CN117285512A - 2, 5-diketopiperazine-imidazole compound, preparation method and application thereof - Google Patents

2, 5-diketopiperazine-imidazole compound, preparation method and application thereof Download PDF

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CN117285512A
CN117285512A CN202210689551.8A CN202210689551A CN117285512A CN 117285512 A CN117285512 A CN 117285512A CN 202210689551 A CN202210689551 A CN 202210689551A CN 117285512 A CN117285512 A CN 117285512A
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徐赟
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Dalian Wanzhong Yisheng Health Co ltd
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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Abstract

The invention discloses a 2, 5-diketopiperazine-imidazole compound, a preparation method and application thereof. Specifically discloses a compound as shown in formula (I)A tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing. The compound has novel structure and better activity.

Description

2, 5-diketopiperazine-imidazole compound, preparation method and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a 2, 5-diketopiperazine-imidazole compound, a preparation method and application thereof.
Background
The Plinabulin (NPI-2358) belongs to a 2, 5-diketopiperazine compound derivative, which is a derivative obtained by structural modification of a metabolite low molecular cyclic dipeptide Phenylahistin produced by marine fungi Aspergillus sp. Prinsensitivity of pline acts selectively near the colchicine binding site in endothelial tubulin, inhibits tubulin polymerization, blocks microtubule assembly, thereby disrupting endothelial cytoskeleton and inhibiting tumor blood flow. Experiments show that the plinabulin acts on cells to stop the cells at the early stage of mitosis and induce cell death. Recent studies have found that plinabulin is a regulator of differentiated immunity and stem cells, and an activator of guanine nucleotide exchange factor (GEF-H1), can target and alter tumor microenvironment and destroy tumor blood vessels by a variety of mechanisms of action; plinabulin acts as an effective Antigen Presenting Cell (APC) inducer (by activating dendritic Cell maturation) and its durable anticancer effects are associated with its and T Cell activation (Cell Reports 2019,28:13, 3367-3386).
The candidate drug is currently developed by BeyondSpring pharmaceutical company, and clinical phase III experiments are being carried out, on the one hand, the candidate drug is used for treating non-small cell lung cancer in combination with docetaxel, and on the other hand, the candidate drug is used for preventing chemotherapy-induced neutropenia (CIN) of non-myelogenous malignancy. Whitening indications have also been in the application for NDA.
The chemical structural formula of Plinabulin (Plinabulin) is as follows:
pranabulin (Plinabulin) has a molecular formula of C 19 H 20 N 4 O 2 Molecular weight 336.39, CAS number 714272-27-2. Has good stability, but poor water solubility and toxic and side effectsWith large, there is still a need to continue to develop highly active tubulin inhibitors.
Disclosure of Invention
The technical problem to be solved by the invention is defects of the plinabulin, and the invention provides a 2, 5-diketopiperazine-imidazole compound, a preparation method and application thereof.
In order to achieve the aim of the invention, the invention is realized by adopting the following technical scheme:
the present invention provides a compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing (refer to a compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof):
Wherein,
R 1 is hydrogen, deuterium, halogen, C 1 -C 8 Alkyl, C substituted by one or more halogens 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C substituted by one or more halogens 1 -C 8 Alkoxy, C 2 -C 8 Alkenyl, benzoyl substituted with one or more halogens, phenoxy, or "phenoxy substituted with one or more halogens";
R 1a 、R 1b and R is 1c Independently hydrogen, deuterium, halogen or C 1 -C 8 An alkyl group;
alternatively, R 1 、R 1a Together with the carbon atoms to which they are attached form C 6 -C 10 Is selected from one or more of N, O and S, 3-10 membered heteroaryl with 1-5 heteroatoms;
alternatively, R 1 、R 1b Together with the carbon atoms to which they are attached form C 6 -C 10 Or "heteroatom" selected from N, O and SOne or more 3-to 10-membered heteroaryl groups having 1 to 5 heteroatoms;
alternatively, R 1b 、R 1c Together with the carbon atoms to which they are attached form C 6 -C 10 Is selected from one or more of N, O and S, 3-10 membered heteroaryl with 1-5 heteroatoms;
R 2 is hydrogen, deuterium, C substituted by one or more halogens 1 -C 8 Alkyl, C 1 -C 8 Alkyl or C 3 -C 10 Cycloalkyl;
l is a hetero atom selected from one or more of N, O, S and Se, C with 1-4 hetero atoms 1 -C 8 Alkylene ", substituted by one or more R 2-2 The substituted hetero atom is one or more of N, O, S and Se, and the hetero atom number is C of 1-4 1 -C 8 Alkylene ", C 1 -C 8 Alkylene or "by one or more R 2-1 Substituted C 1 -C 8 An alkylene group ";
R 2-1 and R is 2-2 Independently deuterium, OH, C 1 -C 8 Alkoxy or "by one or more R 2-1-1 Substituted C 1 -C 8 Alkoxy ";
R 2-1-1 independently C 3 -C 10 Cycloalkyl, C 6 -C 10 Aryl, or "heteroatom selected from one or more of N, O and S, 3-10 membered heteroaryl with 1-5 heteroatoms";
ring A is C 6 -C 10 Aryl, substituted by one or more R A-1 Substituted C 6 -C 10 Aryl, 3-10 membered heteroaryl having 1-5 heteroatoms selected from one or more of N, O and S, substituted with one or more R A-2 The substituted hetero atom is selected from one or more of N, O and S, 3-10 membered heteroaryl with 1-5 hetero atoms, C 3 -C 10 Cycloalkyl, substituted by one or more R A-3 Substituted C 3 -C 10 Cycloalkyl, one or more hetero atoms selected from N, O and S, 3-10 membered hetero atoms with 1-5 hetero atomsCycloalkyl "or" is substituted by one or more R A-4 The substituted hetero atom is selected from one or more of N, O and S, and the hetero atom number is 3-10 membered heterocyclic alkyl';
R A-1 、R A-2 、R A-3 and R is A-4 Independently deuterium, halogen, hydroxy, cyano, nitro, C 1 -C 8 Alkyl, C substituted by one or more halogens 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C substituted by one or more halogens 1 -C 8 Alkoxy, C 3 -C 10 Cycloalkyl, C 6 -C 10 Aryl, substituted by one or more R A-1-1 Substituted C 6 -C 10 Aryl or-C (=o) -R 3-1-2 ；
R 3-1-2 Is C 1 -C 8 Alkoxy, C substituted by one or more halogens 1 -C 8 Alkoxy, C 1 -C 8 Alkyl, C substituted by one or more halogens 1 -C 8 Alkyl, C 6 -C 10 Aryl or "formed by one or more R 3-1-2-1 Substituted C 6 -C 10 Aryl ";
R A-1-1 and R is 3-1-2-1 Independently halogen, hydroxy, cyano, nitro, C 1 -C 8 Alkyl, C substituted by one or more halogens 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C substituted by one or more halogens 1 -C 8 Alkoxy or C 3 -C 10 Cycloalkyl groups.
In a preferred embodiment of the invention, certain groups of the compounds of formula (I), of the tautomers thereof, of the stereoisomers thereof, of the pharmaceutically acceptable salts thereof, or of the solvates of any one of the foregoing are as defined below, the groups not mentioned being as described in any one of the schemes of the present application (abbreviated as "in a certain scheme of the invention"),
when R is 1 In the case of halogen, the halogen is fluorine.
In one embodiment of the invention, when R 1 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 Alkyl groups such as methyl.
In one embodiment of the invention, when R 1 For C substituted by one or more halogens 1 -C 8 In the case of alkyl, said C substituted by one or more halogens 1 -C 8 Alkyl is C substituted by one or more halogens 1 -C 4 Alkyl groups such as trifluoromethyl.
In one embodiment of the invention, when R 1 Is C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is C 1 -C 4 Alkoxy groups such as methoxy.
In one embodiment of the invention, when R 1 For C substituted by one or more halogens 1 -C 8 Alkoxy, said C being substituted by one or more halogens 1 -C 8 Alkoxy is C substituted by one or more halogens 1 -C 4 Alkoxy groups such as trifluoromethoxy.
In one embodiment of the invention, when R 1 In the case of benzoyl substituted with one or more halogens, the halogen is fluorine. Preferably, the benzoyl substituted with one or more halogens is
In one embodiment of the invention, when R 1 In the case of phenoxy substituted by one or more halogens, the halogen is fluorine. Preferably, the phenoxy group substituted by one or more halogens is
In one embodiment of the invention, when R 1a 、R 1b And R is 1c When independently halogen, the halogen is fluorine.
In one embodiment of the invention, when R 1a 、R 1b And R is 1c Independently C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 Alkyl groups such as methyl.
In one embodiment of the invention, when R 1 、R 1a Together with the carbon atoms to which they are attached form C 6 -C 10 The C is aryl 6 -C 10 Is phenyl.
In one embodiment of the invention, when R 1 、R 1a When "heteroatom selected from one or more of N, O and S, 3-to 10-membered heteroaryl having 1 to 5 heteroatoms" is formed together with the carbon atom to which they are attached, the "heteroatom selected from one or more of N, O and S, 3-to 10-membered heteroaryl having 1 to 5 heteroatoms" is "heteroatom selected from one or more of N, O and S, 5-to 6-membered heteroaryl having 1 to 2 heteroatoms"; such as pyridyl.
In one embodiment of the invention, when R 2 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 Alkyl groups such as methyl, ethyl, isopropyl or tert-butyl.
In one embodiment of the invention, when R 2 Is C 3 -C 10 In the case of cycloalkyl, the C 3 -C 10 Cycloalkyl radicals are C 3 -C 6 Cycloalkyl groups such as cyclopropyl.
In one embodiment of the invention, when L is "heteroatom(s) selected from one or more of N, O, S and Se, C having 1-4 heteroatoms 1 -C 8 When the hetero alkyl is, the hetero atom is one or more of N, O, S and Se, and the hetero atom number is C of 1-4 1 -C 8 The hetero-alkyl group is C with hetero atoms of 1-2 and is one or more selected from O and S 1 -C 5 Alkylene ", e.g.
In one embodiment of the invention, when L is C 1 -C 8 In the case of alkylene, the C 1 -C 8 Alkylene is C 1 -C 5 Alkylene groups, e.g. methylene,
In one embodiment of the invention, when ring A is C 6 -C 10 Aryl or "formed by one or more R A-1 Substituted C 6 -C 10 Aryl ", the C 6 -C 10 Aryl is phenyl or naphthyl (e.g) Such as phenyl.
In one embodiment of the invention, when ring A is "heteroatom selected from one or more of N, O and S, 3-to 10-membered heteroaryl having 1 to 5 heteroatoms" or "substituted with one or more R A-2 When the substituted heteroatom is selected from one or more of N, O and S, a 3-to 10-membered heteroaryl group having 1 to 5 heteroatoms is selected from one or more of N, O and S, a 3-to 10-membered heteroaryl group having 1 to 5 heteroatoms is selected from one or more of N, O and S, a 5-to 10-membered heteroaryl group having 1 to 2 heteroatoms is selected from, for example, pyridyl, indolyl, indolinyl, pyrrolyl or tetrahydroquinolinyl, further for example
In one embodiment of the invention, when ring A is C 3 -C 10 Cycloalkyl or "substituted by one or more R A-3 Substituted C 3 -C 10 Cycloalkyl ", C 3 -C 10 Cycloalkyl radicals are C 3 -C 6 Cycloalkyl groups such as cyclopentyl.
In one embodiment of the invention, when ring A is "heteroatom selected from one or more of N, O and S, 3-to 10-membered heterocycloalkyl having 1 to 5 heteroatoms" or "substituted with one or more R A-4 Substituted hetero atoms selected from one or more of N, O and S, 3-to 10-membered heterocycloalkyl having 1-5 hetero atomsThe "heteroatom is selected from one or more of N, O and S, 3-10 membered heterocycloalkyl having 1-5 heteroatoms" is "heteroatom is selected from one or more of N, O and S, 5-6 membered heterocycloalkyl having 1-2 heteroatoms" such as pyrrolidinyl or piperidinyl, and further such as
In one embodiment of the invention, when R A-1 、R A-2 、R A-3 And R is A-4 When independently halogen, the halogen is fluorine, chlorine or bromine.
In one embodiment of the invention, when R A-1 、R A-2 、R A-3 And R is A-4 Independently C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 - C 4 Alkyl groups such as methyl.
In one embodiment of the invention, when R A-1 、R A-2 、R A-3 And R is A-4 Independently C substituted by one or more halogens 1 -C 8 In the case of alkyl, said C substituted by one or more halogens 1 -C 8 Alkyl is C substituted by one or more halogens 1 -C 4 Alkyl groups such as trifluoromethyl.
In one embodiment of the invention, when R A-1 、R A-2 、R A-3 And R is A-4 Independently C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is C 1 -C 4 Alkoxy groups such as methoxy.
In one embodiment of the invention, when R A-1 、R A-2 、R A-3 And R is A-4 Independently C substituted by one or more halogens 1 -C 8 Alkoxy, said C being substituted by one or more halogens 1 -C 8 Alkoxy is C substituted by one or more halogens 1 -C 4 Alkoxy groups such as trifluoromethoxy.
In one embodiment of the invention, when R A-1 、R A-2 、R A-3 And R is A-4 Independently C 6 -C 10 Aryl or "formed by one or more R A-1-1 Substituted C 6 -C 10 Aryl ", the C 6 -C 10 Aryl is phenyl.
In one embodiment of the invention, when R 3-1-2 Is C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is C 1 -C 4 Alkoxy groups such as methoxy.
In one embodiment of the invention, when R 3-1-2 Is C 6 -C 10 Aryl or "formed by one or more R 3-1-2-1 Substituted C 6 -C 10 Aryl ", the C 6 -C 10 Aryl is phenyl.
In one embodiment of the invention, R 1 Is hydrogen, halogen, benzoyl substituted by one or more halogens or "phenoxy substituted by one or more halogens", e.g. R 1 Is hydrogen, F,
In one embodiment of the invention, R 1a Is hydrogen or halogen.
In one embodiment of the invention, R 1b Is hydrogen.
In one embodiment of the invention, R 1c Is hydrogen or halogen.
In one embodiment of the invention, R 2 Is hydrogen, C substituted by one or more halogens 1 -C 8 Alkyl, C 1 -C 8 Alkyl or C 3 -C 10 Cycloalkyl, preferably C substituted by one or more halogens 1 -C 8 Alkyl, C 1 -C 8 Alkyl or C 3 -C 10 Cycloalkyl groups.
In one embodiment of the invention, L is a heteroatom selected from one or more of N, O, S and Se, C having 1-4 heteroatoms 1 -C 8 Alkylene "or C 1 -C 8 Alkylene, preferably C 1 -C 8 An alkylene group.
In one embodiment of the invention, ring A is C 6 -C 10 Aryl, substituted by one or more R A-1 Substituted C 6 -C 10 Aryl, one or more hetero atoms selected from N, O and S, 3-10 membered heteroaryl with 1-5 hetero atoms, C 3 -C 10 Cycloalkyl or "heteroatom is selected from one or more of N, O and S, 3-10 membered heterocycloalkyl having 1-5 heteroatoms"; preferably C 6 -C 10 Aryl, substituted by one or more R A-1 Substituted C 6 -C 10 Aryl or "heteroatom is selected from one or more of N, O and S, 5-6 membered heteroaryl with 1-2 heteroatoms.
In one embodiment of the invention, R A-1 Independently halogen, cyano, nitro, C 1 -C 8 Alkyl, C substituted by one or more halogens 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C substituted by one or more halogens 1 -C 8 Alkoxy, C 6 -C 10 Aryl or-C (=o) -R 3-1-2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably halogen, cyano, nitro, C 1 -C 8 Alkyl, C substituted by one or more halogens 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C substituted by one or more halogens 1 -C 8 Alkoxy or-C (=o) -R 3-1-2 。
In one embodiment of the invention, R 3-1-2 Is C 1 -C 8 Alkoxy or C 6 -C 10 An aryl group; preferably C 1 -C 8 An alkoxy group.
In one aspect of the present invention,is that
At the bookIn one embodiment of the invention, ring A is
In one embodiment of the present invention, the compound represented by formula (I) is not any of the following compounds:
preferably, the compound shown in the formula (I) is any one of the following compounds:
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the invention also provides a preparation method of the compound shown in the formula (I), which comprises the following steps: the compound shown in the formula (II) and the compound shown in the formula (III) undergo condensation reaction as shown below to obtain the compound shown in the formula (I);
therein, L, R 1 、R 1a 、R 1b 、R 1c 、R 2 And ring a is as defined in any one of the preceding claims.
The invention also provides a compound shown as a formula (II):
therein, L, R 2 And ring a is as defined in any one of the preceding claims.
In one embodiment of the present invention, the compound represented by formula (II) is not any of the following compounds:
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preferably, the compound shown as the formula (II) is any one of the following compounds:
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the invention also provides a preparation method of the compound shown in the formula (II), which comprises the following steps: carrying out substitution reaction on the 2, 5-diketopiperazine derivative shown in the formula (A) and the compound shown in the formula (B) to obtain the compound shown in the formula (II);
wherein Y is halogen or-S (=O) 2 -R 8 ，R 8 Is C 1 -C 6 Alkyl or C 6 -C 10 An aryl group; l, R 2 And ring a is as defined in any one of the preceding claims.
Preferably, the substitution reaction is carried out in an aprotic solvent, which may be conventional in the art, preferably, one or more of tetrahydrofuran, dichloromethane, cyclohexane, acetonitrile, acetone, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide, benzene, toluene, nitrobenzene, xylene, carbon tetrachloride and carbon disulfide; such as N, N-dimethylformamide.
Preferably, the substitution reaction is carried out in the presence of a base which may be a base commonly used in such reactions in the art, preferably, the base is one or more of sodium hydrogen, potassium hydroxide, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, 1, 8-diazabicyclo undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, triethylamine and diisopropylethylamine; such as cesium carbonate.
Preferably, the substitution reaction is carried out in the presence of a catalyst which may be a catalyst commonly used in such reactions in the art, preferably one or more of potassium iodide and sodium iodide, for example potassium iodide.
The invention also provides a pharmaceutical composition which comprises the compound shown in the formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate of any one of the above, and a pharmaceutical adjuvant.
In certain embodiments, the pharmaceutical excipients do not comprise a cosolvent.
The invention also provides application of the compound shown in the formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate of any one of the above, or a pharmaceutical composition in preparation of medicines. Preferably, the medicament is for the prevention and/or treatment of cancer. The cancer is preferably lung cancer, pancreatic cancer,One or more of colon cancer and liver cancer. The compounds of the present invention exhibit potent cytotoxicity against various tumor cells, for example, all of the compounds of the present invention exhibit proliferation-inhibiting activity against cells such as NCI-H460, BXPC-3, HT-29, etc., and IC thereof 50 Value of<5μM。
The invention also provides application of the compound shown in the formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate of any of the above, or a pharmaceutical composition in preparation of a tubulin inhibitor.
In such applications, the tubulin inhibitors may be used in mammalian organisms; it is also useful in vitro, mainly as an experimental use, for example: provides a comparison as a standard or control sample, or a kit prepared according to a conventional method in the art, provides a rapid detection of the tubulin inhibitor effect.
The present invention also provides a method for preventing and/or treating cancer, which comprises administering to a patient a therapeutically effective dose of the above-described compound represented by formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing, or a pharmaceutical composition thereof.
The compounds of the invention, their tautomers, their stereoisomers, their pharmaceutically acceptable salts, solvates of any of the foregoing, pharmaceutical compositions may be administered topically or systemically, e.g., for enteral administration, such as rectal or oral administration, or for parenteral administration to a mammal (especially to a human). Exemplary combinations for rectal administration include suppositories, which may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic glycerides or polyethylene glycols, which are solid at ordinary temperatures, but melt and/or dissolve in the rectal cavity to release the drug. The compounds of the invention may also be administered parenterally, for example, by inhalation, injection or infusion, such as by intravenous, intra-arterial, intra-osseous, intramuscular, intra-cerebral, extra-cerebral, intra-synovial, intra-sternal, intrathecal, intralesional, intracranial, intratumoral, intradermal, and subcutaneous injection or infusion.
A therapeutically effective amount of the active ingredient is defined as above and below and depending on the species, weight, age, individual condition, individual pharmacokinetic parameters, disease to be treated and mode of administration of the mammal, for enteral administration, such as oral administration, the compounds of the invention can be formulated in a wide variety of dosage forms.
The effective amount of a compound of the invention, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate of any of the foregoing, or a pharmaceutical composition may be readily determined by routine experimentation, and the most effective and convenient route of administration and most appropriate formulation may also be determined by routine experimentation.
The pharmaceutical excipients can be those which are widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.
Substances that may be pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum stearate, lecithin, serum proteins such as human serum proteins, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; a gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol, phosphate buffer, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating materials, sweetening, flavoring and perfuming agents, preserving and antioxidant agents.
The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
The pharmaceutical dosage forms of the compounds of the present invention may be provided in the form of immediate release, controlled release, sustained release or target drug release systems. For example, common dosage forms include solutions and suspensions, (micro) emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols and freeze-dried formulations. Depending on the route of administration used, special devices may be required to administer or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special bottles (specialty flasks). Pharmaceutical dosage forms often consist of a drug, excipients and a container/sealing system. One or more excipients (also known as inactive ingredients) may be added to the compounds of the present invention to improve or promote the manufacture, stability, administration and safety of the drug, and may provide a means to achieve a desired drug release profile. Thus, the type of excipient added to a drug may depend on various factors, such as the physical and chemical characteristics of the drug, the route of administration, and the manufacturing steps. Pharmaceutically acceptable excipients are present in this field and include those listed in the various pharmacopoeias. (see U.S. Pharmacopeia (U.S.Pharmacopeia, USP), japanese Pharmacopeia (Japanese Pharmacopoeia, JP), european Pharmacopeia (European Pharmacopoeia, EP) and British Pharmacopeia (British pharmacopoeia, BP); U.S. food and drug administration (the U.S. food and Drug Administration, www.fda.gov) drug evaluation and research center (Centerfor Drug Evaluation and Research, CEDR) publications, for example, inactive ingredient guide (Inactive Ingredient Guide, 1996); pharmaceutical additives handbook written by Ash and Ash (Hand book of Pharmaceutical Additives,2002, incorporated information resources, inc. (Synapse Information Resources, inc., endiott NY; etc.).
