Diacyl pyrrole histone deacetylase 6 inhibitor and application thereof

Abstract

The invention belongs to the field of medical chemistry, and particularly discloses a diacylpyrrole histone deacetylase 6 inhibitor and application thereof, and the diacylpyrrole histone deacetylase 6 inhibitor is a compound shown in a general formula (I) or pharmaceutically acceptable salt of the diacylpyrrole histone deacetylase 6 inhibitor. The invention also discloses a pharmaceutical composition containing the compound. The pharmaceutical composition can be used for preventing or treating clinical diseases related to HDAC1 or HDAC6. Compared with a reported clinical selective HDAC6 inhibitor, the enzyme activity and the cell activity of the HDAC6 inhibitor in the patent are remarkably improved.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemicals, and in particular relates to a diacylpyrrole histone deacetylase 6 inhibitor and a use thereof. Background Art

[0002] Histone deacetylases (HDACs) are a class of proteases whose acetylation and deacetylation of histones in chromatin are key regulators of gene expression. Abnormal gene expression underlies the molecular biological basis of tumors and some genetic and metabolic diseases. The degree of histone acetylation is coordinated by histone acetylases (HATs) and histone deacetylases (HDACs). When HDACs are overexpressed and recruited by transcription factors, they lead to the abnormal repression of specific genes, causing tumors and other diseases.

[0003] HDACs are a large family of enzymes, with four known classes and 18 different subtypes. Class I includes four subtypes: HDAC1, 2, 3, and 8; Class II includes six subtypes: HDAC4, 5, 6, 7, 9, and 10 (of which 4, 5, 7, and 9 belong to Class IIa, and 6 and 10 belong to Class IIb); Class IV contains only one subtype, HDAC11, which shares some homology with the first two classes; and Class III includes seven subtypes, SIRT1-7, which lack structural homology with the first three classes.

[0004] According to published clinical results, although HDAC1, 2, and 3 selective inhibitors such as MS275 (Entinostat), cedaranid (already marketed), and CXD101 have significantly fewer toxic side effects than Pan HDAC inhibitors such as vorinostat, romidepsin, belinostat, and panobinostat, serious adverse reactions have still been observed in clinical trials, including hematological adverse reactions, systemic adverse reactions including fatigue and fever, gastrointestinal adverse reactions, metabolic and nutritional system adverse reactions, and other adverse reactions such as dizziness and rash. Summary of the Invention

[0005] In view of the deficiencies in the prior art, the present invention aims to provide a selective HDAC6 inhibitor to reduce off-target toxicity and enhance the therapeutic window.

[0006] To achieve the above object, the present invention is implemented through the following technical solutions:

[0007] In one aspect, the present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof:

[0008]

[0009] or a pharmaceutically acceptable salt or solvate thereof, wherein

[0010] R 1 、R 2 Each independently represents hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl or Het;

[0011] Q 1 is selected from aryl, aralkyl or Het;

[0012] Q 2 is selected from alkyl or aryl;

[0013] The alkyl group is a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms connected to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms;

[0014] Alkoxy is a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms connected to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms; wherein each carbon atom is optionally substituted by oxygen;

[0015] Alkoxyalkyl is an alkoxy group as defined above attached to an alkyl group;

[0016] Alkenyl and alkynyl are straight-chain or branched unsaturated hydrocarbon groups containing double or triple bonds and having 1 to 6 carbon atoms;

[0017] Aryl is a carbocyclic ring selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each of which is optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from hydrogen, alkyl, cyano, halogen, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het;

[0018] Aralkyl and diarylalkyl are aryl groups as defined above linked to an alkyl group;

[0019] Het is a monocyclic heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo[1,4] a bicyclic heterocycle selected from dioxinyl or benzo[1,3]dioxolyl; or a monocyclic saturated hydrocarbon group of 3-6 carbon atoms, or a bicyclic saturated hydrocarbon group of 6-12 carbon atoms, wherein the carbon atoms on the ring are independently optionally substituted with 1 to 4 O, S, N or NH; each monocyclic or bicyclic ring is optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from halogen, haloalkyl, hydroxy, alkyl or alkoxy;

[0020] Halogen is a substituent selected from fluorine, chlorine, bromine or iodine;

[0021] A haloalkyl group is a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms connected to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms; wherein one or more carbon atoms are substituted by one or more halogen atoms.

[0022] As a preferred technical solution,

[0023] R 1 、R 2 each independently represents hydrogen, alkyl, aryl or Het;

[0024] Q 1 is selected from aryl;

[0025] Q 2 is selected from alkyl or aryl.

