CN116924959A - HDAC11 subtype selective inhibitor and preparation method and application thereof - Google Patents

HDAC11 subtype selective inhibitor and preparation method and application thereof Download PDF

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CN116924959A
CN116924959A CN202210329731.5A CN202210329731A CN116924959A CN 116924959 A CN116924959 A CN 116924959A CN 202210329731 A CN202210329731 A CN 202210329731A CN 116924959 A CN116924959 A CN 116924959A
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compound
reacting
room temperature
reaction
tetrahydrofuran
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张颖杰
赵伟
张国真
柴启鹏
李顺达
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Shandong University
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Abstract

The invention provides an HDAC11 subtype selective inhibitor, a preparation method and application thereof. The inhibitor has a structure shown in the following structural general formula A or B, and optical isomer and pharmaceutically acceptable salt thereof. The inhibitor has potential advantages of resisting hepatocellular carcinoma drug resistance, recurrence and metastasis, and can be applied to preparation of drugs for preventing or treating diseases related to abnormal expression or activity of HDAC 11.

Description

HDAC11 subtype selective inhibitor and preparation method and application thereof
Technical Field
The invention relates to the technical field of synthesis and medical application of organic compounds, in particular to an HDAC11 subtype selective inhibitor and a preparation method and application thereof.
Background
Histone Deacetylases (HDACs) are an important class of epigenetic modification related proteins. Currently, there are 18 subtypes of HDACs found in humans, of which HDACs 1-11 are zinc ion-dependent metalloproteases. HDAC11 is the latest discovered zinc ion dependent HDAC, which is distributed in both the cytoplasm and nucleus and develops a variety of physiological and pathological functions. Of note, recent studies have shown that HDAC11 has very strong de-long chain fatty acid acylation activity (see: caoJ.et al, proc Natl Acad Sci USA.2019,116,5487-5492;Kutil Z.et al. ACS chem. Biol.2018,13, 685-693).
HDAC11 is highly expressed and closely associated with the occurrence, development and prognosis of various cancers such as hepatocellular carcinoma, myeloproliferative neoplasm, multiple myeloma, hodgkin's lymphoma, non-small cell lung cancer, glioblastoma, pituitary tumor, prostate cancer, ovarian cancer, acute lymphoblastic leukemia, etc., and thus is considered as a potential cancer therapeutic target (see: liu s.et al., biomed. Pharmacother,2020,131,110607;y.et al, FEBS J.https:// doi.org/10.1111/febs.15895). For example, several recent studies have found that histone deacetylase 11 (HDAC 11) is expressed at significantly higher levels in hepatocellular carcinoma tissue/cells than in normal liver tissue/cells, and that HDAC11 high expression is closely related to sorafenib (sorafenib) resistance and patient prognosis (see: bi L.et al., cancer Res.2021,81,2015-2028;Wang W.et al, front. Cell Dev.Biol.2020,8,724;Freese K.et al, cancer 2019,11,1587;Gong D.et al, am. J. Transl. Res.2019,11, 983-990). Accordingly, HDAC11 knockdown is effective in inhibiting hepatocellular carcinoma growth and invasion metastasis, reducing tumor stem cell (CSC) dryness and sorafenib resistance (see: bi L.et al., cancer Res.2021,81,2015-2028;Wang W.et al, front. Cell Dev. Biol.2020,8,724). Taken together, HDAC11 is a potential cancer therapeutic target. Also, since HDAC11 is critical for the maintenance of CSC dryness (see: bi L.et al., cancer Res.2021,81, 2015-2028), which in turn is closely related to tumor resistance, recurrence and metastasis (see: lytel N, et al., nat. Rev. Cancer 2018,18,669-680), HDAC11 subtype selective inhibitors are also expected to address the troublesome Cancer resistance, recurrence and metastasis problems during Cancer treatment.
In addition, there have been a number of studies showing that HDAC11 selective inhibitors are also promising for the treatment of autoimmune diseases such as inflammation, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and metabolic diseases such as obesity and diabetes (see: liu s.et al, biomed.pharmacothers, 2020,131,110607;Y.et al.,FEBS J.https://doi.org/10.1111/febs.15895)。
at present, research and development of HDAC11 subtype selective inhibitors at home and abroad are on the go, and only 3 compounds (FT 895, SIS17, garcinol) with strong HDAC11 selective inhibitory activity are reported (see:FEBS J.https:// doi.org/10.1111/febs.15895) and their activity was not fully studied.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an HDAC11 subtype selective inhibitor, and also provides a preparation method and application of the compound.
The technical scheme of the invention is as follows:
HDAC11 subtype selective inhibitors
Inhibitors having the structure shown in the following structural general formula A or B, optical isomers and pharmaceutically acceptable salts thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 is an aromatic ring, an aromatic heterocyclic ring, a substituted aromatic ring or a substituted aromatic heterocyclic ring; wherein the substituents in the substituted aromatic ring or substituted aromatic heterocycle are selected from alkyl, aminoalkyl, halogen, haloalkyl, alkoxy, amino, piperazinyl, alkylpiperazinyl, morpholinyl, alkylmorpholinyl, cyano, alkylamido, or amido;
R 2 is hydrogen, alkyl, alkylpiperazinyl, alkylmorpholinyl, or aminoalkyl;
R 3 is a hydroxyl group, an amino group, or a primary amino group.
According to a preferred embodiment of the present invention,
R 1 is a benzene ring, a substituted benzene ring, a pyridine ring, a substituted pyridine ring, a pyrazine ring, a substituted pyrazine ring, a pyrimidine ring or a substituted pyrimidine ring; wherein the substituent of the substituted benzene ring, the substituted pyridine ring, the substituted pyrazine ring or the substituted pyrimidine ring is selected from
R 2 Is that
R 3 Is a hydroxyl group, an amino group, an alkyl-substituted primary amino group having 1 to 16 carbon atoms.
Preferably, the inhibitor has a structure of one of the following:
process for the preparation of HDAC11 subtype selective inhibitors
R in the structural general formula A of the inhibitor 3 The preparation method of the inhibitor for hydroxyl is selected from one of the following:
reaction of compound 1 with p-toluenesulfonyl chloride to form compound 2, reaction of compound 2 with carbon tetrabromide to form compound 3, reaction of compound 3 withCompound 4 is produced by Sonogashira coupling reaction,reacting the compound 4 with potassium hydroxylamine to obtain compounds A1-A13;
alternatively, compound 4 deprotects to form compound 16, compound 16 andthe reaction generates a compound 17, and the compound 17 reacts with potassium hydroxylamine to obtain a compound A51-A55.
The reaction formula is as follows:
wherein in the reaction formula for preparing the compounds A1-A13, the substituent R 1 With substituents R in the corresponding compounds A1 to A13 1 The same; in the reaction formula for preparing the compounds A51-A55, the substituent R 1 、R 2 With substituents R in the corresponding compounds A51 to A55 1 、R 2 The same;
reagents and conditions in the above formulas:
a. p-toluenesulfonyl chloride, sodium hydride, tetrahydrofuran and reacting at room temperature;
b. carbon tetrabromide, lithium diisopropylamide, tetrahydrofuran, and reacting at-78 ℃ and room temperature;
c.reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the like at 70 ℃;
d. potassium hydroxylamine, methanol, room temperature reaction;
e. tetrabutylammonium fluoride; tetrahydrofuran; reacting at 70 ℃;
f.sodium hydride, tetrahydrofuran, room temperature reaction;
(di) reacting compound 1 with di-tert-butyl dicarbonate to form compound 5, reacting compound 5 with carbon tetrabromide to form compound 6, reacting compound 6 with trimethylsilylacetyleneGenerating a compound 7 through a Sonogashira coupling reaction, generating a compound 8 through the reaction of the compound 7, and generating a compound 8 and R 1 And I, generating a compound 9 through a Sonogashira coupling reaction, reacting the compound 9 with potassium hydroxylamine to obtain a compound 10, and removing a protecting group from the compound 10 to obtain a compound A14-A20.