Pharmaceutical dosage forms of the compounds of the present invention may be manufactured by any of the methods well known in the art, for example by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extruding, spray-drying, grinding, emulsifying, (nano/micro) encapsulating, packaging, or lyophilizing processes. As noted above, the compositions of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into a formulation for pharmaceutical use.
The pharmaceutical compositions and dosage forms may comprise as an active ingredient one or more compounds of the invention, one or more pharmaceutically acceptable salts thereof, or one or more solvates of any of the foregoing. The pharmaceutically acceptable carrier may be a solid or a liquid. Solid forms of preparation include powders, tablets, pills, troches, capsules, cachets, suppositories, and dispersible granules. The solid carrier may also be one or more substances that act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is usually a finely divided solid, which is a mixture with the finely divided active component. In tablets, the active ingredient is typically mixed with a carrier having the necessary binding capacity in a suitable ratio and compacted in the shape and size desired. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter and the like. Formulations of the active compounds may include an encapsulating material as a carrier providing a capsule in which the active ingredient with or without the carrier is surrounded by a carrier to which it is bound.
Other forms suitable for oral administration include liquid form preparations, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations intended to be converted to liquid form preparations shortly before use. The emulsion may be prepared in solution, for example in an aqueous propylene glycol solution, or may contain an emulsifier such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, fragrances, stabilizers and thickeners. Aqueous suspensions may be prepared by dispersing the finely divided active component in water with binders such as natural or synthetic gums, resins, methylcellulose, carboxymethylcellulose and other commonly used suspending agents. Solid form preparations include solutions, suspensions and emulsions which may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.
For parenteral administration, the pharmaceutical compositions of the invention may be in the form of sterile injectable or infusible preparations, for example, as sterile aqueous or oleaginous suspensions. The suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., tween 80) and suspending agents. The sterile injectable or infusible formulation may also be a sterile injectable or infusible solution or suspension in a non-toxic parenterally acceptable diluent or solvent. For example, the pharmaceutical composition may be a solution in 1, 3-propanediol. Other examples of acceptable vehicles and solvents that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, mannitol, water, ringer's solution, and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil may be employed for this purpose including synthetic mono-or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant. Solutions for parenteral use may also include suitable stabilizers and, if desired, buffer substances. Suitable stabilizers include antioxidants such as sodium bisulfate, sodium sulfite or ascorbic acid, eurya acid, and salts thereof, and sodium EDTA, alone or in combination. The parenteral solution may also contain preservatives such as benzalkonium chloride, parahydroxybenzoic acid or propyl parahydroxybenzoate and chlorobutanol.
The therapeutically effective dose may be estimated first using various methods well known in the art. The initial dose used for animal studies may be based on the established effective concentration in the cell culture assay. The dosage range suitable for a human individual can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compounds of the present invention may be prepared as medicaments for oral administration.
An effective amount or therapeutically effective amount or dose of an agent (e.g., a compound of the invention) refers to the amount of the agent or compound that results in an improvement in the symptoms or an prolongation of survival of the individual. Toxicity and therapeutic efficacy of the molecules can be determined in cell culture or experimental animals by standard pharmaceutical procedures, e.g., by assaying LD 50 (dose lethal to 50% of population) and ED 50 (50% of the dose therapeutically effective for the population). The dose ratio of toxic effect to therapeutic effect is the therapeutic index and can be expressed as LD 50 /ED 50 . Agents that exhibit high therapeutic indices are preferred.
An effective amount or therapeutically effective amount is that amount of a compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. The dosage is preferably such that it includes ED with little or no toxicity 50 Within a range of circulating concentrations. The dosage may vary within this range depending upon the dosage form employed and/or the route of administration employed. The correct formulation, route of administration, dosage and interval of administration should be selected in consideration of the particularities of the individual condition according to methods known in the art.
The dosage and interval may be individually adjusted to provide a plasma level of the active moiety sufficient to achieve the desired effect; i.e. the minimum effective concentration (minimal effective concentration, MEC). The MEC will vary from compound to compound but can be estimated, for example, from in vitro (in vitro) data and animal experiments. The dosage necessary to obtain MEC will depend on the individual characteristics and route of administration. In the case of local administration or selective uptake, the effective local concentration of the drug may be independent of plasma concentration.
The amount of the agent or composition administered can depend on a variety of factors including the sex, age and weight of the individual being treated, the severity of the affliction, the mode of administration and the discretion of the prescribing physician.
Unless otherwise indicated, the terms used in the present invention have the following meanings:
those skilled in the art will appreciate that, in accordance with the convention used in the art, the present invention describes the structural formula of the group used Meaning that the corresponding group is linked to other fragments, groups in the compound through this site.
The terms preceding and/or following as used herein may be preceded by a single dash "-", or a double dash "=", indicating the bond sequence of the bond between the named substituent and the parent moiety; the single dash represents a single bond and the double dash represents a double bond. Without a single dash or double dash, it is believed that a single bond is formed between the substituent and its parent moiety; in addition, substituents are read "from left to right" unless otherwise indicated.
The term "plurality" means 2, 3, 4 or 5, preferably 2 or 3.
The term "pharmaceutically acceptable" refers to salts, solvents, excipients, and the like, which are generally non-toxic, safe, and suitable for patient use. The "patient" is preferably a mammal, more preferably a human.
The term "solvate" refers to a substance formed by combining a compound of the invention with a stoichiometric or non-stoichiometric solvent. The solvent molecules in the solvate may be present in an ordered or unordered arrangement. Such solvents include, but are not limited to: water, methanol, ethanol, and the like.
The terms "pharmaceutically acceptable salts" and "solvates" in "solvates of pharmaceutically acceptable salts" refer, as described above, to the compounds of the invention formed by combining 1 with 2, prepared with a relatively non-toxic, pharmaceutically acceptable acid or base, with a stoichiometric or non-stoichiometric amount of a solvent.
When any variable (e.g. R 4-1 ) In the definition of a compound, the definition of each position of the variable is independent of the definition of the other positions, and the meanings of the variable are independent and do not influence each other. Thus, if a group is substituted with 1, 2 or 3R 4-1 The radical is substituted, that is to say, it may be substituted by up to 3R 4-1 Substituted, at position R 4-1 Definition of (d) and the remaining position R 4-1 Are defined independently of each other. In addition, combinations of substituents and/or variables are allowed only if the combination yields a stable compound.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "alkyl" refers to a saturated straight or branched chain alkyl group having the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.
The term "alkylene" refers to a saturated straight or branched chain alkane having the indicated number of carbon atoms that formally eliminates two monovalent or one divalent atoms or groups of subunits. The two valences may be on the same carbon atom or on different carbon atoms (e.g., the two valences are on the carbon atoms at each end). For example, the methylene group may be (-CH) 2 (-), the ethylene group can be-CH 2 CH 2 -or-CH (CH) 3 )-。
The term "heteroalkylene" refers to a saturated straight or branched chain heteroalkane that has formally eliminated two monovalent or one divalent atomOr a subunit of a group. The two valences may be on the same atom or on different atoms (e.g., the two valences are on the two opposite atoms, respectively). For example, the propylene group containing an oxygen atom may beEtc.
The term "alkoxy" refers to the group-O-R X Wherein R is X Are alkyl groups as defined above.
The term "alkenyl" refers to a straight or branched chain alkene having one or more carbon-carbon double bonds and no carbon-carbon triple bonds of a specified number of carbon atoms, the one or more carbon-carbon double bonds being internal or terminal, examples of alkene including vinyl, allyl, methyl vinyl, propenyl, butenyl, pentenyl, 1-dimethyl-2 propenyl, hexenyl, and the like.
The term "aryl" refers to C 6 -C 10 Aryl groups such as phenyl or naphthyl.
The term "heteroaryl" refers to an aromatic group containing heteroatoms, preferably an aromatic 3-6 membered monocyclic or 9-10 membered bicyclic ring containing 1-5 atoms independently selected from nitrogen, oxygen and sulfur, at least one of the rings having aromaticity when bicyclic, such as furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, indolinyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisozolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl and the like.
The term "cycloalkyl" refers to a saturated cyclic alkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term "heterocycloalkyl" refers to a saturated cyclic group having heteroatoms, preferably 3-10 membered saturated monocyclic or bicyclic rings containing 1-5 ring heteroatoms independently selected from N, O and S. Examples of heterocycloalkyl groups are: tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyranyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepinyl, oxazepanyl, and the like. Preferred heterocyclyl groups are morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, thiomorpholin-4-yl and 1, 1-dioxo-thiomorpholin-4-yl.
The term "treatment" refers to therapeutic therapy. When specific conditions are involved, treatment refers to: (1) alleviating a disease or one or more biological manifestations of a disorder, (2) interfering with (a) one or more points in a biological cascade that results in or causes a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of a disorder or one or more biological manifestations of a disorder.
The term "preventing" refers to a reduced risk of acquiring or developing a disease or disorder.
The term "patient" refers to any animal, preferably a mammal, most preferably a human, that is about to or has received administration of the compound or composition according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being preferred.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that:
the compound of the present invention is a novel compound obtained by chemical synthesis through structural and synthetic route design by the inventor of the present invention, and is not reported in the literature. Compared with control Plinabulin (Plinabulin), part of the compounds have antitumor activity equivalent to or even better than Plinabulin, and have good development prospects.
Drawings
FIG. 1 shows immunofluorescence results of 2, 5-diketopiperazine-imidazole H460 cell line.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention.
Example 1 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- (5-tert-butyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-1)
1) A50 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-tert-butyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (500 mg,1.72 mmol), potassium carbonate (714.04 mg,5.17 mmol) and DMF (8 ml) followed by stirring at room temperature and benzyl bromide (589.13 mg,3.62 mmol) and stirring was continued at 60℃for 2.5H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, vacuum drying at 50 ℃, pulping with methanol by ultrasonic waves, standing in a refrigerator at-30 ℃ overnight, filtering, washing the filter cake with cold methanol, and vacuum drying at 50 ℃ to obtain 185mg of off-white solid with a yield of 28.24%.
2) 10ml of dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-tert-butyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.40 mmol), 3-p-fluorobenzoyl benzaldehyde (107.97 mg,0.47 mmol), cesium carbonate (192.69 mg,0.59mmol), anhydrous sodium sulfate (112.13 mg,0.79 mmol), DMF (3 ml), vented, nitrogen blanket, placed in 45℃oil bath and stirred for 20h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was added dropwise to cold water (40 ml) at 4 ℃, suction-filtered, the cake was washed with cold water (30 ml×2), the cake was dissolved in a mixed solution of methanol and dichloromethane (1:3), filtered, and concentrated under reduced pressure. The aqueous phase EA was extracted to clear, the organic phases were combined and concentrated under reduced pressure. Mixing the filter cake with the organic phase sample, pulping with methanol under ultrasonic wave, standing in a refrigerator at-30deg.C for 5 hr, suction filtering, washing the filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 96.7mg with a yield of 44.70%.
1 H NMR(500MHz,DMSO-d 6 )δ12.27(s,1H),10.37(s,1H),7.96(s,1H),7.93–7.89(m,2H),7.82(s, 1H),7.76(d,J＝7.69Hz,1H),7.64(d,J＝7.74Hz,1H),7.59(t,J＝7.63Hz,1H),7.43–7.34(m,4H),7.29 (t,J＝7.35Hz,1H),7.02(s,1H),6.94(d,J＝7.42Hz,2H),6.82(s,1H),5.55(s,2H),1.36(s,9H).MS(ESI): m/z 549.78[M+H] + .Mp:116-118℃.
Example 2 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- (5-isopropyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-2)
1) A25 ml dry round bottom flask was taken and was charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (500 mg,1.81 mmol), potassium carbonate (750.27 mg,5.43 mmol), DMF (4 ml), stirred at room temperature for 20min, then benzyl bromide (619.05 mg,3.62 mmol) was added and the reaction was continued at room temperature for 2.5H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, carrying out suction filtration, washing a filter cake with water, carrying out vacuum drying at 50 ℃, pulping with methanol, standing in a refrigerator at-30 ℃ for overnight, carrying out suction filtration, washing the filter cake with cold methanol, and carrying out vacuum drying at 50 ℃ to obtain 483.2mg of brown yellow solid, wherein the yield is 72.87%.
2) A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.41 mmol), 3-p-fluorobenzoyl benzaldehyde (112.10 mg,0.49 mmol), cesium carbonate (200.05 mg,0.61mmol), anhydrous sodium sulfate (116.29 mg,0.82 mmol), DMF (3 ml), vented, nitrogen blanket, placed in an oil bath at 60℃and stirred for 24h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (30 ml) at 4 ℃, suction filtration was performed, the filter cake was washed with cold water (20 ml×2), EA: pe=1:10 (15 ml), the filter cake was dissolved in a mixed solution of methanol and dichloromethane (1:3), filtration and concentration under reduced pressure were performed to obtain brown solid, reverse column chromatography was performed, and gradient elution was performed to obtain 64mg of pale yellow solid, the yield was 29.24%.
1 H NMR(500MHz,DMSO-d 6 )δ12.00(s,2H),10.39(s,1H),8.07(s,1H),7.91(dd,J＝8.5,5.6Hz,2H), 7.84(s,1H),7.77(d,J＝7.6Hz,1H),7.63(d,J＝7.7Hz,1H),7.58(t,J＝7.6Hz,1H),7.39(dt,J＝12.4,8.2 Hz,4H),7.30(t,J＝7.3Hz,1H),7.13(d,J＝7.5Hz,2H),6.81(s,1H),6.67(s,1H),5.35(s,2H),3.12(dt,J ＝14.2,7.1Hz,1H),1.12(d,J＝7.1Hz,6H).MS(ESI):m/z 535.06[M+H] + .Mp:216-219℃.
Example 3 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-3)
A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (141.2 mg,0.38 mmol), 3- (p-fluorobenzyloxy) benzaldehyde (100.0 mg,0.46 mmol), cs 2 CO 3 (188.36 mg，0.58mmol)、Na 2 SO 4 (109.48 mg,0.77 mmol), DMF (3 ml), nitrogen blanket, and 3 times with programmed temperature to 60℃for 24h. The reaction was poured into cold water (40 ml) and a large amount of solids precipitated, filtered, the filter cake was washed with water, EA: pe=1:8, methanol and dichloromethane redissolved. Aqueous phase EA extraction, combining organic phases, concentrating under reduced pressure, and drying. Pulping with methanol (ultrasonic for 20 min), suction filtering, washing filter cake with methanol, and drying to obtain yellow solid 135.3mg with yield of 67.18%. 1 H NMR(400MHz,DMSO-d 6 )δ12.00 (s,1H),10.18(s,1H),8.07(s,1H),7.45–7.08(m,12H),6.91(s,1H),6.70(d,J＝21.2Hz,2H),5.35(s,2H), 3.12(s,1H),1.11(s,6H). 13 C NMR(125MHz,DMSO-d 6 )δ159.12,157.33,157.22,157.03,156.20,152.57, 138.56,137.79,137.08,135.19,132.67,130.27,128.75,127.69,127.20,126.59,124.43,123.99,120.55, 120.49,118.91,117.75,116.62,116.43,113.26,103.95,47.97,23.84,22.32.MS(ESI):m/z 523.21[M+H]+. Mp:184-187℃.
Example 4 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- (5-isopropyl-1- (2-pyridinyl) imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-4)
1) A50 ml dry round bottom flask was taken and was charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), cesium carbonate (1.42 g,4.34 mmol), anhydrous sodium sulfate (616.91 mg,4.34 mmol), DMF (8 ml) and stirred at room temperature for 10min, and then 2- (bromomethyl) pyridine hydrobromide (628.53 mg,2.17 mmol) was added and the stirring reaction was continued at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solid, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing for more than 2 hours in a refrigerator at-30 ℃, filtering, washing with cold methanol, and drying to obtain 326.3mg of white solid with a yield of 81.79%.
2) 10ml of dry brown round bottom flask was taken, and (Z) -1-acetyl-3- ((5-isopropyl-1- (2-pyridyl) imidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.41 mmol), 3-p-fluorobenzoyl benzaldehyde (111.90 mg,0.49 mmol), cesium carbonate (199.66 mg,0.61 mmol), anhydrous sodium sulfate (116.06 mg,0.82 mmol), DMF (4 ml) was added in sequence, and the mixture was placed in an oil bath at 45℃under nitrogen with stirring for 18h under the protection of air and nitrogen. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was added dropwise to cold water (40 ml) at 4 ℃, suction filtration was performed, the cake was washed with cold water (50 ml. Times.3), the cake was dissolved in a mixed solution of methanol and dichloromethane (1:3), filtration was performed, and concentration was performed under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain 147.6mg yellow solid with a yield of 33.73%.
1 H NMR(500MHz,DMSO-d 6 )δ12.01(s,1H),10.36(s,1H),8.53(d,J＝4.76Hz,1H),8.04(s,1H), 7.91(dd,J＝5.78,8.17Hz,2H),7.85–7.79(m,2H),7.76(d,J＝7.54Hz,1H),7.64(d,J＝7.62Hz,1H),7.59 (t，J＝7.63Hz，1H)，7.40(t，J＝8.67Hz，2H)，7.33(dd，J＝4.93，7.42Hz，1H)，7.22(d，J＝7.82Hz，1H)，6.82 (s,1H),6.69(s,1H),5.43(s,2H),3.14(dt,J＝7.10,14.22Hz,1H),1.13(d,J＝7.06Hz,6H).MS(ESI):m/z 536.17[M+H] + .Mp:191-193℃.
Example 5 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- (5-cyclopropyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-5)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-cyclopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.73 mmol), potassium carbonate (201.55 mg,1.46 mmol) and DMF (4 ml) followed by stirring at room temperature and then benzyl bromide (249.44 mg,1.46 mmol) and stirring was continued at 40℃for 1.5H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, vacuum drying at 50 ℃, pulping with methanol by ultrasonic waves, standing in a refrigerator at-30 ℃ for overnight, filtering, washing the filter cake with cold methanol, and vacuum drying at 50 ℃ to obtain 245mg of brown yellow solid with a yield of 92.20%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-cyclopropyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (70 mg,0.19 mmol), 3-p-fluorobenzoyl benzaldehyde (52.60 mg,0.23 mmol), cesium carbonate (93.87 mg,0.29mmol), anhydrous sodium sulfate (54.57 mg,0.38 mmol), DMF (2 ml), vented, nitrogen blanket, placed in an oil bath at 45℃and stirred for 20h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was added dropwise to cold water (20 ml) at 4 ℃, suction-filtered, the cake was washed with cold water (30 ml×2), the cake was dissolved in a mixed solution of methanol and dichloromethane (1:3), filtered, and concentrated under reduced pressure. Aqueous EA (40 ml x 3) was extracted to clear, the organic phases were combined and concentrated under reduced pressure. Mixing the filter cake with the organic phase sample, pulping with methanol under ultrasonic wave, standing in a refrigerator at-30deg.C, vacuum filtering, washing the filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 76.1mg with yield of 74.38%.
1 H NMR(500MHz,DMSO-d 6 )δ11.89(s,1H),10.35(s,1H),8.08(s,1H),7.94–7.87(m,2H),7.81(s, 1H),7.75(d,J＝7.71Hz,1H),7.60(dt,J＝7.69,15.27Hz,2H),7.43–7.34(m,4H),7.31(t,J＝7.32Hz,1H), 7.21(d,J＝7.17Hz,2H),6.81(s,1H),6.69(s,1H),5.34(s,2H),1.48(tt,J＝5.40,8.32Hz,1H),1.04–0.90 (m,2H),0.68–0.43(m,2H).MS(ESI):m/z 533.37[M+H] + .Mp:197-200℃.
Example 6 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- (5-methyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-6)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-methyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (500 mg,2.01 mmol), potassium carbonate (835.08 mg,6.04 mmol) and DMF (8 ml) followed by stirring at room temperature for 20min and benzyl bromide (689.02 mg,4.03 mmol) and stirring at room temperature for 2.5H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, carrying out suction filtration, washing a filter cake with water, carrying out vacuum drying at 50 ℃, pulping with methanol, standing in a refrigerator at-30 ℃ for overnight, carrying out suction filtration, washing the filter cake with cold methanol, and carrying out vacuum drying at 50 ℃ to obtain 480mg of brown yellow solid, wherein the yield is 70.43%.
2) A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-methyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (236 mg,0.70 mmol), 3-p-fluorobenzoyl benzaldehyde (191.02 mg,0.84 mmol), cesium carbonate (340.91 mg,1.05mmol), anhydrous sodium sulfate (198.15 mg,1.40 mmol), DMF (4 ml), vented, nitrogen blanket, placed in an oil bath at 60℃and stirred for 24h. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, methanol and methylene chloride were dissolved, filtered, concentrated under reduced pressure, and EA was slurried, and then the mixture was left standing in a refrigerator at-30℃for 3 hours, suction-filtered, and cold EA was washed to give 147.3mg of yellow solid, with a yield of 41.69%.
1 H NMR(500MHz,DMSO-d 6 )δ11.87(s,1H),10.36(s,1H),8.11(s,1H),7.91(dd,J＝8.4,5.8Hz,2H), 7.84(s,1H),7.78(d,J＝7.5Hz,1H),7.63(d,J＝7.7Hz,1H),7.58(t,J＝7.6Hz,1H),7.39(dd,J＝18.9,8.3 Hz,4H),7.31(t,J＝7.3Hz,1H),7.18(d,J＝7.5Hz,2H),6.80(s,1H),6.56(s,1H),5.28(s,2H),2.20(s,3H). MS(ESI):m/z 507.10[M+H] + .Mp:219-221℃.
Example 7 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- (5-trifluoromethyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-7)
1) A25 mL dry round bottom flask was taken and 5-trifluoromethyl-1H-imidazole-4-carbaldehyde (284 mg,1.73 mmol), 1, 4-diacetylpiperazine-2, 5-dione (686.00 mg,3.46 mmol), cesium carbonate (845.87 mg,2.60 mmol), DMF (4 mL) was added sequentially, replaced with nitrogen protection, and reacted at room temperature for 17.5H. After the reaction, pouring the reaction solution into cold water, precipitating a large amount of solids, filtering, washing a filter cake with cold water, drying, pulping by EA, standing in a refrigerator at-30 ℃, carrying out suction filtration, washing the filter cake by EA, and drying to obtain 274mg of white-like solid with the yield of 52.38%.
2) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-trifluoromethyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.50 mmol), potassium carbonate (137.19 mg,0.99 mmol), anhydrous sodium sulfate (141.00 mg,0.99 mmol), DMF (2 ml) and stirred at room temperature for 20min, benzyl bromide (137.19 mg,0.99 mmol) was added and the reaction stirred at room temperature for 1.5H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, carrying out suction filtration, washing a filter cake with water, carrying out vacuum drying at 50 ℃, pulping with methanol, standing in a refrigerator at-30 ℃ overnight, carrying out suction filtration, washing the filter cake with cold methanol, and carrying out vacuum drying at 50 ℃ to obtain 145mg of white solid, wherein the yield is 74.47%.
3) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-trifluoromethyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (100 mg,0.25 mmol), 3-p-fluorobenzoyl benzaldehyde (69.81 mg,0.31 mmol), potassium carbonate (52.83 mg,0.38 mmol), anhydrous sodium sulfate (72.41 mg,0.51 mmol), DMF (3 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 10h. LC-MS monitoring reaction, completely reacting, dripping the reaction solution into cold water (30 ml) at 4 ℃, carrying out suction filtration, dissolving methanol and dichloromethane, filtering, concentrating under reduced pressure, pulping the methanol, standing in a refrigerator at-30 ℃ for 3h, carrying out suction filtration, washing with cold methanol to obtain off-white solid 129.6mg, wherein the yield is 90.71%.
1 H NMR(500MHz,DMSO-d 6 )δ11.69(s,1H),10.62(s,1H),8.50(s,1H),7.94–7.88(m,2H),7.83(s, 1H),7.77(d,J＝7.59Hz,1H),7.65(d,J＝7.59Hz,1H),7.59(t,J＝7.62Hz,1H),7.39(dd,J＝7.59,15.64 Hz,4H),7.34(d,J＝6.75Hz,1H),7.18(d,J＝7.43Hz,2H),6.89(s,1H),6.57(s,1H),5.45(s,2H).MS (ESI):m/z 561.41[M+H] + .Mp:231-232℃.
EXAMPLE 8 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- (1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-8)
1) A50 ml dry round bottom flask was taken and was charged with (Z) -1-acetyl-3- ((1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (600 mg,2.06 mmol), potassium carbonate (1.06 g,7.69 mmol), DMF (8 ml) and stirred at room temperature, benzyl bromide (877.13 mg, 5.13 mmol) was added and the reaction was continued with stirring at room temperature for 2.5H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, vacuum drying at 50 ℃, pulping with methanol by ultrasonic waves, standing in a refrigerator at-30 ℃ overnight, filtering, washing the filter cake with methanol, and vacuum drying at 50 ℃ to obtain 762mg of white solid with a yield of 91.63%.
2) A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.46 mmol), 3-p-fluorobenzoyl benzaldehyde (126.66 mg,0.56 mmol), cesium carbonate (226.02 mg, 0.69 mmol), anhydrous sodium sulfate (131.38 mg,0.92 mmol), DMF (3 ml), vented, nitrogen blanket, placed in a 45℃oil bath and stirred for 25h. LC-MS monitors the reaction, after the reaction, the reaction liquid is dripped into cold water (40 ml) at 4 ℃, suction filtration is carried out, filter cake cold water (30 ml is 3) is washed, suction drying is carried out, methanol and dichloromethane (1:3) are dissolved, filtration, decompression concentration and ultrasonic beating of methanol are carried out, standing is carried out at-30 ℃ for overnight, suction filtration is carried out, filter cake is washed by cold methanol, vacuum drying is carried out at 50 ℃, and 109.2mg of yellow solid is obtained, and the yield is 47.94%.
1 H NMR(500MHz,DMSO-d 6 )δ11.75(s,1H),10.34(s,1H),8.13(s,1H),7.95–7.88(m,2H),7.83(s, 1H),7.76(d,J＝7.15Hz,1H),7.66–7.55(m,3H),7.35(ddd,J＝7.87,16.01,22.93Hz,7H),6.82(s,1H), 6.61(s,1H),5.28(s,2H).MS(ESI):m/z 493.10[M+H] + .Mp:186-188℃.
Example 9 Synthesis of (3Z, 6Z) -3-benzylidene-6- ((5-tert-butyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-9)
A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-tert-butyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (185 mg,0.49 mmol), benzaldehyde (61.92 mg,0.58 mmol), cesium carbonate (237.65 mg,0.73 mmol), anhydrous sodium sulfate (138.14 mg,0.97 mmol), DMF (3 ml), vented, nitrogen protected, and stirred in a 50℃oil bath in the dark for 24h. After the reaction, the reaction solution was added dropwise to cold water (30 ml) at 4 ℃, suction filtration was performed, the cake was washed with cold water (20 ml. Times.3), the cake was dissolved in a mixed solution of methanol and dichloromethane (1:3), filtration was performed, and concentration was performed under reduced pressure. The aqueous phase EA was extracted to clear, the organic phases were combined and concentrated under reduced pressure. Mixing the filter cake with the organic phase sample, pulping with methanol by ultrasonic, standing in a refrigerator at-30deg.C for 5h, suction filtering, washing the filter cake with cold methanol, and vacuum drying at 50deg.C to obtain 169.6mg of yellow solid with a yield of 81.77%.
1 H NMR(500MHz,DMSO-d 6 )δ12.24(s,1H),10.06(s,1H),7.96(s,1H),7.53(d,J＝7.54Hz,2H), 7.42(t,J＝7.70Hz,2H),7.37(t,J＝7.56Hz,2H),7.30(dt,J＝7.39,17.80Hz,2H),7.02(s,1H),6.94(d,J ＝7.35Hz,2H),6.76(s,1H),5.55(s,2H),1.37(s,9H).MS(ESI):m/z 427.12[M+H] + .Mp:220-223℃.
EXAMPLE 10 Synthesis of (3Z, 6Z) -3-benzylidene-6- ((5-isopropyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-10)
A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (172 mg,0.47 mmol), benzaldehyde (59.77 mg,0.56 mmol), cesium carbonate (229.41 mg,0.70 mmol), anhydrous sodium sulfate (133.35 mg,0.94 mmol), DMF (3 ml), vented, nitrogen protected, and stirred in a 55℃oil bath in the dark for 20h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (30 ml) at 4 ℃ to precipitate yellow solid, suction filtration was performed, filter cake was washed with cold water (30 ml x 2), EA: pe=1:10 (20 ml) was washed, filter cake was dissolved in a mixed solution of methanol and dichloromethane (1:3), filtration was performed, concentration was performed under reduced pressure, EA was beaten, the mixture was allowed to stand in a refrigerator at-30 ℃ overnight, suction filtration was performed, filter cake was washed with cold EA, and 111.2mg of yellow solid was obtained by vacuum drying at 50 ℃ in 57.43% yield.
1 H NMR(500MHz,DMSO-d 6 )δ11.97(s,1H),10.07(s,1H),8.06(s,1H),7.53(d,J＝7.7Hz,2H),7.39 (dt,J＝21.0,7.6Hz,4H),7.30(q,J＝7.5Hz,2H),7.13(d,J＝7.5Hz,2H),6.76(s,1H),6.68(s,1H),5.34 (s,2H),3.12(dq,J＝14.2,7.1Hz,1H),1.12(d,J＝7.1Hz,6H).MS(ESI):m/z 413.10[M+H] + .Mp:231- 233℃.
EXAMPLE 11 Synthesis of (3Z, 6Z) -3-benzylidene-6- ((5-cyclopropyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-11)
A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-cyclopropyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (70 mg,0.19 mmol), benzaldehyde (24.46 mg,0.23 mmol), cesium carbonate (93.87 mg,0.29 mmol), anhydrous sodium sulfate (54.57 mg,0.38 mmol), DMF (2 ml), vented, nitrogen protected, and placed in an oil bath at 45℃with stirring in the dark for 24h. After the reaction, the reaction solution was added dropwise to cold water (30 ml) at 4 ℃, suction filtration was performed, the cake was washed with cold water (30 ml×3), the cake was dissolved in a mixed solution of methanol and dichloromethane (1:3), filtration was performed, and concentration was performed under reduced pressure. Aqueous EA (40 ml x 3) was extracted to clear, the organic phases were combined and concentrated under reduced pressure. Mixing the filter cake with the organic phase sample, pulping with methanol under ultrasonic wave, standing in a refrigerator at-30deg.C, vacuum filtering, washing the filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 60.7mg with yield 76.98%.
1 H NMR(500MHz,DMSO-d 6 )δ11.87(s,1H),10.05(s,1H),8.09(s,1H),7.53(d,J＝7.53Hz,2H), 7.40(dt,J＝7.59,18.94Hz,4H),7.34–7.29(m,2H),7.22(d,J＝7.28Hz,2H),6.76(s,1H),6.70(s,1H),5.34 (s,2H),1.49(tt,J＝5.42,8.29Hz,1H),1.04–0.90(m,2H),0.72–0.45(m,2H).MS(ESI):m/z 411.09[M+ H] + .Mp:246-249℃.
EXAMPLE 12 Synthesis of (3Z, 6Z) -3-benzylidene-6- ((5-methyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-12)
A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-methyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (197.80 mg,0.58 mmol), benzaldehyde (74.44 mg,0.70 mmol), cesium carbonate (285.71 mg,0.88 mmol), anhydrous sodium sulfate (166.06 mg,1.17 mmol), DMF (3 ml), vented, nitrogen protected, and placed in an oil bath at 60℃with stirring in the dark for 24h. After the reaction, the reaction solution was dropped into cold water (30 ml) at 4 ℃, suction-filtered, filter cake cold water washed (20 ml. Times.3), EA: PE=1:10 (20 ml) washed, filter cake was dissolved in a mixed solution of methanol and dichloromethane (1:3), filtered, concentrated under reduced pressure, EA was slurried, and left standing overnight in a refrigerator at-30 ℃, suction-filtered, filter cake cold EA washed, and vacuum dried at 50 ℃ to obtain 140mg of yellow solid with a yield of 62.29%.
1 H NMR(500MHz,DMSO-d 6 )δ11.86(s,1H),10.02(s,1H),8.11(s,1H),7.53(d,J＝7.6Hz,2H),7.41 (dd,J＝12.9,5.0Hz,2H),7.37(d,J＝7.7Hz,2H),7.34–7.28(m,2H),7.18(d,J＝7.2Hz,2H),6.76(s,1H), 6.57(s,1H),5.27(d,J＝14.2Hz,2H),2.20(s,3H).MS(ESI):m/z 385.05[M+H] + .Mp:236-238℃.
EXAMPLE 13 Synthesis of (3Z, 6Z) -3-benzylidene-6- ((1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-13)
A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.46 mmol), benzaldehyde (58.90 mg,0.56 mmol), cesium carbonate (226.02 mg,0.69 mmol), anhydrous sodium sulfate (131.38 mg,0.97 mmol), DMF (3 ml), vented, nitrogen protected, and placed in an oil bath at 50℃with stirring in the dark for 24h. After the reaction, the reaction solution was added dropwise to cold water (40 ml) at 4 ℃, suction filtration was performed, the cake was washed with cold water (30 ml×3), the cake was dissolved in a mixed solution of methanol and dichloromethane (1:3), filtration was performed, and concentration was performed under reduced pressure. The aqueous phase EA was extracted to clear, the organic phases were combined and concentrated under reduced pressure. Mixing the filter cake with the organic phase sample, pulping with methanol under ultrasonic wave, standing in a refrigerator at-30deg.C, vacuum filtering, washing the filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 106.2mg with yield 61.99%.
1 H NMR(500MHz,DMSO-d 6 )δ11.75(s,1H),10.04(s,1H),8.14(s,1H),7.63(d,J＝0.86Hz,1H), 7.54(d,J＝7.60Hz,2H),7.45–7.37(m,4H),7.35–7.28(m,4H),6.78(s,1H),6.62(s,1H),5.29(s,2H).MS (ESI):m/z 371.00[M+H] + .Mp:204-206℃.
EXAMPLE 14 Synthesis of (3Z, 6Z) -3- (2, 5-difluorobenzene) methylene-6- ((5-tert-butyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-14)
10ml of dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-tert-butyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.39 mmol), 2, 5-difluorobenzaldehyde (67.23 mg,0.47 mmol), cesium carbonate (192.69mg,0.59 mmol), anhydrous sodium sulfate (112.13 mg,0.79 mmol), DMF (3 ml), vented, nitrogen protected, and placed in 45℃oil bath with stirring for 18h in the absence of light. LC-MS monitors the reaction, after the reaction, the reaction solution is dripped into cold water (40 ml) at 4 ℃, suction filtration is carried out, a filter cake is washed with cold water (30 ml x 3), suction drying is carried out, the filter cake is dissolved in a mixed solution of methanol and dichloromethane (1:3), filtration and decompression concentration are carried out. Aqueous EA (50 ml x 2) was extracted to clear, the organic phases were combined and concentrated under reduced pressure. Mixing the filter cake with the organic phase sample, pulping with methanol under ultrasonic wave, standing in a refrigerator at-30deg.C, vacuum filtering, washing the filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 157.8mg with 86.53% yield.
1 H NMR(500MHz,DMSO-d 6 )δ12.31(s,1H),10.48(s,1H),7.97(s,1H),7.48–7.34(m,3H),7.29(td, J＝4.96,9.64Hz,2H),7.24–7.16(m,1H),7.05(s,1H),6.94(d,J＝7.38Hz,2H),6.63(s,1H),5.56(s,2H), 1.37(s,9H).MS(ESI):m/z 463.15[M+H] + .Mp:196-198℃.
EXAMPLE 15 Synthesis of (3Z, 6Z) -3- (2, 5-difluorobenzene) methylene-6- ((5-isopropyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-15)
A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.55 mmol), 2, 5-difluorobenzaldehyde (93.08 mg,0.66 mmol), cesium carbonate (266.75mg,0.82 mmol), anhydrous sodium sulfate (155.06 mg,1.09 mmol), DMF (4 ml), vented, nitrogen protected, and placed in an oil bath at 50℃with stirring for 18h in the absence of light. LC-MS monitors the reaction, after the reaction, the reaction solution is dripped into cold water (40 ml) at 4 ℃, suction filtration is carried out, a filter cake is washed with cold water (30 ml x 3), suction drying is carried out, the filter cake is dissolved in a mixed solution of methanol and dichloromethane (1:3), filtration and decompression concentration are carried out. The aqueous phase EA was extracted to clear, the organic phases were combined and concentrated under reduced pressure. Mixing the filter cake with the organic phase sample, pulping with methanol under ultrasonic wave, standing in a refrigerator at-30deg.C, vacuum filtering, washing the filter cake with cold methanol, and vacuum drying at 50deg.C to obtain 157.8mg of yellow solid with 62.51% yield.
1 H NMR(500MHz,DMSO-d 6 )δ12.05(s,1H),10.47(s,1H),8.07(s,1H),7.40(ddd,J＝5.41,10.31, 20.45Hz,3H),7.33–7.26(m,2H),7.23–7.17(m,1H),7.13(d,J＝7.37Hz,2H),6.70(s,1H),6.63(s,1H), 5.35(s,2H),3.12(dt,J＝7.11,14.24Hz,1H),1.12(d,J＝7.11Hz,6H).MS(ESI):m/z 449.11[M+H] + . Mp:205-207℃.
EXAMPLE 16 Synthesis of (3Z, 6Z) -3- (2, 5-difluorobenzene) methylene-6- ((5-cyclopropyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-16)
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10ml of a dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-cyclopropyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (70 mg,0.19 mmol), 2, 5-difluorobenzaldehyde (32.75 mg,0.23 mmol), cesium carbonate (93.87mg,0.29 mmol), anhydrous sodium sulfate (54.57 mg,0.38 mmol), DMF (2 ml), vented, nitrogen protected and placed in an oil bath at 45℃with stirring in the absence of light for 21h. LC-MS monitors the reaction, after the reaction, the reaction solution is dripped into cold water (20 ml) at 4 ℃, suction filtration is carried out, a filter cake is washed (20 ml x 3) by cold water, suction drying is carried out, the filter cake is dissolved in a mixed solution of methanol and dichloromethane (1:3), filtration and reduced pressure concentration are carried out. Aqueous EA (30 ml x 3) was extracted to clear, the organic phases were combined and concentrated under reduced pressure. Mixing the filter cake with the organic phase sample, pulping with methanol under ultrasonic wave, standing in a refrigerator at-30deg.C, vacuum filtering, washing the filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 55.8mg with a yield of 65.07%.
1 H NMR(500MHz,DMSO-d 6 )δ11.93(s,1H),10.47(s,1H),8.09(s,1H),7.39(ddd,J＝5.40,10.22, 19.64Hz,3H),7.34–7.24(m,2H),7.24–7.16(m,3H),6.72(s,1H),6.62(s,1H),5.34(s,2H),1.49(tt,J＝ 5.40,8.29Hz,1H),1.01–0.88(m,2H),0.70–0.45(m,2H).MS(ESI):m/z 447.10[M+H] + .Mp:228-229℃.
EXAMPLE 17 Synthesis of (3Z, 6Z) -3- (2, 5-difluorobenzene) methylene-6- ((5-methyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-17)
A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.59 mmol), 2, 5-difluorobenzaldehyde (100.79 mg,0.71 mmol), cesium carbonate (288.87mg,0.89 mmol), anhydrous sodium sulfate (167.91 mg,1.18 mmol), DMF (4 ml), vented, nitrogen protected, and placed in an oil bath at 50℃with stirring in the dark for 24h. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4 ℃, suction filtration was performed, the filter cake was washed with cold water (30 ml. Times.3), suction drying was performed, the filter cake was dissolved in a mixed solution of methanol and dichloromethane (1:3), filtration was performed, concentration under reduced pressure was performed, EA was pulped, the mixture was allowed to stand in a refrigerator at-30 ℃ overnight, suction filtration was performed, the filter cake was washed with EA, and vacuum drying was performed at 50 ℃ to obtain 176.7mg of yellow solid, the yield was 71.10%.
1 H NMR(500MHz,DMSO-d 6 )δ11.92(s,1H),10.45(s,1H),8.12(s,1H),7.31(ddd,J＝18.78,45.59, 66.30Hz,6H),6.61(d,J＝15.76Hz,2H),5.29(s,2H),2.50(s,3H).MS(ESI):m/z 421.06[M+H] + .Mp: 180-182℃.
EXAMPLE 18 Synthesis of (3Z, 6Z) -3- (2, 5-difluorobenzene) methylene-6- ((1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-18)
A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((1-benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.46 mmol), 2, 5-difluorobenzaldehyde (7.86 mg,0.56 mmol), cesium carbonate (226.02 mg,0.69 mmol), anhydrous sodium sulfate (131.38 mg,0.92 mmol), DMF (3 ml), vented, nitrogen protected, and placed in an oil bath at 45℃with stirring in the dark for 19h. LC-MS monitors the reaction, after the reaction, the reaction solution is dripped into cold water (40 ml) at 4 ℃, suction filtration is carried out, a filter cake is washed with cold water (30 ml x 3), suction drying is carried out, the filter cake is dissolved in a mixed solution of methanol and dichloromethane (1:3), filtration and decompression concentration are carried out. Aqueous EA (50 ml x 2) was extracted to clear, the organic phases were combined and concentrated under reduced pressure. Mixing the filter cake with the organic phase sample, pulping with methanol under ultrasonic wave, standing in a refrigerator at-30deg.C, vacuum filtering, washing the filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 97.4mg with a yield of 51.82%.
1 H NMR(500MHz,DMSO-d 6 )δ11.81(s,1H),10.45(s,1H),8.14(s,1H),7.64(s,1H),7.39(dd,J＝ 7.16,14.38Hz,3H),7.36–7.25(m,4H),7.24–7.16(m,1H),6.64(d,J＝2.97Hz,2H),5.28(s,2H).MS(ESI): m/z 407.03[M+H] + .Mp:201-205℃.
EXAMPLE 19 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- (5-isopropyl-1- (4-fluoro) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-19)
1) A25 ml dry round bottom flask was taken and was charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.72 mmol), potassium carbonate (300.13 mg,2.18 mmol), DMF (4 ml) and stirred at room temperature for 20min, then 4-fluorobenzyl bromide (247.63 mg,1.45 mmol) was added and the reaction was continued with stirring at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying at 50 ℃, pulping with methanol, standing for more than 2 hours in a refrigerator at-30 ℃, filtering, washing with cold methanol, and drying to obtain 252mg of brown yellow solid with the yield of 95.00%.
2) A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (4-fluoro) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.39 mmol), 3-p-fluorobenzoyl benzaldehyde (106.88 mg,0.47 mmol), cesium carbonate (190.70 mg,0.58 mmol), anhydrous sodium sulfate (110.85 mg,0.78 mmol), DMF (4 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 18h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 106.0 mg with a yield of 49.16%.
1 H NMR(500MHz,DMSO-d 6 )δ11.99(s,1H),10.37(s,1H),8.07(s,1H),7.93–7.88(m,2H),7.82(s, 1H),7.76(d,J＝7.54Hz,1H),7.64(d,J＝7.68Hz,1H),7.59(t,J＝7.62Hz,1H),7.40(t,J＝8.73Hz,2H), 7.21(d，J＝7.05Hz，4H)，6.82(s，1H)，6.68(s，1H)，5.33(s，2H)，3.13(dt，J＝7.11，14.24Hz，1H).1.13(d，J ＝7.04Hz,6H).MS(ESI):m/z 553.06[M+H] + .Mp:172-176℃.
EXAMPLE 20 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- (5-isopropyl-1- (3-fluoro) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-20)
A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (3-fluoro) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.39 mmol), 3-fluorobenzoyl benzaldehyde (106.88 mg,0.47 mmol), cesium carbonate (190.70 mg,0.58 mmol), anhydrous sodium sulfate (110.85 mg,0.78 mmol), DMF (4 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 14h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and filtered by suction, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3) by washing with cold water, filtered and concentrated under reduced pressure. Pulping with methanol by ultrasonic, standing in a refrigerator at-30deg.C, filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 116.4 mg with a yield of 53.98%.
1 H NMR(500MHz,DMSO-d 6 )δ11.99(s,1H),10.37(s,1H),8.08(s,1H),7.95–7.88(m,2H),7.82(s, 1H),7.76(d,J＝7.57Hz,1H),7.64(d,J＝7.51Hz,1H),7.59(t,J＝7.61Hz,1H),7.46–7.37(m,3H),7.15 (t,J＝8.47Hz,1H),7.01(d,J＝9.78Hz,1H),6.94(d,J＝7.65Hz,1H),6.82(s,1H),6.68(s,1H),5.37(s, 2H),3.12(dt,J＝6.95,13.97Hz,1H),1.13(d,J＝6.91Hz,6H).MS(ESI):m/z 553.00[M+H] + .Mp:182- 183℃.