[0026] As a preferred technical solution,

[0027] R 1 represents hydrogen or phenyl, and substituents include but are not limited to alkyl, methoxy, and halogen;

[0028] R 2 It is hydroxyl;

[0029] Q 1 It is phenyl;

[0030] Q 2 It is selected from phenyl or a straight chain of 4-5 carbon atoms.

[0031] In another aspect, the present invention provides a pharmaceutical composition comprising any one of the aforementioned compounds or a pharmaceutically acceptable carrier.

[0032] In another aspect, the present invention provides use of the above-mentioned compound in the preparation of a medicament for preventing or treating a clinical disorder associated with HDAC6.

[0033] In a specific embodiment, the disease associated with HDAC1 or HDAC6 can be lung cancer, melanoma, liver cancer, kidney cancer, leukemia, prostate cancer, thyroid cancer, skin cancer, pancreatic cancer, ovarian cancer, testicular cancer, breast cancer, bladder cancer, gallbladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, gastrointestinal cancer, astrocytoma, neuroblastoma, glioma, neurilemmoma, mesothelioma, non-insulin-dependent diabetes mellitus, or autoimmune disease.

[0034] In another aspect, the present invention provides a method for preparing the above compound.

[0035]

[0036] The compounds of the present invention can be prepared by the above or similar preparation methods, and the corresponding raw materials can be selected according to the different substituents and the different positions of the substituents.

[0037] Due to the adoption of the above technical solution, the beneficial effects of the present invention include:

[0038] (1) Selectively act on HDAC6 isoenzyme, avoid interfering with other HDAC subtypes (such as class I HDACs), and reduce toxic side effects caused by broad inhibition (such as bone marrow suppression, gastrointestinal reactions, etc.).

[0039] (2) Compared with the reported clinically selective HDAC6 inhibitors, the enzyme activity and cell activity of the HDAC6 inhibitor in this patent are significantly improved. DETAILED DESCRIPTION

[0040] The following description will elaborate on various specific aspects, characteristics, and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions so that the present invention will be readily apparent. It should be understood that the following detailed description and examples describe specific embodiments and are provided for reference only. After reading the present description, those skilled in the art may make various changes or modifications to the present invention, and such equivalents are within the scope of the present invention.

[0041] The starting materials used in the examples of the present invention are known and can be purchased commercially, or can be used or synthesized according to methods known in the art.

[0042] Example 1: Synthesis of 5-benzoyl-1-benzyl-N-(7-(hydroxyamino)-7-oxoheptyl)-1H-pyrrole-2-carboxamide (KI-38)

[0043]

[0044] (1) Synthesis of methyl 4-benzoyl-1H-pyrrole-2-carboxylate

[0045] Anhydrous AlCl3 (2.00 g, 14.99 mmol) was added to a 200 mL two-necked flask. The air was replaced three times and the mixture was protected by argon. Anhydrous dichloromethane (50 mL) was added at -20 °C and stirred for 30 min. Benzoyl chloride (0.86 mL, 7.49 mmol) was slowly added dropwise. After 1 h, methyl 2-pyrrolidone (0.85 g, 6.81 mmol) was added. The temperature was gradually increased to 40 °C over another 1 h. After 6 h, TLC detected that the reaction was complete. 6 mL of water was slowly added dropwise. After the reaction was completely quenched, 14 mL of water was added, and the mixture was extracted with DCM (60 mL × 3). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain the target compound in a yield of 95%.

[0046] (2) Synthesis of methyl 4-benzoyl-1-benzyl-1H-pyrrole-2-carboxylate

[0047] Methyl 4-benzoyl-1H-pyrrole-2-carboxylate (0.69 g, 3.00 mmol), iodomethane (0.51 g, 3.60 mmol), and NaH (0.11 g, 4.50 mmol) were placed in a 100 mL eggplant flask and added with 12 mL of DMF. The mixture was allowed to react at room temperature for 8–12 h. TLC confirmed the reaction was complete. Excess NaH was quenched by the addition of 5 mL of ammonium chloride solution. 75 mL of water was added, and the mixture was extracted with ethyl acetate (150 mL x 3). The combined organic phases were concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain the title compound as a white solid in a 72% yield.

[0048] (3) Synthesis of 4-benzoyl-1-benzyl-1H-pyrrole-2-carboxylic acid

[0049] Methyl 4-benzoyl-1-benzyl-1H-pyrrole-2-carboxylate (0.42 g, 1.50 mmol) and NaOH (0.24 g, 6.00 mmol) were weighed into a 100 mL eggplant flask, and 30 mL of methanol was added. The reaction was carried out at 90 °C for 16 h. The reaction was complete after TLC. The solvent was removed by concentration under reduced pressure, and 10 mL of water was added. 30% hydrochloric acid (30 mL) was added dropwise to adjust the pH to acidic. White flocculent material precipitated, and the filter cake was filtered and dried to obtain a white solid with a yield of 80%.