The reaction formula is as follows:
wherein the substituent R in the formula 1 With substituents R in the corresponding compounds A14 to A20 1 The same;
reagents and conditions in the above formulas:
a. di-tert-butyl dicarbonate, triethylamine, methylene dichloride and reacting at room temperature;
b. carbon tetrabromide, lithium diisopropylamide, tetrahydrofuran, and reacting at-78 ℃ and room temperature;
c.reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the like at 70 ℃;
d. tetrabutylammonium fluoride; tetrahydrofuran; reacting at 70 ℃;
e.R 1 i, reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the temperature of 70 ℃;
f. potassium hydroxylamine, methanol, room temperature reaction;
g. trifluoroacetic acid and dichloromethane, and reacting at room temperature;
(III) Compounds 1 and R 2 I, reacting to obtain a compound 11, reacting the compound 11 with elemental iodine to obtain a compound 12, performing a Sonogashira coupling reaction on the compound 12 and trimethylsilylacene to obtain a compound 13, reacting the compound 13 to obtain a compound 14, and reacting the compound 14 with R 1 I, generating a compound 15 through a Sonogashira coupling reaction, and reacting the compound 15 with potassium hydroxylamine to obtain a compound A21-A50;
the reaction formula is as follows:
wherein the substituent R in the formula 1 、R 2 With substituents R in the corresponding compounds A21 to A50 1 、R 2 The same;
reagents and conditions in the above formulas:
a.R 2 i, sodium hydride, tetrahydrofuran, and reacting at room temperature;
b. iodine, n-butyllithium, tetrahydrofuran, and reacting at-78 ℃ and room temperature;
c.reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the like at 70 ℃;
d. tetrabutylammonium fluoride; tetrahydrofuran; reacting at 70 ℃;
e.R 1 i, reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the temperature of 70 ℃;
f. potassium hydroxylamine, methanol, room temperature reaction;
r in the structural general formula A of the inhibitor 3 The preparation method of the inhibitor which is amino or primary amino is selected from one of the following:
(IV) Compounds 8 and R 1 The compound 18 is generated through a Sonogashira coupling reaction, the compound 18 is hydrolyzed to generate a compound 19, the compound 19 is condensed with hydrazine hydrate to obtain a compound 20, and the compound 20 is deprotected to generate a compound A56;
alternatively, the compound 20 and fatty aldehyde undergo reductive amination reaction to generate a compound 21, and the compound 21 is subjected to deprotection to generate a compound A57;
the reaction formula is as follows:
wherein the reaction isWherein the substituents R 1 With substituent R in compound A56, compound A57 1 The same is phenyl; in the compounds 21 and the compounds a57, n is 2.
Reagents and conditions in the above formulas:
a.R 1 i, reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the temperature of 70 ℃;
b. sodium hydroxide, methanol, 50 ℃;
c. hydrazine hydrate, O-benzotriazol-N, N, N ', N' -tetramethyl urea tetrafluoroboric acid, triethylamine, dimethyl sulfoxide and reacting at room temperature;
d. trifluoroacetic acid and dichloromethane, and reacting at room temperature;
e. fatty aldehyde, sodium cyanoborohydride, methanol and glacial acetic acid, and reacting at room temperature;
hydrolyzing the compound 15 to generate a compound 22, and condensing the compound 22 with hydrazine hydrate to obtain a compound A58;
alternatively, the compound A58 undergoes a reductive amination reaction with a fatty aldehyde to produce the compounds A59-A61.
The reaction formula is as follows:
wherein the substituent R in the formula 1 、R 2 With substituents R in compounds A58-A61 1 、R 2 The same; in the compound A59, n is 2; in the compound A60, n is 15; in the compound A61, n is 2;
reagents and conditions in the above formulas:
a. sodium hydroxide, methanol, 50 ℃;
b. hydrazine hydrate, O-benzotriazol-N, N, N ', N' -tetramethyl urea tetrafluoroboric acid, triethylamine, dimethyl sulfoxide and reacting at room temperature;
c. fatty aldehyde, sodium cyanoborohydride, methanol and glacial acetic acid, and reacting at room temperature;
the inhibitor has the structural general formula B R 3 The preparation method of the inhibitor which is hydroxyl is selected from the followingAnd (3) a step of:
reaction of compound 23 with p-toluenesulfonyl chloride to form compound 24, reaction of compound 24 with carbon tetrabromide to form compound 25, and reaction of compound 25 withCompound 26 is generated through a Sonogashira coupling reaction, and compound 26 reacts with potassium hydroxylamine to obtain compounds B1-B3.
The reaction formula is as follows:
wherein the substituent R in the formula 1 With substituents R in the corresponding compounds B1 to B3 1 The same;
reagents and conditions in the above formulas:
a. p-toluenesulfonyl chloride, sodium hydride, tetrahydrofuran and reacting at room temperature;
b. carbon tetrabromide, lithium diisopropylamide, tetrahydrofuran, and reacting at-78 ℃ and room temperature;
c.reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the like at 70 ℃;
d. potassium hydroxylamine, methanol, room temperature reaction;
(seven) reacting compound 23 with di-tert-butyl dicarbonate to form compound 27, reacting compound 27 with carbon tetrabromide to form compound 28, reacting compound 28 with trimethylsilylacene to form compound 29 through Sonogashira coupling reaction, reacting compound 29 to form compound 30, reacting compound 30 with R 1 And I is subjected to a Sonogashira coupling reaction to generate a compound 31, the compound 31 is reacted with potassium hydroxylamine to obtain a compound 32, and the compound 32 is deprotected to obtain a compound B4-B6.
The reaction formula is as follows:
wherein the substituent R in the formula 1 With substituents R in the corresponding compounds B4 to B6 1 The same;
reagents and conditions in the above formulas:
a. di-tert-butyl dicarbonate, triethylamine, methylene dichloride and reacting at room temperature;
b. carbon tetrabromide, lithium diisopropylamide, tetrahydrofuran, and reacting at-78 ℃ and room temperature;
c.reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the like at 70 ℃;
d. tetrabutylammonium fluoride; tetrahydrofuran; reacting at 70 ℃;
e.R 1 i, reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the temperature of 70 ℃;
f. potassium hydroxylamine, methanol, room temperature reaction;
g. trifluoroacetic acid and dichloromethane, and reacting at room temperature;
(eight) Compounds 23 and R 2 I generates a compound 33, the compound 33 reacts with elemental iodine to generate a compound 34, the compound 34 reacts with trimethylsilylacene through a Sonogashira coupling reaction to generate a compound 35, the compound 35 reacts to generate a compound 36, and the compound 36 reacts with R 1 And I, generating a compound 37 through a Sonogashira coupling reaction, and reacting the compound 37 with potassium hydroxylamine to obtain a compound B7.