EXAMPLE 21 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- (5-isopropyl-1- (2-fluoro) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-21)
A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (2-fluoro) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.39 mmol), 3-fluorobenzoyl benzaldehyde (106.88 mg,0.47 mmol), cesium carbonate (190.70 mg,0.58 mmol), anhydrous sodium sulfate (110.85 mg,0.78 mmol), DMF (4 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 18h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 145.6 mg with yield of 67.53%.
1 H NMR(500MHz,DMSO-d 6 )δ11.97(s,1H),10.37(s,1H),8.01(s,1H),7.94–7.89(m,2H),7.82(s, 1H),7.76(d,J＝7.52Hz,1H),7.64(d,J＝7.57Hz,1H),7.59(t,J＝7.58Hz,1H),7.40(t,J＝8.37Hz,3H), 7.31–7.24(m,1H),7.21(t,J＝7.50Hz,1H),7.01(t,J＝7.64Hz,1H),6.82(s,1H),6.69(s,1H),5.40(s,2H), 3.14(dt,J＝7.03,14.09Hz,1H),1.16(d,J＝6.94Hz,6H).MS(ESI):m/z 553.34[M+H] + .Mp:178-180 ℃.
Example 22 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-p-chlorobenzimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-22)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), potassium carbonate (450.16 mg,3.26 mmol), 4-chlorobenzyl bromide (446.22 mg,2.17 mmol) in DMF (6 ml) and stirring was continued at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, carrying out suction filtration, washing a filter cake, drying in a vacuum drying oven at 50 ℃, pulping with methanol, standing in a refrigerator at-30 ℃ for more than 2 hours, carrying out suction filtration, washing with cold methanol, and drying to obtain off-white solid 314.3mg, wherein the yield is 72.21%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (4-chloro) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.37 mmol), 3-p-fluorobenzoyl benzaldehyde (102.47 mg,0.45 mmol), cesium carbonate (182.88 mg,0.56 mmol), anhydrous sodium sulfate (106.30 mg,0.75 mmol), DMF (4 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 13.5h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol by ultrasonic, standing in a refrigerator at-30deg.C, filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 173.0 mg with a yield of 81.25%.
1 H NMR(500MHz,DMSO-d 6 )δ11.99(s,1H),10.37(s,1H),8.07(s,1H),7.91(s,2H),7.82(s,1H), 7.76(d,J＝6.44Hz,1H),7.67–7.55(m,2H),7.43(dd,J＝8.16,17.35Hz,4H),7.16(d,J＝7.47Hz,2H), 6.82(s,1H),6.68(s,1H),5.35(s,2H),3.11(d,J＝6.37Hz,1H),1.13(d,J＝6.45Hz，6H).MS(ESI):m/z 570.31[M+H] + .Mp:174-176℃.
Example 23 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-m-chlorobenzimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-23)
1) 1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.06 mmol), potassium carbonate (450.16 mg,3.26 mmol), 3-chlorobenzyl bromide (446.22 mg,2.1716 mmol) in DMF (6 ml) and the reaction stirred at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing in a refrigerator at-30 ℃ for more than 2 hours, filtering, washing with cold methanol, and drying to obtain white solid 330.9mg with a yield of 76.03%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (3-chloro) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.37 mmol), 3-p-fluorobenzoyl benzaldehyde (102.47 mg,0.45 mmol), cesium carbonate (182.88 mg,0.56 mmol), anhydrous sodium sulfate (106.30 mg,0.75 mmol), DMF (3.5 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 13.5h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 131.0mg with yield of 61.52%.
1 H NMR(500MHz,DMSO-d 6 )δ11.98(s,1H),10.37(s,1H),8.08(s,1H),7.97–7.71(m,4H),7.63(s, 2H),7.40(s,4H),7.23(s,1H),7.07(s,1H),6.82(s,1H),6.68(s,1H),5.37(s,2H),3.12(s,1H),1.14(s,6H). MS(ESI):m/z 570.53[M+H] + .Mp:254-256℃.
Example 24 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-o-chlorobenzimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-24)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), potassium carbonate (450.16 mg,3.26 mmol), 2-chlorobenzyl bromide (446.22 mg,2.17 mmol) in DMF (6 ml) and stirring was continued at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing in a refrigerator at-30 ℃ for more than 2 hours, filtering, washing with cold methanol, and drying to obtain white solid 362.5mg with a yield of 83.29%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (2-chloro) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.37 mmol), 3-p-fluorobenzoyl benzaldehyde (102.47 mg,0.45 mmol), cesium carbonate (182.88 mg,0.56 mmol), anhydrous sodium sulfate (106.30 mg,0.75 mmol), DMF (3.5 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 13.0h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 127.4mg with a yield of 59.84%.
1 H NMR(500MHz,DMSO-d 6 )δ11.98(s,1H),10.38(s,1H),7.99(s,1H),7.95–7.88(m,2H),7.83(s, 1H),7.76(d,J＝7.26Hz,1H),7.66–7.52(m,3H),7.45–7.32(m,4H),6.83(s,1H),6.71(s,2H),5.41(s,2H), 3.04(dt,J＝6.84,14.04Hz,1H),1.18(d,J＝6.93Hz,6H).MS(ESI):m/z 570.16[M+H] + .Mp:179-181 ℃.
Example 25 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-p-bromobenzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-25)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), potassium carbonate (450.16 mg,3.26 mmol), 4-bromobenzyl bromide (542.75 mg,2.17 mmol) in DMF (6 ml) and stirring was continued at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing in a refrigerator at-30 ℃ for more than 2 hours, filtering, washing with cold methanol, and drying to obtain white solid 372.4mg with a yield of 77.02%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (4-bromo) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.34 mmol), 3-p-fluorobenzoyl benzaldehyde (92.25 mg,0.40 mmol), cesium carbonate (164.64 mg,0.50 mmol), anhydrous sodium sulfate (95.69 mg,0.67 mmol), DMF (3.5 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 15.5h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered, concentrated under reduced pressure and dried. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain 162.7mg yellow solid with yield of 78.74%.
1 H NMR(500MHz,DMSO-d 6 )δ11.99(s,1H),10.41(s,1H),8.08(s,1H),7.94–7.88(m,2H),7.83(s, 1H),7.76(d,J＝7.47Hz,1H),7.64(d,J＝7.57Hz,1H),7.59(t,J＝7.32Hz,3H),7.40(t,J＝8.22Hz,2H), 7.09(d,J＝7.68Hz,2H),6.82(s,1H),6.67(s,1H),5.34(s,2H),3.09(dt,J＝7.05,14.04Hz,1H),1.12(d,J ＝6.92Hz,6H).MS(ESI):m/z 614.89[M+H] + .Mp:154-155℃.
EXAMPLE 26 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-m-bromobenzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-26)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), potassium carbonate (450.16 mg,3.26 mmol), 3-bromobenzyl bromide (542.75 mg,2.17 mmol) in DMF (6 ml) and stirring was continued at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solid, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing in a refrigerator at-30 ℃ for more than 2 hours, filtering, washing with cold methanol, and drying to obtain white solid 368.7mg with a yield of 76.25%.
2) 10ml of dry brown round bottom flask was taken, and (Z) -1-acetyl-3- ((5-isopropyl-1- (3-bromo) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.34 mmol), 3-p-fluorobenzoyl benzaldehyde (92.25 mg,0.40 mmol), cesium carbonate (164.64 mg,0.50 mmol), anhydrous sodium sulfate (95.69 mg,0.67 mmol), DMF (3.5 ml) was added sequentially, and the mixture was placed in 45℃oil bath under stirring for 24h under the protection of nitrogen and then vented. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered, concentrated under reduced pressure and dried. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 121.1mg with a yield of 58.61%.
1 H NMR(500MHz,DMSO-d 6 )δ11.99(s,1H),10.41(s,1H),8.09(s,1H),7.94–7.88(m,2H),7.83(s, 1H),7.76(d,J＝7.45Hz,1H),7.64(d,J＝7.55Hz,1H),7.58(t,J＝7.53Hz,1H),7.51(d,J＝7.93Hz,1H), 7.44–7.30(m,4H),7.10(d,J＝7.70Hz,1H),6.82(s,1H),6.67(s,1H),5.37(s,2H),3.11(dt,J＝6.86,13.98 Hz,1H),1.13(d,J＝6.87Hz,6H).MS(ESI):m/z 614.63[M+H] + .Mp:174-176℃.
EXAMPLE 27 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-o-bromobenzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-27)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), potassium carbonate (450.16 mg,3.26 mmol), 2-bromobenzyl bromide (254.75 mg,2.17 mmol) in DMF (6 ml) and stirring was continued at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing in a refrigerator at-30 ℃ for more than 2 hours, filtering, washing with cold methanol, and drying to obtain 391.1mg of brown yellow solid with the yield of 80.88%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (2-bromo) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.34 mmol), 3-p-fluorobenzoyl benzaldehyde (92.25 mg,0.40 mmol), cesium carbonate (164.64 mg,0.50 mmol), anhydrous sodium sulfate (95.69 mg,0.67 mmol), DMF (3.5 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 18h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered, concentrated under reduced pressure and dried. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 165.0mg with yield of 79.86%.
1 H NMR(500MHz,DMSO-d 6 )δ11.99(s,1H),10.42(s,1H),8.00(s,1H),7.95–7.89(m,2H),7.83(s, 1H),7.76(d,J＝7.55Hz,1H),7.71(d,J＝7.93Hz,1H),7.64(d,J＝7.61Hz,1H),7.59(t,J＝7.62Hz,1H), 7.40(dd,J＝8.14,16.45Hz,3H),7.29(t,J＝7.56Hz,1H),6.83(s,1H),6.71(s,1H),6.63(d,J＝7.68Hz, 1H),5.37(s,2H),3.01(dt,J＝6.98,14.10Hz,1H),1.18(d,J＝7.02Hz,6H).MS(ESI):m/z 614.60[M+ H] + .Mp:177-178℃.
EXAMPLE 28 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (2, 5-difluorobenzyl) imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-28)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), potassium carbonate (450.16 mg,3.26 mmol), 2, 5-difluorobenzyl bromide (449.56 mg,2.17 mmol) in DMF (6 ml) and the reaction stirred at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solid, filtering, washing a filter cake with water, vacuum drying at 50 ℃, pulping with methanol, standing in a refrigerator at-30 ℃ for more than 2 hours, filtering, washing with cold methanol, and drying to obtain off-white solid 107.0mg with a yield of 24.49%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (2, 5-difluorobenzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.37 mmol), 3-p-fluorobenzoyl benzaldehyde (102.08 mg,0.45 mmol), cesium carbonate (182.17 mg,0.56 mmol), anhydrous sodium sulfate (105.89 mg,0.75 mmol), DMF (4 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 14h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 79.1mg with a yield of 37.19%.
1 H NMR(600MHz,DMSO-d 6 )δ11.95(s,1H),10.38(s,1H),8.02(s,1H),7.91(dd,J＝5.60,8.53Hz, 2H),7.83(s,1H),7.76(d,J＝7.60Hz,1H),7.64(d,J＝7.66Hz,1H),7.59(t,J＝7.64Hz,1H),7.40(t,J＝ 8.74Hz,2H),7.34(td,J＝4.42,9.29Hz,1H),7.26(ddd,J＝3.35,8.13,11.87Hz,1H),6.91(ddd,J＝3.28, 5.59,8.62Hz,1H),6.82(s,1H),6.68(s,1H),5.39(s,2H),3.20-3.09(m,1H),1.18(d,J＝7.08Hz,6H).MS (ESI):m/z 571.20[M+H] + .Mp:193-195℃.
Example 29 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (2, 6-difluorobenzyl) imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-29)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.72 mmol), potassium carbonate (300.20 mg,2.17 mmol) and DMF (6 ml) of 2, 6-difluorobenzyl bromide (299.8mg,1.45 mmol) was added dropwise and the reaction was stirred at 45℃for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing in a refrigerator at-30 ℃ for more than 2 hours, filtering, washing with cold methanol, and drying to obtain white solid 174.76mg with a yield of 59.99%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (2, 6-difluorobenzylimidazol-4-yl) methylene) piperazine-2, 5-dione (174.76 mg,0.43 mmol), 3-fluorobenzoyl benzaldehyde (118.95 mg,0.52 mmol), cesium carbonate (212.27 mg,0.65 mmol), anhydrous sodium sulfate (123.39 mg,0.87 mmol), DMF (4 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 20h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 191.6mg with yield 64.43%.
1 H NMR(600MHz,DMSO-d 6 )δ11.92(s,1H),10.36(s,1H),7.94–7.88(m,3H),7.81(s,1H),7.75(d, J＝7.73Hz,1H),7.63(d,J＝7.70Hz,1H),7.58(t,J＝7.66Hz,1H),7.54–7.47(m,1H),7.39(t,J＝8.78Hz, 2H),7.18(t,J＝8.23Hz,2H),6.81(s,1H),6.66(s,1H),5.39(s,2H),3.20(dt,J＝7.42,14.87Hz,1H),1.17 (d,J＝7.08Hz,6H).MS(ESI):m/z 571.31[M+H] + .Mp:226-228℃.
Example 30 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (2, 4-difluorobenzyl) imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-30)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.72 mmol), potassium carbonate (300.2 mg,2.17 mmol), anhydrous sodium sulfate (205.7 mg,0.14 mmol) and DMF (6 ml) dropwise 2, 4-difluorobenzyl bromide (299.8 mg,1.45 mmol) and stirred at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solid, filtering, washing a filter cake with water, vacuum drying at 50 ℃, pulping with methanol, standing in a refrigerator at-30 ℃ for more than 2 hours, filtering, washing with cold methanol, and drying to obtain white solid 216.2mg with a yield of 74.22%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (2, 4-difluorobenzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.37 mmol), 3-p-fluorobenzoyl benzaldehyde (102.08 mg,0.45 mmol), cesium carbonate (182.17 mg,0.56 mmol), anhydrous sodium sulfate (105.89 mg,0.75 mmol), DMF (4 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 19h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 175.2mg with yield 82.37%.
1 H NMR(600MHz,DMSO-d 6 )δ11.96(s,1H),10.38(s,1H),8.00(s,1H),7.93-7.89(m,2H),7.82(s, 1H),7.76(d,J＝7.72Hz,1H),7.64(d,J＝7.71Hz,1H),7.59(t,J＝7.65Hz,1H),7.43-7.37(m,2H),7.33 (dd,J＝5.69,15.04Hz,1H),7.12(dd,J＝4.24,10.64Hz,2H),6.82(s,1H),6.69(s,1H),5.37(s,2H),3.21- 3.10(m,1H),1.17(d,J＝7.13Hz,6H).MS(ESI):m/z 571.04[M+H] + .Mp:184-188℃.
Example 31 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (3, 4-difluorobenzyl) imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-31)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.72 mmol), potassium carbonate (300.2 mg,2.17 mmol), anhydrous sodium sulfate (205.7 mg,0.14 mmol) and DMF (5 ml) dropwise 3, 4-difluorobenzyl bromide (299.8 mg,1.45 mmol) and stirred at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing in a refrigerator at-30 ℃ for more than 2 hours, filtering, washing with cold methanol, and drying to obtain white solid 216.9mg with a yield of 74.46%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (3, 4-difluorobenzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.37 mmol), 3-p-fluorobenzoyl benzaldehyde (102.08 mg,0.45 mmol), cesium carbonate (182.17 mg,0.56 mmol), anhydrous sodium sulfate (105.89 mg,0.75 mmol), DMF (4 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 19h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 166.1mg with yield 78.09%.
1 H NMR(600MHz,DMSO-d 6 )δ11.98(s,1H),10.38(s,1H),8.07(s,1H),7.94-7.89(m,2H),7.83(s, 1H),7.76(d,J＝7.71Hz,1H),7.64(d,J＝7.71Hz,1H),7.59(t,J＝7.65Hz,1H),7.45(dt,J＝8.52,10.55 Hz,1H),7.42-7.37(m,2H),7.31(ddd,J＝1.90,7.69,10.12Hz,1H),6.97(d,J＝8.37Hz,1H),6.82(s,1H), 6.68(s,1H),5.34(s,2H),3.20-3.04(m,1H),1.14(d,J＝7.12Hz,6H).MS(ESI):m/z 571.03[M+H] + .Mp: 202-204℃.
Example 32 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (3, 5-difluorobenzyl) imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-32)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.72 mmol), potassium carbonate (300.2 mg,2.17 mmol), anhydrous sodium sulfate (205.7 mg,0.15 mmol) and DMF (5 ml) dropwise 3, 5-difluorobenzyl bromide (299.8 mg,1.45 mmol) and stirred at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing for more than 2 hours in a refrigerator at-30 ℃, filtering, washing with cold methanol, and drying to obtain 136.9mg of off-white solid with the yield of 47.0%.
2) 10ml of dry brown round bottom flask was taken, and (Z) -1-acetyl-3- ((5-isopropyl-1- (3, 5-difluorobenzylimidazol-4-yl) methylene) piperazine-2, 5-dione (100 mg,0.25 mmol), 3-p-fluorobenzoyl benzaldehyde (68.06 mg,0.30 mmol), cesium carbonate (121.47 mg,0.37 mmol), anhydrous sodium sulfate (70.60 mg,0.50 mmol), DMF (4 ml) was added in sequence, and the mixture was placed in an oil bath at 45℃under stirring for 13h under the protection of nitrogen and then vented. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 107.3 mg with a yield of 50.44%.
1 H NMR(600MHz,DMSO-d 6 )δ11.97(s,1H),10.39(s,1H),8.08(s,1H),7.95-7.88(m,2H),7.83(s, 1H),7.76(d,J＝7.72Hz,1H),7.64(d,J＝7.71Hz,1H),7.59(t,J＝7.65Hz,1H),7.40(t,J＝8.79Hz,2H), 7.21(ddd,J＝2.17,5.74,9.29Hz,1H),6.88(d,J＝6.22Hz,2H),6.83(s,1H),6.68(s,1H),5.38(s,2H),3.12 (dt,J＝7.10,14.25Hz,1H),1.15(d,J＝7.12Hz,6H).MS(ESI):m/z 571.01[M+H] + .Mp:237-239℃.
Example 33 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (3, 4-dichlorobenzyl) imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-33)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.72 mmol), potassium carbonate (300.2 mg,2.17 mmol), anhydrous sodium sulfate (205.7 mg,0.14 mmol) and DMF (5 ml) dropwise 3, 4-dichlorobenzyl bromide (347.40 mg,1.45 mmol) was stirred at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, re-dissolving methanol and methylene dichloride, concentrating under reduced pressure, drying, pulping with methanol by ultrasonic waves, standing in a refrigerator at-30 ℃, filtering, washing the filter cake with cold methanol, and drying in vacuum at 50 ℃ to obtain 190.2mg of white solids with the yield of 60.36%.
2) A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (3, 4-dichlorobenzylimidazol-4-yl) methylene) piperazine-2, 5-dione (130 mg,0.30 mmol), 3-p-fluorobenzoyl benzaldehyde (81.79 mg,0.36 mmol), cesium carbonate (145.97 mg,0.45 mmol), anhydrous sodium sulfate (84.84 mg,0.60 mmol), DMF (4 ml), vented, nitrogen protected, placed in a 45℃oil bath and stirred for 14h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol by ultrasonic, standing in a refrigerator at-30deg.C, filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 151.4 mg with a yield of 84.02%.
1 H NMR(600MHz,DMSO-d 6 )δ11.97(s,1H),10.38(s,1H),8.08(s,1H),7.93-7.89(m,2H),7.82(s, 1H),7.75(d,J＝7.73Hz,1H),7.64(dd,J＝5.23,8.00Hz,2H),7.58(t,J＝7.66Hz,1H),7.47(d,J＝1.94 Hz,1H),7.42-7.37(m,2H),7.07(dd,J＝1.95,8.37Hz,1H),6.82(s,1H),6.67(s,1H),5.36(s,2H),3.11 (1H),1.14(d,J＝7.09Hz,6H).MS(ESI):m/z 603.05[M+H] + .Mp:205-207℃.
Example 34 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (2, 6-dichlorobenzyl) imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-34)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.72 mmol), potassium carbonate (300.2 mg,2.17 mmol), anhydrous sodium sulfate (205.7 mg,0.14 mmol) and DMF (5 ml) dropwise 2, 6-dichlorobenzyl bromide (347.40 mg,1.45 mmol) was stirred at 45℃for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, re-dissolving methanol and dichloromethane, concentrating under reduced pressure, drying, pulping with methanol by ultrasonic waves, standing in a refrigerator at-30 ℃, filtering, washing the filter cake with cold methanol, and drying in vacuum at 50 ℃ to obtain 208.5mg of white solid with the yield of 66.17%.
2) A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (2, 6-dichlorobenzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.34 mmol), 3-p-fluorobenzoyl benzaldehyde (94.37 mg,0.41 mmol), cesium carbonate (168.42 mg,0.52 mmol), anhydrous sodium sulfate (97.89 mg,0.69 mmol), DMF (4 ml), vented, nitrogen protected, placed in a 45℃oil bath and stirred for 12h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 173.0 mg with yield of 83.19%.
1 H NMR(600MHz,DMSO-d 6 )δ11.89(s,1H),10.37(s,1H),7.94–7.89(m,2H),7.82(s,1H),7.75(d, J＝7.72Hz,1H),7.63(t,J＝8.17Hz,3H),7.58(t,J＝7.65Hz,1H),7.52(dd,J＝7.72,8.54Hz,1H),7.40 (dd,J＝4.96,11.87Hz,3H),6.80(s,1H),6.70(s,1H),5.43(s,2H),3.39–3.33(m,1H),1.32(d,J＝7.11Hz, 6H).MS(ESI):m/z 603.04[M+H] + .Mp:218-221℃.