[0050] (4) Synthesis of methyl 7-(4-benzoyl-1-benzyl-1H-pyrrole-2-carboxamido)heptanoate

[0051] In a 200 mL two-necked reaction flask under ice-bath conditions, compound 5a (1.57 g, 5.86 mmol) and HATU (2.44 g, 6.44 mmol) were weighed and dissolved in DMF (30 mL). DIPEA (4.59 mL, 26.37 mmol) was then added dropwise. After the solution temperature dropped to 0°C, methyl 4-aminomethylbenzoate (1.06 g, 6.44 mmol) was added and allowed to react for 8 h. TLC confirmed the reaction was complete. Water (150 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (250 mL x 3). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 1:2) to obtain the title compound as a white solid in an 81% yield.

[0052] (5) Synthesis of 5-benzoyl-1-benzyl-N-(7-(hydroxyamino)-7-oxoheptyl)-1H-pyrrole-2-carboxamide

[0053] To an eggplant-shaped flask containing 9 mL of methanol, hydroxylamine hydrochloride (1.70 g, 24.46 mmol) was added. To another eggplant-shaped flask containing 18 mL of methanol, potassium hydroxide (1.70 g, 30.30 mmol) was added. The two solutions were stirred to dissolve, then mixed and ice-cooled at 0°C for 30 min. The filtrate was filtered. Methyl 7-(4-benzoyl-1-benzyl-1H-pyrrole-2-carboxamido)heptanoate (0.25 g, 0.69 mmol) was weighed and added to the filtrate. The mixture was reacted on ice for 6 h. After TLC, the methanol was removed by vacuum distillation. The mixture was dissolved in water (10 mL), adjusted to pH 7-8 with acetic acid, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were separated and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain the target compound as a pale yellow solid in a 61.8% yield with a melting point of 151.7-153.1°C. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.69 (s, 1H),8.30 (t, J = 5.7 Hz, 1H), 7.87 – 7.68 (m, 3H), 7.58 (dt, J = 34.3, 7.4 Hz,3H), 7.27 (dq, J = 14.5, 7.0 Hz, 4H), 7.17 (d, J = 6.9 Hz, 2H), 5.65 (s, 2H), 3.12 (q, J = 6.6 Hz, 2H), 1.92 (t, J = 7.3 Hz, 2H), 1.50 – 1.36 (m, 4H), 1.21(dq, J = 7.7, 4.1 Hz, 4H). HR-MS (ESI, m / z): Calcd for 448.2230. (C 26 H 30 N3O4 + [M+H] + ). Found 448.2230.

[0054] Example 2: Synthesis of 5-benzoyl-N-(7-(hydroxyamino)-7-oxoheptyl)-1-(3-methoxybenzyl)-1H-pyrrole-2-carboxamide (KI-39)

[0055]

[0056] White solid, yield 63.5%, melting point 153.1~154.8℃. 1H NMR (400 MHz, DMSO-d6) δ10.35 (s, 1H), 8.68 (s, 1H), 8.32 (t, J = 5.7 Hz, 1H), 7.84 – 7.73 (m, 3H), 7.62 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.5 Hz, 2H), 7.27 (d, J = 1.9 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.77 – 6.70 (m, 2H), 5.62(s, 2H), 3.69 (s, 3H), 3.13 (q, J = 6.7 Hz, 2H), 1.92 (t, J = 7.4 Hz, 2H), 1.50 – 1.38 (m, 4H), 1.22 (q, J = 3.6 Hz, 4H). HR-MS (ESI, m / z): Calcd for478.2336. (C 27 H 32 N3O5 + [M+H] + ). Found 478.2334.

[0057] Example 3: Synthesis of 5-benzoyl-1-(4-fluorobenzyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-1H-pyrrole-2-carboxamide (KI-44)

[0058]

[0059] White solid, yield 57.1%, melting point 119.9~121.9℃. 1H NMR (400 MHz, DMSO-d6) δ11.39 (s, 1H), 10.35 (s, 1H), 8.69 (s, 1H), 8.13 (dt, J = 11.3, 5.7 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.47 – 7.39 (m, 4H), 7.27 – 7.05 (m, 4H), 6.92 (d,J = 2.4 Hz, 1H), 5.61 (s, 2H), 3.09 (q, J = 6.6 Hz, 2H), 2.01 – 1.84 (m, 2H),1.51 – 1.35 (m, 4H), 1.24 – 1.18 (m, 4H). HR-MS (ESI, m / z): Calcd for466.2136. (C 26 H 29 FN3O4 + [M+H] + ). Found 466.2135.