The reaction formula is as follows:
wherein the substituent R in the formula 1 、R 2 With substituents R in the corresponding compounds B7 1 、R 2 The same;
reagents and conditions in the above formulas:
a.R 2 i, sodium hydride, tetrahydrofuran, and reacting at room temperature;
b. iodine, n-butyllithium, tetrahydrofuran, and reacting at-78 ℃ and room temperature;
c.reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the like at 70 ℃;
d. tetrabutylammonium fluoride; tetrahydrofuran; reacting at 70 ℃;
e.R 1 i, reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the temperature of 70 ℃;
f. potassium hydroxylamine, methanol, room temperature reaction;
use of HDAC11 subtype selective inhibitors
Use of a selective inhibitor of HDAC11 subtype in the manufacture of a medicament for the prevention or treatment of a disease associated with aberrant HDAC11 expression or activity.
The diseases related to abnormal expression or activity of HDAC11 are cancers, autoimmune diseases or metabolic diseases.
The cancer is liver cancer, myeloproliferative neoplasm, multiple myeloma, hodgkin's lymphoma, non-small cell lung cancer, glioblastoma, pituitary tumor, prostate cancer, ovarian cancer or acute lymphoblastic leukemia.
The autoimmune disease is inflammation, psoriasis, rheumatic arthritis, rheumatoid arthritis or systemic lupus erythematosus.
The metabolic disease is obesity or diabetes.
A pharmaceutical composition for preventing or treating cancer, autoimmune disease or metabolic disease, comprising an HDAC subtype 11 selective inhibitor of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.
The beneficial effects of the invention are as follows:
the HDAC11 subtype selective inhibitor has a brand new structure; compared with the existing inhibitor, the anti-hepatoma drug has the potential advantages of resisting drug resistance, recurrence and metastasis of the hepatoma. The HDAC11 subtype selective inhibitor has better inhibition activity and subtype selectivity on HDAC 11; shows a certain antiproliferative activity on tumor cells and has lower toxicity on normal cells; can inhibit the formation of cell colony of hepatocellular carcinoma and the balling of tumor stem cells; meanwhile, can effectively inhibit migration of hepatocellular carcinoma cells.
Drawings
FIG. 1. Inhibitory Activity of Compounds A1 and sorafenib on Huh7 cell colony formation in test example 3;
FIG. 2 inhibition activity of Compounds A1 and sorafenib on Huh7 tumor stem cell spheroidization in test example 3;
FIG. 3 inhibition of Huh7 cell migration by Compounds A1 and sorafenib in test example 4.
Detailed Description
The invention is further illustrated, but not limited, by the following examples.
Meanwhile, the reagents used in the examples are all commercially available unless otherwise specified; the methods and apparatus used, unless otherwise specified, may be as per the prior art.
Example 1. Preparation of Compounds A1-A13, B1-B3, compound A1 is exemplified.
The synthetic route is as follows:
the specific synthesis method comprises the following steps:
compound 2: naH (150 mg,60 wt%) was added to the flask, and then 5mL of THF was added to the flask at 0deg.C. Compound 1 was dissolved in 10mL of HF, then compound 1 (1 g,5.7 mmol) was added to a stirred solution of NaH via syringe, and after 30 minutes TsCl (p-toluenesulfonyl chloride, 1.19g,6.2 mmol) was added to the solution. The resulting mixture was stirred at 20℃for 6 hours. After the reaction was completed, 100mL of ice water was added thereto, and after precipitation of a solid, the solid was filtered, and after drying, etOAc/PE (1/5, 20 mL) was further slurried to give white solid 2 (1.76 g, yield)Rate 94%). The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ8.23(d,J＝8.3Hz,1H),8.01(d,J＝3.7Hz,1H),7.90(dd,J＝7.6,5.4Hz,3H),7.48(t,J＝8.0Hz,1H),7.39(d,J＝8.2Hz,2H),7.29(d,J＝3.6Hz,1H),3.89(s,3H),2.32(s,3H)。ESI-MS,m/z＝330.3[M+H] + 。
compound 3: LDA (lithium diisopropylamide, 1.2mL of 2M in THF) was added to compound 2 (660 mg,2 mmol) in THF (5 mL) at-78deg.C, and CBr was added dropwise after 30 min 4 (797 mg,2.4 mmol) in THF (5 mL) was reacted at this temperature for 30 minutes and then transferred to room temperature for 30 minutes. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (50 mL) and HCl (0.5M, 40 mL), the organic layer was washed with brine and dried over MgSO 4 The mixture was dried over, and then concentrated to give a residue, which was subjected to column chromatography to give white solid 3 (130 mg, yield 16%) in the form of petroleum ether/ethyl acetate (volume ratio: 100/10). The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ8.46(d,J＝8.5Hz,1H),7.93(d,J＝7.7Hz,1H),7.81-7.76(m,2H),7.52(t,J＝8.1Hz,1H),7.47-7.40(m,3H),3.88(s,3H),2.34(s,3H)。
compound 4a: compound 3 (340 mg,0.8 mmol), cuI (32 mg,0.2 eq), pd (PPh 3 ) 2 Cl 2 (bis (triphenylphosphine) palladium dichloride, 130mg,0.2 eq) was dissolved in 1, 4-dioxane (4 mL) and Et was added after argon was replaced 3 N (1.5 mL), ethynylbenzene (102 mg,1 mmol), the resulting mixture was stirred at 70 ℃ for 20 hours, the reaction was concentrated, and purified with a silica gel column (PE/ea=5/1) to give brown oil 4a (280 mg, 82% yield). The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ8.46(d,J＝8.5Hz,1H),7.93(d,J＝7.6Hz,2H),7.79(d,J＝8.4Hz,2H),7.77-7.58(m,1H),7.52(t,J＝8.1Hz,2H),7.45(s,2H),7.42(d,J＝8.2Hz,2H),3.88(s,3H),2.34(s,3H)。ESI-MS,m/z＝428.3[M-H] - 。
target compound A1: hydroxylamine hydrochloride (5.0 g,72 mmol) was weighed into 12mL dry methanol and stirred in an ice bath. KOH (6.06 g,108 mmol) was weighed out and added to 20mL dry methanol and stirred until dissolved. Dropwise adding KOH solution into hydroxylamine hydrochloride solution under ice bath condition, and stirring for 1 hrWhen (1). Filtering to obtain the potassium hydroxylamine solution. Compound 4a (180 mg,0.42 mmol) was dissolved in potassium hydroxylamine solution (6 mL) and stirred at room temperature for 10 hours. After the reaction is completed, the liquid is dried by spinning, after the water is added for uniform dissolution, 1N hydrochloric acid is added dropwise to adjust the pH to neutral, solid is separated out, and the crude product is obtained by filtering. By reverse phase column chromatography (MeCN/H 2 O=50%/50%, HAc conditions) to give a pale yellow solid A1 (90 mg, yield 50%). The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ11.92(s,1H),11.02(s,1H),8.99(s,1H),7.64-7.56(m,2H),7.52-7.43(m,4H),7.36(d,J＝7.2Hz,1H),7.21(t,J＝7.7Hz,1H),7.13(s,1H)。ESI-MS,m/z＝277.1[M+H] + 。
the preparation method of the compounds A2-A13 and B1-B3 is similar to that of the compound A1.
Example 2. Preparation of Compounds A14-A20, B4-B6, compound A17 is exemplified.