Example 35 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-p-trifluoromethylbenzyl imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-35)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), potassium carbonate (450.16 mg,3.26 mmol), 4-trifluoromethyl benzyl bromide (519.08mg,2.17 mmol) in DMF (6 ml) and stirring was continued at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing in a refrigerator at-30 ℃ for more than 2 hours, filtering, washing with cold methanol, and drying to obtain white solid 300.7mg with a yield of 63.75%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (4-trifluoromethyl) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.34 mmol), 3-p-fluorobenzoyl benzaldehyde (94.55 mg,0.41 mmol), potassium carbonate (71.57 mg,0.52 mmol), anhydrous sodium sulfate (98.09 mg,0.69 mmol), DMF (3 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 20h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 170.6mg with a yield of 81.99%.
1 H NMR(500MHz,DMSO-d 6 )δ11.99(s,1H),10.38(s,1H),8.10(s,1H),7.94–7.88(m,2H),7.83(s, 1H),7.76(d,J＝7.72Hz,3H),7.64(d,J＝7.59Hz,1H),7.59(t,J＝7.57Hz,1H),7.40(t,J＝8.44Hz,2H), 7.32(d,J＝7.85Hz,2H),6.83(s,1H),6.69(s,1H),5.48(s,2H),3.09(dt,J＝7.05,14.09Hz,1H),1.13(d,J ＝6.95Hz,6H).MS(ESI):m/z 603.44[M+H] + .Mp:216-218℃.
Example 36 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-m-trifluoromethylbenzyl imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-36)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), potassium carbonate (450.16 mg,3.26 mmol) and DMF (6 ml) of 3-trifluoromethyl benzyl bromide (519.08mg,2.17 mmol) was stirred at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing in a refrigerator at-30 ℃ for more than 2 hours, filtering, washing with cold methanol, and drying to obtain white solid 355.9mg with a yield of 75.45%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (3-trifluoromethyl) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.34 mmol), 3-p-fluorobenzoyl benzaldehyde (94.55 mg,0.41 mmol), potassium carbonate (71.57 mg,0.52 mmol), anhydrous sodium sulfate (98.09 mg,0.69 mmol), DMF (3 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 19h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 137.2mg with yield of 65.94%.
1 H NMR(500MHz,DMSO-d 6 )δ11.98(s,1H),10.38(s,1H),8.11(s,1H),7.94–7.88(m,2H),7.83(s, 1H),7.76(d,J＝7.52Hz,1H),7.69(d,J＝7.73Hz,1H),7.61(dt,J＝7.57,19.56Hz,3H),7.54(s,1H),7.40 (t,J＝8.54Hz,3H),6.82(s,1H),6.68(s,1H),5.47(s,2H),3.13(dt,J＝6.97,14.04Hz,1H),1.12(d,J＝6.99 Hz,6H).MS(ESI):m/z 603.00[M+H] + .Mp:203-206℃.
Example 37 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-o-trifluoromethylbenzyl imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-37)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.72 mmol), potassium carbonate (300.13 mg,2.17 mmol), DMF (4 ml) was added with stirring at room temperature 2-trifluoromethyl benzyl bromide (346.04 mg,1.45 mmol) and the reaction was continued with stirring at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing for more than 2 hours in a refrigerator at-30 ℃, filtering, washing with cold methanol, and drying to obtain white solid 215.3mg with a yield of 68.46%.
2) 10ml of dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (2-trifluoromethyl) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (120 mg,0.28 mmol), 3-fluorobenzoyl benzaldehyde (75.04 mg,0.33 mmol), potassium carbonate (57.26 mg,0.41 mmol), anhydrous sodium sulfate (78.47 mg,0.55 mmol), DMF (3 ml), vented, nitrogen protected, placed in 45℃oil bath and stirred for 19h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 85.3mg with a yield of 51.25%.
1 H NMR(500MHz,DMSO-d 6 )δ11.99(s,1H),10.40(s,1H),8.05(s,1H),7.95–7.89(m,2H),7.83(s, 2H),7.76(d,J＝7.50Hz,1H),7.66(dd,J＝7.82,16.13Hz,2H),7.57(dt,J＝7.52,20.10Hz,2H),7.40(t,J ＝8.51Hz,2H),6.83(s,1H),6.72(s,1H),6.63(d,J＝7.83Hz,1H),5.53(s,2H),2.92(dt,J＝6.91,14.13Hz, 1H),1.16(d,J＝6.98Hz,6H).MS(ESI):m/z 603.23[M+H] + .Mp:227-229℃.
Example 38 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-p-trifluoromethoxybenzimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-38)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), potassium carbonate (450.16 mg,3.26 mmol), 4-trifluoromethoxybenzyl bromide (553.82mg,2.17 mmol) in DMF (6 ml) and stirring was continued at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing in a refrigerator at-30 ℃ for more than 2 hours, filtering, washing with cold methanol, and drying to obtain white solid 286.2mg with a yield of 58.52%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (4-trifluoromethoxybenzylimidazole-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.33 mmol), 3-p-fluorobenzoyl benzaldehyde (91.20 mg,0.40 mmol), potassium carbonate (69.03 mg,0.50 mmol), anhydrous sodium sulfate (94.61 mg,0.67 mmol), DMF (3 ml), vented, nitrogen protected, placed in 45℃oil bath and stirred for 15h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 103.0mg with a yield of 50.00%.
1 H NMR(500MHz,DMSO-d 6 )δ12.00(s,1H),10.41(s,1H),8.09(s,1H),7.95–7.88(m,2H),7.83(s, 1H),7.76(d,J＝7.57Hz,1H),7.64(d,J＝7.60Hz,1H),7.58(t,J＝7.62Hz,1H),7.43–7.37(m,4H),7.26 (d,J＝8.31Hz,2H),6.82(s,1H),6.67(s,1H),5.40(s,2H),3.11(dt,J＝7.00,14.18Hz,1H),1.12(d,J＝ 7.03Hz,6H).MS(ESI):m/z 619.13[M+H] + .Mp:198-200℃.
Example 39 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-o-trifluoromethoxybenzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-39)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), potassium carbonate (450.16 mg,3.26 mmol), 4-trifluoromethoxybenzyl bromide (553.82mg,2.17 mmol) in DMF (6 ml) and stirring was continued at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing for more than 2 hours in a refrigerator at-30 ℃, filtering, washing with cold methanol, and drying to obtain 204.8mg of white solid with the yield of 41.88%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (3-trifluoromethoxybenzylimidazole-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.33 mmol), 3-p-fluorobenzoyl benzaldehyde (91.20 mg,0.40 mmol), potassium carbonate (69.03 mg,0.50 mmol), anhydrous sodium sulfate (94.61 mg,0.67 mmol), DMF (3 ml), vented, nitrogen protected, placed in 45℃oil bath and stirred for 17h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 156.7mg with a yield of 76.07%.
1 H NMR(500MHz,DMSO-d 6 )δ11.99(s,1H),10.42(s,1H),8.11(s,1H),7.95–7.89(m,2H),7.83(s, 1H),7.76(d,J＝7.56Hz,1H),7.64(d,J＝7.67Hz,1H),7.58(t,J＝7.62Hz,1H),7.52(t,J＝8.16Hz,1H), 7.40(t,J＝8.71Hz,2H),7.32(d,J＝8.19Hz,1H),7.15(d,J＝5.82Hz,2H),6.82(s,1H),6.67(s,1H),5.42 (s,2H),3.12(dt,J＝6.99,14.12Hz,1H),1.11(d,J＝7.05Hz,6H).MS(ESI):m/z 619.49[M+H] + .Mp: 208-210℃.
Example 40 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-p-cyanobenzimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-40)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), potassium carbonate (450.16 mg,3.26 mmol), 4-cyanobenzyl bromide (425.72 mg,2.17 mmol) in DMF (6 ml) and stirring was continued at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing in a refrigerator at-30 ℃ for more than 2 hours, filtering, washing with cold methanol, and drying to obtain white solid 351.4mg with a yield of 82.68%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (4-cyano) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.38 mmol), 3-fluorobenzoyl benzaldehyde (104.96 mg,0.46 mmol), cesium carbonate (187.28 mg,0.57 mmol), anhydrous sodium sulfate (108.86 mg,0.77 mmol), DMF (3.5 ml), vented, nitrogen protected, placed in a 45℃oil bath and stirred for 20h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered, concentrated under reduced pressure and dried. Pulping with methanol under ultrasonic wave, standing in a refrigerator at-30deg.C, filtering, and washing filter cake with cold methanol. Chromatography, reduced pressure concentration, drying, ultrasonic pulping with methanol, standing in a refrigerator at-30deg.C, suction filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 89.5 mg with yield of 41.74%.
1 H NMR(500MHz,DMSO-d 6 )δ11.98(s,1H),10.42(s,1H),8.10(s,1H),7.94–7.81(m,5H),7.76(d, J＝7.43Hz,1H),7.64(d,J＝7.51Hz,1H),7.59(t,J＝7.58Hz,1H),7.40(t,J＝8.49Hz,2H),7.29(d,J＝ 7.90Hz,2H),6.83(s,1H),6.68(s,1H),5.48(s,2H),3.06(dt,J＝6.96,14.05Hz,1H),1.12(d,J＝6.94Hz, 6H).MS(ESI):m/z 560.28[M+H] + .Mp:162-164℃.
Example 41 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-m-cyanobenzimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-41)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), potassium carbonate (450.16 mg,3.26 mmol), 3-cyanobenzyl bromide (425.72 mg,2.17 mmol) in DMF (6 ml) and stirring was continued at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solid, filtering, washing a filter cake with water, vacuum drying at 50 ℃, pulping with methanol, standing in a refrigerator at-30 ℃ for more than 2 hours, filtering, washing with cold methanol, and drying to obtain off-white solid 294.1mg with a yield of 69.20%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (3-cyano) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.38 mmol), 3-p-fluorobenzoyl benzaldehyde (104.96 mg,0.46 mmol), potassium carbonate (79.44 mg,0.57 mmol), anhydrous sodium sulfate (108.86 mg,0.77 mmol), DMF (3.5 ml), vented, nitrogen protected, placed in a 45℃oil bath and stirred for 20h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered, concentrated under reduced pressure and dried. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 178.6mg with yield 83.29%.
1 H NMR(500MHz,DMSO-d 6 )δ11.99(s,1H),10.41(s,1H),8.10(s,1H),7.93–7.88(m,2H),7.85–7.78 (m,2H),7.75(d,J＝7.49Hz,1H),7.68(s,1H),7.61(dt,J＝7.62,23.34Hz,3H),7.46–7.37(m,3H),6.82(s, 1H),6.67(s,1H),5.42(s,2H),3.11(dt,J＝7.03,14.16Hz,1H),1.12(d,J＝7.00Hz,6H).MS(ESI):m/z 560.25[M+H] + .Mp:209-212℃.
Example 42 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (3, 5-dimethylbenzyl) imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-42)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.72 mmol), potassium carbonate (300.2 mg,2.17 mmol), anhydrous sodium sulfate (205.7 mg,0.14 mmol) and 3, 5-dimethylbenzyl bromide (288.28 mg,1.45 mmol) in DMF (5 ml) was added dropwise and the reaction stirred at 45℃for 2H. Dropping the reaction solution into cold water at 4 deg.c to separate out solid, suction filtering, water washing the filter cake, re-dissolving methanol and dichloromethane to obtain oily coarse product 158.59mg with 55.64% yield
2) A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (3, 5-dimethylbenzylimidazole-4-yl) methylene) piperazine-2, 5-dione (158.59 mg,0.70 mmol), 3-p-fluorobenzoyl benzaldehyde (228.44 mg,0.58 mmol), cesium carbonate (283.04 mg,0.87 mmol), anhydrous sodium sulfate (164.52 mg,1.16 mmol), DMF (4 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 16h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (50 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 110.5mg with yield of 28.26%.
1 H NMR(600MHz,DMSO-d 6 )δ12.01(s,1H),10.36(s,1H),8.03(s,1H),7.94-7.88(m,2H),7.82(s, 1H),7.76(d,J＝7.65Hz,1H),7.63(d,J＝7.69Hz,1H),7.58(t,J＝7.65Hz,1H),7.40(t,J＝8.77Hz,2H), 6.92(s,1H),6.81(s,1H),6.72(s,2H),6.68(s,1H),5.25(s,2H),3.10(tt,J＝7.18,14.58Hz,1H),2.23(s, 6H),1.14(d,J＝7.11Hz,6H).MS(ESI):m/z 563.64[M+H] + .Mp:167-170℃.
Example 43 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (3, 5-bistrifluoromethylbenzyl) imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-43)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.72 mmol), potassium carbonate (300.2 mg,2.17 mmol), anhydrous sodium sulfate (205.7 mg,0.14 mmol) and 3, 5-bistrifluoromethylbenzyl bromide (444.6 mg,1.45 mmol) in turn in DMF (5 ml) and stirred at 45℃for 2H. Dropping the reaction solution into cold water at 4deg.C to precipitate solid, suction filtering, washing the filter cake with water, re-dissolving methanol and dichloromethane, concentrating under reduced pressure, drying, ultrasonic pulping with methanol, standing in a refrigerator at-30deg.C, suction filtering, washing the filter cake with cold methanol, vacuum drying at 50deg.C to obtain off-white solid 137.2mg with yield 37.72%
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (3, 5-bistrifluoromethylbenzyl imidazol-4-yl) methylene) piperazine-2, 5-dione (100 mg,0.20 mmol), 3-p-fluorobenzoyl benzaldehyde (54.50 mg,0.24 mmol), cesium carbonate (97.29 mg,0.30 mmol), anhydrous sodium sulfate (56.54 mg,0.40 mmol), DMF (4 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 13h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 70.6mg with yield 52.90%.
1 H NMR(600MHz,DMSO-d 6 )δ11.94(s,1H),10.39(s,1H),8.14(s,1H),8.10(s,1H),7.93-7.89(m, 2H),7.85(s,2H),7.82(s,1H),7.76(d,J＝7.72Hz,1H),7.64(d,J＝7.72Hz,1H),7.58(t,J＝7.66Hz,1H), 7.43-7.37(m,2H),6.82(s,1H),6.67(s,1H),5.57(s,2H),3.20-3.11(m,1H),1.12(d,J＝7.10Hz,6H).MS (ESI):m/z 671.51[M+H] + .Mp:234-236℃.
Example 44 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (3, 5-dimethoxybenzyl) imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-44)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), potassium carbonate (450.45 mg,3.26 mmol), anhydrous sodium sulfate (308.55 mg,2.17 mmol), DMF (5 ml) dropwise 3, 5-dimethoxybenzyl bromide (501.9 mg,2.17 mmol) and stirred at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, re-dissolving methanol and methylene dichloride, concentrating under reduced pressure, drying, pulping with methanol by ultrasonic waves, standing in a refrigerator at-30 ℃, filtering, washing a filter cake with cold methanol, and drying in vacuum at 50 ℃ to obtain 77.2mg of white solid with the yield of 16.67%.
2) A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (3, 5-dimethoxybenzylimidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.47 mmol), 3-fluorobenzoyl benzaldehyde (128.42 mg,0.56 mmol), cesium carbonate (229.18 mg,0.70 mmol), anhydrous sodium sulfate (133.22 mg,0.94 mmol), DMF (5 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 17h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (50 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 117.80mg with yield of 42.24%.
1 H NMR(600MHz,DMSO-d 6 )δ12.00(s,1H),10.37(s,1H),8.05(s,1H),7.91(dd,J＝5.59,8.55Hz, 2H),7.82(s,1H),7.75(d,J＝7.66Hz,1H),7.64(d,J＝7.67Hz,1H),7.59(t,J＝7.65Hz,1H),7.40(t,J＝8.75Hz,2H),6.82(s,1H),6.69(s,1H),6.44(s,1H),6.27(d,J＝1.82Hz,2H),5.25(s,2H),3.70(s,6H), 3.15(dt,J＝7.06,14.19Hz,1H),1.17(d,J＝7.10Hz,6H).MS(ESI):m/z 595.46[M+H] + .Mp:201-203 ℃.
Example 45 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-p-phenylbenzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-45)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), potassium carbonate (450.16 mg,3.26 mmol), anhydrous sodium sulfate (308.6 mg,2.17 mmol), 4-bromomethylbiphenyl (536.85 mg,2.17 mmol) DMF (6 ml) and stirred at 45℃for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing in a refrigerator at-30 ℃ for more than 2 hours, filtering, washing with cold methanol, and drying to obtain white solid 367.1mg with a yield of 76.40%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (4-phenylbenzylimidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.34 mmol), 3-p-fluorobenzoyl benzaldehyde (92.84 mg,0.41 mmol), cesium carbonate (165.68 mg,0.51 mmol), anhydrous sodium sulfate (96.29 mg,0.68 mmol), DMF (4 ml), vented, nitrogen blanket, placed in a 45℃oil bath and stirred for 15h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 146.6 mg with yield of 70.81%.
1 H NMR(500MHz,DMSO-d 6 )δ12.03(s,1H),10.41(s,1H),8.11(s,1H),7.95-7.88(m,2H),7.83(s, 1H),7.76(d,J＝7.46Hz,1H),7.63(ddd,J＝7.80,15.24,29.98Hz,6H),7.49-7.32(m,5H),7.22(d,J＝7.85 Hz,2H),6.82(s,1H),6.69(s,1H),5.39(s,2H),3.17(dt,J＝6.95,13.99Hz,1H),1.15(d,J＝6.95Hz,6H). MS(ESI):m/z 611.14[M+H] + .Mp:160-163℃.
Example 46 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (2-naphthylmethyl) imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-46)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), potassium carbonate (450.16 mg,3.26 mmol), anhydrous sodium sulfate (308.6 mg,2.17 mmol), 2-bromomethylnaphthalene (480.15 mg,2.17 mmol) DMF (6 ml) and stirred at 45℃for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solid, filtering, washing a filter cake with water, vacuum drying at 50 ℃, pulping with methanol, standing in a refrigerator at-30 ℃ for more than 2 hours, filtering, washing with cold methanol, and drying to obtain 236.3mg of off-white solid with a yield of 52.25%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (2-naphthylmethylimidazole-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.36 mmol), 3-fluorobenzoyl benzaldehyde (98.64 mg,0.43 mmol), cesium carbonate (176.01 mg,0.54 mmol), anhydrous sodium sulfate (102.31 mg,0.72 mmol), DMF (4 ml), vented, nitrogen blanket, placed in 45℃oil bath and stirred for 21h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and was suction-filtered, the cake was washed with cold water, and the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 136.9 mg with yield of 65.01%.
1 H NMR(500MHz,DMSO-d 6 )δ12.05(s,1H),10.41(s,1H),8.15(s,1H),7.91(td,J＝6.95,12.58Hz, 5H),7.84(s,1H),7.76(d,J＝7.56Hz,1H),7.66–7.56(m,3H),7.53–7.48(m,2H),7.40(t,J＝8.70Hz,2H), 7.31(d,J＝8.50Hz,1H),6.83(s,1H),6.69(s,1H),5.52(s,2H),3.17(dt,J＝7.03,14.20Hz,1H),1.10(d,J ＝7.04Hz,6H).MS(ESI):m/z 585.48[M+H] + .Mp:166-168℃.
Example 47 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-p-benzoylbenzyl imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-47)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.72 mmol), potassium carbonate (300.2 mg,2.17 mmol) and DMF (6 ml) of 4-benzoylbenzyl bromide (398.4mg,1.45 mmol) was added dropwise and the reaction stirred at room temperature for 2H. The reaction solution was dropped into cold water at 4℃to precipitate a solid, which was suction-filtered, and the cake was washed with water and dried under vacuum at 50℃to give 226.9mg of an off-white solid, with a yield of 66.61%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (4-benzoylbenzyl imidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.32 mmol), 3-p-fluorobenzoyl benzaldehyde (87.29 mg,0.38 mmol), potassium carbonate (66.09 mg,0.48 mmol), anhydrous sodium sulfate (90.56 mg,0.64 mmol), DMF (3 ml), vented, nitrogen protected, placed in 45℃oil bath and stirred for 30h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4℃and filtered, the cake was dissolved in a mixed solution of methanol and methylene chloride (1:3) by washing with cold water, filtered, concentrated under reduced pressure and dried. Pulping with methanol under ultrasonic wave, standing in a refrigerator at-30deg.C, filtering, and washing with cold filter cake with methanol. Chromatography, reduced pressure concentration, drying, meOH beating, methanol ultrasonic beating, standing in a refrigerator at-30 ℃, suction filtering, washing a filter cake with cold methanol, and vacuum drying at 50 ℃ to obtain 105.0mg of yellow solid with a yield of 51.57%.
1 H NMR(500MHz,DMSO-d 6 )δ12.01(s,1H),10.41(s,1H),8.12(s,1H),7.95–7.88(m,2H),7.83(s, 1H),7.75(d,J＝7.76Hz,3H),7.72–7.63(m,4H),7.57(dt,J＝7.51,14.83Hz,3H),7.40(t,J＝8.34Hz,2H), 7.29(d,J＝7.76Hz,2H),6.82(s,1H),6.69(s,1H),5.49(s,2H),3.12(dt,J＝6.92,13.98Hz,1H),1.15(d,J ＝6.96Hz,6H).MS(ESI):m/z 639.30[M+H] + .Mp:175-177℃.
EXAMPLE 48 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- (5-isopropyl-1- (4-nitro) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-48)
1) A25 ml dry round bottom flask was taken and was charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.72 mmol), potassium carbonate (300.13 mg,2.17 mmol), DMF (4 ml) and stirred at room temperature for 20min, then p-nitrobenzyl bromide (247.63 mg,1.45 mmol) was added and the reaction was continued with stirring at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing for more than 2 hours in a refrigerator at-30 ℃, filtering, washing with cold methanol, and drying to obtain 252mg of brown yellow solid with the yield of 95.00%.
2) A25 ml dry brown round bottom flask was taken, followed by (Z) -1-acetyl-3- ((5-isopropyl-1- (4-nitro) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.49 mmol), 3-p-fluorobenzoyl benzaldehyde (133.12 mg,0.58 mmol), DBN (90.55 mg,0.73 mmol), anhydrous sodium sulfate (138.09 mg,0.97 mmol), DMF (4 ml), venting, nitrogen protection, placed in 45℃oil bath and stirred for reaction for 12h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was dropped into cold water (40 ml) at 4 ℃, suction filtration was performed, the cake was washed with cold water (30 ml x 2), the cake was dissolved in a mixed solution of methanol and dichloromethane (1:3), filtration, concentration under reduced pressure, loading of C18, reverse column chromatography, gradient elution, concentration under reduced pressure, and yield of 62.3mg of pale yellow solid was obtained, with a yield of 22.11%.