[0060] Example 4: Synthesis of 5-benzoyl-N-(7-(hydroxyamino)-7-oxoheptyl)-1-(4-(trifluoromethyl)benzyl)-1H-pyrrole-2-carboxamide (KI-52)

[0061]

[0062] Pale yellow solid, yield 55%, melting point 138.1 ~139.8 ℃. 1 H NMR (400 MHz, DMSO-d6) δ11.41 (s, 1H), 10.32 (s, 1H), 8.66 (s, 1H), 8.14 (dt, J = 11.4, 5.9 Hz, 1H), 7.80 (s, 1H), 7.66 (t, J = 8.7 Hz, 2H), 7.45 (dd, J = 15.7, 5.2 Hz, 4H), 7.25 (dd, J = 18.3, 8.0 Hz, 2H), 6.98 (s, 1H), 5.73 (s, 2H), 3.06 (t, J = 6.7 Hz,2H), 1.90 (t, J = 7.3 Hz, 2H), 1.39 (dt, J = 29.7, 7.2 Hz, 4H), 1.18 (s, 4H).HR-MS (ESI, m / z): Calcd for 516.2104. (C27 H 29 F3N3O4 + [M+H] + ). Found 516.2104.

[0063] Example 5: Synthesis of 5-benzoyl-1-(4-chlorobenzyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-1H-pyrrole-2-carboxamide (KI-56)

[0064]

[0065] Pale yellow solid, yield 59.5%, melting point 142.2~143.7℃. 1 H NMR (400 MHz, DMSO-d6) δ11.98 (s, 1H), 10.94 (s, 1H), 9.28 (s, 1H), 8.70 (s, 1H), 8.05 – 7.95 (m,4H), 7.94 – 7.86 (m, 3H), 7.69 (dd, J = 19.2, 8.1 Hz, 2H), 7.56 – 7.51 (m,1H), 6.19 (s, 2H), 3.74 (dd, J = 5.3, 2.2 Hz, 2H), 3.66 (t, J = 6.8 Hz, 2H), 2.05 – 1.91 (m, 4H), 1.80 – 1.72 (m, 4H). 13 C NMR (101 MHz, dmso) δ 169.25,160.94, 150.14, 138.23, 137.54, 131.86, 128.90, 128.83, 128.72, 128.63,128.42, 128.37, 128.22, 128.03, 124.67, 120.34, 114.12, 48.71, 38.46, 32.34,29.16, 28.41, 26.23, 25.18. HR-MS (ESI, m / z): Calcd for 482.1841. (C 26 H 29 ClN3O4 + [M+H] + ). Found 482.1841.

[0066] Example 6: Synthesis of 5-benzoyl-N-(7-(hydroxyamino)-7-oxoheptyl)-1-(4-methoxybenzyl)-1H-pyrrole-2-carboxamide (KI-64)

[0067]

[0068] Pale yellow solid, yield 61.9%, melting point 158.5~159.9℃. 1 H NMR (400 MHz, DMSO-d6) δ10.34 (s, 1H), 8.67 (s, 1H), 8.28 (t, J = 5.7 Hz, 1H), 7.83 – 7.73 (m, 3H), 7.62 (t, J = 7.3 Hz, 1H), 7.54 (t, J = 7.4 Hz, 2H), 7.24 (d, J = 1.9 Hz, 1H), 7.19 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 5.56 (s, 2H), 3.70 (s,3H), 3.17 – 3.12 (m, 2H), 1.93 (t, J = 7.3 Hz, 2H), 1.44 (dd, J = 13.1, 5.9Hz, 4H), 1.23 (s, 4H). HR-MS (ESI, m / z): Calcd for 478.2336. (C 27 H 32 N3O5 + [M+H] + ). Found 478.2333.

[0069] Example 7: Synthesis of 5-benzoyl-1-(2-chlorobenzyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-1H-pyrrole-2-carboxamide (KI-51)

[0070]

[0071] Pale yellow solid, yield 66.4%, melting point 152.1~153.9℃. 1H NMR (400 MHz, DMSO-d6) δ11.39 (s, 1H), 10.32 (s, 1H), 8.58 (s, 1H), 8.25 – 8.02 (m, 1H), 7.84 – 7.58(m, 1H), 7.51 – 7.39 (m, 5H), 1.90 (t, J = 7.3 Hz, 2H), 1.38 (dt, J = 27.5, 5.4 Hz, 4H), 1.22 –1.09 (m, 4H). HR-MS (ESI, m / z): Calcd for 482.1841. C 26 H 29 ClN3O4 + [M+H] + ). Found482.1840.

