CN116640106B - Phenylpiperazine compound and preparation method and application thereof - Google Patents

Phenylpiperazine compound and preparation method and application thereof Download PDF

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CN116640106B
CN116640106B CN202310527295.7A CN202310527295A CN116640106B CN 116640106 B CN116640106 B CN 116640106B CN 202310527295 A CN202310527295 A CN 202310527295A CN 116640106 B CN116640106 B CN 116640106B
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bromide
phenylpiperazine
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nmr
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CN116640106A (en
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孙凯
马莉莉
郑一超
王博
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Zhengzhou University
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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a phenylpiperazine compound, and a preparation method and application thereof. The phenylpiperazine compound provided by the invention is a compound shown in a formula (I) or pharmaceutically acceptable salt thereof:

Description

Phenylpiperazine compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a phenylpiperazine compound, and a preparation method and application thereof.
Background
Nowadays, tumors have gradually become a major factor that poses serious threats to human life health, and their incidence has risen year by year. The national cancer center published the latest stage of national cancer statistics: in 2016, the new cancer cases in China are about 406.4 ten thousand, and the new cancer death cases are 241.35 ten thousand. This means that on average more than 1 million people per day in our country will be diagnosed with new cancer, and on average about 7 people will be diagnosed every minute. Cancer presents a great hazard to human health, and achieving scientific and efficient cancer prevention and treatment has become a common expectation and demand for all humans.
With the recent progress of epigenetic science, the focus of research on cancer has also shifted from activation of oncogenes or silencing of cancer suppressor genes by gene mutation to epigenetic abnormalities. It is increasingly recognized that almost all cancers are caused by both epigenetic abnormalities and genetic changes. Epigenetic refers to the discipline of studying phenotypic changes that can be stably inherited without variation in DNA sequence. Epigenetics can be classified into DNA methylation, non-coding RNA changes, histone modification, chromosomal remodeling, and the like, according to their regulatory mechanisms.
Histone modification is a key molecular mechanism that regulates gene transcription and tissue cell development, and it also can regulate chromatin state and gene expression. Unlike other histone modifications, histone methylation has long been considered an irreversible process. However, this knowledge has been subverted, and so far about 20 lysine demethylases have been found by humans. The first histone lysine-specific demethylase 1 (lysine specific demethylase, lsd 1) was found in 2004 by Shi Yang et al. This finding allows histone methylation to be redefined and also provides a new approach for further protein modification.
LSD1 can regulate and control expression of tumor-associated genes, and promote proliferation, invasion and metastasis of tumor cells. Current studies indicate that LSD1 is overexpressed in a variety of solid tumors, including gastric, lung, liver, esophageal, breast, bladder, prostate, colorectal, leukemia, glioma, and the like. Several experiments have now demonstrated that inhibiting LSD1 over-expression in tumor cells can affect tumor cell proliferation, enhance tumor immunity and the anti-tumor effect of immune checkpoint blockers. Thus, it is of great clinical importance to find novel potent compound backbones to develop targeted potent LSD1 inhibitors.
To date, 10 LSD1 inhibitors have been approved for clinical trials, with 8 compounds being phencyclized propylamine (TCP) and its structurally engineered derivatives. TCP is used as monoamine oxidase (MAO) inhibitor for treating depression at the earliest time, has better safety and has better inhibiting effect on LSD1, thereby smoothly entering the clinical research stage. Currently, 3 clinical trials of TCP are used to evaluate the therapeutic effects of single or combined use on the treatment of Acute Myelogenous Leukemia (AML) and myelodysplastic syndrome (MDS), and the clinical phase II study has been successfully entered. Considering the moderate inhibitory activity of TCP on LSD1 and better research progress, currently, LSD1 inhibitors are mostly studied using phencyclimine (TCP) as a positive control compound.
As a research target of the emerging hot antitumor drugs in recent years, due to insufficient selectivity between the phencyclidine inhibitor and MAO or insufficient efficacy on tumor cells or at animal level, there is a possibility of off-target, LSD1 inhibitor drugs on the market have not yet been successfully marketed, and several compound entities enter the clinical research stage, and several low nanomolar inhibitors based on TCP structure derivatives have terminated the clinical research. Therefore, the design and development of novel LSD1 inhibiting compounds with high efficiency and excellent selectivity, which are different from the TCP structure, has very important research significance and potential application value for the development of inhibitors based on LSD1 targets and targeted antitumor drugs.
Disclosure of Invention
The first aim of the invention is to provide a phenylpiperazine compound which has a novel structure and good inhibitory activity on LSD1 protein.
The second object of the present invention is to provide a preparation method of phenylpiperazine compounds, which has simple process and mild conditions, and can effectively prepare phenylpiperazine compounds with good inhibitory activity on LSD1 protein.
The third purpose of the invention is to provide an application of phenylpiperazine compounds, in particular to an application in preparing an inhibitor or an anti-tumor drug based on LSD1 targets.
In order to achieve the above purpose, the phenylpiperazine compound of the present invention adopts the following technical scheme:
a phenylpiperazine compound, which is a compound represented by the formula (I):
in the formula (I), R 1 Is aryl or heteroaryl; r is R 1 When selected from aryl, the aryl is unsubstituted, optionally mono-substituted or di-substituted phenyl; r is R 1 When aryl is substituted, the substituent is one or two of nitrile, methyl, ethyl, isopropyl, carboxyl, nitro, trifluoromethyl, methylthio, fluorine, chlorine and methoxy; r is R 1 When the heteroaryl is selected from heteroaryl, the heteroaryl is one of unsubstituted, monosubstituted or disubstituted pyridyl, furyl, benzothiophene and benzopyridine at any position; r is R 1 When heteroaryl is substituted, the substituent is one or two of chlorine, bromine and methyl;
R 2 is aryl or cycloalkyl; r is R 2 When selected from aryl, the aryl is unsubstituted, optionally mono-substituted or di-substituted phenyl; r is R 2 When aryl is substituted, the substituent is one or two of nitrile, nitro, fluorine, chlorine, trifluoromethyl, methoxy, methyl, ethyl and isopropyl; the cycloalkyl is cyclobutyl or cyclopentyl.
To improve the inhibitory activity of phenylpiperazines on LSD1 proteins, R in formula (I) 1 One selected from 4-cyanobenzyl, 4-methylbenzyl, 4-ethylbenzyl, 4-isopropylbenzyl, 4-carboxybenzyl, 4-nitrobenzyl, 4-trifluoromethylbenzyl, 4-methylthiobenzyl, 3-fluoro-4-methylbenzyl, 4-chlorobenzyl, 2, 4-difluorobenzyl, 2-hydroxy-4-methylbenzyl, 3-hydroxy-4-methoxybenzyl, benzothiophene-2-methyl, 6-chloropyridine-3-methyl, 5-bromofuran-2-methyl, isoquinoline-7-methyl, 5-methylpyridine-3-methyl, benzothiophene-3-methyl, 4-methylthiobenzyl, 3-fluoro-4-cyanobenzyl; r is R 2 One selected from 4-cyanobenzyl, 4-nitrobenzyl, 2-fluoro-4-cyanobenzyl, 4-chlorobenzyl, 3-fluorobenzyl, 2, 3-difluorobenzyl, 2, 5-difluorobenzyl, 3-fluoro-4- (trifluoromethyl) benzyl, 3-fluoro-4-methylbenzyl, 3-fluoro-4-methoxybenzyl, 4-methylbenzyl, 3-methylbenzyl, 2, 4-dimethylbenzyl, 4-ethylbenzyl, 4-isopropylbenzyl, cyclobutylmethyl, cyclopentylmethyl.
More preferably, the phenylpiperazine compound is selected from the group consisting of compounds having the following structures or pharmaceutically acceptable salts thereof, which are sequentially designated as compounds 1 to 43, in view of further improving the LSD1 protein inhibitory effect of the compound:
the phenylpiperazine compound belongs to a compound containing basic functional groups, and can be easily reacted with various inorganic acids and organic acids to prepare corresponding salts through simple acid-base reaction. Therefore, the compound of the invention can also be in the form of pharmaceutically acceptable salts during drug development and application, and can be reasonably selected by a person skilled in the art according to the needs. Further, the pharmaceutically acceptable salt is one of hydrochloride, hydrobromide, sulfate, phosphate, borate, mesylate, p-toluenesulfonate, naphthalenesulfonate, benzenesulfonate, citrate, lactate, pyruvate, tartrate, acetate, trifluoroacetate, maleate, succinate, mandelate, fumarate, salicylate and phenylacetate of the phenylpiperazine compound.
The preparation method of the phenylpiperazine compound comprises the following steps:
(1) Reacting 1-Boc-4- (4-aminophenyl) piperazine and formaldehyde compounds in a solvent, then adding a reducing agent for continuous reaction, and extracting, filtering and purifying after the reaction to obtain an intermediate compound A;
(2) Reacting the intermediate compound A, an alkaline substance and a bromine-containing compound in a solvent, and extracting, filtering and purifying the reaction product to obtain an intermediate compound B;
(3) Reacting the intermediate compound B with an acidic substance in a solvent, and recrystallizing after the reaction.