1 H NMR(500MHz,DMSO-d 6 )δ11.98(s,1H),10.39(s,1H),8.18(d,J＝72.15Hz,3H),8.05–7.72(m, 4H),7.63(s,2H),7.38(s,4H),6.76(d,J＝68.46Hz,2H),5.54(s,2H),3.07(s,1H),1.14(s,6H).MS(ESI): m/z 580.32[M+H] + .Mp:152-154℃.
EXAMPLE 49 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- (5-isopropyl-1- (3-nitro) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-49)
1) A25 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (500 mg,1.81 mmol), potassium carbonate (750.26 mg,5.43 mmol) and DMF (10 ml) followed by stirring at room temperature for 10min, and then with m-nitrobenzyl bromide (781.88 mg,3.62 mmol) followed by stirring at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solid, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing for more than 2 hours in a refrigerator at-30 ℃, filtering, washing with cold methanol, and drying to obtain 608.1mg of white solid with the yield of 81.68%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (3-nitro) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (500 mg,1.22 mmol), 3-p-fluorobenzoyl benzaldehyde (332.84 mg,1.46 mmol), potassium carbonate (251.94 mg,1.82 mmol), anhydrous sodium sulfate (345.24 mg,2.43 mmol), DMF (5 ml), vented, nitrogen protected, placed in 45℃oil bath and stirred for 19h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was added dropwise to cold water (30 ml) at 4 ℃, suction filtration was performed, the cake was washed with cold water (20 ml×2), the cake was dissolved in a mixed solution of methanol and dichloromethane (1:3), filtration was performed, and concentration was performed under reduced pressure. Pulping methanol by ultrasonic, standing in a refrigerator at-30deg.C, suction filtering, washing filter cake with cold methanol, pulping again by ultrasonic with methanol and dichloromethane (10:1), standing in a refrigerator at-30deg.C, suction filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 482.3mg with yield of 68.47%.
1 H NMR(500MHz,DMSO-d 6 )δ11.93(s,1H),10.38(s,1H),8.18(dd,J＝1.42,8.15Hz,1H),8.12(s, 1H),8.04(s,1H),7.96–7.88(m,2H),7.82(s,1H),7.75(d,J＝7.65Hz,1H),7.69(t,J＝7.97Hz,1H),7.64 (d,J＝7.72Hz,1H),7.58(dd,J＝8.09,16.01Hz,2H),7.40(t,J＝8.82Hz,2H),6.82(s,1H),6.68(s,1H), 5.59–5.43(m,2H),3.13(dt,J＝7.10,14.24Hz,1H),1.29–0.95(m,6H).MS(ESI):m/z 580.21[M+H] + . Mp:250-252℃.
EXAMPLE 50 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- (5-isopropyl-1- (2-nitro) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-50)
1) A25 ml dry round bottom flask was taken and was charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.72 mmol), potassium carbonate (300.1 mg,2.17 mmol), DMF (4 ml) and stirred at room temperature for 10min, then 2-nitrobenzyl bromide (781.88 mg,3.62 mmol) was added and the reaction was continued with stirring at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing for more than 2 hours in a refrigerator at-30 ℃, filtering, washing with cold methanol, and drying to obtain 225.7mg of earthy yellow solid with a yield of 75.78%.
2) 10ml of dry brown round bottom flask was taken, and (Z) -1-acetyl-3- ((5-isopropyl-1- (2-nitro) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (100 mg,0.24 mmol), 3-p-fluorobenzoyl benzaldehyde (66.57 mg,0.29 mmol), potassium carbonate (50.42 mg,0.36 mmol), anhydrous sodium sulfate (69.05 mg,0.49 mmol), DMF (3 ml) was added in sequence, and the mixture was placed in an oil bath at 45℃under stirring for reaction for 12h under the protection of nitrogen and vented. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution is dripped into cold water (30 ml) at 4 ℃, suction filtration is carried out, a filter cake is washed with cold water (20 ml x 2), the filter cake is dissolved in a mixed solution of methanol and methylene dichloride (1:3), filtration, decompression concentration, drying, ultrasonic beating of methanol, standing in a refrigerator at-30 ℃, suction filtration, filter cake cold methanol washing and vacuum drying at 50 ℃ are carried out, thus obtaining 101.0mg of yellow solid with the yield of 71.68%.
1 H NMR(500MHz,DMSO-d 6 )δ11.98(s,1H),10.40(s,1H),8.20(dd,J＝0.84,8.13Hz,1H),7.99(d, J＝11.03Hz,1H),7.92(dd,J＝5.58,8.71Hz,2H),7.82(d,J＝13.60Hz,1H),7.75(dd,J＝7.34,14.25Hz, 2H),7.62(dt,J＝7.73,24.43Hz,3H),7.45–7.35(m,2H),6.83(s,1H),6.73(s,1H),6.60(t,J＝11.11Hz, 1H),5.74(s,2H),3.16–2.93(m,1H),1.36–1.02(m,6H).MS(ESI):m/z 580.18[M+H] + .Mp:176-179℃.
EXAMPLE 51 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- (5-isopropyl-1- (4-methoxyacyl) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-51)
1) A25 ml dry round bottom flask was taken and was charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (500 mg,1.81 mmol), potassium carbonate (750.27 mg,5.43 mmol), anhydrous sodium sulfate (514.07 mg,3.62 mmol), DMF (10 ml) and stirred at room temperature for 10min, and then methyl benzyl bromide (829.05 mg,3.62 mmol) was added and the reaction was continued with stirring at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solids, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing for more than 2 hours in a refrigerator at-30 ℃, filtering, washing with cold methanol, and drying to obtain white solid 653.8mg with a yield of 85.12%.
2) A10 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (4-methoxyacyl) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (500 mg,1.18 mmol), 3-fluorobenzoyl benzaldehyde (322.77 mg,1.41 mmol), cesium carbonate (575.98 mg,1.77 mmol), anhydrous sodium sulfate (334.80 mg,2.36 mmol), DMF (10 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 12h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was added dropwise to cold water (100 ml) at 4 ℃, suction-filtered, the cake was washed with cold water (100 ml. Times.3), and the cake was dissolved in a mixed solution of methanol and dichloromethane (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain 476.5mg yellow solid with a yield of 68.22%.
1 H NMR(500MHz,DMSO-d 6 )δ11.99(s,1H),10.37(s,1H),8.10(s,1H),7.97(d,J＝8.21Hz,2H), 7.91(dd,J＝5.62,8.55Hz,2H),7.82(s,1H),7.76(d,J＝7.64Hz,1H),7.64(d,J＝7.67Hz,1H),7.59(t,J ＝7.63Hz,1H),7.40(t,J＝8.75Hz,2H),7.25(d,J＝8.19Hz,1H),6.82(s,1H),6.68(s,1H),5.46(s,2H), 3.84(s,3H),3.07(dt,J＝7.14,14.27Hz,1H),1.11(d,J＝7.08Hz,6H).MS(ESI):m/z 593.19[M+H] + . Mp:202-204℃.
EXAMPLE 52 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- (5-isopropyl-1- (3-methoxyacyl) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-52)
1) A25 ml dry round bottom flask was taken and was charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (500 mg,1.81 mmol), potassium carbonate (750.27 mg,5.43 mmol), anhydrous sodium sulfate (514.07 mg,3.62 mmol), DMF (10 ml) and stirred at room temperature for 10min, and then methyl-m-formate benzyl bromide (829.05 mg,3.62 mmol) was added and the reaction was continued with stirring at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solid, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing for more than 2 hours in a refrigerator at-30 ℃, filtering, washing with cold methanol, and drying to obtain white solid 669.4mg with a yield of 87.15%.
2) A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (3-methoxyacyl) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (500 mg,1.18 mmol), 3-fluorobenzoyl benzaldehyde (322.77 mg,1.41 mmol), cesium carbonate (575.98 mg,1.77 mmol), anhydrous sodium sulfate (334.80 mg,2.36 mmol), DMF (10 ml), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for 17h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was added dropwise to cold water (100 ml) at 4 ℃, suction-filtered, the cake was washed with cold water (100 ml. Times.3), and the cake was dissolved in a mixed solution of methanol and dichloromethane (1:3), filtered and concentrated under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain 464.8mg yellow solid with a yield of 66.55%.
1 H NMR(500MHz,DMSO-d 6 )δ11.99(s,1H),10.37(s,1H),8.10(s,1H),7.95–7.88(m,3H),7.83(s, 1H),7.76(d,J＝9.23Hz,2H),7.64(d,J＝7.64Hz,1H),7.61–7.52(m,2H),7.40(t,J＝8.79Hz,3H),6.82 (s,1H),6.68(s,1H),5.45(s,2H),3.84(s,3H),3.12(dt,J＝7.04,14.18Hz,1H),1.12(d,J＝7.06Hz,6H). MS(ESI):m/z 593.19[M+H] + .Mp:219-220℃.
EXAMPLE 53 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- (5-isopropyl-1- (2-methoxyacyl) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-53)
1) A25 ml dry round bottom flask was taken and was charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), potassium carbonate (450.15 mg,3.26 mmol), anhydrous sodium sulfate (308.45 mg,2.17 mmol), DMF (8 ml) and stirred at room temperature for 10min, and then methyl benzyl orthoformate bromide (497.44 mg,2.17 mmol) was added and the reaction stirred at room temperature for 2H. Dropping the reaction solution into cold water at 4 ℃ to precipitate solid, filtering, washing a filter cake with water, drying in vacuum at 50 ℃ and pulping with methanol, standing for more than 2 hours in a refrigerator at-30 ℃, filtering, washing with cold methanol, and drying to obtain 365.10mg of white solid with the yield of 79.22%.
2) 10ml of dry brown round bottom flask was taken and added successively with (Z) -1-acetyl-3- ((5-isopropyl-1- (2-methoxyacyl) benzylimidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.47 mmol), 3-p-fluorobenzoyl benzaldehyde (129.10 mg,0.57 mmol), cesium carbonate (230.39 mg,0.71 mmol), anhydrous sodium sulfate (133.92 mg,0.94 mmol), DMF (4 ml), vented, nitrogen protection, placed in 45℃oil bath and stirred for 15h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction solution was added dropwise to cold water (40 ml) at 4 ℃, suction filtration was performed, the cake was washed with cold water (50 ml. Times.3), the cake was dissolved in a mixed solution of methanol and dichloromethane (1:3), filtration was performed, and concentration was performed under reduced pressure. Pulping with methanol under ultrasound, standing in a refrigerator at-30deg.C, vacuum filtering, washing filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 220.5mg with yield of 78.93%.
1 H NMR(500MHz,DMSO-d 6 )δ12.01(s,1H),10.38(s,1H),7.99(d,J＝6.53Hz,2H),7.92(dd,J＝ 5.76,8.27Hz,2H),7.83(s,1H),7.77(d,J＝7.42Hz,1H),7.64(d,J＝7.60Hz,1H),7.59(t,J＝7.64Hz,2H), 7.46(t,J＝7.57Hz,1H),7.41(t,J＝8.71Hz,2H),6.83(s,1H),6.73(s,1H),6.54(d,J＝7.83Hz,1H),5.69 (s,2H),3.89(s,3H),2.99(dt,J＝7.02,14.16Hz,1H),1.17(d,J＝7.05Hz,6H).MS(ESI):m/z 593.14[M +H] + .Mp:234-236℃.
Example 54 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-cyclohexylmethylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-54)
A50 ml dry round bottom flask was taken, and was charged with (Z) -1-acetyl-3- ((5-cyclopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.73mmol, cesium carbonate (471.65 mg,1.45 mmol), potassium iodide (120.17 mg,0.72 mmol), 4A molecular sieve (200 mg), bromomethylcyclohexane (192.28 mg,1.08 mmol) in DMF (4 ml), vented, nitrogen-protected, placed in an oil bath at 70℃with stirring for 24H, cooled to room temperature, 3-p-fluorobenzoyl benzaldehyde (132.17 mg, 0.58 mmol) in DMF (2 ml) was added, warmed to an oil bath at 45℃with stirring for 20H, LC-MS monitoring, dropping the reaction solution into cold water at 4℃with suction, washing the filter cake with cold water, dissolving methanol and methylene chloride (1:3), filtration, drying, chromatography (MeOH: DCM=1:40℃), separation, ultrasonic isolation (10:10), drying for 10 mg, drying for 42 mg, and yellow solid, and a proper amount of PE was obtained by vacuum filtration, which was concentrated to obtain yellow solid, which was dried and concentrated to obtain yellow solid.
1 H NMR(600MHz,DMSO-d 6 )δ12.02(s,1H),10.35(s,1H),7.91(dd,J＝5.58,8.61Hz,2H),7.84(s, 1H),7.82(d,J＝7.73Hz,1H),7.75(d,J＝7.66Hz,1H),7.63(d,J＝7.68Hz,1H),7.58(t,J＝7.64Hz,1H), 7.40(t,J＝8.77Hz,2H),6.80(s,1H),6.70(s,1H),3.85(d,J＝7.49Hz,2H),3.19(dq,J＝6.99,14.20Hz, 1H),1.71-1.56(m,4H),1.49(d,J＝11.69Hz,2H),1.31(d,J＝7.07Hz,6H),1.14(d,J＝9.39Hz,2H),0.96 (dd,J＝10.67,22.47Hz,2H).MS(ESI):m/z 541.23[M+H] + .Mp:163-165℃.
Example 55 preparation of (3Z, 6Z) -3- (-3- (4-fluorophenoxy) benzene) methylene) -6- ((5-isopropyl-1- (3-cyclohexylpropyl)) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-55)
1) 3-Cyclohexylpropyl 4-methylbenzenesulfonate
A50 ml dry round bottom flask was taken, 3-cyclohexylpropan-1-ol (2 g,14.06 mmol) was dissolved in 10ml anhydrous DCM at 0deg.C, triethylamine (7 g,70.30 mmol) was added, nitrogen-blanketed, p-toluenesulfonyl chloride (4 g,21.09 mmol) dissolved in 10ml anhydrous DCM was added dropwise, transferred to room temperature and the reaction stirred for 6h. The reaction was diluted with dichloromethane, washed with purified water (100 ml x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography, PE: ea=10:1, to give 3.9g of a white solid with a yield of 94.66%.
2) (Z) -1-acetyl-3- ((1- (3-cyclohexylpropyl) -5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
A50 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.08 mmol), 3-cyclohexylpropyl 4-methylbenzenesulfonate (639 mg,2.16 mmol), cesium carbonate (704 mg,2.16 mmol), potassium iodide (180 mg,1.08 mmol), 4A molecular sieve (500 mg), DMF (6 ml), nitrogen protection, placed in an oil bath at 70℃and stirred for 24H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure to obtain orange oily substance, re-dissolving with a mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:5), leaching a filter cake with the mixed solvent (vethanol: vdichloromethane=1:5), concentrating under reduced pressure to obtain 400mg of brown oily mixture, and directly carrying out the next step without purification.
3) (3Z, 6Z) -3- (-3- (4-fluorophenoxy) benzene) methylene) -6- ((5-isopropyl-1- (3-cyclohexylpropyl)) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of a dry reaction flask, (Z) -1-acetyl-3- ((1- (3-cyclohexylpropyl) -5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.75 mmol), 3- (4-fluorophenoxy) benzaldehyde (194 mg,0.90 mmol), cesium carbonate (366 mg,1.12 mmol), anhydrous sodium sulfate (213 mg,1.50 mmol), DMF (6 mL), nitrogen protection, light shielding, and stirring reaction at 45℃for 20H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:3), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:3), and concentrating under reduced pressure. Flash purification (methanol: 87%, water: 13%) afforded the product, which was concentrated under reduced pressure to give 88mg of a pale yellow solid in 14.42% yield.
1 H NMR(500MHz,dmso)δ12.00(s,1H),10.12(s,1H),7.88(s,1H),7.41(t,J＝7.9Hz,1H),7.26(d, J＝7.8Hz,1H),7.23(t,J＝8.7Hz,2H),7.17(s,1H),7.12(dd,J＝8.8,4.4Hz,2H),6.90(d,J＝8.0Hz,1H), 6.72(s,1H),6.70(s,1H),3.98(t,J＝7.0Hz,2H),3.28-3.11(m,1H),1.73-1.53(m,7H),1.32(d,J＝7.0Hz, 6H),1.22-1.08(m,6H),0.83(dd,J＝22.1,10.7Hz,2H).MS(ESI):m/z 557.20[M+H] + .Mp:189-191℃.
Example 56 preparation of (3Z, 6Z) -3- (3- (4-fluorophenoxy) benzene) methylene) -6- ((5-isopropyl-1- ((cyclohexylmethoxy) ethyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-56)
1) 2-cyclohexylmethoxy-1-ethanol
A50 ml dry round bottom flask was taken, followed by (bromomethyl) cyclohexane (2 g,11.30 mmol), 4mL of 25.5M NaOH, ethylene glycol (10 ml), venting, nitrogen protection, placed in an oil bath at 80℃and stirred for 16h. Cooled to room temperature, extracted with ethyl acetate (100 ml x 3), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography (PE: ea=5:1) to give 800mg of orange oily liquid in 44.94% yield.
2) 2- (Cyclohexylmethoxy) ethyl 4-methylbenzenesulfonate
A50 ml dry round bottom flask was taken, 2-cyclohexylmethoxy-1-ethanol (1 g,6.33 mmol) was dissolved in 10ml anhydrous DCM at 0deg.C, triethylamine (3.19 g,31.65 mmol) was added, vented, nitrogen-protected, p-toluenesulfonyl chloride (1.44 g,7.60 mmol) dissolved in 10ml anhydrous DCM was added dropwise, and the mixture was transferred to room temperature and stirred for 6h. Purified water (100 ml x 2), dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography, PE: ea=10:1, to give 1.38g of pale yellow oily liquid in 70.12% yield.
3) (Z) -1-acetyl-3- ((1- (2- (cyclohexylmethoxy) ethyl) -5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
A50 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.08 mmol), 2- (cyclohexylmethoxy) ethyl 4-methylbenzenesulfonate (675 mg,2.16 mmol), cesium carbonate (704 mg,2.16 mmol), potassium iodide (180 mg,1.08 mmol), 4A molecular sieve (500 mg), DMF (6 ml), nitrogen protection, and placed in an oil bath at 70℃and stirred for 24H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure with water to obtain orange oily substance, re-dissolving with a mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:5), leaching a filter cake with the mixed solvent (vethanol: vdichloromethane=1:5), concentrating under reduced pressure to obtain 400mg of brown oily mixture, and directly carrying out the next step without purification.
4) (3Z, 6Z) -3- (3- (4-fluorophenoxy) benzene) methylene) -6- ((5-isopropyl-1- ((cyclohexylmethoxy) ethyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of a dry reaction flask, (Z) -1-acetyl-3- ((5-isopropyl-1- (2-cyclohexylmethoxyethyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.72 mmol), 3- (4-fluorophenoxy) benzaldehyde (186 mg,0.86 mmol), cesium carbonate (351 mg,1.08 mmol), anhydrous sodium sulfate (204 mg,1.44 mmol), DMF (6 mL), nitrogen protection, light shielding, and stirring at 45℃for 20H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:3), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:3), and concentrating under reduced pressure. Pulping with methanol, standing at-20deg.C for 2 hr, filtering, and oven drying to obtain 84mg pale yellow solid with yield of 13.53%.
1 H NMR(500MHz,dmso)δ11.97(s,1H),10.13(s,1H),7.82(s,1H),7.48(d,J＝7.8Hz,1H),7.40(t, J＝7.9Hz,1H),7.28(d,J＝7.6Hz,1H),7.22(d,J＝7.9Hz,2H),7.15-7.07(m,2H),6.89(d,J＝8.1Hz,1H), 6.69(s,2H),4.18(t,J＝4.6Hz,2H),3.60(t,J＝4.6Hz,2H),3.28-3.22(m,1H),3.18(d,J＝6.3Hz,2H), 2.29(s,1H),1.62(t,J＝12.0Hz,4H),1.31(d,J＝7.0Hz,6H),1.22–1.04(m,4H),0.85(dd,J＝22.6,11.4 Hz,2H).MS(ESI):m/z 573.21[M+H] + .Mp:168-170℃.
Example 57 preparation of (3Z, 6Z) -3- (3- (4-fluorophenoxy) benzene) methylene) -6- ((5-isopropyl-1- (2-phenoxyethyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-57)
1. 2-phenoxyethyl-1-ol
A50 ml dry round bottom flask was taken and charged with bromobenzene (2 g,12.74 mmol), potassium carbonate (5.28 g,38.22 mmol), copper chloride (108 mg,0.64 mmol), ethylene glycol (16 ml), nitrogen blanket, placed in a 130℃oil bath and stirred for 12h. Cooled to room temperature, diluted hydrochloric acid adjusted to pH 3, extracted with ethyl acetate (100 ml x 2), combined with the organic phase, dried over anhydrous sodium sulphate, filtered, concentrated under reduced pressure, purified by column chromatography, PE: ea=5:1, giving 1.1g of pale yellow oily liquid with a yield of 62.50%.
2. 2-phenoxyethyl-4-methylbenzenesulfonate
A50 ml dry round bottom flask was taken, 2-phenoxyethyl-1-ol (1 g,7.25 mmol) was dissolved in 10ml anhydrous DCM, triethylamine (3.66 g,36.25 mmol) was added, nitrogen-protected, p-toluenesulfonyl chloride (2.48 g, 13.05 mmol) dissolved in 10ml anhydrous DCM was added dropwise, transferred to room temperature and the reaction stirred for 6h. Purified water (100 ml x 2) was washed, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography, PE: ea=4:1, to give 1.65g of a white solid with a yield of 77.94%.
3. (Z) -1-acetyl-3- ((5-isopropyl-1- (2-phenoxyethyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
A50 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.08 mmol), 2-phenoxyethyl-4-methylbenzenesulfonate (630 mg,2.16 mmol), cesium carbonate (704 mg,2.16 mmol), potassium iodide (180 mg,1.08 mmol), 4A molecular sieve (500 mg), DMF (6 ml), nitrogen protection, and placed in an oil bath at 70℃with stirring for 24H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure to obtain orange oily substance, re-dissolving with a mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:5), leaching a filter cake with the mixed solvent (vethanol: vdichloromethane=1:5), concentrating under reduced pressure to obtain 400mg of brown oily mixture, and directly carrying out the next step without purification.