[0072] Example 8: Synthesis of 5-benzoyl-1-(3-chlorobenzyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-1H-pyrrole-2-carboxamide (DBY-I-180-1)

[0073]

[0074] Pale yellow solid, yield 56.2%, melting point 122.9~124.3℃. 1 H NMR (400 MHz, DMSO-d6) δ11.40 (s, 1H), 10.32 (s, 1H), 8.15 (q, J = 5.5 Hz, 1H), 7.78 (d, J = 1.7 Hz,1H), 7.47 – 7.44 (m, 2H), 7.43 – 7.41 (m, 3H), 7.34 – 7.28 (m, 3H), 7.16 (s,1H), 6.93 (d, J = 1.7 Hz, 1H), 5.63 (s, 2H), 1.40 (dt, J = 24.4, 6.4 Hz, 6H),1.24 – 1.14 (m, 6H). HR-MS (ESI, m / z): Calcd for 482.1841. (C 26 H29 ClN3O4 + [M+H] + ). Found 482.1841.

[0075] Example 9: Synthesis of 5-benzoyl-1-(3-chlorobenzyl)-N-(6-(hydroxyamino)-6-oxohexyl)-1H-pyrrole-2-carboxamide (DBY-I-181-1)

[0076]

[0077] Pale yellow solid, yield 63.3%, melting point 104.6~106.2℃. 1 H NMR (400 MHz, DMSO-d6) δ11.40 (s, 1H), 10.32 (s, 1H), 8.15 (q, J = 5.5 Hz, 1H), 7.78 (d, J = 1.7 Hz,1H), 7.47 – 7.44 (m, 2H), 7.43 – 7.41 (m, 3H), 7.34 – 7.28 (m, 3H), 7.16 (s,1H), 6.93 (d, J = 1.7 Hz, 1H), 5.63 (s, 2H), 1.40 (dt, J = 24.4, 6.4 Hz, 6H),1.24 – 1.14 (m, 6H). 13 C NMR (101 MHz, DMSO) δ 160.88, 150.02, 141.68, 137.45,133.00, 130.32, 128.62, 128.15, 126.77, 125.66, 124.61, 114.45, 114.06,32.25, 29.09, 28.34, 26.13, 25.09. HR-MS (ESI, m / z): Calcd for 468.1684.(C 25 H 27 ClN3O4 + [M+H] + ). Found 468.1684.

[0078] Example 10: Synthesis of 5-benzoyl-N-(4-(hydroxycarbamoyl)benzyl)-1-methyl-1H-pyrrole-2-carboxamide (DBY-I-164-1)

[0079]

[0080] White solid, yield 51.2%, melting point 137.3~138.9℃. 1 H NMR (400 MHz, DMSO-d6) δ11.35 (s, 1H), 11.16 (s, 1H), 8.71 (t, J = 6.0 Hz, 1H), 7.68 (d, J = 8.1 Hz,2H), 7.59 (s, 1H), 7.47 – 7.40 (m, 5H), 7.32 (d, J = 8.1 Hz, 2H), 7.04 – 7.01(m, 1H), 4.37 (d, J = 5.9 Hz, 2H), 3.88 (s, 3H). HR-MS (ESI, m / z): Calcd for378.1448. (C 21 H 20 N3O4 + [M+H] + ). Found 378.1446.

[0081] Example 11: Synthesis of 5-benzoyl-1-(cyclopropylmethyl)-N-(4-(hydroxycarbamoyl)benzyl)-1H-pyrrole-2-carboxamide (DBY-I-165-1)

[0082]

[0083] White solid, yield 62.5%, melting point 138.9~140.5℃. 1 H NMR (400 MHz, DMSO-d6) δ11.35 (s, 1H), 11.16 (s, 1H), 8.73 (t, J = 6.1 Hz, 1H), 7.68 (d, J = 8.0 Hz, 3H), 7.46 (dd, J = 6.7, 3.2 Hz, 2H), 7.44 – 7.40 (m, 3H), 7.32 (d, J = 8.2Hz, 2H), 7.01 (d, J = 1.6 Hz, 1H), 4.38 (d, J = 6.0 Hz, 2H), 4.22 (d, J = 7.1Hz, 2H), 1.23 (s, 1H), 0.42 (d, J = 9.5 Hz, 2H), 0.30 (d, J = 4.9 Hz, 2H).HR-MS (ESI, m / z): Calcd for 418.1761. (C 24 H 24 N3O4 +[M+H] + ). Found 418.1759.