Preferably, in the step (1), the formaldehyde compound is one of 4-cyanobenzaldehyde, 4-methylbenzaldehyde, 4-ethylbenzaldehyde, 4-isopropylbenzaldehyde, 4-carboxybenzaldehyde, 4-nitrobenzaldehyde, 4-trifluoromethylbenzaldehyde, 4-methylthiobenzaldehyde, 3-fluoro-4-methylbenzaldehyde, 4-chlorobenzaldehyde, 2, 4-difluorobenzaldehyde, 2-hydroxy-4-methylbenzaldehyde, 3-hydroxy-4-methoxybenzaldehyde, benzothiophene-2-carbaldehyde, 6-chloropyridine-3-carbaldehyde, 5-bromofuran-2-carbaldehyde, isoquinoline-7-carbaldehyde, 5-methylpyridine-3-carbaldehyde, 6-chloropyridine-3-carbaldehyde, benzothiophene-2-carbaldehyde, isoquinoline-7-carbaldehyde, 4-methylthiobenzaldehyde, 4-trifluoromethylbenzaldehyde, 3-fluoro-4-cyanobenzaldehyde, 3-hydroxy-4-methoxybenzaldehyde; the reducing agent is one or more of sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride.
Further, in the step (2), the bromine-containing compound is one of 4-cyanobenzyl bromide, 4-nitrobenzyl bromide, 2-fluoro-4-cyanobenzyl bromide, 4-chlorobenzyl bromide, 3-fluorobenzyl bromide, 2, 3-difluorobenzyl bromide, 2, 5-difluorobenzyl bromide, 3-fluoro-4- (trifluoromethyl) benzyl bromide, 3-fluoro-4-methylbenzyl bromide, 3-fluoro-4-methoxybenzyl bromide, 4-methylbenzyl bromide, 3-methylbenzyl bromide, 2, 4-dimethylbenzyl bromide, 4-ethylbenzyl bromide, 4-isopropylbenzyl bromide, cyclobutylmethyl bromide and cyclopentylmethyl bromide; the alkaline substance is one or more of triethylamine, sodium carbonate and potassium carbonate.
In the step (3), the purpose of the reaction with an acidic substance is to remove the t-butoxycarbonyl protecting group in the intermediate compound B. Preferably, the acidic substance is one of trifluoroacetic acid, hydrogen chloride gas and hydrogen chloride solution. After the tert-butoxycarbonyl protecting group in the intermediate compound B is removed by acid, the obtained product is a salt corresponding to the acid, and the obtained salt can be directly applied or can be further neutralized with alkali to be a neutral compound, and can be further subjected to salt forming reaction with other kinds of acid, so that the skeleton structure and the use effect of the phenylpiperazine compound are not affected.
In order to promote the conversion of raw materials and improve the reaction efficiency and the product yield, preferably, the solvent adopted in the step (1) and the step (2) is one or more of methanol, dichloromethane and ethanol; the solvent adopted in the step (3) is one or more of dichloromethane, methanol, ethanol and ethyl acetate; the reaction temperature in the step (1) is 25-80 ℃, the reaction time is 4-10 h, and the continuous reaction time is 3-5 h; the reaction temperature in the step (2) is-10-50 ℃, and the reaction time is 4-10 hours; the reaction temperature in the step (3) is 10-30 ℃, and the reaction time is 6-10 h.
The invention relates to application of phenylpiperazine compounds, in particular to application in preparation of an LSD1 target-based inhibitor or an anti-tumor drug.
The invention has the beneficial effects that:
the phenylpiperazine compound provided by the invention has a novel skeleton. Proved by LSD1 protein inhibition activity experiments, the phenylpiperazine compound with the characteristic structure has good inhibition activity on LSD1 protein, lays a good foundation for research and development of LSD1 inhibition compounds with better activity, has potential for further developing anti-tumor drugs, enriches skeleton types of the anti-tumor drugs, provides new compound entities and research directions for research and development of LSD1 target-based inhibition compounds and anti-tumor new drugs, and has good application prospects.
The preparation method of the phenylpiperazine compound has the characteristics of mild reaction conditions and simple operation, and the prepared phenylpiperazine compound has good LSD1 protein inhibition activity.
The application of the phenylpiperazine compound in preparing an inhibitor or an anti-tumor drug based on an LSD1 target spot provided by the invention shows good inhibition activity on LSD1, shows good drug development potential, and provides a new direction for research and development of the inhibitor and the anti-tumor drug based on the LSD1 target spot.
Detailed Description
The invention is further described below in connection with examples which are given solely for the purpose of illustration and are not intended to limit the scope of the invention.
In the following examples, the structure of the compounds was determined by Nuclear Magnetic Resonance (NMR) and High Resolution Mass Spectrometry (HRMS). The nuclear magnetic resonance apparatus is Bruker DPX-400 or Bruker DPX-300 superconducting nuclear magnetic resonance apparatus, and Tetramethylsilane (TMS) is used as an internal standard; the high resolution mass spectrum used was a Waters-Micromass Q-Tof mass spectrometer. 43 compounds according to the invention were synthesized as novel compounds, whose structure was determined by melting point, 1 H NMR、 13 Modern spectroscopic means such as C NMR and HRMS confirm.
The phenylpiperazine compounds related to the following examples were designated as compounds 1 to 43 in order, and the structural formulas are as follows:
example 1
The structural formula of the phenylpiperazine compound of the present embodiment is shown as compound 1, and the preparation process is as follows:
(1) The route is as follows:
1-Boc-4- (4-aminophenyl) piperazine (designated 45 a) (539 mg,0.85 eq.) was placed in a 100mL eggplant-shaped bottle and dissolved by adding 15mL Dichloroethane (DCE). 4-cyanobenzaldehyde (designated 44 a) (300 mg,1.0 eq.) and glacial acetic acid (137 mg,1.0 eq.) were then added to the system and stirred at room temperature for 4h, and the completion of the amination reaction was monitored by TLC (PE: ea=1:1). The reducing agent sodium triacetoxyborohydride (969 mg,2 eq.) was added in portions at 0℃and reacted for 0.5h before returning to room temperature and stirring for 4h. The reaction was monitored by TLC (PE: ea=1:1) for completion and the solvent was removed under reduced pressure. This was then extracted three times with dichloromethane and water, washed once with saturated brine and the organic phase was dried over anhydrous sodium sulfate. After drying, it was filtered, concentrated by distillation under reduced pressure, and purified by column chromatography (PE: ea=3:1) to give intermediate compound a, designated 46a.
(2) The route is as follows:
intermediate 46a (300 mg,1.0 eq.) and triethylamine (77 mg,1.0 eq.) were placed in a 100mL eggplant-shaped bottle and dissolved by adding 15mL dichloromethane. 4-cyanobenzyl bromide (47 a) (449 mg,3.0 eq.) was slowly added dropwise at 0deg.C for 0.5h, then allowed to return to room temperature and stirred for 4h. The reaction was monitored by TLC (PE: ea=1:1) for completion and the solvent was removed under reduced pressure. It was then extracted three times with ethyl acetate and water, washed once with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. After drying, it was filtered, concentrated by distillation under reduced pressure, and purified by column chromatography (PE: ea=3:1) to give intermediate compound B, designated 48a.
(3) The route is as follows:
intermediate 48a (300 mg,1.0 eq.) was placed in a 50mL eggplant bottle and dissolved by adding 5mL of dichloromethane. 5mL of trifluoroacetic acid (TFA) was slowly added dropwise with stirring and reacted overnight at room temperature. The completion of the reaction was monitored by TLC (PE: ea=1:3), the solvent was removed under reduced pressure, methylene chloride was supplemented multiple times during which time compound 1 was obtained as the trifluoroacetate salt by final recrystallization from ethyl acetate, and its structure was then characterized.
The characterization results are as follows: pale yellow solid, 75% yield. Melting point 192.8-193.6 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ8.74(s,2H),7.79(d,J＝8.0Hz,4H),7.43(d,J＝8.1Hz,4H),6.79(d,J＝8.7Hz,2H),6.56(d,J＝8.8Hz,2H),4.74(s,4H),3.18(s,4H),3.10(dd,J＝7.0,3.4Hz,4H). 13 C NMR(101MHz,DMSO-d 6 )δ158.31,157.68,145.52,142.00,141.77,132.35,127.68,118.84,118.26,113.72,109.47,54.55,46.94,42.92.HR-MS(ESI):Calcd.C 26 H 25 N 5 ,[M+H] + m/z 408.2183, found 408.2184. From the above characterization results, the structure of Compound 1 can be confirmed.
Example 2
The phenylpiperazine compound of this example has a structural formula shown as compound 2, and its preparation process is substantially the same as that of example 1, except that: the 4-cyanobenzyl bromide in step (2) is replaced with 4-nitrobenzyl bromide.