2. (3Z, 6Z) -3- (3- (4-fluorophenoxy) benzene) methylene) -6- ((5-isopropyl-1- (2-phenoxyethyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of dry reaction flask, (Z) -1-acetyl-3- ((5-isopropyl-1- (2-phenoxyethyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.76 mmol), 3- (4-fluorophenoxy) benzaldehyde (164 mg,0.76 mmol), cesium carbonate (371 mg,1.14 mmol), anhydrous sodium sulfate (215 mg,1.52 mmol), DMF (6 mL), displacement nitrogen protection, light shielding, and stirring reaction at 45℃for 20H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:3), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:3), and concentrating under reduced pressure. Flash purification (methanol: 87%, water: 13%) afforded the product, which was concentrated under reduced pressure to give 168mg of a pale yellow solid in 40.10% yield.
1 H NMR(500MHz,DMSO-d6)δ11.97(s,1H),10.13(s,1H),7.96(s,1H),7.41(t,J＝7.8Hz,1H),7.28 (dd,J＝14.2,7.3Hz,3H),7.23(t,J＝8.6Hz,2H),7.17(s,1H),7.14-7.09(m,2H),7.00-6.85(m,4H),6.72 (s,2H),4.45(s,2H),4.24(s,2H),3.20-3.14(m,1H),1.35(d,J＝6.8Hz,2H).MS(ESI):m/z 553.02[M+ H] + .Mp:159-161℃.
Example 58 preparation of (3Z, 6Z) -3- (3- (4-fluorophenoxy) benzene) methylene) -6- ((5-isopropyl-1- (2- (p-tolyloxy) ethyl)) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-58)
1. 2- (p-tolyloxy) ethyl-1-ol
A50 ml dry round bottom flask was taken, followed by p-methyl bromobenzene (2 g,11.69 mmol), potassium carbonate (4.85 g,35.08 mmol), copper chloride (99 mg,0.58 mmol), ethylene glycol (16 ml), nitrogen blanket, placed in an oil bath at 130℃and stirred for 12h. Cooled to room temperature, diluted hydrochloric acid pH 3, extracted with ethyl acetate (100 ml x 2), the combined organic phases dried over anhydrous sodium sulphate, filtered, concentrated under reduced pressure, purified by column chromatography, PE: ea=1:1, to give 730mg of white solid with a yield of 41.10%.
2. 2- (p-tolyloxy) ethyl-4-methylbenzenesulfonate
A50 ml dry round bottom flask was taken, 2- (p-tolyloxy) ethyl-1-ol (1 g,6.58 mmol) was dissolved in 10ml anhydrous DCM, triethylamine (3.32 g,32.90 mmol) was added, nitrogen protected, p-toluenesulfonyl chloride (2.25 g,11.84 mmol) dissolved in 10ml anhydrous DCM was added dropwise, transferred to room temperature and stirred for 6h. Purified water (100 ml x 2) was washed, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography, PE: ea=4:1, to give 1.65g of a white solid with a yield of 81.96%.
3. (Z) -1-acetyl-3- ((5-isopropyl-1- (2- (p-tolyloxy) ethyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
A50 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.08 mmol), 2- (p-tolyloxy) ethyl-4-methylbenzenesulfonate (660 mg,2.16 mmol), cesium carbonate (704 mg,2.16 mmol), potassium iodide (180 mg,1.08 mmol), 4A molecular sieve (500 mg), DMF (6 ml), nitrogen blanket, placed in an oil bath at 70℃and stirred for 24H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure to obtain orange oily substance, re-dissolving with a mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:5), leaching a filter cake with the mixed solvent (vethanol: vdichloromethane=1:5), concentrating under reduced pressure to obtain 400mg of brown oily mixture, and directly carrying out the next step without purification.
2. (3Z, 6Z) -3- (3- (4-fluorophenoxy) benzene) methylene) -6- ((5-isopropyl-1- (2- (p-tolyloxy) ethyl)) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of a dry reaction flask was taken, (Z) -1-acetyl-3- ((5-isopropyl-1- (2- (p-tolyloxy) ethyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.73 mmol), 3- (4-fluorophenoxy) benzaldehyde (158 mg,0.73 mmol), cesium carbonate (87 mg,1.09 mmol), anhydrous sodium sulfate (207 mg,1.46 mmol), DMF (6 mL), under nitrogen substitution protection, protected from light, and placed in an oil bath at 45℃to stir for 20H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:3), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:3), and concentrating under reduced pressure. Flash purification, methanol: 90%, water: the product was obtained at 10% and concentrated under reduced pressure to give 150mg of a pale yellow solid in 36.32% yield.
1 H NMR(500MHz,DMSO-d6)δ11.97(s,1H),10.13(s,1H),7.95(s,1H),7.40(t,J＝7.9Hz,1H),7.26 (d,J＝7.8Hz,1H),7.23(t,J＝8.7Hz,2H),7.17(s,1H),7.12(dd,J＝8.0,3.9Hz,2H),7.07(d,J＝7.8Hz, 2H),6.90(d,J＝8.1Hz,1H),6.81(d,J＝7.9Hz,2H),6.72(s,2H),4.43(s,2H),4.19(s,2H),3.31-3.26(m, 1H),2.21(s,3H),1.34(d,J＝6.9Hz,6H).MS(ESI):m/z 567.63[M+H] + .Mp:157-160℃.
Example 59 preparation of (3Z, 6Z) -3- (3- (4-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (2- (3-phenoxypropyl)) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-59)
1. 3-Phenoxypropyl-1-ol
A50 ml dry round bottom flask was taken, followed by bromobenzene (2 g,12.74 mmol), potassium carbonate (5.28 g,38.22 mmol), cupric chloride (108 mg,0.64 mmol), 1, 3-propanediol (16 ml), nitrogen blanket, placed in an oil bath at 130℃and stirred for 12h. Cooled to room temperature, diluted hydrochloric acid adjusted to pH 3, extracted with ethyl acetate (100 ml x 2), combined with the organic phase, dried over anhydrous sodium sulphate, filtered, concentrated under reduced pressure, purified by column chromatography, PE: ea=4:1, giving 1.1g of pale yellow oily liquid in 56.70% yield.
2. 3-Phenoxypropyl 4-methylbenzenesulfonate
A50 ml dry round bottom flask, 3-phenoxypropyl-1-ol (1 g,6.58 mmol) was dissolved in 10ml anhydrous DCM, triethylamine (3.32 g,32.90 mmol) was added, nitrogen-protected, and p-toluenesulfonyl chloride (2.25 g, 11.84 mmol) dissolved in 10ml anhydrous DCM was added dropwise, transferred to room temperature and stirred for 6h. Purified water (100 ml x 2) was washed, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography, PE: ea=10:1, to give 1.60g of a white solid with a yield of 79.46%.
3. (Z) -1-acetyl-3- ((5-isopropyl-1- (3-phenoxypropyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
A50 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.08 mmol), 3-phenoxypropyl 4-methylbenzenesulfonate (660 mg,2.16 mmol), cesium carbonate (704 mg,2.16 mmol), potassium iodide (180 mg,1.08 mmol), 4A molecular sieve (500 mg), DMF (6 ml), nitrogen protection, placed in an oil bath at 70℃and stirred for 24H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure to obtain orange oily substance, re-dissolving with a mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:5), leaching a filter cake with the mixed solvent (vethanol: vdichloromethane=1:5), concentrating under reduced pressure to obtain 400mg of brown oily mixture, and directly carrying out the next step without purification.
2. (3Z, 6Z) -3- (3- (4-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (2- (3-phenoxypropyl)) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of dry reaction flask, (Z) -1-acetyl-3- ((5-isopropyl-1- (3-phenoxypropyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.73 mmol), 3- (4-fluorophenoxy) benzaldehyde (158 mg,0.73 mmol), cesium carbonate (357 mg,1.09 mmol), anhydrous sodium sulfate (207 mg,1.46 mmol), DMF (6 mL), displacement nitrogen protection, light shielding, and stirring reaction at 45℃for 20H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:3), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:3), and concentrating under reduced pressure. Flash purification, methanol: 87%, water: 13% of the product was obtained, which was concentrated under reduced pressure to give 168mg of a pale yellow solid, the yield was 40.67%.
1 H NMR(500MHz,DMSO-d6)δ11.81(s,1H),10.13(s,1H),7.84(s,1H),7.54(s,1H),7.43(d,J＝7.5 Hz,1H),7.33(t,J＝7.9Hz,1H),7.29(t,J＝7.7Hz,2H),7.21(t,J＝8.6Hz,2H),7.08(dd,J＝8.7,4.5Hz, 2H),6.96-6.90(m,3H),6.79(d,J＝8.0Hz,1H),6.56(s,1H),6.53(s,1H),4.18(t,J＝7.0Hz,2H),3.98(t,J ＝5.7Hz,2H),3.25–3.12(m,1H),2.24–2.04(m,2H),1.29(d,J＝7.0Hz,6H).MS(ESI):m/z 567.26[M +H] + .Mp:178-181℃.
Example 60 preparation of (3Z, 6Z) -3- (3- (4-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (2- (2- (benzyloxy) ethyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-60)
1. 2- (benzyloxy) ethyl-1-ol
A50 ml dry round bottom flask was taken, followed by the addition of p-bromobenzyl (2 g,11.69 mmol), potassium carbonate (4.85 g,35.08 mmol), copper chloride (99 mg,0.58 mmol), ethylene glycol (16 ml), nitrogen protection, and the reaction was stirred in an oil bath at 130℃for 12h. Cooling to room temperature, adjusting pH to 3 with dilute hydrochloric acid, extracting with ethyl acetate (100 ml×2), mixing the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying with column chromatography, and purifying with PE: EA=10:1 to obtain white solid 700mg with a yield of 39.41%.
2. 2- (benzyloxy) ethyl-4-methylbenzenesulfonate
A50 ml dry round bottom flask, at 0deg.C, 2- (benzyloxy) ethyl-1-ol (1 g,6.58 mmol) was dissolved in 10ml anhydrous DCM, triethylamine (3.32 g,32.90 mmol) was added, nitrogen-protected, p-toluenesulfonyl chloride (2.25 g, 11.84 mmol) dissolved in 10ml anhydrous DCM was added dropwise, and the mixture was transferred to room temperature and stirred for 6h. Purified water (100 ml x 2) was washed, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography, PE: ea=4:1, to give 1.60g of a white solid with a yield of 79.46%.
3. (Z) -1-acetyl-3- ((1- (2- (benzyloxy) ethyl) -5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dioneA50 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.08 mmol), 2- (benzyloxy) ethyl-4-methylbenzenesulfonate (660 mg,2.16 mmol), cesium carbonate (704 mg,2.16 mmol)) Potassium iodide (180 mg,1.08 mmol), 4A molecular sieves (500 mg), DMF (6 ml), nitrogen protection, were placed in an oil bath at 70℃and stirred for 24h. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure to obtain orange oily substance, re-dissolving with a mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:5), leaching a filter cake with the mixed solvent (vethanol: vdichloromethane=1:5), concentrating under reduced pressure to obtain 400mg of brown oily mixture, and directly carrying out the next step without purification.
2. (3Z, 6Z) -3- (3- (4-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (2- (2- (benzyloxy) ethyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of a dry reaction flask, (Z) -1-acetyl-3- ((1- (2- (benzyloxy) ethyl) -5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.73 mmol), 3- (4-fluorophenoxy) benzaldehyde (158 mg,0.73 mmol), cesium carbonate (87 mg,1.09 mmol), anhydrous sodium sulfate (207 mg,1.46 mmol), DMF (6 mL), displacement nitrogen protection, light shielding, and stirring at 45℃for 20H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:3), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:3), and concentrating under reduced pressure. Flash purification, methanol: 80%, water: the product was obtained at 20% and concentrated under reduced pressure to give 150mg of a pale yellow solid in 36.32% yield.
1 H NMR(500MHz,DMSO-d6)δ12.00(s,1H),10.13(s,1H),7.88(s,1H),7.41(t,J＝7.9Hz,1H), 7.31(t,J＝7.1Hz,2H),7.29-7.25(m,2H),7.22(d,J＝6.0Hz,4H),7.18(s,1H),7.12(dd,J＝8.3,4.5Hz, 2H),6.90(d,J＝8.0Hz,1H),6.72(s,1H),6.70(s,1H),4.49(s,2H),4.24(s,2H),3.67(s,2H),3.25-3.19(m, 1H),1.26(d,J＝7.0Hz,6H).MS(ESI):m/z 567.90[M+H] + .Mp:129-131℃.
Example 61 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (3-piperidinyl) propylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-61)
1) A250 ml dry round bottom flask was charged with piperidine (3.0 g,35.23 mmol), potassium carbonate (7.29 g,52.75 mmol), potassium iodide (1.17 mg,7.05 mmol), acetonitrile (120 ml), 1-chloro-3-bromopropane (6.66 g,42.30 mmol) in sequence, and stirred at 25℃with an oil bath for 16h, TLC (MeOH: DCM=1:10) monitored and the reaction was complete. Filtration, cake EA washing, concentration under reduced pressure gave a pale brown oily liquid, 2.61g, yield: 45.79%.
2) A50 ml dry round bottom flask was taken and a solution of (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), cesium carbonate (707.55 mg,2.17 mmol), potassium iodide (180.24 mg,1.09 mmol), 4A molecular sieve (500 mg), N-3-chloropropylpiperidine (263.31 mg,1.63 mmol) in DMF (5 ml) was added sequentially, vented, nitrogen protected, placed in an oil bath at 70℃and stirred for 24H. After the reaction, the temperature was naturally lowered to room temperature, 3-p-fluorobenzoyl benzaldehyde (247.80 mg,1.09 mmol) DMF (2 ml) was added thereto, the temperature was raised to 45℃in an oil bath, and the reaction was stirred for 24 hours. LC-MS monitors the reaction, after the reaction, the reaction liquid is dripped into cold water (80 ml) at 4 ℃, suction filtration is carried out, a filter cake is washed by cold water, suction drying is carried out, methanol and methylene dichloride (1:3) are dissolved, filtration, drying and ultrasonic beating of methanol are carried out, the mixture is placed in a refrigerator at-30 ℃ for standing, suction filtration is carried out, the filter cake is washed by cold methanol, vacuum drying is carried out at 50 ℃ to obtain 142.2mg of yellow solid, and the yield is 22.90%.
1 H NMR(400MHz,DMSO-d 6 ))δ12.02(s,1H),10.36(s,1H),7.84(dd,J＝19.67,39.85Hz,5H),7.61 (d,J＝9.85Hz,2H),7.40(s,2H),6.80(s,1H),6.70(s,1H),4.03(s,2H),3.43(s,4H),3.26(s,1H),2.24(d, J＝34.68Hz,8H),1.82(s,2H),1.49(s,6H).MS(ESI):m/z 570.27[M+H] + .Mp:195-197℃.
Example 62 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (3-piperidinyl) propylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-62)
1. 1- (3-chloropropyl) piperidine
A250 ml dry round bottom flask was charged with piperidine (1.0 g,11.74 mmol), potassium carbonate (2.91 g,17.61 mmol), potassium iodide (195 mg,1.17 mmol), acetonitrile (15 ml), 1-chloro-3-bromopropane (1.85 g,11.74 mmol) in sequence, and the reaction was stirred for 5h at 25℃with an oil bath and monitored by TLC (MeOH: DCM=1:10) to completion. Ethyl acetate (50 ml x 3) and the combined organic phases were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give 1.20g of a colourless oily liquid with a yield of 63.49%.
2. (Z) -1-acetyl-3- ((5-isopropyl-1- (3- (piperidin-1-yl) propyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
A50 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.08 mmol), 1- (3-chloropropyl) piperidine
(348 mg,2.16 mmol), cesium carbonate (704 mg,2.16 mmol), potassium iodide (180 mg,1.08 mmol), 4A molecular sieve (500 mg), DMF (6 ml), degassing, nitrogen protection, and placing in an oil bath at 70 ℃ and stirring for reaction for 24h. Transferring into a 100ml single-port bottle, flushing with ethanol, concentrating under reduced pressure to obtain orange oily matter, re-dissolving with a mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:5), leaching a filter cake with the mixed solvent (vethanol: vdichloromethane=1:5), concentrating under reduced pressure to obtain 400mg of orange oily mixture, and directly carrying out the next step without purification.
2. (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (3-piperidinyl) propylimidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of dry reaction flask, (Z) -1-acetyl-3- ((5-isopropyl-1- (3- (piperidin-1-yl) propyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.75 mmol), 3- (4-fluorophenoxy) benzaldehyde (194 mg,0.90 mmol), DMF (6 mL), cesium carbonate (367 mg,1.12 mmol), anhydrous sodium sulfate (213 mg,1.50 mmol), displacement nitrogen protection, light shielding, and stirring at 45℃for 20H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:3), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:3), and concentrating under reduced pressure. Methanol (3 mL) was added, sonicated, and dispersed overnight at-20 ℃. Filtration and drying gave 85mg of yellow solid in 20.43% yield.
1 H NMR(500MHz,DMSO-d6)δ12.00(s,1H),10.12(s,1H),7.87(s,1H),7.41(t,J＝7.9Hz,1H),7.27 (d,J＝7.8Hz,1H),7.23(t,J＝8.8Hz,2H),7.17(s,1H),7.15-7.09(m,2H),6.90(dd,J＝8.1,1.7Hz,1H), 6.71(s,2H),4.03(t,J＝7.0Hz,2H),3.26-3.20(m,1H),2.28(s,4H),2.20(t,J＝6.7Hz,2H),1.88-1.73(m, 2H),1.47-1.51(m,4H),1.37(s,2H),1.33(d,J＝7.1Hz,6H).MS(ESI):m/z 558.27[M+H] + .Mp:166-168 ℃.
Example 63 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (3-pyrrolidinyl) propylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-63)
1. 1- (3-chloropropyl) pyrrolidine
A250 ml dry round bottom flask was charged with pyrrolidine (1.0 g,14.06 mmol), potassium carbonate (2.91 g,14.06 mmol), potassium iodide (233 mg,1.41 mmol) acetonitrile (18 ml), 1-chloro-3-bromopropane (2.21 g,14.06 mmol) and stirred at 25℃for 12h under an oil bath, and TLC (MeOH: DCM=1:10) monitored to completion. Ethyl acetate (50 ml x 3) and the combined organic phases were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give 1.25g of a colourless oily liquid in 60.68% yield.
2, (Z) -1-acetyl-3- ((5-isopropyl-1- (3- (pyrrolidin-1-yl) propyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
A50 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.08 mmol), 1- (3-chloropropyl) pyrrolidine
(319 mg,2.16 mmol), cesium carbonate (704 mg,2.16 mmol), potassium iodide (180 mg,1.08 mmol), 4A molecular sieve (500 mg), DMF (6 ml), degassing, nitrogen protection, and placing in an oil bath at 70 ℃ C. And stirring for reaction for 24h. Transferring into a 100ml single-port bottle, flushing with ethanol, concentrating under reduced pressure to obtain orange oily matter, re-dissolving with a mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:5), leaching a filter cake with the mixed solvent (vethanol: vdichloromethane=1:5), concentrating under reduced pressure to obtain 400mg of orange oily mixture, and directly carrying out the next step without purification.
3. (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (3-pyrrolidinyl) propylimidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of dry reaction flask, (Z) -1-acetyl-3- ((5-isopropyl-1- (3- (pyrrolidin-1-yl) propyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.78 mmol), 3- (4-fluorophenoxy) benzaldehyde (168 mg,0.78 mmol), DMF (6 mL), cesium carbonate (381 mg,1.17 mmol), anhydrous sodium sulfate (221 mg,1.56 mmol), displacement nitrogen protection, light shielding, and stirring at 45℃for 20H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:3), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:3), and concentrating under reduced pressure. Methanol (3 mL) was added, sonicated, and dispersed overnight at-20 ℃. Filtration and drying gave 110mg of yellow solid in 26.01% yield.
1 H NMR(500MHz,DMSO-d6)δ12.00(s,1H),10.12(s,1H),7.87(s,1H),7.41(t,J＝7.9Hz,1H),7.27 (d,J＝7.7Hz,1H),7.23(t,J＝8.8Hz,2H),7.18(s,1H),7.14-7.10(m,2H),6.90(dd,J＝8.1,1.9Hz,1H), 6.70(s,2H),4.05(t,J＝7.1Hz,2H),3.26-3.20(m,1H),2.41(s,4H),2.36(t,J＝6.8Hz,2H),1.89-1.79(m, 2H),1.68(s,4H),1.33(d,J＝7.1Hz,6H).MS(ESI):m/z 544.24[M+H] + .Mp:172-174℃.
Example 64 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (indolin-1-yl) propylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-64)
1. 1- (3-chloropropyl) indoline
Indoline (1.0 g,8.39 mmol), cesium carbonate (4.1 g,12.58 mmol), potassium iodide (279 mg,1.68 mmol), acetonitrile (15 ml), 1-chloro-3-bromopropane (2.64 g,16.78 mmol) were added sequentially to a 100ml dry round bottom flask, the reaction was stirred for 20h at 25℃with oil bath and TLC (EA: PE=1:20) monitored to completion. Ethyl acetate (50 ml x 2) and the combined organic phases were dried over anhydrous sodium sulphate, filtered, concentrated under reduced pressure, and purified by column chromatography, PE: ea=100:1, to give 0.90g of a pale yellow oily liquid with a yield of 54.88%.
3. (Z) -1-acetyl-3- ((1- (3- (indolin-1-yl) propyl) -5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
A50 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.08 mmol), 1- (3-chloropropyl) indoline (426 mg,2.16 mmol), cesium carbonate (704 mg,2.16 mmol), potassium iodide (180 mg,1.08 mmol), 4A molecular sieve (500 mg), DMF (6 ml), vented, nitrogen blanket, placed in a 70℃oil bath and stirred for 24H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure to obtain orange oily substance, re-dissolving with a mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:5), leaching a filter cake with the mixed solvent (vethanol: vdichloromethane=1:5), concentrating under reduced pressure to obtain 450mg of brown oily mixture, and directly carrying out the next step without purification.
4. (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (indolin-1-yl) propylimidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of dry reaction flask, (Z) -1-acetyl-3- ((1- (3- (indolin-1-yl) propyl) -5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.69 mmol), 3- (4-fluorophenoxy) benzaldehyde (149 mg,0.69 mmol), cesium carbonate (339 mg,1.04 mmol), anhydrous sodium sulfate (196 mg,1.38 mmol), DMF (6 mL), protected by replacement nitrogen, were placed in a dark place at 45℃under oil bath and stirred for 20H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:3), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:3), and concentrating under reduced pressure. Flash purification, methanol: 81%, water: 29% of the product was obtained and concentrated under reduced pressure to give 128mg of a pale yellow solid in a yield of 31.45%.