[0084] Example 12: Synthesis of 5-benzoyl-1-(3-chlorobenzyl)-N-(4-(hydroxycarbamoyl)benzyl)-1H-pyrrole-2-carboxamide (DBY-I-182-1)

[0085]

[0086] Pale yellow solid, yield 58%, melting point 154.1~155.7℃. 1 H NMR (400 MHz, DMSO-d6) δ11.43 (s, 1H), 11.16 (s, 1H), 8.99 (s, 1H), 8.78 (dt, J = 12.2, 6.1 Hz, 1H), 7.84 (d, J = 1.6 Hz, 1H), 7.65 (dd, J = 8.2, 3.6 Hz, 2H), 7.49 – 7.38 (m,5H), 7.33 (d, J = 5.8 Hz, 2H), 7.23 – 7.19 (m, 2H), 7.06 (dd, J = 8.5, 6.8Hz, 2H), 5.65 (s, 2H), 4.35 (t, J = 6.3 Hz, 2H). HR-MS (ESI, m / z): Calcd for488.1371. (C 27 H 23 ClN3O4 + [M+H] + ). Found 488.1371.

[0087] Example 13: Synthesis of 5-benzoyl-1-(4-fluorobenzyl)-N-(4-(hydroxycarbamoyl)benzyl)-1H-pyrrole-2-carboxamide (KI-87)

[0088]

[0089] White solid, yield 62.5%, melting point 138.9~140.5℃. 1H NMR (400 MHz, DMSO-d6) δ11.18 (s, 1H), 8.76 (dt, J = 12.3, 6.1 Hz, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.67 (dd, J = 8.1, 3.9 Hz, 2H), 7.50 – 7.29 (m, 5H), 7.26 – 6.98 (m, 8H), 5.63 (s, 2H), 4.35 (d, J = 6.0 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 164.13,160.89, 149.94, 143.96, 143.06, 137.40, 131.76, 128.65, 128.56, 128.36,128.17, 127.54, 127.36, 126.89, 126.83, 125.35, 125.31, 124.12, 115.06,114.32, 50.73, 41.60.

[0090] Example 14: Synthesis of 5-benzoyl-N-(4-(hydroxycarbamoyl)benzyl)-1-(3-methoxybenzyl)-1H-pyrrole-2-carboxamide (ZTT-5)

[0091]

[0092] White solid, yield 64.0%, melting point 135.3~136.4℃. 1 H NMR (400 MHz, DMSO-d6) δ11.42 (s, 1H), 10.37 (s, 1H), 8.78 (q, J = 6.4 Hz, 2H), 7.71 – 7.63 (m, 2H),7.50 – 7.30 (m, 5H), 7.27 – 7.17 (m, 3H), 7.05 (d, J = 1.8 Hz, 1H), 6.86 –6.79 (m, 1H), 6.72 – 6.62 (m, 2H), 5.64 (s, 2H), 4.37 (s, 2H), 3.68 (s, 3H).

[0093] Example 15: Synthesis of 5-benzoyl-N-(4-(hydroxycarbamoyl)benzyl)-1-(4-(trifluoromethyl)benzyl)-1H-pyrrole-2-carboxamide (ZTT-11)

[0094]

[0095] White solid, yield 61.0%, melting point 132.1~133.2℃. 1 H NMR (400 MHz, DMSO-d6) δ11.15 (s, 1H), 8.99 (s, 1H), 8.76 (t, J = 6.2 Hz, 1H), 7.88 – 7.79 (m, 1H),7.70 – 7.61 (m, 4H), 7.58 – 7.45 (m, 2H), 7.45 – 7.31 (m, 3H), 7.30 – 7.16(m, 4H), 7.13 – 7.01 (m, 1H), 5.75 (s, 2H), 4.33 (s, 2H).

[0096] Example 16: Synthesis of 5-benzoyl-1-(4-chlorophenyl)-N-(4-(hydroxycarbamoyl)benzyl)-1H-pyrrole-2-carboxamide

[0097]

[0098] White solid, yield 70%, melting point 130.5~131.4℃. 1 H NMR (400 MHz, DMSO-d6) δ 11.13(s, 1H), 9.00 (s, 1H), 8.94 (t, J = 6.0 Hz, 1H), 7.90 (d, J = 1.9 Hz, 1H),7.84 – 7.76 (m, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 7.4 Hz, 1H), 7.55(t, J = 7.4 Hz, 2H), 7.40 (d, J = 1.8 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.24(d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 5.64 (s, 2H), 4.39 (d, J = 6.0Hz, 2H).

[0099] Example 17: Synthesis of 5-benzoyl-1-(cyclopropylmethyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-1H-pyrrole-2-carboxamide

[0100]

[0101] White solid, yield 60%, melting point 172.5~173.2℃. 1 H NMR (400 MHz, DMSO-d6) δ 11.32(s, 1H), 10.33 (s, 1H), 8.67 (s, 1H), 8.11 (t, J = 6.1 Hz, 1H), 7.67 – 7.58(m, 1H), 7.49 – 7.35 (m, 4H), 6.92 – 6.78 (m, 1H), 4.21 (dd, J = 11.5, 7.1Hz, 2H), 3.11 (q, J = 6.5 Hz, 2H), 1.91 (t, J = 7.2 Hz, 2H), 1.45 (d, J = 6.9Hz, 4H), 1.23 (s, 4H), 0.84 (d, J = 6.9 Hz, 1H), 0.46 – 0.38 (m, 2H), 0.33 –0.21 (m, 2H).