The characterization results are as follows: pale yellow solid, 73% yield. Melting point 232.7-234.4 deg.C. 1 H NMR(300MHz,DMSO-d 6 )δ8.73(s,2H),8.19(d,J＝8.6Hz,2H),7.80(d,J＝8.0Hz,2H),7.48(dd,J＝20.9,8.2Hz,4H),6.79(d,J＝8.6Hz,2H),6.58(d,J＝8.8Hz,2H),4.79(s,2H),4.76(s,2H),3.17(s,4H),3.10(d,J＝5.4Hz,4H). 13 C NMR(101MHz,DMSO-d 6 )δ159.01,158.38,147.83,146.45,145.47,141.96,141.84,132.36,127.86,127.71,123.59,118.26,113.77,109.49,54.57,54.41,46.93,42.91.HR-MS(ESI):Calcd.C 25 H 25 N 5 O 2 ,[M+H] + m/z:428.2081,found:428.2090.
Example 3
The phenylpiperazine compound of this example has a structural formula shown in compound 3, and its preparation process is substantially the same as that of example 1, except that: the 4-cyanobenzyl bromide in step (2) is replaced with 2-fluoro-4-cyanobenzyl bromide; the trifluoroacetic acid in step (3) is replaced with an ethyl acetate solution of hydrogen chloride to give the hydrochloride salt of compound 3, which is then structurally characterized.
The characterization results are as follows: pale yellow solid, 67% yield. Melting point 233.6-234.9 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ7.86(d,J＝10.0Hz,1H),7.79(d,J＝7.9Hz,2H),7.65(d,J＝7.9Hz,1H),7.44(d,J＝7.9Hz,2H),7.36(t,J＝7.7Hz,1H),6.78(d,J＝8.4Hz,2H),6.56(d,J＝8.5Hz,2H),4.76(s,2H),4.73(s,2H),3.40(t,J＝4.9Hz,4H),2.85(t,J＝5.0Hz,4H). 13 C NMR(101MHz,DMSO-d 6 )δ160.96,153.78,145.48,143.03,141.35,132.34,129.81,128.72,127.68,119.30,118.85,118.26,113.75,111.00,110.90,109.45,78.84,54.42,49.84,48.98,28.02.HR-MS(ESI):Calcd.C 26 H 24 N 5 ,[M+H] + m/z:426.2089,found:426.2085.
Example 4
The phenylpiperazine compound of this example has a structural formula shown in compound 4, and its preparation process is substantially the same as that of example 1, except that: the 4-cyanobenzyl bromide in step (2) is replaced with 4-chlorobenzyl bromide.
The characterization results are as follows: pale yellow solid, yield 80%. Melting point 249.8-250.1 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.91(s,2H),7.79(d,J＝8.0Hz,2H),7.40(dd,J＝22.4,8.1Hz,4H),7.27(d,J＝8.0Hz,2H),6.80(d,J＝8.7Hz,2H),6.59(d,J＝8.6Hz,2H),4.70(s,2H),4.63(s,2H),3.19(s,4H),3.11(t,J＝4.8Hz,4H).1H NMR(400MHz,DMSO-d6)δ8.91(s,2H),7.79(d,J＝8.0Hz,2H),7.40(dd,J＝22.4,8.1Hz,4H),7.27(d,J＝8.0Hz,2H),6.80(d,J＝8.7Hz,2H),6.59(d,J＝8.6Hz,2H),4.70(s,2H),4.63(s,2H),3.19(s,4H),3.11(t,J＝4.8Hz,4H). 13 C NMR(101MHz,DMSO-d 6 )δ145.56,142.17,141.60,138.12,132.26,131.12,128.59,128.29,127.62,118.79,118.17,113.76,109.36,54.35,54.13,46.92,42.84,28.49.HR-MS(ESI):Calcd.C 25 H 25 ClN 4 ,[M+H] + m/z:416.1768,found:416.1759.
Example 5
The phenylpiperazine compound of this example has a structural formula shown in compound 5, and its preparation process is substantially the same as that of example 1, except that: the 4-cyanobenzyl bromide in step (2) is replaced with 3-fluorobenzyl bromide.
The characterization results are as follows: pale yellow solid, yield 79%. Melting point 266.8-268.3 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ8.71(s,2H),7.79(d,J＝8.1Hz,2H),7.43(d,J＝8.1Hz,2H),7.39–7.30(m,1H),7.14–7.06(m,1H),7.03(d,J＝9.6Hz,2H),6.80(d,J＝9.0Hz,2H),6.58(d,J＝8.9Hz,2H),4.73(s,2H),4.66(s,2H),3.17(d,J＝6.0Hz,4H),3.10(dd,J＝7.0,3.4Hz,4H). 13 C NMR(101MHz,DMSO-d 6 )δ158.59,158.24,145.56,142.42,142.36,142.28,141.48,132.32,130.42,130.34,127.68,122.74,118.83,118.30,117.34,114.43,113.76,113.57,113.48,113.36,113.27,109.46,54.47,54.39,47.05,42.89.HR-MS(ESI):Calcd.C 26 H 27 FN 4 ,[M+H] + m/z:401.2136,found:401.2145.
Example 6
The phenylpiperazine compound of this example, having a structural formula shown as compound 6, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzyl bromide in step (2) is replaced by 2, 3-difluorobenzyl bromide; the trifluoroacetic acid in step (3) is replaced by ethyl acetate solution of hydrogen chloride to obtain hydrochloride, and then the hydrochloride of the compound 6 is subjected to structural characterization.
The characterization results are as follows: pale yellow solid, 77% yield. Melting point 244.1-246.0 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.86(s,2H),7.81(d,J＝7.8Hz,2H),7.47(d,J＝7.8Hz,2H),7.40–7.12(m,4H),7.04(s,1H),6.77(d,J＝8.5Hz,2H),4.85(s,2H),4.83(s,2H),3.59(s,4H),3.44(s,4H). 13 C NMR(101MHz,DMSO-d 6 )δ132.40,127.69,124.71,123.75,120.40,118.80,116.17,116.00,113.37,109.63,54.06,49.10,48.70.HR-MS(ESI):Calcd.C 25 H 24 F 2 N 4 ,[M+H] + m/z:418.1969,found:418.1973.
Example 7
The phenylpiperazine compound of this example, having a structural formula shown as compound 7, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzyl bromide in step (2) is replaced with 2, 5-difluorobenzyl bromide.
The characterization results are as follows: pale yellow solid, 76% yield. Melting point 255.7-257.6 ℃.1H NMR (300 MHz, DMSO-d) 6 )δ8.73(s,2H),7.78(d,J＝8.1Hz,2H),7.43(d,J＝8.0Hz,2H),7.26(td,J＝9.3,4.4Hz,1H),7.14(dq,J＝8.7,4.9,4.2Hz,1H),6.96(ddd,J＝9.1,5.7,3.3Hz,1H),6.87–6.75(m,2H),6.59(d,J＝9.0Hz,2H),4.74(s,2H),4.68(s,2H),3.18(d,J＝5.6Hz,4H),3.11(dd,J＝7.1,3.3Hz,4H). 13 CNMR(101MHz,DMSO-d 6 )δ159.39,157.50,157.01,155.11,145.50,141.92,141.82,132.32,127.65,118.84,118.22,117.06,116.81,115.12,114.88,113.79,109.45,54.30,48.86,46.89,42.89.HR-MS(ESI):Calcd.C 25 H 24 F 2 N 4 ,[M+H] + m/z:419.2042,found:419.2045.
Example 8
The phenylpiperazine compound of this example has a structural formula shown in compound 8, and its preparation process is substantially the same as that of example 1, except that: the 4-cyanobenzyl bromide in step (2) is replaced with 3-fluoro-4- (trifluoromethyl) benzyl bromide.
The characterization results are as follows: pale yellow solid, 75% yield. Melting point 267.2-268.1 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ8.74(s,2H),7.79(d,J＝8.1Hz,2H),7.59(dt,J＝5.1,2.5Hz,2H),7.48(d,J＝10.3Hz,1H),7.42(d,J＝8.1Hz,2H),6.87–6.73(m,2H),6.62(d,J＝8.9Hz,2H),4.73(s,2H),4.70(s,2H),3.18(d,J＝5.9Hz,4H),3.11(dd,J＝7.1,3.5Hz,4H). 13 C NMR(101MHz,DMSO-d 6 )δ158.97,145.49,142.00,141.91,136.43,136.39,133.45,133.36,132.30,127.73,125.35,118.82,118.20,117.26,117.06,113.99,109.46,54.35,53.79,46.88,42.89.HR-MS(ESI):Calcd.C 26 H 24 F 4 N 4 ,[M+H] + m/z:469.2010,found:469.2008.
Example 9
The phenylpiperazine compound of this example, having a structural formula shown as compound 9, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzyl bromide in step (2) is replaced with 3-fluoro-4-methylbenzyl bromide.