The synthetic route is as follows:
the specific synthesis method comprises the following steps:
compound 5: compound 1 (1 g,5.71 mmol) was dissolved in 20mL of CM (dichloromethane), triethylamine (1 mL) and di-tert-butyl dicarbonate (1.49 g,6.85 mmol) were added and stirred at room temperature for 5h. After the completion of the reaction, column chromatography was performed to obtain a transparent oily substance 5 (1.4 g, yield 89%) from petroleum ether/ethyl acetate (volume ratio 100/1). The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ8.36(d,J＝8.2Hz,1H),7.94-7.83(m,2H),7.45(t,J＝8.0Hz,1H),7.20(d,J＝3.7Hz,1H),3.92(s,3H),1.64(s,9H)。ESI-MS,m/z＝310.1[M+Cl] - 。
compound 6: compound 5 (0.24 g,0.87 mmol) was dissolved in 5mL of ultra-dry THF, LDA (0.65 mL,2M in THF) was added to the solution of compound 5 at-78deg.C, and after 30 minutes of reaction at this temperature, CBr was added dropwise 4 (0.36 g,1.1 mmol) in THF (5 mL) was allowed to react at this temperature for 30 minutes, then allowed to warm to room temperature for 30 minutes. After completion of the reaction, extracted with ethyl acetate and HCl (0.5M), washed with brineThe organic layer was combined with MgSO 4 Dried and then concentrated to give a residue, which was subjected to column chromatography using petroleum ether/ethyl acetate (volume ratio 100/10) to give 6 (0.1 g, yield 33%) as a pale yellow oil. The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ8.27(d,J＝8.4Hz,1H),7.90(d,J＝7.6Hz,1H),7.45(t,J＝8.0Hz,1H),7.39(s,1H),3.92(s,3H),1.67(s,9H)。
compound 7: compound 6 (100 mg,0.28 mmol), cuI (11 mg,0.05 mmol), pd (PPh) 3 ) 2 Cl 2 (35 mg,0.05 mmol) was dissolved in 1, 4-dioxane (4 mL) and Et was added after argon was replaced 3 N (2 mL), trimethylsilylacetylene (41 mg,0.42 mmol), the resulting mixture was stirred at 70℃for 20 hours, the reaction was concentrated, and purified by column chromatography on silica gel (PE/EA=5/1) to give brown oil 7 (70 mg, 67% yield). The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ8.35(d,J＝8.4Hz,1H),7.91(d,J＝7.6Hz,1H),7.53-7.48(m,2H),3.91(s,3H),1.64(s,9H),0.26(s,9H)。
compound 8: compound 7 (170 mg,0.45 mmol) was dissolved in THF (5 mL), TBAF (tetrabutylammonium fluoride, 0.18g,0.69 mmol) was added and stirred at 70℃for 4 hours. After the completion of the reaction, column chromatography was performed, and petroleum ether/ethyl acetate (volume ratio 100/1) gave solid 8 (92 mg, yield 68%). The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ8.41(d,J＝8.4Hz,1H),7.99(d,J＝7.6Hz,1H),7.62-7.55(m,2H),4.86(s,1H),3.98(s,3H),1.71(s,9H)。
compound 9a: the compound 1- (4-iodophenyl) -N, N-dimethylmethylamine (73 mg,0.28 mmol), cuI (11 mg,0.05 mmol), pd (PPh) 3 ) 2 Cl 2 (35 mg,0.05 mmol) was dissolved in 1, 4-dioxane (4 mL) and Et was added after argon was replaced 3 N (2 mL), compound 8 (125 mg,0.42 mmol), the resulting mixture was stirred at 70 ℃ for 20 hours, the reaction solution was concentrated, and purified by column chromatography on a silica gel column (PE/ea=5/1) to give brown oil 9a (67 mg, yield 55%). ESI-MS, m/z=433.4 [ m+h ]] + 。
Compound 10a: hydroxylamine hydrochloride (5.0 g,72 mmol) was weighed into 12mL dry methanol and stirred in an ice bath. KOH (6.06 g, 108) was weighed outmmol) was added to 20mL of anhydrous methanol and stirred until dissolved. The KOH solution was added dropwise to the hydroxylamine hydrochloride solution under ice bath conditions and stirring was continued for 1 hour. Filtering to obtain the potassium hydroxylamine solution. Compound 9a (130 mg,0.30 mmol) was dissolved in potassium hydroxylamine solution (6 mL) and stirred at room temperature for 10 hours. After the reaction is completed, the liquid is dried by rotation, after the water is added for uniform dissolution, 1N hydrochloric acid is added dropwise to adjust the pH until the solid is completely separated out, and the crude product is obtained by filtration. By reverse phase column chromatography (MeCN/H 2 O=50%/50%, HAc conditions) to give 10a (87 mg, 67% yield) as a pale yellow solid. The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ11.02(s,1H),8.97(s,1H),7.76-7.23(m,8H),3.39(s,2H),2.13(s,6H),1.63(s,9H)。
target compound a17: to CH of Compound 10a (433 mg,1.0 mmol) 2 Cl 2 To the solution (5 mL) was added 2mL of LTFA (trifluoroacetic acid) and the mixture was stirred at room temperature for 3 hours. After the reaction, the reaction mixture was treated with saturated Na 2 CO 3 The solution was washed three times, then concentrated to give a residue, which was subjected to column chromatography using petroleum ether/ethyl acetate (volume ratio 100/10) to give A17 (217 mg, yield 65%) as a pale yellow solid. The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ11.92(s,1H),11.02(s,1H),8.97(s,1H),7.64-7.15(m,8H),3.37(s,2H),2.15(s,6H)。ESI-MS,m/z＝334.3[M+H] + 。
the preparation of the compounds A14-A16, A18-A20, B4-B6 is similar to that of the compound A17.
Example 3 preparation of Compounds A21-A50, B7, compound A21 is exemplified.
The synthetic route is as follows:
the specific synthesis method comprises the following steps:
compound 11a: compound 1 (1.0 g,5.7 mmol) was dissolved in THF (5 mL), naH (150 mg,60 wt%) was slowly added in ice bath, and CH was added dropwise after stirring at 0deg.C for 30 min 3 I (1.2 g,8.4 mmol) was allowed to react for 5 hours at room temperature. After the reaction is completed, NH is added 4 Cl quenchingThe organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated to give 11a (0.82 g, 77% yield) as a colorless transparent oil. The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ7.77(dd,J＝7.7,3.7Hz,2H),7.53(d,J＝2.9Hz,1H),7.27(t,J＝7.8Hz,1H),6.93(d,J＝2.5Hz,1H),3.90(s,3H),3.85(s,3H)。ESI-MS,m/z＝378.6[2M+H] + 。
compound 12a: compound 11a (0.27 g,0.85 mmol) was dissolved in 10mL of ultra-dry THF, n-BuLi (0.4 mL,2.5M in hexane) was added to the solution of compound 11a at-78deg.C, and after reaction at that temperature for 30 minutes, a solution of iodine (0.24 g,0.95 mmol) in 5mL HF was added, and after reaction at that temperature for 30 minutes, the reaction was continued at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the organic layer was washed with brine, and dried over MgSO 4 Dried and then concentrated to give crude compound 12a for the next reaction.