[0102] Example 18: Synthesis of 5-benzoyl-N-(7-(hydroxyamino)-7-oxoheptyl)-1-methyl-1H-pyrrole-2-carboxamide

[0103]

[0104] White solid, yield 70.4%, melting point 176.3~177.5℃. 1 H NMR (400 MHz, DMSO-d6) δ11.32 (s, 1H), 10.34 (s, 1H), 8.67 (s, 1H), 8.09 (q, J = 5.4 Hz, 1H), 7.55(d, J = 1.8 Hz, 1H), 7.43 (dt, J = 7.2, 5.2 Hz, 4H), 6.90 (d, J = 1.9 Hz,1H), 3.86 (s, 3H), 3.11 (p, J = 6.6 Hz, 2H), 1.92 (td, J = 7.4, 3.4 Hz, 2H), 1.44 (dt, J = 14.8, 7.4 Hz, 4H), 1.22 (dd, J = 9.0, 4.3 Hz, 4H).

[0105] Example 19: Synthesis of 5-benzoyl-1-benzyl-N-(4-(hydroxycarbamoyl)benzyl)-1H-pyrrole-2-carboxamide

[0106]

[0107] White solid, yield 67%, melting point 144.9~145.5℃. 1 H NMR (400 MHz, DMSO-d6) δ 11.20(s, 1H), 9.03 (s, 1H), 8.94 (t, J = 6.1 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H),7.83 – 7.76 (m, 2H), 7.71 – 7.58 (m, 3H), 7.54 (dd, J = 8.1, 6.7 Hz, 2H), 7.38 (d, J = 1.9 Hz, 1H), 7.34 – 7.20 (m, 5H), 7.19 – 7.11 (m, 2H), 5.67 (s, 2H), 4.40 (d, J = 6.0 Hz, 2H).

[0108] Example 20: Synthesis of 5-benzoyl-N-(4-(hydroxycarbamoyl)benzyl)-1-(4-methoxybenzyl)-1H-pyrrole-2-carboxamide

[0109]

[0110] White solid, yield 59%, melting point 128.9~130.5℃. 1 H NMR (400 MHz, DMSO-d6) δ 11.18(s, 1H), 9.00 (s, 1H), 8.92 (t, J = 6.1 Hz, 1H), 7.85 (d, J = 1.9 Hz, 1H),7.82 – 7.75 (m, 2H), 7.68 (d, J = 8.2 Hz, 2H), 7.65 – 7.60 (m, 1H), 7.54 (dd,J = 8.1, 6.8 Hz, 2H), 7.33 (d, J = 1.8 Hz, 1H), 7.27 (d, J = 8.1 Hz, 2H), 7.20 – 7.11 (m, 2H), 6.87 – 6.78 (m, 2H), 5.57 (s, 2H), 4.41 (d, J = 6.0 Hz, 2H), 3.72 (s, 3H).

[0111] Some pharmacological tests and results:

[0112] (1) Determination of HDAC inhibitory activity of target compounds and results

[0113] The inhibitory activity of the synthesized compounds against HDAC was determined using the fluorescence resonance energy transfer (FRET) method and compared with the positive control drug to screen out compounds with better activity. HDAC was obtained by purification or direct purchase of the kit.

[0114] Method: Add enzyme to reaction wells and reaction buffer to control wells. Add samples dissolved in DMSO to the reaction wells and incubate using a contactless nanoliter acoustic pipetting system. Add the corresponding fluorescent substrate to each reaction well and vortex. Seal and incubate at 30°C for 1-2 hours. Add a colorimetric reagent containing TMP26 to terminate the reaction and generate fluorescence. Fluorescence intensity is measured using an EnVision multi-label microplate reader (Perkin Elmer) (excitation: 490 nM, emission: 520 nM). Endpoint values ​​are read after color development reaches stability. Percentages (relative to the DMSO control group) and half-maximal inhibition rates are calculated using GraphPad Prism 4 software.