The characterization results are as follows: pale yellow solid, yield 74%. Melting point 249.9-251.1 deg.c. 1 H NMR(300MHz,DMSO-d 6 )δ8.72(s,2H),7.79(d,J＝8.0Hz,2H),7.42(d,J＝8.0Hz,2H),7.22(t,J＝8.0Hz,1H),7.03–6.91(m,2H),6.79(d,J＝8.7Hz,2H),6.58(d,J＝8.7Hz,2H),4.65(d,J＝29.8Hz,4H),3.18(d,J＝6.4Hz,4H),3.14–3.02(m,4H),2.18(d,J＝1.7Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ145.68,142.27,141.63,132.32,131.58,127.67,122.49,122.23,118.85,118.21,113.81,113.24,113.02,109.41,54.42,54.21,46.97,42.94,13.78.HR-MS(ESI):Calcd.C 26 H 27 FN 4 ,[M+H] + m/z:415.2293,found:415.2299.
Example 10
The phenylpiperazine compound of this example, having a structural formula shown as compound 10, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzyl bromide in step (2) is replaced with 3-fluoro-4-methoxybenzyl bromide.
The characterization results are as follows: pale yellow solid, yield 74%. Melting point 230.8-233.8 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ8.72(s,1H),7.78(d,J＝8.0Hz,2H),7.42(d,J＝8.1Hz,2H),7.12(d,J＝8.5Hz,1H),7.08–6.98(m,2H),6.79(d,J＝9.0Hz,2H),6.60(d,J＝8.7Hz,2H),4.68(s,2H),4.56(s,2H),3.79(s,3H),3.18(dd,J＝7.1,3.4Hz,4H),3.10(dd,J＝7.1,3.6Hz,4H). 13 C NMR(101MHz,DMSO-d 6 )δ145.76,145.70,142.30,141.68,132.31,132.04,131.99,127.69,122.90,118.85,118.18,114.43,114.26,113.97,113.87,109.40,56.00,54.32,54.00,46.98,42.95.HR-MS(ESI):Calcd.C 26 H 29 FN 4 O,[M+H] + m/z:431.2252,found:431.2243.
Example 11
The phenylpiperazine compound of this example, having a structural formula as compound 11, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzyl bromide in step (2) is replaced with 4-methylbenzyl bromide.
The characterization results are as follows: pale yellow solid, yield 72%. Melting point 216.8-218.1 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ8.70(s,2H),7.78(d,J＝8.0Hz,2H),7.42(d,J＝8.0Hz,2H),7.12(s,4H),6.79(d,J＝8.7Hz,2H),6.59(d,J＝8.6Hz,2H),5.75(s,1H),4.68(s,2H),4.58(s,2H),3.18(s,4H),3.14–3.00(m,4H),2.25(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ158.59,158.23,145.49,141.31,135.82,135.63,132.29,128.97,127.76,126.85,118.83,118.28,117.08,114.18,114.00,109.45,54.80,54.44,47.13,42.87,20.59.HR-MS(ESI):Calcd.C 26 H 28 N 4 ,[M+H] + m/z:397.2387,found:397.2397.
Example 12
The phenylpiperazine compound of this example, having a structural formula as compound 12, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzyl bromide in step (2) is replaced with 3-methylbenzyl bromide.
The characterization results are as follows: yellow solid, 73% yield. Melting point 290.8-292.1 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.77(s,2H),7.79(dd,J＝8.2,2.4Hz,2H),7.44(t,J＝7.5Hz,2H),7.25–6.99(m,4H),6.80(d,J＝8.4Hz,2H),6.57(dd,J＝24.1,8.7Hz,2H),4.70(d,J＝5.2Hz,2H),4.60(s,2H),3.19(s,4H),3.11(t,J＝4.8Hz,4H),2.27(d,J＝6.6Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ158.56,158.21,145.77,137.49,135.54,132.31,130.18,128.32,127.69,127.60,127.42,127.32,126.46,125.85,125.67,123.84,118.86,118.44,118.31,117.43,114.52,113.64,113.22,109.40,47.12,42.86,28.53,21.02,18.58.HR-MS(ESI):Calcd.C 26 H 28 N 4 ,[M] + m/z:396.2314,found:397.2317.
Example 13
The phenylpiperazine compound of this example, having a structural formula as compound 13, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzyl bromide in step (2) is replaced with 2-methylbenzyl bromide.
The characterization results are as follows: pale yellow solid, yield 69%. Melting point 279.7-280.3 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.79(s,2H),7.79(d,J＝7.9Hz,2H),7.45(d,J＝7.9Hz,2H),7.22–6.98(m,4H),6.80(d,J＝8.4Hz,2H),6.54(d,J＝8.6Hz,2H),4.69(s,2H),4.59(s,2H),3.19(s,4H),3.11(t,J＝4.9Hz,4H),2.28(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ158.51,158.17,145.80,142.71,136.12,135.54,132.32,130.18,127.60,126.45,125.84,125.67,118.87,118.41,117.55,114.63,113.21,109.37,54.07,52.69,47.17,42.90,28.54,18.59,18.54.HR-MS(ESI):Calcd.C 26 H 28 N 4 ,[M] + m/z:396.2314,found:396.2316.
Example 14
The phenylpiperazine compound of this example, having a structural formula as compound 14, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzyl bromide in step (2) is replaced with 2, 4-dimethylbenzyl bromide.
The characterization results are as follows: pale yellow solid, 78% yield. Melting point 277.4-279.6 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.97(s,2H),7.78(d,J＝7.7Hz,2H),7.55(d,J＝8.0Hz,1H),7.44(d,J＝8.0Hz,1H),7.00(s,1H),6.92–6.75(m,4H),6.67–6.51(m,2H),4.63(d,J＝21.8Hz,2H),4.55–4.34(m,2H),3.20(s,4H),3.16–3.01(m,4H),2.34–2.08(m,6H). 13 C NMR(101MHz,DMSO-d 6 )δ158.57,158.23,145.79,141.25,135.38,135.31,132.91,132.27,132.13,130.93,128.31,127.58,127.44,126.15,126.05,118.84,118.32,117.81,113.29,109.32,53.94,52.50,47.15,47.10,42.85,42.81,28.50,20.45,20.41,18.48.HR-MS(ESI):Calcd.C 27 H 3 0N 4 ,[M] + m/z:410.2470,found:410.2466.
Example 15
The phenylpiperazine compound of this example, having a structural formula as compound 15, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzyl bromide in step (2) is replaced with 4-ethylbenzyl bromide.
The characterization results are as follows: yellow solid, 79% yield. Melting point 289.0-290.6 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.99(s,2H),7.77(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,2H),7.19–7.06(m,4H),6.79(d,J＝8.5Hz,2H),6.60(d,J＝8.5Hz,2H),4.68(s,2H),4.59(s,2H),3.19(d,J＝6.2Hz,4H),3.15–3.04(m,4H),1.55(q,J＝7.4Hz,2H),0.87(t,J＝7.3Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ166.30,166.11,145.78,142.60,140.52,136.20,132.29,128.36,127.65,126.70,118.24,113.66,109.36,54.60,54.29,47.03,42.89,36.88,24.09,13.63.HR-MS(ESI):Calcd.C 28 H 32 N 4 ,[M] + m/z:424.2627,found:424.2625.
Example 16
The phenylpiperazine compound of this example, having a structural formula as compound 16, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzyl bromide in step (2) is replaced with 4-isopropyl benzyl bromide.
The characterization results are as follows: pale yellow solid, 76% yield. Melting point 258.3-239.6 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.96(s,2H),7.78(d,J＝7.9Hz,2H),7.58–7.38(m,2H),7.17(s,2H),6.95(d,J＝37.5Hz,2H),6.80(d,J＝8.2Hz,2H),6.57(dd,J＝28.6,8.4Hz,2H),4.75–4.55(m,2H),4.44(d,J＝75.4Hz,2H),3.19(s,4H),3.15–3.06(m,4H),2.23(d,J＝3.0Hz,3H),1.36(s,1H),1.23–1.05(m,3H). 13 C NMR(101MHz,DMSO-d 6 )δ166.06,165.52,145.71,141.32,136.26,135.36,135.29,132.92,132.25,132.10,130.91,128.06,127.57,126.68,126.25,126.14,126.03,118.82,118.40,118.28,118.22,113.58,113.26,109.31,64.82,53.92,52.48,47.27,47.05,46.99,42.84,32.98,28.50,23.82,20.44,18.48.HR-MS(ESI):Calcd.C 28 H 32 N 4 ,[M] + m/z:424.2627,found:424.2626.
Example 17
The phenylpiperazine compound of this example, having a structural formula as compound 17, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzyl bromide in step (2) is replaced with cyclobutylmethyl bromide.
The characterization results are as follows: yellow solid, 66% yield. Melting point 199.3-200.5 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ8.76(s,2H),7.76(d,J＝7.9Hz,2H),7.36(d,J＝7.9Hz,2H),6.82(d,J＝8.5Hz,2H),6.62(d,J＝8.5Hz,2H),4.58(s,2H),3.43(q,J＝7.1Hz,3H),3.19(s,4H),3.13(d,J＝5.4Hz,3H),2.61(q,J＝7.4Hz,1H),1.90(tt,J＝13.2,8.3Hz,2H),1.74(dq,J＝26.7,8.4Hz,3H),1.05(t,J＝7.0Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ158.86,158.51,144.50,142.34,132.16,128.12,118.75,118.00,117.67,115.12,109.63,57.95,55.16,46.86,42.78,33.48,26.24,18.02.HR-MS(ESI):Calcd.C 23 H 28 N 4 ,[M] + m/z:360.2314,found:360.2310.