Compound 13a: crude compound 12a (160 mg), cuI (20 mg,0.11 mmol), pd (PPh) 3 ) 2 Cl 2 (77 mg,0.11 mmol) was dissolved in 1, 4-dioxane (4 mL), and Et was added after the argon was replaced 3 N (2 mL), trimethylsilylacetylene (62 mg,0.63 mmol), the resulting mixture was stirred at 70℃for 20 hours, the reaction was concentrated, and purified with a silica gel column (PE/EA=10/1) to give 13a (100 mg) as a brown oil. The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ7.84(s,1H),7.66(d,J＝8.2Hz,1H),7.43(d,J＝7.3Hz,1H),7.24(t,J＝7.8Hz,1H),3.78(s,3H),3.76(s,3H),0.15(s,9H)。ESI-MS,m/z＝286.1[M+H] + 。
compound 14a: compound 13a (131 mg,0.46 mmol) was dissolved in THF (5 mL), TBAF (0.18 g,0.69 mmol) was added and stirred at 70℃for 4 hours. After the completion of the reaction, column chromatography was performed, and petroleum ether/ethyl acetate (volume ratio 100/1) gave solid 14a (69 mg, yield 70%). The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ7.88(s,1H),7.74(d,J＝8.2Hz,1H),7.50(d,J＝7.3Hz,1H),7.31(t,J＝7.8Hz,1H),3.97(s,1H),3.85(s,3H),3.84(s,3H)。
compound 15a: the compound iodobenzene (108 mg)，0.53mmol)，CuI(20mg，0.11mmol)、Pd(PPh 3 ) 2 Cl 2 (77 mg,0.11 mmol) was dissolved in 1, 4-dioxane (4 mL), and Et was added after the argon was replaced 3 N (2 mL), compound 14a (134 mg,0.63 mmol), the resulting mixture was stirred at 70 ℃ for 20 hours, the reaction was concentrated, and purified with a silica gel column (PE/ea=10/1) to give brown oil 15a (101 mg, yield 66%). The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ7.85-7.80(m,2H),7.68(dd,J＝6.1Hz,2.7Hz,2H),7.52-7.47(m,3H),7.38(t,J＝7.8Hz,1H),7.33(s,1H),3.94(s,3H),3.93(s,3H)。
target compound a21: hydroxylamine hydrochloride (5.00 g,72 mmol) was weighed into 12mL anhydrous methanol and stirred in an ice bath. KOH (6.06 g,108 mmol) was weighed out and added to 20mL dry methanol and stirred until dissolved. The KOH solution was added dropwise to the hydroxylamine hydrochloride solution under ice bath conditions and stirring was continued for 1 hour. Filtering to obtain the potassium hydroxylamine solution. Compound 15a (90 mg,0.31 mmol) was dissolved in potassium hydroxylamine solution (6 mL) and stirred at room temperature for 10 hours. After the reaction is completed, the liquid is dried by spinning, after the water is added for uniform dissolution, 1N hydrochloric acid is added dropwise to adjust the pH to neutral, solid is separated out, and the crude product is obtained by filtering. By reverse phase column chromatography (MeCN/H 2 O=50%/50%, HAc conditions) to afford a21 (60 mg, 67% yield) as a pale yellow solid. The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ11.08(s,1H),9.04(s,1H),7.70-7.64(m,3H),7.51-7.46(m,3H),7.41(d,J＝7.2Hz,1H),7.33-7.27(m,1H),7.19(s,1H),3.91(s,3H)。ESI-MS,m/z＝291.5[M+H] + 。
the preparation method of the compounds A22-A50 and B7 is similar to that of the compound A21.
Example 4 preparation of Compounds A51-A55, compound A51 is taken as an example.
The synthetic route is as follows:
the specific synthesis method comprises the following steps:
compound 16a: compound 4a (0.2 g,0.46 mmol) was dissolved in THF (5 mL) and addedTBAF (0.18 g,0.69 mmol) and stirred at 70℃for 4 hours. After completion of the reaction, column chromatography was performed, and petroleum ether/ethyl acetate (volume ratio 100/1) gave 16a (90 mg, yield 70%) as a white solid. The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ12.06(s,1H),7.75(d,J＝7.3Hz,1H),7.55-7.42(m,3H),7.50-7.44(m,3H),7.34-7.22(m,2H),3.84(s,3H)。
compound 17a: compound 16a (0.55 g,2.0 mmol) was dissolved in THF (10 mL), naH (55 mg,60 wt%) was slowly added under ice-bath, stirred at 0deg.C for 30 min, then a solution of 2- (dimethylamino) ethyl 4-methylbenzenesulfonate (0.61 g,2.5 mmol) in 8mL of THF was added dropwise and reacted at room temperature for 8 h. After the reaction is completed, NH is added 4 Cl quench, ethyl acetate extraction, combined organic phases, dried over anhydrous magnesium sulfate, concentrated and purified on a silica gel column (PE/ea=10/1) to give 17a (0.52 g, 75%) as an oil for use. ESI-MS, m/z=347.3 [ m+h ]] + 。
Target compound a51: hydroxylamine hydrochloride (5.00 g,72 mmol) was weighed into 12mL anhydrous methanol and stirred in an ice bath. KOH (6.06 g,108 mmol) was weighed out and added to 20mL dry methanol and stirred until dissolved. The KOH solution was added dropwise to the hydroxylamine hydrochloride solution under ice bath conditions and stirring was continued for 1 hour. Filtering to obtain the potassium hydroxylamine solution. Compound 17a (104 mg,0.30 mmol) was dissolved in potassium hydroxylamine solution (6 mL) and stirred at room temperature for 10 hours. After the reaction is completed, the liquid is dried by rotation, after the water is added for uniform dissolution, 1N hydrochloric acid is added dropwise to adjust the pH until the solid is completely separated out, and the crude product is obtained by filtration. Purification by reverse phase column chromatography (MeCN/h2o=50%/50%, HAc conditions) afforded a51 (64 mg, 61% yield) as a pale yellow solid. The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ11.02(s,1H),8.98(s,1H),7.78(d,J＝7.4Hz,1H),7.54-7.47(m,3H),7.51-7.44(m,3H),7.30-7.24(m,2H),4.57-4.50(m,2H),2.75-2.69(m,2H),2.90(s,6H)。ESI-MS,m/z＝348.6[M+H] + 。
the preparation method of the compound A52-A55 is similar to that of the compound A51.
Example 5 preparation of compound a 56.