[0115] Table 1: IC values ​​of some compounds against HDAC6 / HDAC1 50 (nM)

[0116]

[0117] Table 2: Inhibitory activity of Example 3 against different subtypes of HDACs (IC 50, nM)

[0118]

[0119] (2) Determination of the in vitro antitumor activity of the target compound

[0120] This experiment used the CTG method to determine the inhibitory effects of compounds on the gastric cancer cell line AGS. Experimental Method: Cells in the exponential growth phase were harvested and viable cells were counted. The cell suspension concentration was adjusted using the appropriate culture medium for each cell type. 90 µL of the cell suspension was added to each well of a 96-well cell culture plate. Each test compound was dissolved in DMSO to a 10 mM or 5 mM stock solution. The solution was then diluted to a 10-fold solution using culture medium and replicated in duplicate. For each cell line, 10 µL of the corresponding 10-fold solution was added to each well, resulting in a final drug concentration of 10 µM or 25 µM. The final DMSO concentration was 0.1% to 0.5%, respectively (see Compound Preparation and Sample Loading Design: Experimental Well Plate Loading Design). The cells were cultured in a 37°C, 5% CO2 incubator for 72 hours. After 72 hours of drug treatment, 50 μL (1 / 2 of the culture volume) of pre-melted and room temperature CTG solution was added to each well. The mixture was mixed using a microplate shaker for 2 minutes. After standing at room temperature for 10 minutes, the fluorescence signal was measured using an Envision 2104 plate reader. The cell inhibition rate was calculated using the formula: (1-Vsample / V vehicle control ×100%). Where V sample is the mean value of the drug-treated group, V vehicle control The values ​​are the average values ​​of the solvent control group.

[0121]

[0122] These results indicate that compound 3 has superior anti-proliferative activity against AGS cells compared to the similarly selective HDAC6 inhibitor ACY-1215 and comparable activity to the non-selective HDAC inhibitor SAHA. Compound 3 also has no toxicity against normal human bone marrow stromal cells, surpassing SAHA in terms of anti-proliferative activity.

[0123] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. However, any equivalent changes, modifications and evolutions made by ordinary technicians in this field without departing from the scope of the technical solution of the present invention by using the technical content disclosed above are all equivalent embodiments of the present invention. At the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present invention are still within the scope of protection of the technical solution of the present invention.

Claims

1. Compounds of general formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 、R 2 Each independently represents hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl or Het; Q 1 is selected from aryl, aralkyl or Het; Q 2 is selected from alkyl or aryl; The alkyl group is a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms connected to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms; Alkoxy is a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms connected to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms; wherein each carbon atom is optionally substituted by oxygen; Alkoxyalkyl is an alkoxy group as defined above attached to an alkyl group; Alkenyl and alkynyl are straight-chain or branched unsaturated hydrocarbon groups containing double or triple bonds and having 1 to 6 carbon atoms; Aryl is a carbocyclic ring selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each of which is optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from hydrogen, alkyl, cyano, halogen, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het; Aralkyl and diarylalkyl are aryl groups as defined above linked to an alkyl group; Het is a monocyclic heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo[1,4] a bicyclic heterocycle selected from dioxinyl or benzo[1,3]dioxolyl; or a monocyclic saturated hydrocarbon group of 3-6 carbon atoms, or a bicyclic saturated hydrocarbon group of 6-12 carbon atoms, wherein the carbon atoms on the ring are independently optionally substituted with 1 to 4 O, S, N or NH; each monocyclic or bicyclic ring is optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from halogen, haloalkyl, hydroxy, alkyl or alkoxy; Halogen is a substituent selected from fluorine, chlorine, bromine or iodine; A haloalkyl group is a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms connected to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms; wherein one or more carbon atoms are substituted by one or more halogen atoms.

2. The compound according to claim 1, wherein in, R 1 、R 2 each independently represents hydrogen, alkyl, aryl or Het; Q 1 is selected from aryl; Q 2 is selected from alkyl or aryl.

3. The compound according to claim 2, wherein in, R 1 represents hydrogen or phenyl, and substituents include but are not limited to alkyl, methoxy, and halogen; R 2 It is hydroxyl group; Q 1 It is phenyl; Q 2 is selected from phenyl or a straight chain of 4-5 carbon atoms.

4. The compound according to claim 1, wherein Selected from the following compounds: ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， 。 5. A pharmaceutical composition comprising the compound according to any one of the preceding claims or a pharmaceutically acceptable carrier.

6. Use of the compound according to any one of claims 1 to 4 in the preparation of a medicament for preventing or treating a clinical disorder associated with HDAC1 or HDAC6.

7. The use according to claim 6, characterized in that Diseases associated with HDAC1 or HDAC6 can be lung cancer, melanoma, liver cancer, kidney cancer, leukemia, prostate cancer, thyroid cancer, skin cancer, pancreatic cancer, ovarian cancer, testicular cancer, breast cancer, bladder cancer, gallbladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, gastrointestinal cancer, astrocytoma, neuroblastoma, glioma, neurilemmoma, mesothelioma, non-insulin-dependent diabetes mellitus, and autoimmune diseases.

8. The method for preparing the compound according to claim 1, wherein ； The corresponding raw materials can be selected according to the different substituents and the different positions of the substituents.

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