Example 18
The phenylpiperazine compound of this example, having a structural formula as compound 18, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzyl bromide in step (2) is replaced with cyclopentylmethyl bromide.
The characterization results are as follows: yellow solid, 63% yield. Melting point 187.6-188.5 deg.c. 1 H NMR(300MHz,DMSO-d 6 )δ8.73(s,2H),7.76(d,J＝7.9Hz,2H),7.37(d,J＝8.0Hz,2H),6.82(d,J＝8.5Hz,2H),6.63(d,J＝8.4Hz,2H),4.61(s,2H),3.32(d,J＝7.2Hz,2H),3.19(s,4H),3.13(d,J＝5.5Hz,4H),1.73–1.39(m,6H),1.29–1.10(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ158.94,158.58,144.01,142.04,132.11,128.30,118.69,118.08,117.36,115.41,114.45,109.74,57.73,55.63,46.95,42.70,38.00,30.18,24.43.HR-MS(ESI):Calcd.C 24 H 30 N 4 ,[M] + m/z:374.2470,found:374.2469.
Example 19
The phenylpiperazine compound of this example, having a structural formula as compound 19, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with 4-methylbenzaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 4-methylbenzyl bromide.
The characterization results are as follows: yellow solid, 79% yield. Melting point 278.1-279.6 deg.C. 1 H NMR(400MHz,DMSO-d 6 )δ8.74(s,2H),7.12(d,J＝1.7Hz,8H),6.78(d,J＝8.7Hz,2H),6.61(d,J＝8.7Hz,2H),4.52(s,4H),3.19(s,4H),3.10(t,J＝5.0Hz,4H),2.26(s,6H). 13 C NMR(101MHz,DMSO-d 6 )δ143.07,136.03,135.62,128.93,126.74,118.17,113.86,54.40,47.12,42.89,20.62,20.56.HR-MS(ESI):Calcd.C 26 H 31 N 3 ,[M] + m/z:385.2518,found:385.2518.
Example 20
The phenylpiperazine compound of this example, having a structural formula shown as compound 20, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with 4-ethylbenzaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 4-methylbenzyl bromide.
The characterization results are as follows: yellow solid, yield 68%. Melting point 269.3-270.9 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.94(s,2H),7.14(s,4H),7.12(s,4H),6.78(d,J＝8.6Hz,2H),6.61(d,J＝8.5Hz,2H),4.53(s,4H),3.29–3.15(m,4H),3.10(t,J＝4.9Hz,4H),2.26(s,3H),1.15(t,J＝7.6Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ143.10,141.93,136.36,136.07,135.53,128.87,127.69,126.65,126.63,118.15,113.60,54.26,47.08,42.86,27.70,20.53,15.56.HR-MS(ESI):Calcd.C 27 H 33 N 3 ,[M] + m/z:399.2674,found:399.2675.
Example 21
The phenylpiperazine compound of this example, having a structural formula as compound 21, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with 4-isopropylbenzaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 4-methylbenzyl bromide.
The characterization results are as follows: yellow solid, 88% yield. Melting point 253.5-256.0 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.77(s,2H),7.19–7.13(m,4H),7.12(d,J＝2.1Hz,4H),6.79(d,J＝8.7Hz,2H),6.63(d,J＝8.5Hz,2H),4.54(s,4H),3.18(s,4H),3.11(d,J＝5.2Hz,4H),2.26(s,3H),1.17(d,J＝6.9Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ146.75,135.70,128.93,126.85,126.26,118.17,54.53,47.08,42.84,33.02,23.87,23.85.HR-MS(ESI):Calcd.C 28 H 35 N 3 ,[M] + m/z:413.2831,found:413.2839.
Example 22
The phenylpiperazine compound of this example, having a structural formula as compound 22, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with 4-carboxybenzaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 4-methylbenzyl bromide; the trifluoroacetic acid in step (3) is replaced with ethyl acetate solution of hydrogen chloride to obtain hydrochloride of the compound 22, and then the hydrochloride of the compound 22 is subjected to structural characterization.
The characterization results are as follows: yellow solid, 69% yield. Melting point 254.3-255.7 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.53(s,2H),7.90(d,J＝7.5Hz,2H),7.34(d,J＝7.7Hz,2H),7.21(s,2H),7.18(d,J＝9.0Hz,2H),7.11(d,J＝7.4Hz,2H),7.02(s,2H),4.75(s,2H),4.66(s,2H),3.47–3.34(m,4H),3.29(s,4H),2.25(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ165.33,137.39,133.07,129.01,128.07,66.00,41.85,20.70.HR-MS(ESI):Calcd.C 26 H 29 N 3 O 2 ,[M] + m/z:415.2260,found:415.2261.
Example 23
The phenylpiperazine compound of this example, having a structural formula as compound 23, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with 4-nitrobenzaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 4-methylbenzyl bromide.
The characterization results are as follows: yellow solid, 71% yield. Melting point 281.1-283.0 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.73(s,2H),8.19(d,J＝8.3Hz,2H),7.51(d,J＝8.3Hz,2H),7.13(d,J＝4.1Hz,4H),6.79(d,J＝8.5Hz,2H),6.61(d,J＝8.6Hz,2H),4.73(s,2H),4.60(s,2H),3.18(s,4H),3.10(t,J＝4.9Hz,4H),2.26(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ148.14,142.49,141.52,135.85,135.76,128.99,127.83,126.77,123.57,118.23,113.77,54.18,47.00,42.94.HR-MS(ESI):Calcd.C 25 H 28 N 4 O 2 ,[M] + m/z:416.2212,found:416.2208.
Example 24
The phenylpiperazine compound of this example, having a structural formula shown as compound 24, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with 4-trifluoromethyl benzaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 4-methylbenzyl bromide.
The characterization results are as follows: yellow solid, 66% yield. Melting point 277.2-279.2 ℃.1H NMR (400 MHz, DMSO-d) 6 )δ8.77(s,2H),7.68(d,J＝8.1Hz,2H),7.46(d,J＝8.0Hz,2H),7.19–7.06(m,4H),6.79(d,J＝8.9Hz,2H),6.61(d,J＝8.9Hz,2H),4.68(s,2H),4.59(s,2H),3.18(s,4H),3.11(dd,J＝6.6,3.6Hz,4H),2.26(s,3H).. 13 C NMR(101MHz,DMSO-d 6 )δ144.53,142.70,141.46,135.89,135.72,128.97,127.43,126.77,125.23,118.23,113.81,54.62,54.20,47.03,42.88,20.57.HR-MS(ESI):Calcd.C 26 H 28 F 3 N 3 ,[M] + m/z:439.2235,found:439.2233.
Example 25
The phenylpiperazine compound of this example, having a structural formula shown as compound 25, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with 4-methylthiobenzaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 4-methylbenzyl bromide.
The characterization results are as follows: yellow solid, 80% yield. Melting point 268.3-269.9 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.88(d,J＝39.0Hz,2H),7.27(d,J＝7.6Hz,1H),7.20(s,2H),7.14(d,J＝15.2Hz,4H),6.90(s,2H),6.79(d,J＝8.4Hz,1H),6.64(s,1H),4.54(s,2H),4.30(s,2H),3.21(s,4H),3.13(s,4H),2.44(s,3H),2.27(d,J＝7.2Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ158.84,158.49,158.16,128.94,128.92,127.69,126.10,117.11,46.98,45.99,42.81,42.59,20.63.HR-MS(ESI):Calcd.C 26 H 31 N 3 S,[M] + m/z:417.2239,found:417.2245.
Example 26
The phenylpiperazine compound of this example, having a structural formula as compound 26, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with 3-fluoro-4-methylbenzaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 4-methylbenzyl bromide.
The characterization results are as follows: yellow solid, 82% yield. Melting point 273.9-275.2 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.75(s,2H),7.87(t,J＝7.4Hz,1H),7.31(dd,J＝22.0,9.3Hz,2H),7.12(s,4H),6.80(d,J＝8.7Hz,2H),6.60(d,J＝8.8Hz,2H),4.69(s,2H),4.59(s,2H),3.19(s,4H),3.15–3.08(m,4H),2.26(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ163.83,150.01,142.31,141.69,135.79,135.75,133.87,128.98,126.79,123.68,118.18,114.52,114.35,114.05,113.87,98.17,98.02,54.66,54.11,46.97,42.88,20.61,20.55.HR-MS(ESI):Calcd.C 26 H 27 FN 4 ,[M] + m/z:414.2222,found:414.2222.
Example 27
The phenylpiperazine compound of this example, having a structural formula as compound 27, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with 4-chlorobenzaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 4-methylbenzyl bromide.