The synthetic route is as follows:
the specific synthesis method comprises the following steps:
compound 18a: the compound iodobenzene (0.11 g,0.53 mmol), cuI (20 mg,0.11 mmol), pd (PPh) 3 ) 2 Cl 2 (77 mg,0.11 mmol) was dissolved in 1, 4-dioxane (4 mL), and Et was added after the argon was replaced 3 N (2 mL), compound 8 (189 mg,0.63 mmol), the resulting mixture was stirred at 70 ℃ for 20 hours, the reaction was concentrated, and purified by silica gel column (PE/ea=10/1) to give 18a (139 mg, yield 70%) as a brown oil. The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ8.39(d,J＝8.4Hz,1H),7.95(d,J＝7.5Hz,1H),7.66-7.60(m,3H),7.54(d,J＝8.0Hz,1H),7.51-7.45(m,3H),3.94(s,3H),1.65(s,9H)。
compound 19a: compound 18a (0.42 g,1.12 mmol) was dissolved in methanol, 2.5N NaOH (5 mL) was added and the mixture was heated to 50℃and reacted for 12 hours. After the reaction was completed, methanol was dried by swirling, pH was adjusted with 1N HCl until the precipitated solid was complete, and yellow solid 19a (0.24 g, yield 60%) was obtained by filtration. The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ12.70(s,1H),7.76(d,J＝7.4Hz,1H),7.51-7.49(m,3H),7.51-7.44(m,3H),7.30-7.23(m,2H),1.64(s,9H)。
compound 20a: compound 19a (0.23 g,0.65 mmol) was dissolved in DMSO (5 mL), TBTU (O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate, 0.25g,0.78 mmol), TEA (triethylamine, 180 uL) was added under ice-bath, and after 30 minutes 80wt% hydrazine hydrate was added and reacted at room temperature for 3 hours. After the completion of the reaction, water was added thereto to precipitate a solid, which was filtered to obtain yellow solid 20a (0.11 g, yield 45%). The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ9.63(s,1H),7.76(d,J＝7.4Hz,1H),7.58-7.48(m,3H),7.52-7.43(m,3H),7.32-7.23(m,2H),4.42(s,2H),1.65(s,9H)。
target compound a56: to CH of Compound 20a (375 mg,1.0 mmol) 2 Cl 2 To the solution (5 mL) was added 2mL of LTFA and the mixture was stirred at room temperature for 3 hours. After the reaction, the reaction mixture was treated with saturated Na 2 CO 3 Washing the solution three times, and concentratingThe residue was subjected to column chromatography using petroleum ether/ethyl acetate (volume ratio 100/10) to give A56 (220 mg, yield 80%) as a pale yellow solid. The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ11.93(s,1H),9.60(s,1H),7.61-7.23(m,7H),7.21-7.20(m,2H),4.75(s,2H)。ESI-MS,m/z＝276.2[M+H] + 。
example 6 preparation of compound a 57.
The synthetic route is as follows:
the specific synthesis method comprises the following steps:
compound 21a: compound 20a (108.9 mg,0.29 mmol) was dissolved in 15mL of methanol, one drop of glacial acetic acid was added, and after 5 minutes propanal (17 mg,0.29 mmol) was added, and after 1 hour NaCNBH was added 3 (55 mg,0.87 mmol) was stirred at room temperature for 2 hours. By reverse phase column chromatography (CH 3 OH/H 2 O=90%/10%, HAc conditions) to afford 21a (66 mg, 55% yield) as a pale yellow solid. The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ9.50(s,1H),7.60(dd,J＝6.6,3.0Hz,2H),7.52-7.45(m,4H),7.36(d,J＝7.3Hz,1H),7.22(t,J＝7.7Hz,1H),7.07-7.01(m,1H),5.08(s,1H),2.77(t,J＝7.2Hz,2H),1.36-1.45(m,2H),1.62(s,9H),0.85-0.90(m,3H)。
target compound a57: to CH of Compound 21a (417 mg,1.0 mmol) 2 Cl 2 To the solution (5 mL) was added 2mL of LTFA and the mixture was stirred at room temperature for 3 hours. After the reaction, the reaction mixture was treated with saturated Na 2 CO 3 The solution was washed three times, then concentrated to give a residue, which was subjected to column chromatography using petroleum ether/ethyl acetate (volume ratio 100/10) to give A57 (238 mg, yield 75%) as a pale yellow solid. The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ11.90(s,1H),9.51(s,1H),7.75(d,J＝7.4Hz,1H),7.59(s,3H),7.52-7.43(m,3H),7.32-7.23(m,2H),5.05(s,1H),2.76(t,J＝7.2Hz,2H),1.43-1.51(m,2H),0.85-0.91(m,3H)。ESI-MS,m/z＝318.42[M+H] + 。
example 7 preparation of compound a 58.
The synthetic route is as follows:
the specific synthesis method comprises the following steps:
compound 22a: compound 15a (0.32 g,1.12 mmol) was dissolved in 20mL of methanol, 2.5N NaOH (5 mL) was added, and the mixture was heated to 50℃and reacted for 12 hours. After the reaction was completed, methanol was dried by swirling, pH was adjusted with 1N HCl until the precipitated solid was complete, and yellow solid 22a (0.21 g, yield 68%) was obtained by filtration. The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ12.66(s,1H),7.83(s,1H),7.65-7.60(m,3H),7.41-7.25(m,4H),7.15-7.12(m,1H),3.81(s,3H)。
target compound a58: compound 22a (0.18 g,0.65 mmol) was dissolved in DMSO (5 mL), TBTU (0.25 g,0.78 mmol), TEA (180 uL) was added under ice-bath, and after 30 minutes 80wt% hydrazine hydrate was added and reacted at room temperature for 3 hours. After the completion of the reaction, water was added thereto to precipitate a solid, which was filtered to obtain yellow solid A58 (90 mg, yield 48%). The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ9.49(s,1H),7.82(s,1H),7.65-7.60(m,3H),7.40-7.26(m,4H),7.16-7.13(m,1H),4.49(s,2H),3.85(s,3H)。ESI-MS,m/z＝290.3[M+H] + 。
example 8 preparation of Compounds A59-A61, compound A59 was taken as an example.
The synthetic route is as follows:
the specific synthesis method comprises the following steps:
target compound a59: compound A58 (83.8 mg,0.29 mmol) was dissolved in 10mL of methanol, one drop of glacial acetic acid was added, and after 5 minutes propanal (17 mg,0.29 mmol) was added, and after 1 hour NaCNBH was added 3 (55 mg,0.87 mmol) was stirred at room temperature for 2 hours. By reverse phase column chromatography (CH 3 OH/H 2 O=90%/10%, HAc conditions) to yield a pale yellow solid a59 (53 mg, yieldRate 55%). The nuclear magnetic data of the product are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ9.51(s,1H),7.82(s,1H),7.65-7.60(m,3H),7.40-7.26(m,4H),7.16-7.13(m,1H),5.06(s,1H),3.85(s,3H),2.78(t,J＝7.2Hz,2H),1.38-1.53(m,2H),0.83-0.93(m,3H)。ESI-MS,m/z＝332.4[M+H] + 。
the preparation method of the compound A60-A61 is similar to that of the compound A59.
Test example 1 evaluation of in vitro HDAC inhibitory Activity and subtype Selectivity of target Compounds
The present invention uses fluorescence analysis to determine the inhibition activity of HDAC11, HDAC1 and HDAC6 of target compound, and takes the approved marketed HDAC inhibitor SAHA as positive control.
The experimental results (table 1) show that most of the target compounds of the present invention have an inhibition rate of over 50% on HDAC11 at a concentration of 0.5 μm, but have an inhibition rate of less than 20% on HDAC1 and HDAC6, and thus have a good HDAC11 subtype selective inhibition activity. Whereas 0.5 μM SAHA significantly inhibited HDAC1 and HDAC6 (greater than 50%), it inhibited HDAC11 poorly (less than 10%).
TABLE 1 results of in vitro HDAC11, HDAC1 and HDAC6 inhibition test of compounds
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The half-maximal Inhibitory Concentrations (IC) of the target compounds A1 and B1 on HDAC1, HDAC4, HDAC6, HDAC8 and HDAC11 were determined 50 ). The results in Table 2 show that A1 and B1 pair HDAC11 IC 50 0.031. Mu.M and 0.17. Mu.M, respectively, are far lower than IC for other HDAC subtypes 50 It was further confirmed that A1 and B1 have excellent HDAC11 subtype selective inhibitory activity.
