylamine to obtain compound v, then, under the action of trifluoroacetic acid, compound v removes the tert-butyloxycarbonyl protecting group in dichloromethane to obtain compound w, compound w and compound b undergo an imine reduction reaction in an acetic acid / methanol mixture system under the action of sodium cyanoborohydride to obtain compound x, then, under the action of trifluoroacetic acid, compound x removes the tert-butyl protecting group in dichloromethane to obtain compound y, compound y and compound g undergo an amidation reaction in N,N-diisopropylethylamine using a polypeptide condensation reagent HATU to obtain compound z, and compound z reacts with p-toluenesulfonic acid monohydrate in methanol to obtain a compound having a chemical structure represented by formula III2; or, The HDAC8 inhibitor is a compound having a chemical structure as shown in Formula IV, and its synthetic route D includes: In synthetic route D, compound f and compound a1 undergo an amidation reaction in N,N-diisopropylethylamine using a polypeptide condensation reagent HATU to obtain compound a2. Subsequently, compound a2 is deprotected from the tert-butyloxycarbonyl protecting group in dichloromethane under the action of trifluoroacetic acid to obtain compound a3. Compound a3 and compound a4 undergo an amidation reaction in N,N-diisopropylethylamine using a polypeptide condensation reagent HATU to obtain compound a5. Subsequently, compound a5 is deprotected from the tert-butyl protecting group in dichloromethane under the action of trifluoroacetic acid to obtain compound a6. Compound a6 and compound g undergo an amidation reaction in N,N-diisopropylethylamine using a polypeptide condensation reagent HATU to obtain compound a7. Compound a7 is reacted with p-toluenesulfonic acid monohydrate in methanol to obtain a compound having the chemical structure shown in Formula IV; or, The HDAC8 inhibitor is a compound having a chemical structure as shown in Formula V, and its synthetic route E includes: In synthetic route E, X is a halogen atom, compound b1 and compound b2 react in a 2-methylimidazole / N,N-dimethylformamide mixed system of PdCl2 and K2CO3 to obtain compound b3, compound b3 reacts with compound a and compound c in a Cs2CO3 N,N-dimethylformamide solution to obtain compound b4, then the acetyl protecting group of compound b4 is removed in a methanol solution of triethylamine under the action of hydrazine acetate to obtain compound b5, then the tert-butyl protecting group of compound b5 is removed in dichloromethane under the action of trifluoroacetic acid to obtain compound b6, compound b6 and compound g undergo amidation reaction in N,N-diisopropylethylamine using a polypeptide condensation reagent HATU to obtain compound b7, and compound b7 reacts with p-toluenesulfonic acid monohydrate in methanol to obtain a compound having a chemical structure shown in Formula V.

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