The characterization results are as follows: yellow solid, 83% yield. Melting point 269.3-271.1 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.77(s,2H),7.36(d,J＝8.2Hz,2H),7.26(d,J＝8.2Hz,2H),7.12(s,4H),6.78(d,J＝8.7Hz,2H),6.61(d,J＝8.8Hz,2H),4.57(s,2H),4.54(s,2H),3.19(s,4H),3.11(d,J＝4.9Hz,4H),2.26(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ138.34,135.90,135.69,131.09,128.95,128.64,128.29,126.78,118.18,113.95,54.53,53.97,47.07,42.91,20.62.HR-MS(ESI):Calcd.C 25 H 28 ClN 3 ,[M] + m/z:405.1972,found:405.1978.
Example 28
The phenylpiperazine compound of this example, having a structural formula shown as compound 28, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with 2, 4-difluorobenzaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 4-methylbenzyl bromide.
The characterization results are as follows: yellow solid, 78% yield. Melting point 201.5-204.7 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.73(s,2H),7.22(td,J＝9.8,9.0,4.5Hz,2H),7.11(d,J＝1.3Hz,4H),7.01(td,J＝8.5,2.5Hz,1H),6.80(d,J＝9.0Hz,2H),6.63(d,J＝9.0Hz,2H),4.58(s,2H),4.54(s,2H),3.24–3.16(m,4H),3.11(dd,J＝6.6,3.5Hz,4H),2.26(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ142.62,141.63,135.88,135.67,129.94,128.94,126.71,121.93,121.89,118.18,113.93,111.30,111.09,104.10,103.84,54.27,48.22,47.02,42.91,20.61,20.56.HR-MS(ESI):Calcd.C 25 H 27 F 2 N 3 ,[M] + m/z:407.2173,found:407.2180.
Example 29
The phenylpiperazine compound of this example, having a structural formula as compound 29, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with 2-hydroxy-4-methylbenzaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 4-methylbenzyl bromide; the trifluoroacetic acid in step (3) is replaced with a hydrogen chloride/ethyl acetate solution to give the hydrochloride salt of compound 29, which is then structurally characterized.
The characterization results are as follows: yellow solid, yield 81%. Melting point 221.3-223.2 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.56(d,J＝26.3Hz,2H),7.36(s,1H),7.35–7.19(m,3H),7.16(s,1H),7.12–6.88(m,4H),6.66(s,1H),6.52(d,J＝7.7Hz,1H),4.76–4.65(m,2H),4.60(s,2H),3.50–3.34(m,4H),3.20(s,4H),2.24(s,3H),2.16(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ155.70,130.26,128.85,119.63,116.27,115.91,45.12,42.18,41.81,20.87,20.71.HR-MS(ESI):Calcd.C 26 H 31 N 3 O,[M+H] + m/z:401.2467,found:401.2471.
Example 30
The phenylpiperazine compound of this example, having a structural formula shown as compound 30, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with 3-hydroxy-4-methoxybenzaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 4-methylbenzyl bromide; the trifluoroacetic acid in step (3) is replaced by a hydrogen chloride/ethyl acetate solution to obtain the hydrochloride of the compound 30, and then the hydrochloride of the compound 30 is subjected to structural characterization.
The characterization results are as follows: yellow solid, yield 87%. The melting point is 256.2-258.0 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.55(s,2H),7.37(d,J＝7.6Hz,1H),7.30(s,2H),7.16(d,J＝8.0Hz,1H),7.07(d,J＝7.5Hz,2H),6.84–6.25(m,3H),4.64(s,2H),4.57(s,2H),3.71(s,3H),3.39(s,4H),3.19(s,4H),2.23(s,3H) .13 C NMR(101MHz,DMSO-d 6 )δ145.99,128.79,111.60,55.50,55.44,41.88,20.70.HR-MS(ESI):Calcd.C 26 H 31 N 3 ,[M] + m/z:417.2416,found:418.2415.
Example 31
The phenylpiperazine compound of this example, having a structural formula shown as compound 31, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with benzothiophene-2-carbaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 4-methylbenzyl bromide; the trifluoroacetic acid in step (3) is replaced by a hydrogen chloride/ethyl acetate solution to obtain the hydrochloride of the compound 31, and then the hydrochloride of the compound 31 is subjected to structural characterization.
The characterization results are as follows: pale yellow solid, yield 88%. Melting point 241.3-243.6 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.46(s,2H),7.87(d,J＝7.5Hz,1H),7.76(d,J＝7.5Hz,1H),7.32(q,J＝8.7,7.8Hz,4H),7.17(d,J＝29.4Hz,4H),7.03(s,2H),6.81(s,1H),4.91(s,2H),4.77–4.45(m,2H),3.37(s,4H),3.29(s,4H),2.26(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ139.11,136.33,129.01,127.58,124.32,124.16,123.30,122.38,41.67,20.68.HR-MS(ESI):Calcd.C 27 H 29 N 3 S,[M] + m/z:427.2082,found:427.2078.
Example 32
The phenylpiperazine compound of this example, having a structural formula shown as compound 32, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with 6-chloropyridine-3-carbaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 4-methylbenzyl bromide; the trifluoroacetic acid in step (3) is replaced by a hydrogen chloride/ethyl acetate solution to obtain the hydrochloride of the compound 32, and then the hydrochloride of the compound 32 is subjected to structural characterization.
The characterization results are as follows: yellow solid, 78% yield. Melting point 233.3-235.3 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.51(s,2H),8.32(d,J＝2.4Hz,1H),7.81(s,1H),7.46(d,J＝8.2Hz,1H),7.22(s,2H),7.10(d,J＝7.7Hz,4H),4.73(d,J＝11.0Hz,2H),4.68(s,2H),3.42(s,4H),3.29(s,4H),2.25(s,3H). 13 CNMR(101MHz,DMSO-d 6 )δ128.87,123.83,41.55,20.60,20.55.HR-MS(ESI):Calcd.C 24 H 27 ClN 4 ,[M] + m/z:406.1924,found:406.1927.
Example 33
The phenylpiperazine compound of this example, having a structural formula shown as compound 33, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with 5-bromofuran-2-carbaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 4-methylbenzyl bromide; the trifluoroacetic acid in step (3) is replaced with a hydrogen chloride/ethyl acetate solution to give the hydrochloride salt of compound 33, which is then structurally characterized.
The characterization results are as follows: yellow solid, 79% yield. Melting point 237.8-239.1 deg.C. 1 H NMR(400MHz,DMSO-d 6 )δ9.67(s,2H),7.42–6.80(m,8H),6.46(d,J＝12.2Hz,2H),4.65(s,2H),4.59(s,2H),3.46(d,J＝22.1Hz,4H),3.34(s,4H),2.25(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ128.95,112.37,41.65,20.67,20.62.HR-MS(ESI):Calcd.C 23 H 26 BrN 3 O,[M] + m/z:439.1259,found:439.1253.
Example 34
The phenylpiperazine compound of this example, having a structural formula shown as compound 34, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with isoquinoline-7-carbaldehyde and the 4-cyanobenzyl bromide in step (2) is replaced with 4-methylbenzyl bromide; the trifluoroacetic acid in step (3) is replaced with a hydrogen chloride/ethyl acetate solution to provide the hydrochloride salt of compound 34, which is then structurally characterized.
The characterization results are as follows: pale yellow solid, 63% yield. Melting point 250.0-254.2 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.75(s,2H),9.24(d,J＝5.2Hz,1H),9.09(d,J＝8.4Hz,1H),8.41(d,J＝8.8Hz,1H),8.21(s,1H),8.15–7.99(m,2H),7.26–6.73(m,8H),4.97(s,2H),4.77(s,2H),3.47(s,4H),3.34(s,4H),2.26(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ145.48,144.76,137.45,136.35,134.16,129.04,128.40,127.37,122.35,121.29,41.36,34.09,20.66,14.06.HR-MS(ESI):Calcd.C 28 H 30 N 4 ,[M+H] + m/z:422.2470,found:422.2477.
Example 35
The phenylpiperazine compound of this example, having a structural formula as compound 35, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) was replaced with 5-methylpyridine-3-carbaldehyde and the 4-cyanobenzyl bromide in step (2) was replaced with 4-methylbenzyl bromide.
The characterization results are as follows: yellow solid, 73% yield. Melting point 249.1-250.3 deg.c. 1 H NMR(400MHz,DMSO-d 6 )δ9.21–8.96(m,1H),8.53(s,1H),7.87(d,J＝8.0Hz,1H),7.40(d,J＝8.2Hz,1H),7.30–6.95(m,4H),6.73(dd,J＝60.2,8.5Hz,4H),4.74(s,2H),4.64(s,2H),3.19(s,4H),3.14(s,4H),2.30(d,J＝31.5Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ154.48,145.84,142.35,141.74,141.07,135.80,135.63,133.10,128.97,126.87,122.33,118.15,114.05,54.86,54.64,46.97,42.83,20.61.HR-MS(ESI):Calcd.C 25 H 30 N 4 ,[M] + m/z:386.2470,found:386.2469.
Example 36
The phenylpiperazine compound of this example, having a structural formula as compound 36, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with 6-chloropyridine-3-carbaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 3-fluoro-4 methoxybenzyl bromide; the trifluoroacetic acid in step (3) is replaced with a hydrogen chloride/ethyl acetate solution to provide the hydrochloride salt of compound 36, which is then subjected to structural characterization.