TABLE 2 in vitro HDAC1, HDAC4, HDAC6, HDAC8 and HDAC11 compoundsIC 50 Test results
Test example 2 in vitro anti-proliferation test and Normal cytotoxicity test of target Compounds against tumor cells
The target compound A1 is selected as a representative, and the toxicity of the compound on human liver cell cancer cells (Huh 7 and PLC/PRF/5), human erythroleukemia cells (HEL), mouse myeloma cells P3x63Ag8.653 and human normal liver cells HL-7702 and human umbilical vein endothelial cells HUVEC is evaluated. The results in Table 3 show that compound A1 exhibits some antiproliferative activity on several tumor cells and has low toxicity to normal cells. It is worth noting that the activity of the compound A1 for inhibiting the proliferation of HCC cells Huh7 and PLC/PRF/5 is equivalent to that of the clinical first-line hepatocellular carcinoma therapeutic drug sorafenib, and has lower cytotoxicity than that of the sorafenib on human normal hepatocytes HL-7702 and human umbilical vein endothelial cells HUVEC.
TABLE 3 in vitro anti-proliferation assay and Normal cytotoxicity results of Compounds on tumor cells
Test example 3 in vitro experiments of target Compounds to inhibit the formation of hepatocellular carcinoma cell colonies and the balling of tumor Stem cells
Selecting a target compound A1 as a representative, and evaluating the inhibition activity of the compound on the formation of a hepatic cell cancer cell colony and the balling of a tumor stem cell in vitro. Colony formation experiments showed that both compound A1 and sorafenib were effective in inhibiting the formation of Huh7 colonies in hepatocellular carcinoma cells compared to Ctrl group (dmso treatment) at a concentration of 2 μm, and that A1 had a greater ability to inhibit the formation of Huh7 colonies than sorafenib (fig. 1), which may be related to the inhibition of HCC tumor stem cells by A1. The stem cell balling experiments further demonstrate that both compound A1 and sorafenib are effective in inhibiting Huh7 tumor stem cell balling (primary balling and secondary balling) at a concentration of 2 μm compared to Ctrl group (dmso treatment), and that A1 has significantly better activity in inhibiting Huh7 tumor stem cell balling than sorafenib (fig. 2). And (3) injection: primary balling refers to balling experiments of Huh7 cells, and secondary balling refers to balling experiments performed on tumor stem cells obtained by ball digestion of tumor stem cells after primary balling of Huh7 cells.
Test example 4. Target Compounds inhibit in vitro migration of hepatocellular carcinoma cells (scratch test)
Selecting a target compound A1 as a representative, and evaluating the inhibitory activity of the compound on in vitro hepatocellular carcinoma cell migration. The results of the scratch experiments (FIG. 3) showed that both compound A1 and sorafenib were effective in inhibiting Huh7 cell migration compared to the Ctrl group (dmso treatment) after 12h treatment of cells with 2. Mu.M concentration of compound, and that A1 had a stronger activity against Huh7 cell migration than sorafenib.
The results indicate that the HDAC11 subtype selective inhibitor has good treatment prospect on cancers such as hepatocellular carcinoma and the like, and also has potential advantages of drug resistance, relapse resistance and metastasis resistance.

Claims (10)

1. An HDAC11 subtype selective inhibitor, wherein the inhibitor is an inhibitor having a structure represented by the following structural general formula a or B, and optical isomers, pharmaceutically acceptable salts thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 is an aromatic ring, an aromatic heterocyclic ring, a substituted aromatic ring or a substituted aromatic heterocyclic ring; wherein the substituents in the substituted aromatic ring or substituted aromatic heterocycle are selected from alkyl, aminoalkyl, halogen, haloalkyl, alkoxy, amino, piperazinyl, alkylpiperazinyl, morpholinyl, alkylmorpholinyl, cyano, alkylamido, or amido;
R 2 is hydrogen, alkyl, alkylpiperazinyl, alkylmorpholinyl, or aminoalkyl;
R 3 is a hydroxyl group, an amino group, or a primary amino group.
2. The HDAC11 subtype selective inhibitor of claim 1, wherein,
R 1 is a benzene ring, a substituted benzene ring, a pyridine ring, a substituted pyridine ring, a pyrazine ring, a substituted pyrazine ring, a pyrimidine ring or a substituted pyrimidine ring; wherein the substituent of the substituted benzene ring, the substituted pyridine ring, the substituted pyrazine ring or the substituted pyrimidine ring is selected from
R 2 Is that
R 3 Is a hydroxyl group, an amino group, an alkyl-substituted primary amino group having 1 to 16 carbon atoms.
3. The HDAC11 subtype selective inhibitor of claim 2, wherein the inhibitor has a structure that is one of:
4. a method of preparing an HDAC11 subtype selective inhibitor according to claim 3 selected from one of the following:
(one)) Reacting compound 1 with p-toluenesulfonyl chloride to form compound 2, reacting compound 2 with carbon tetrabromide to form compound 3, reacting compound 3 withGenerating a compound 4 through a Sonogashira coupling reaction, and reacting the compound 4 with potassium hydroxylamine to obtain a compound A1-A13;
alternatively, compound 4 deprotects to form compound 16, compound 16 andreacting to generate a compound 17, and reacting the compound 17 with potassium hydroxylamine to obtain a compound A51-A55;
the reaction formula is as follows:
wherein in the reaction formula for preparing the compounds A1-A13, the substituent R 1 With substituents R in the corresponding compounds A1 to A13 1 The same; in the reaction formula for preparing the compounds A51-A55, the substituent R 1 、R 2 With substituents R in the corresponding compounds A51 to A55 1 、R 2 The same;
reagents and conditions in the above formulas:
a. p-toluenesulfonyl chloride, sodium hydride, tetrahydrofuran and reacting at room temperature;
b. carbon tetrabromide, lithium diisopropylamide, tetrahydrofuran, and reacting at-78 ℃ and room temperature;
c.reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the like at 70 ℃;
d. potassium hydroxylamine, methanol, room temperature reaction;
e. tetrabutylammonium fluoride; tetrahydrofuran; reacting at 70 ℃;
f.sodium hydride, tetrahydrofuran, room temperature reaction;
(di) reacting compound 1 with di-tert-butyl dicarbonate to obtain compound 5, reacting compound 5 with carbon tetrabromide to obtain compound 6, reacting compound 6 with trimethylsilylacene to obtain compound 7 through Sonogashira coupling reaction, reacting compound 7 to obtain compound 8, reacting compound 8 with R 1 I, generating a compound 9 through a Sonogashira coupling reaction, reacting the compound 9 with potassium hydroxylamine to obtain a compound 10, removing a protecting group from the compound 10 to obtain a compound A14-A20;
the reaction formula is as follows:
wherein the substituent R in the formula 1 With substituents R in the corresponding compounds A14 to A20 1 The same;
reagents and conditions in the above formulas:
a. di-tert-butyl dicarbonate, triethylamine, methylene dichloride and reacting at room temperature;
b. carbon tetrabromide, lithium diisopropylamide, tetrahydrofuran, and reacting at-78 ℃ and room temperature;
c.reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the like at 70 ℃;
d. tetrabutylammonium fluoride; tetrahydrofuran; reacting at 70 ℃;
e.R 1 i, reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the temperature of 70 ℃;
f. potassium hydroxylamine, methanol, room temperature reaction;
g. trifluoroacetic acid and dichloromethane, and reacting at room temperature;