The characterization results are as follows: yellow solid, 70% yield. Melting point 231.1-232.7 deg.c. 1 H NMR(400MHz,DMSO-d 6 )δ9.65(s,2H),8.33(s,1H),7.77(d,J＝8.2Hz,1H),7.47(d,J＝8.2Hz,2H),7.31(d,J＝8.7Hz,3H),7.09(s,3H),6.85(s,1H),4.77(s,2H),4.68(s,2H),3.79(s,3H),3.46(s,4H),3.31(s,4H). 13 CNMR(101MHz,DMSO-d6)δ149.44,146.50,123.90,113.59,55.96,55.89,41.64.HR-MS(ESI):Calcd.C 24 H 26 ClFN 4 O,[M+H]+m/z:441.1852,found:441.1856.
Example 37
The phenylpiperazine compound of this example, having a structural formula shown as compound 37, was prepared in substantially the same manner as in example 1, except that: 4-cyanobenzaldehyde in step (1) is replaced with benzothiophene-3-carbaldehyde, and 4-cyanobenzyl bromide in step (2) is replaced with 3-fluoro-4 methoxybenzyl bromide; the trifluoroacetic acid in step (3) is replaced with a hydrogen chloride/ethyl acetate solution to give the hydrochloride salt of compound 37, which is then subjected to structural characterization.
The characterization results are as follows: yellow solid, 63% yield. Melting point 279.3-281.1 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.02(d,J＝104.3Hz,2H),9.12–8.49(m,2H),8.14(d,J＝7.8Hz,2H),7.96(s,2H),7.80–7.52(m,2H),7.50–7.34(m,2H),7.33–6.87(m,2H),5.66(s,4H),5.10(s,4H),3.79(s,3H),3.52–3.34(m,2H),3.21(s,2H). 13 C NMR(101MHz,DMSO-d 6 )δ190.76,186.69,149.44,146.16,139.97,135.45,134.68,128.40,125.95,125.89,124.03,123.94,123.72,123.34,123.06,122.79,116.51,115.04,114.85,113.72,56.45,56.40,55.87,45.15,42.22.HR-MS(ESI):Calcd.C 27 H 30 FN 3 OS,[M+Na] + m/z:486.1986,found:486.1984.
Example 38
The phenylpiperazine compound of this example, having a structural formula as compound 38, was prepared in substantially the same manner as in example 1, except that: 4-cyanobenzaldehyde in step (1) is replaced with benzothiophene-2-carbaldehyde, and 4-cyanobenzyl bromide in step (2) is replaced with 3-fluoro-4 methoxybenzyl bromide; the trifluoroacetic acid in step (3) is replaced with a hydrogen chloride/ethyl acetate solution to provide the hydrochloride salt of compound 38, which is then structurally characterized.
The characterization results are as follows: pale yellow solid, 61% yield. Melting point 251.1-253.5 deg.c. 1 H NMR(400MHz,DMSO-d 6 )δ10.03(d,J＝113.9Hz,2H),7.89(d,J＝7.1Hz,1H),7.77(d,J＝7.2Hz,1H),7.59(s,1H),7.45–7.26(m,4H),7.24(d,J＝8.4Hz,1H),7.19–6.85(m,4H),5.00(s,2H),4.73(s,2H),3.80(s,3H),3.50(d,J＝62.0Hz,4H),3.23(d,J＝15.1Hz,4H). 13 C NMR(101MHz,DMSO-d 6 )δ190.85,186.36,136.05,128.38,126.70,125.46,124.32,124.00,123.48,123.30,122.39,116.55,113.72,55.96,45.48,45.19,42.30,29.24.HR-MS(ESI):Calcd.C 27 H 28 FN 3 OS,[M+H] + m/z:462.2010,found:462.2006.
Example 39
The phenylpiperazine compound of this example, having a structural formula as compound 39, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with isoquinoline-7-carbaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 3-fluoro-4 methoxybenzyl bromide; the trifluoroacetic acid in step (3) is replaced with a hydrogen chloride/ethyl acetate solution to give the hydrochloride salt of compound 39, which is then structurally characterized.
The characterization results are as follows: yellow solid, 70% yield. Melting point 211.1-213.5 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.02(s,2H),9.29(d,J＝5.0Hz,1H),9.17(d,J＝8.2Hz,1H),8.47(d,J＝8.9Hz,1H),8.25(s,1H),8.14(s,1H),8.09(d,J＝3.1Hz,1H),7.33(s,1H),7.32–7.19(m,2H),7.12(d,J＝5.2Hz,2H),6.90(s,1H),5.04(s,2H),4.81(s,2H),3.81(s,3H),3.62(s,4H),3.43(s,4H). 13 C NMR(101MHz,DMSO-d 6 )δ171.94,152.46,150.03,146.25,145.86,144.63,137.09,134.40,128.40,122.40,121.00,113.79,56.01,55.94,41.16,21.10,21.07,14.05.HR-MS(ESI):Calcd.C 28 H 29 FN 4 O,[M] + m/z:456.2325,found:456.2327
Example 40
The phenylpiperazine compound of this example, having a structural formula shown as compound 40, was prepared in substantially the same manner as in example 1, except that: 4-cyanobenzaldehyde in step (1) is replaced with 4-methylthiobenzaldehyde, and 4-cyanobenzyl bromide in step (2) is replaced with 3-fluoro-4 methoxybenzyl bromide; the trifluoroacetic acid in step (3) is replaced with a hydrogen chloride/ethyl acetate solution to give the hydrochloride salt of compound 40, which is then subjected to structural characterization.
The characterization results are as follows: yellow solid, 70% yield. Melting point 231.4-234.0 deg.C. 1 H NMR(400MHz,DMSO-d 6 )δ9.65(s,2H),7.42(s,2H),7.18(d,J＝24.9Hz,4H),6.81(d,J＝69.2Hz,2H),4.69(s,2H),3.40(s,4H),3.16(s,4H),2.42(s,6H). 13 C NMR(101MHz,DMSO-d 6 )δ125.43,41.79,27.94,14.47,14.07.HR-MS(ESI):Calcd.C 26 H 30 FN 3 OS,[M-H] – m/z:450.2021,found:450.2016.
Example 41
The phenylpiperazine compound of this example, having a structural formula as compound 41, was prepared in substantially the same manner as in example 1, except that: 4-cyanobenzaldehyde in step (1) is replaced with 4-trifluoromethyl benzaldehyde, and 4-cyanobenzyl bromide in step (2) is replaced with 3-fluoro-4 methoxybenzyl bromide; the trifluoroacetic acid in step (3) is replaced with a hydrogen chloride/ethyl acetate solution to give the hydrochloride salt of compound 41, which is then subjected to structural characterization.
The characterization results are as follows: yellow solid, 65% yield. Melting point 201.8-203.3 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.66(s,2H),7.80–7.63(m,2H),7.50(s,2H),7.11(s,4H),6.75(s,2H),4.82(s,2H),4.68(s,2H),3.80(s,3H),3.47(s,4H),3.36(s,4H). 13 C NMR(101MHz,DMSO-d 6 )δ146.30,125.53,125.24,122.83,113.73,55.96,55.90,41.50.HR-MS(ESI):Calcd.C 26 H 27 F 4 N 3 O,[M] + m/z:473.2090,found:473.2095.
Example 42
The phenylpiperazine compound of this example, having a structural formula as compound 42, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with 3-fluoro-4-cyanobenzaldehyde and the 4-cyanobenzyl bromide in step (2) is replaced with 3-fluoro-4 methoxybenzyl bromide.
The characterization results are as follows: yellow solid, yield 68%. Melting point 226.5-228.1 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.82(s,2H),7.88(t,J＝3.7Hz,1H),7.41(dd,J＝55.4,10.5Hz,2H),7.09(d,J＝10.6Hz,1H),7.08(s,2H),6.82(d,J＝8.9Hz,2H),6.63(d,J＝8.8Hz,2H),4.64(d,J＝48.9Hz,2H),4.41(d,J＝11.8Hz,2H),3.81(d,J＝4.7Hz,3H),3.21(s,4H),3.14(d,J＝5.7Hz,4H). 13 C NMR(101MHz,DMSO-d 6 )δ158.64,158.29,149.85,145.81,142.12,141.54,133.88,133.76,131.79,131.74,124.52,123.71,122.96,122.39,118.32,118.26,114.98,114.26,114.07,114.02,114.00,113.83,61.92,55.94,55.88,54.10,54.01,47.16,47.03,42.86,42.79.HR-MS(ESI):Calcd.C 26 H 26 F 2 N 4 O,[M+H] + m/z:449.2148,found:449.2140.
Example 43
The phenylpiperazine compound of this example, having a structural formula shown as compound 43, was prepared in substantially the same manner as in example 1, except that: the 4-cyanobenzaldehyde in step (1) is replaced with 3-hydroxy-4-methoxybenzaldehyde, and the 4-cyanobenzyl bromide in step (2) is replaced with 3-fluoro-4-methoxybenzyl bromide.
The characterization results are as follows: yellow solid, 78% yield. The melting point is 256.3-257.2 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.98(s,2H),7.23(d,J＝12.4Hz,1H),7.13(d,J＝7.6Hz,2H),6.88(q,J＝7.9Hz,4H),6.50(d,J＝145.4Hz,2H),4.28(s,2H),3.81(s,3H),3.69(d,J＝27.8Hz,3H),3.22(s,4H) .13 C NMR(101MHz,DMSO-d 6 )δ158.65,152.36,149.94,146.47,146.36,124.74,117.62,115.89,115.72,113.59,55.96,55.90,46.53,42.75.HR-MS(ESI):Calcd.C 26 H 30 FN 3 O 3 ,[M+H] + m/z:452.2344,found:452.2346.
Test example histone lysine demethylase inhibition activity assay:
the experimental method comprises the following steps: the samples are phenylpiperazine compounds 1 to 43 synthesized in examples 1 to 43; sample stock solution: 1-2 mg of the sample was weighed and placed in a 1.5mL EP tube, and 100% DMSO was added to prepare 10mM stock solutions of the compound, respectively. The same solution was used for dilution according to the measured concentration. Then 5nM of recombinant LSD1 protein, 25mM of a mixture of substrate H3K4me2, fluorescent reagent and horseradish peroxidase were added and incubated for 30min at room temperature. Monitoring fluorescence value at wavelength of 530nm/590nm by enzyme-labeled instrument, and calculating IC by SPSS software 50 Values.
The experimental results are shown in table 1.
The inhibition rate calculation formula is as follows:
TABLE 1 inhibitory Activity data for the LSD1 protein for Compounds 1-43 of the invention
Note that: a not measured; b positive control.
As shown in the test results of Table 1, the phenylpiperazine compounds provided by the invention all have good histone lysine demethylase inhibition activity, and IC 50 Is obviously superior to positive control drug phencyclized propylamine TCP. Wherein, the invention provides compounds 5, 7, 10-11, 14-17, 19, 21, 23-26, 28, 30-36, 39, inhibiting IC of LSD1 50 All are smaller than 1 mu M, especially the compound 30 reaches 0.146 mu M, which is only 1/186 of the positive control drug TCP, and is obviously lower than the traditional clinical-stage inhibitor TCP. Therefore, the phenylpiperazine compound provided by the invention has high inhibitory activity on LSD1, low concentration for playing effective inhibitory activity and low biotoxicity.
In conclusion, the phenylpiperazine compound shown in the general formula (I) provided by the invention has good inhibition activity on histone lysine demethylase 1, and part of the compound has obvious advantages compared with the clinical-stage inhibitor in the present stage. In addition, the structure of the compound provided by the invention is obviously different from other LSD1 inhibitors in the present stage, can provide a new compound entity and research direction for the research and development of inhibitors or anti-tumor drugs based on LSD1 as a target point, and has good application prospect.

Claims (9)

1. A phenylpiperazine compound represented by the formula (I):
in the formula (I), R 1 Is aryl or heteroaryl; r is R 1 When selected from aryl, the aryl is unsubstituted, optionally mono-substituted or di-substituted phenyl; r is R 1 When aryl is substituted, the substituent is one or two of nitrile, methyl, ethyl, isopropyl, carboxyl, nitro, trifluoromethyl, methylthio, fluorine, chlorine and methoxy; r is R 1 When the heteroaryl is selected from heteroaryl, the heteroaryl is one of unsubstituted, monosubstituted or disubstituted pyridyl, furyl, benzothiophene and benzopyridine at any position; r is R 1 When heteroaryl is substituted, the substituent is one or two of chlorine, bromine and methyl;
R 2 is aryl or cycloalkyl; r is R 2 When selected from aryl, the aryl is unsubstituted, optionally mono-substituted or di-substituted phenyl; r is R 2 When aryl is substituted, the substituent is one or two of nitrile, nitro, fluorine, chlorine, trifluoromethyl, methoxy, methyl, ethyl and isopropyl; the cycloalkyl is cyclobutyl or cyclopentyl.
2. The phenylpiperazine compound according to claim 1, characterized in that the phenylpiperazine compound is selected from the group consisting of compounds of the following structures or pharmaceutically acceptable salts thereof, which are sequentially denoted as compounds 1 to 43:
3. the phenylpiperazine compound according to claim 1, wherein the pharmaceutically acceptable salt is one of hydrochloride, hydrobromide, sulfate, phosphate, borate, methanesulfonate, p-toluenesulfonate, naphthalenesulfonate, benzenesulfonate, citrate, lactate, pyruvate, tartrate, acetate, trifluoroacetate, maleate, succinate, mandelate, fumarate, salicylate, and phenylacetate of the phenylpiperazine compound.
4. A process for the preparation of phenylpiperazine compounds according to claim 1, comprising the steps of:
(1) Reacting 1-Boc-4- (4-aminophenyl) piperazine and formaldehyde compounds in a solvent, then adding a reducing agent for continuous reaction, and extracting, filtering and purifying after the reaction to obtain an intermediate compound A;
(2) Reacting the intermediate compound A, an alkaline substance and a bromine-containing compound in a solvent, and extracting, filtering and purifying the reaction product to obtain an intermediate compound B;
(3) Reacting the intermediate compound B with an acidic substance in a solvent, and recrystallizing after the reaction.
5. The method for producing phenylpiperazine compound according to claim 4, wherein in the step (1), the formaldehyde compound is one of 4-cyanobenzaldehyde, 4-methylbenzaldehyde, 4-ethylbenzaldehyde, 4-isopropylbenzaldehyde, 4-carboxybenzaldehyde, 4-nitrobenzaldehyde, 4-trifluoromethylbenzaldehyde, 4-methylthiobenzaldehyde, 3-fluoro-4-methylbenzaldehyde, 4-chlorobenzaldehyde, 2, 4-difluorobenzaldehyde, 2-hydroxy-4-methylbenzaldehyde, 3-hydroxy-4-methoxybenzaldehyde, benzothiophene-2-carbaldehyde, 6-chloropyridine-3-carbaldehyde, 5-bromofuran-2-carbaldehyde, isoquinoline-7-carbaldehyde, 5-methylpyridine-3-carbaldehyde, 6-chloropyridine-3-carbaldehyde, benzothiophene-2-carbaldehyde, isoquinoline-7-carbaldehyde, 4-methylthiobenzaldehyde, 4-trifluoromethylbenzaldehyde, 3-fluoro-4-cyanobenzaldehyde, 3-hydroxy-4-methoxybenzaldehyde; the reducing agent is one or more of sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride.
6. The method for producing phenylpiperazine compound according to claim 4, wherein in the step (2), the bromine-containing compound is one of 4-cyanobenzyl bromide, 4-nitrobenzyl bromide, 2-fluoro-4-cyanobenzyl bromide, 4-chlorobenzyl bromide, 3-fluorobenzyl bromide, 2, 3-difluorobenzyl bromide, 2, 5-difluorobenzyl bromide, 3-fluoro-4- (trifluoromethyl) benzyl bromide, 3-fluoro-4-methylbenzyl bromide, 3-fluoro-4-methoxybenzyl bromide, 4-methylbenzyl bromide, 3-methylbenzyl bromide, 2, 4-dimethylbenzyl bromide, 4-ethylbenzyl bromide, 4-isopropylbenzyl bromide, cyclobutylmethyl bromide, cyclopentylmethyl bromide; the alkaline substance is one or more of triethylamine, sodium carbonate and potassium carbonate.
7. The method for producing a phenylpiperazine compound according to claim 4, wherein in the step (3), the acidic substance is one of trifluoroacetic acid, hydrogen chloride gas, and hydrogen chloride solution.
8. The method for producing a phenylpiperazine compound according to any of claims 4 to 7, characterized in that the solvent used in step (1) and step (2) is one or more of methanol, dichloromethane and ethanol; the solvent adopted in the step (3) is one or more of dichloromethane, methanol, ethanol and ethyl acetate; the reaction temperature in the step (1) is 25-80 ℃, the reaction time is 4-10 h, and the continuous reaction time is 3-5 h; the reaction temperature in the step (2) is-10-50 ℃, and the reaction time is 4-10 hours; the reaction temperature in the step (3) is 10-30 ℃, and the reaction time is 6-10 h.
9. The use of phenylpiperazine compounds according to any of claims 1 to 3 for the preparation of inhibitors or antitumor drugs based on LSD1 targets.
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CN1705670A (en) * 2002-10-11 2005-12-07 大塚制药株式会社 2,3-dihydro-6-nitroimidazo[2,1-b]oxazoles
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CN1705670A (en) * 2002-10-11 2005-12-07 大塚制药株式会社 2,3-dihydro-6-nitroimidazo[2,1-b]oxazoles
CN110156729A (en) * 2019-05-14 2019-08-23 浙江大学 A kind of phenylpiperazine class UBE2F micromolecular inhibitor and its synthetic method
WO2021017996A1 (en) * 2019-07-26 2021-02-04 暨南大学 Phenylpiperazine quinazoline compound or pharmaceutically acceptable salt thereof, and preparation method therefor and use thereof

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