(III) Compounds 1 and R 2 I reaction to give Compound 11, chemical conversionThe compound 11 reacts with elemental iodine to generate a compound 12, the compound 12 reacts with trimethylsilylacene to generate a compound 13 through Sonogashira coupling reaction, the compound 13 reacts to generate a compound 14, and the compound 14 reacts with R 1 I, generating a compound 15 through a Sonogashira coupling reaction, and reacting the compound 15 with potassium hydroxylamine to obtain a compound A21-A50;
the reaction formula is as follows:
wherein the substituent R in the formula 1 、R 2 With substituents R in the corresponding compounds A21 to A50 1 、R 2 The same;
reagents and conditions in the above formulas:
a.R 2 i, sodium hydride, tetrahydrofuran, and reacting at room temperature;
b. iodine, n-butyllithium, tetrahydrofuran, and reacting at-78 ℃ and room temperature;
c.reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the like at 70 ℃;
d. tetrabutylammonium fluoride; tetrahydrofuran; reacting at 70 ℃;
e.R 1 i, reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the temperature of 70 ℃;
f. potassium hydroxylamine, methanol, room temperature reaction;
(IV) Compounds 8 and R 1 The compound 18 is generated through a Sonogashira coupling reaction, the compound 18 is hydrolyzed to generate a compound 19, the compound 19 is condensed with hydrazine hydrate to obtain a compound 20, and the compound 20 is deprotected to generate a compound A56;
alternatively, the compound 20 and fatty aldehyde undergo reductive amination reaction to generate a compound 21, and the compound 21 is subjected to deprotection to generate a compound A57;
the reaction formula is as follows:
wherein the substituent R in the formula 1 With substituent R in compound A56, compound A57 1 The same is phenyl; in the compound 21 and the compound A57, n is 2;
reagents and conditions in the above formulas:
a.R 1 i, reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the temperature of 70 ℃;
b. sodium hydroxide, methanol, 50 ℃;
c. hydrazine hydrate, O-benzotriazol-N, N, N ', N' -tetramethyl urea tetrafluoroboric acid, triethylamine, dimethyl sulfoxide and reacting at room temperature;
d. trifluoroacetic acid and dichloromethane, and reacting at room temperature;
e. fatty aldehyde, sodium cyanoborohydride, methanol and glacial acetic acid, and reacting at room temperature;
hydrolyzing the compound 15 to generate a compound 22, and condensing the compound 22 with hydrazine hydrate to obtain a compound A58;
or, the compound A58 and fatty aldehyde undergo reductive amination reaction to generate compounds A59-A61;
the reaction formula is as follows:
wherein the substituent R in the formula 1 、R 2 With substituents R in compounds A58-A61 1 、R 2 The same; in the compound A59, n is 2; in the compound A60, n is 15; in the compound A61, n is 2;
reagents and conditions in the above formulas:
a. sodium hydroxide, methanol, 50 ℃;
b. hydrazine hydrate, O-benzotriazol-N, N, N ', N' -tetramethyl urea tetrafluoroboric acid, triethylamine, dimethyl sulfoxide and reacting at room temperature;
c. fatty aldehyde, sodium cyanoborohydride, methanol and glacial acetic acid, and reacting at room temperature;
reaction of compound 23 with p-toluenesulfonyl chloride to form compound 24, reaction of compound 24 with carbon tetrabromide to form compound 25, and reaction of compound 25 withGenerating a compound 26 through a Sonogashira coupling reaction, and reacting the compound 26 with potassium hydroxylamine to obtain compounds B1-B3;
the reaction formula is as follows:
wherein the substituent R in the formula 1 With substituents R in the corresponding compounds B1 to B3 1 The same;
reagents and conditions in the above formulas:
a. p-toluenesulfonyl chloride, sodium hydride, tetrahydrofuran and reacting at room temperature;
b. carbon tetrabromide, lithium diisopropylamide, tetrahydrofuran, and reacting at-78 ℃ and room temperature;
c.reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the like at 70 ℃;
d. potassium hydroxylamine, methanol, room temperature reaction;
(seven) reacting compound 23 with di-tert-butyl dicarbonate to form compound 27, reacting compound 27 with carbon tetrabromide to form compound 28, reacting compound 28 with trimethylsilylacene to form compound 29 through Sonogashira coupling reaction, reacting compound 29 to form compound 30, reacting compound 30 with R 1 The I generates a compound 31 through a Sonogashira coupling reaction, the compound 31 reacts with potassium hydroxylamine to obtain a compound 32, and the compound 32 is deprotected to obtain a compound B4-B6;
the reaction formula is as follows:
wherein the substituent R in the formula 1 With substituents R in the corresponding compounds B4 to B6 1 The same;
reagents and conditions in the above formulas:
a. di-tert-butyl dicarbonate, triethylamine, methylene dichloride and reacting at room temperature;
b. carbon tetrabromide, lithium diisopropylamide, tetrahydrofuran, and reacting at-78 ℃ and room temperature;
c.reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the like at 70 ℃;
d. tetrabutylammonium fluoride; tetrahydrofuran; reacting at 70 ℃;
e.R 1 i, reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the temperature of 70 ℃;
f. potassium hydroxylamine, methanol, room temperature reaction;
g. trifluoroacetic acid and dichloromethane, and reacting at room temperature;
(eight) Compounds 23 and R 2 I generates a compound 33, the compound 33 reacts with elemental iodine to generate a compound 34, the compound 34 reacts with trimethylsilylacene through a Sonogashira coupling reaction to generate a compound 35, the compound 35 reacts to generate a compound 36, and the compound 36 reacts with R 1 I generates a compound 37 through a Sonogashira coupling reaction, and the compound 37 reacts with potassium hydroxylamine to obtain a compound B7;
the reaction formula is as follows:
wherein the substituent R in the formula 1 、R 2 With the corresponding compound B7Substituent R of (2) 1 、R 2 The same;
reagents and conditions in the above formulas:
a.R 2 i, sodium hydride, tetrahydrofuran, and reacting at room temperature;
b. iodine, n-butyllithium, tetrahydrofuran, and reacting at-78 ℃ and room temperature;
c.reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the like at 70 ℃;
d. tetrabutylammonium fluoride; tetrahydrofuran; reacting at 70 ℃;
e.R 1 i, reacting cuprous iodide, triethylamine, bis (triphenylphosphine) palladium dichloride, 1, 4-dioxane and the temperature of 70 ℃;
f. potassium hydroxylamine, methanol, and at room temperature.
5. Use of a selective inhibitor of HDAC11 subtype according to any one of claims 1 to 3 for the manufacture of a medicament for the prevention or treatment of a disease associated with aberrant HDAC11 expression or activity.
6. The use according to claim 5, wherein the disorder associated with aberrant HDAC11 expression or activity is cancer, an autoimmune disorder or a metabolic disorder.
7. The use according to claim 6, wherein the cancer is liver cancer, myeloproliferative neoplasm, multiple myeloma, hodgkin's lymphoma, non-small cell lung cancer, glioblastoma, pituitary tumor, prostate cancer, ovarian cancer or acute lymphoblastic leukemia.
8. The use according to claim 6, wherein the autoimmune disease is inflammation, psoriasis, rheumatoid arthritis or systemic lupus erythematosus.
9. The use according to claim 6, wherein the metabolic disease is obesity or diabetes.
10. A pharmaceutical composition for preventing or treating cancer, autoimmune disease or metabolic disease comprising the HDAC11 subtype selective inhibitor of any one of claims 1-3 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.
CN202210329731.5A 2022-03-30 2022-03-30 HDAC11 subtype selective inhibitor and preparation method and application thereof Pending CN116924959A (en)

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