1 H NMR(500MHz,DMSO-d6)δ12.00(s,1H),10.13(s,1H),7.92(s,1H),7.41(t,J＝7.8Hz,1H),7.27 (d,J＝7.8Hz,1H),7.23(t,J＝8.4Hz,2H),7.17(s,1H),7.13(d,J＝4.0Hz,2H),7.03(d,J＝6.8Hz,1H), 7.00-6.96(m,1H),6.90(d,J＝7.5Hz,1H),6.71(d,J＝5.8Hz,2H),6.57(t,J＝7.2Hz,1H),6.45(d,J＝7.6 Hz,1H),4.12(s,2H),3.28(t,J＝7.5Hz,2H),3.25-3.20(m,1H),3.06(t,J＝6.2Hz,2H),2.88(t,J＝7.8Hz, 2H),2.00-1.96(m,2H),1.32(d,J＝6.7Hz,6H).MS(ESI):m/z 592.43[M+H] + .Mp:143-145℃.
Example 65 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (dihydroisoquinolin-2-yl) propylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-65)
1. 2- (3-chloropropyl) -1,2,3, 4-tetrahydroisoquinoline
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A100 ml dry round bottom flask was charged with 1,2,3, 4-tetrahydroisoquinoline (1.0 g,7.50 mmol), cesium carbonate (3.66 g,11.25 mmol), potassium iodide (124 mg,0.75 mmol), acetonitrile (10 ml), 1-chloro-3-bromopropane (2.36 g,15.00 mmol) in sequence, stirred at 25℃with oil for 20h, and TLC (EA: PE=1:10) monitored to completion. Ethyl acetate (50 ml x 2) and the combined organic phases were dried over anhydrous sodium sulphate, filtered, concentrated under reduced pressure, purified by column chromatography, PE: ea=100:1, yielding 220g of a pale yellow oily liquid with a yield of 14.01%.
3. (Z) -1-acetyl-3- ((1- (3, 4-dihydroisoquinolin-2 (1H) -yl) propyl) -5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
A50 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.08 mmol), 2- (3-chloropropyl) -1,2,3, 4-tetrahydroisoquinoline (457 mg,2.16 mmol), cesium carbonate (704 mg,2.16 mmol), potassium iodide (180 mg,1.08 mmol), 4A molecular sieve (500 mg), DMF (6 ml), vented, nitrogen protected, placed in an oil bath at 70℃and stirred for 24H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure to obtain orange oily substance, re-dissolving with a mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:5), leaching a filter cake with the mixed solvent (vethanol: vdichloromethane=1:5), concentrating under reduced pressure to obtain 450mg of brown oily mixture, and directly carrying out the next step without purification.
4. (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (dihydroisoquinolin-2-yl) propylimidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of the dry reaction flask was taken, (Z) -1-acetyl-3- ((1- (3, 4-dihydroisoquinolin-2 (1H) -yl) propyl) -5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
(300 mg,0.67 mmol), 3- (4-fluorophenoxy) benzaldehyde (144 mg,0.67 mmol), cesium carbonate (327 mg,1.00 mmol), anhydrous sodium sulfate (190 mg,1.34 mmol), DMF (6 mL), replaced with nitrogen protection, protected from light, and placed in 45℃oil bath under stirring to react for 20h. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:3), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:3), and concentrating under reduced pressure. Flash purification, methanol: 82%, water: the product was obtained at 18% and concentrated under reduced pressure to give 135mg of a pale yellow solid in 33.33% yield.
1 H NMR(500MHz,DMSO-d6)δ11.99(s,1H),10.13(s,1H),7.93(s,1H),7.41(t,J＝7.9Hz,1H),7.27 (d,J＝8.0Hz,1H),7.23(t,J＝8.8Hz,2H),7.17(s,1H),7.14-7.08(m,2H),6.95-6.88(m,2H),6.86(d,J＝ 7.3Hz,1H),6.72(s,1H),6.69(s,1H),6.49(d,J＝8.2Hz,1H),6.46(t,J＝7.3Hz,1H),4.09(t,J＝7.3Hz, 2H),3.28(t,J＝7.5Hz,2H),3.23-3.19(m,3H),2.66(t,J＝6.2Hz,2H),1.97-1.89(m,2H),1.87-1.82(m, 2H),1.30(d,J＝7.1Hz,6H).MS(ESI):m/z 606.48[M+H] + .Mp:166-169℃.
Example 66 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (1H-pyrrol-1-yl) propylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-66)
1. 1- (3-chloropropyl) -1H-pyrrole
A100 ml dry round bottom flask was charged with 1H-pyrrole (1.0 g,14.90 mmol), cesium carbonate (7.28 g,22.35 mmol), potassium iodide (247 mg,1.49 mmol), acetonitrile (15 ml), 1-chloro-3-bromopropane (2.35 g,14.90 mmol) in sequence, and stirred at 25℃for 20H with stirring and TLC (EA: PE=1:20) monitoring to completion. Ethyl acetate (50 ml x 2) and the combined organic phases were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give 0.64g of a pale yellow oily liquid with a yield of 30.05%.
3. (Z) -3- ((1- (3- (1H-pyrrol-1-yl) propyl) -5-isopropyl-1H-imidazol-4-yl) methylene) -1-acetylpiperazine-2, 5-dione
A50 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.08 mmol), 1- (3-chloropropyl) -1H-pyrrole (309 mg,2.16 mmol), cesium carbonate (704 mg,2.16 mmol), potassium iodide (180 mg,1.08 mmol), 4A molecular sieve (500 mg), DMF (6 ml), vented, nitrogen blanket, placed in a 70℃oil bath and stirred for 24H. Transferring into a 100ml single-port bottle, flushing with ethanol, concentrating under reduced pressure with water, gas and oil pump to obtain orange oily substance, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:5), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:5), concentrating under reduced pressure to obtain 400mg brown oily mixture, and directly carrying out the next step without purification.
4. (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (1H-pyrrol-1-yl) propylimidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of dry reaction flask, (Z) -3- ((1- (3- (1H-pyrrol-1-yl) propyl) -5-isopropyl-1H-imidazol-4-yl) methylene) -1-acetylpiperazine-2, 5-dione (300 mg,0.78 mmol), 3- (4-fluorophenoxy) benzaldehyde (203 mg,0.94 mmol), cesium carbonate (381 mg,1.17 mmol), anhydrous sodium sulfate (221 mg,1.56 mmol), DMF (6 mL), protected by nitrogen substitution, were placed in a dark place at 45℃under oil bath and stirred for 20H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:3), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:3), and concentrating under reduced pressure. Flash purification, methanol: 70%, water: the product was obtained at 30% and concentrated under reduced pressure to give 90mg of pale yellow solid in 21.33% yield.
1 H NMR(500MHz,DMSO-d6)δ11.97(s,1H),10.13(s,1H),7.87(s,1H),7.41(t,J＝7.9Hz,1H),7.27 (d,J＝7.8Hz,1H),7.23(t,J＝8.6Hz,2H),7.17(s,1H),7.12(dd,J＝8.0,4.7Hz,2H),6.90(d,J＝8.1Hz, 1H),6.79(s,2H),6.72(s,1H),6.68(s,1H),6.02(d,J＝1.1Hz,2H),3.95(t,J＝8.5Hz,4H),3.13-3.07(m, 1H),2.25-2.05(m,2H),1.27(d,J＝7.0Hz,6H).MS(ESI):m/z 540.17[M+H] + .Mp:190-192℃.
EXAMPLE 67 preparation of (3Z, 6Z) -3- (3- (4-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (1H-pyrrol-1-yl) propylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-67)
1. (Z) -3- ((1- (3- (1H-pyrrol-1-yl) propyl) -5-isopropyl-1H-imidazol-4-yl) methylene) -6- ((Z) -3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione
25mL of dry reaction flask, (Z) -3- ((1- (3- (1H-pyrrol-1-yl) propyl) -5-isopropyl-1H-imidazol-4-yl) methylene) -1-acetylpiperazine-2, 5-dione (300 mg,0.78 mmol), 3- (4-fluorobenzoyl) benzaldehyde (214 mg,0.94 mmol), cesium carbonate (381 mg,1.17 mmol), anhydrous sodium sulfate (221 mg,1.56 mmol), DMF (6 mL) were taken and placed in 45℃oil bath under stirring to react for 20H under nitrogen-substituted protection, protected from light. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:3), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:3), and concentrating under reduced pressure. Flash purification, methanol: 80%, water: the product was obtained at 20% and concentrated under reduced pressure to give 66mg of a pale yellow solid in 15.38% yield.
1 H NMR(500MHz,DMSO-d6)δ12.00(s,1H),10.35(s,1H),7.90(t,J＝7.5Hz,2H),7.87(s,1H),7.82 (s,1H),7.75(d,J＝7.5Hz,1H),7.63(d,J＝7.6Hz,1H),7.58(t,J＝7.6Hz,1H),7.40(t,J＝8.6Hz,2H), 6.81(s,1H),6.79(s,2H),6.68(s,1H),6.02(s,2H),4.04-3.85(m,4H),3.13-3.07(m,1H),2.16-2.11(m,2H), 1.27(d,J＝7.0Hz,6H)MS(ESI):m/z 552.22[M+H] + .Mp:199-201℃.
Example 68 preparation of (3Z, 6Z) -3- (3- (4-fluorobenzoyl) benzene) methylene-6- ((5-cyclopropyl-1- (1H-pyrrol-1-yl) propylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-68)
1. (Z) -3- ((1- (3- (1H-pyrrol-1-yl) propyl) -5-cyclopropyl-1H-imidazol-4-yl) methylene) -1-acetylpiperazine-2, 5-dione
A50 ml dry round bottom flask was taken, and ((Z) -1-acetyl-3- ((5-cyclopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), 1- (3-chloropropyl) -1H-pyrrole (311 mg,2.18 mmol), cesium carbonate (710 mg,2.18 mmol), potassium iodide (180 mg,1.09 mmol), 4A molecular sieve (500 mg), DMF (6 ml), air-bleed, nitrogen protection, placed in an oil bath at 70 ℃ and stirred for 24 h.100 ml single-neck flask, ethanol rinsed, concentrated under reduced pressure to give an orange oil, re-dissolved with a mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:5), filtered with suction, the mixed solvent (vethanol: vdichloromethane=1:5) filter cake, concentrated under reduced pressure to give 400mg of a brown oily mixture, which was directly subjected to the next step without purification.
2. (Z) -3- ((1- (3- (1H-pyrrol-1-yl) propyl) -5-cyclopropyl-1H-imidazol-4-yl) methylene) -6- ((Z) -3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione
25mL of dry reaction flask, (Z) -3- ((1- (3- (1H-pyrrol-1-yl) propyl) -5-cyclopropyl-1H-imidazol-4-yl) methylene) -1-acetylpiperazine-2, 5-dione (300 mg,0.78 mmol), 3- (4-fluorobenzoyl) benzaldehyde (214 mg,0.94 mmol), cesium carbonate (381 mg,1.17 mmol), anhydrous sodium sulfate (221 mg,1.56 mmol), DMF (6 mL) were taken and placed in 45℃oil bath under stirring to react for 20H under nitrogen-substituted protection, protected from light. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:3), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:3), and concentrating under reduced pressure. Flash purification, methanol: 80%, water: the product was obtained at 20% and concentrated under reduced pressure to give 100mg of pale yellow solid in 23.26% yield.
1 H NMR(500MHz,DMSO-d6)δ11.90(s,1H),10.34(s,1H),7.90(d,J＝8.0Hz,3H),7.82(s,1H), 7.75(d,J＝7.3Hz,1H),7.63(d,J＝7.2Hz,1H),7.58(t,J＝7.5Hz,1H),7.40(t,J＝8.5Hz,2H),6.80(d,J ＝1.9Hz,3H),6.70(s,1H),6.01(s,2H),4.00(t,J＝6.5Hz,1H),3.96(t,J＝6.5Hz,1H),2.29-2.17(m,2H), 1.71-1.66(m,1H),0.99-0.93(m,2H),0.59-0.54(m,2H).MS(ESI):m/z 550.10[M+H] + .Mp:166.2-168.3 ℃.
Example 69 preparation of (3Z, 6Z) -3- (3- (4-fluorophenoxy) benzene) methylene-6- ((5-cyclopropyl-1- (1H-pyrrol-1-yl) propylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-69)
25mL of dry reaction flask, (Z) -3- ((1- (3- (1H-pyrrol-1-yl) propyl) -5-cyclopropyl-1H-imidazol-4-yl) methylene) -1-acetylpiperazine-2, 5-dione (300 mg,0.78 mmol), 3- (4-fluorophenoxy) benzaldehyde (203 mg,0.94 mmol), cesium carbonate (381 mg,1.17 mmol), anhydrous sodium sulfate (221 mg,1.56 mmol), DMF (6 mL), protected by nitrogen substitution, were placed in a dark place at 45℃under oil bath and stirred for 20H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:3), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:3), and concentrating under reduced pressure. Flash purification, methanol: 80%, water: the product was obtained at 20% and concentrated under reduced pressure to give 60mg of a pale yellow solid in 14.33% yield.
1 H NMR(500MHz,DMSO-d6)δ11.88(s,1H),10.13(s,1H),7.91(s,1H),7.41(t,J＝7.9Hz,1H),7.26 (d,J＝7.8Hz,1H),7.23(t,J＝8.8Hz,2H),7.17(s,1H),7.12(dd,J＝8.4,4.4Hz,2H),6.90(d,J＝8.0Hz, 1H),6.80(s,2H),6.71(d,J＝7.5Hz,2H),6.01(s,2H),4.00(t,J＝7.3Hz,2H),3.96(t,J＝6.6Hz,2H),2.26- 2.20(m,2H),1.76-1.56(m,1H),0.99-0.94(m,2H),0.58-0.52(m,2H).MS(ESI):m/z 538.32[M+H] + .Mp: 190.2-192.3℃.
Example 70 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (1H-pyrrol-1-yl) butylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-70)
1) 1- (4-chlorobutyl) -1H-pyrrole
A100 ml dry round bottom flask was charged with 1H-pyrrole (1.0 g,14.90 mmol), cesium carbonate (7.28 g,22.35 mmol), potassium iodide (247 mg,1.49 mmol), acetonitrile (15 ml), 1-chloro-4-bromobutane (2.55 g,14.90 mmol) in sequence, stirred for 20H at 25℃in an oil bath and TLC (EA: PE=1:10) monitored to completion. Ethyl acetate (50 ml x 2) and the combined organic phases were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give 0.50g of a pale yellow oily liquid with a yield of 21.36%.
2) (Z) -3- ((1- (4- (1H-pyrrol-1-yl) butyl) -5-isopropyl-1H-imidazol-4-yl) methylene) -1-acetylpiperazine-2, 5-dione
A50 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.08 mmol), 1- (4-chlorobutyl) -1H-pyrrole (319 mg,2.16 mmol), cesium carbonate (704 mg,2.16 mmol), potassium iodide (180 mg,1.08 mmol), 4A molecular sieve (500 mg), DMF (6 ml), vented, nitrogen blanket, placed in a 70℃oil bath and stirred for 24H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure to obtain orange oily substance, re-dissolving with a mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:5), leaching a filter cake with the mixed solvent (vethanol: vdichloromethane=1:5), concentrating under reduced pressure to obtain 400mg of brown oily mixture, and directly carrying out the next step without purification.
3) (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (1H-pyrrol-1-yl) butylimidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of dry reaction flask was taken, (Z) -3- ((1- (4- (1H-pyrrol-1-yl) butyl) -5-isopropyl-1H-imidazol-4-yl) methylene) -1-acetylpiperazine-2, 5-dione (300 mg,0.76 mmol), 3- (4-fluorobenzoyl) benzaldehyde (196 mg,0.91 mmol), cesium carbonate (371 mg,1.14 mmol), anhydrous sodium sulfate (215 mg,1.52 mmol), DMF (6 mL), nitrogen-protected, protected from light, and placed in 45℃oil bath under stirring for reaction for 20H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:3), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:3), and concentrating under reduced pressure. Flash purification, methanol: 80%, water: the product was obtained at 20% and concentrated under reduced pressure to give 80mg of pale yellow solid in 13.31% yield.
1 H NMR(500MHz,dmso)δ11.98(s,1H),10.09(s,1H),7.86(s,1H),7.41(t,J＝7.9Hz,1H),7.27(d, J＝7.8Hz,1H),7.23(t,J＝8.7Hz,2H),7.17(s,1H),7.12(dd,J＝8.6,4.4Hz,2H),6.90(d,J＝7.9Hz,1H), 6.73(s,2H),6.72(s,1H),6.68(s,1H),5.97(s,2H),3.98(t,J＝7.0Hz,2H),3.91(t,J＝6.6Hz,2H),3.26- 3.03(m,1H),1.74-1.64(m,2H),1.62-1.51(m,2H),1.28(d,J＝7.0Hz,6H).MS(ESI):m/z 554.45[M+ H] + .Mp:178-180℃.
Example 71 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (1H-indol-1-yl) propyl) imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-71)
1. 1- (3-chloropropyl) -1H-indole
A100 ml dry two-neck round bottom flask was taken, 1H-indole (1.0 g,8.54 mmol), sodium hydride (307 mg, 12.80 mmol), potassium iodide (142 mg,0.85 mmol) were added sequentially, DMF (18 ml) was added dropwise, after stirring for 2H at room temperature, 1-chloro-3-bromopropane (2.02 g,12.80 mmol) was added dropwise, the reaction was stirred for 12H at 25℃with an oil bath, and TLC (EA: PE=1:10) monitored to complete the reaction. Dichloromethane (50 ml x 2) was extracted, the organic phases combined, dried over anhydrous sodium sulphate, filtered, concentrated under reduced pressure, purified by column chromatography, PE: ea=80:1, to give 660mg of colorless oily liquid in 40% yield.
3. (Z) -3- ((1- (3- (1H-indol-1-yl) propyl) -5-isopropyl-1H-imidazol-4-yl) methylene) -1-acetylpiperazine-2, 5-dione
A50 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.08 mmol), 1- (3-chloropropyl) -1H-indole (416 mg,2.16 mmol), cesium carbonate (704 mg,2.16 mmol), potassium iodide (180 mg,1.08 mmol), 4A molecular sieve (500 mg), DMF (6 ml), vented, nitrogen blanket, placed in an oil bath at 70℃and stirred for 24H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure to obtain orange oily substance, re-dissolving with a mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:5), leaching a filter cake with the mixed solvent (vethanol: vdichloromethane=1:5), concentrating under reduced pressure to obtain 450mg of brown oily mixture, and directly carrying out the next step without purification.
4. (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (1H-indol-1-yl) propyl) imidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of dry reaction flask was taken, (Z) -3- ((1- (3- (1H-indol-1-yl) propyl) -5-isopropyl-1H-imidazol-4-yl) methylene) -1-acetylpiperazine-2, 5-dione (300 mg,0.69 mmol), 3- (4-fluorophenoxy) benzaldehyde (149 mg,0.69 mmol), cesium carbonate (339 mg,1.04 mmol), anhydrous sodium sulfate (196 mg,1.38 mmol), DMF (6 mL), protected by replacement nitrogen, and placed in a 45℃oil bath under stirring to react for 20H. Transferring into a 100ml single-port bottle, flushing with ethanol, concentrating under reduced pressure with water, gas and oil pump, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:3), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:3), and concentrating under reduced pressure. Flash purification, methanol: 81%, water: 29% of the product was obtained and concentrated under reduced pressure to give 150. 150 mg as a pale yellow solid with a yield of 36.95%.
1 H NMR(500MHz,DMSO-d6)δ11.97(s,1H),10.13(s,1H),7.91(s,1H),7.56(d,J＝7.8Hz,1H), 7.46(d,J＝8.2Hz,1H),7.41(d,J＝3.3Hz,1H),7.39(s,1H),7.26(d,J＝7.9Hz,1H),7.23(t,J＝8.7Hz, 2H),7.17(s,1H),7.15–7.09(m,3H),7.03(t,J＝7.3Hz,1H),6.90(d,J＝7.6Hz,1H),6.71(s,1H),6.66(s, 1H),6.46(d,J＝2.4Hz,1H),4.27(t,J＝6.7Hz,2H),4.01(t,J＝7.5Hz,2H),3.06-3.00(m,1H),2.30-2.11 (m,2H),1.19(d,J＝7.0Hz,6H).MS(ESI):m/z 590.67[M+H] + .Mp:171-173℃.
Example 72 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (3-phenyl) propylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-72)
A25 ml dry round bottom flask was taken and charged with a solution of (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.72 mmol), cesium carbonate (471.65 mg,1.45 mmol), potassium iodide (120.17 mg,0.72 mmol), 4A molecular sieve (500 mg), 1-bromo-3-phenylpropane (216.17 mg,1.09 mmol) in DMF (4 ml), vented, nitrogen protected, placed in an oil bath at 70℃and stirred for 24H. After the reaction, naturally cooling to room temperature, adding DMF (2 ml) of 3-p-fluorobenzoyl benzaldehyde (132.17 mg,0.58mmol), heating to 45 ℃ in an oil bath, and stirring for reaction for 18.5h. LC-MS monitors the reaction, after the reaction, the reaction liquid is dripped into cold water (70 ml) at 4 ℃, suction filtration is carried out, a filter cake is washed by cold water, suction drying is carried out, methanol and methylene dichloride (1:3) are dissolved, filtration, drying and ultrasonic beating of methanol are carried out, the mixture is placed in a refrigerator at-30 ℃ for standing, suction filtration is carried out, the filter cake is washed by cold methanol, vacuum drying is carried out at 50 ℃ to obtain 98.5mg of yellow solid, and the yield is 24.18%.
1 H NMR(600MHz,DMSO)δ12.03(s,1H),10.35(s,1H),7.94-7.89(m,3H),7.82(s,1H),7.75(d,J＝ 7.72Hz,1H),7.64(d,J＝7.71Hz,1H),7.59(t,J＝7.65Hz,1H),7.40(dd,J＝5.31,12.28Hz,2H),7.30(t, J＝7.56Hz,2H),7.25-7.18(m,3H),6.81(s,1H),6.70(s,1H),4.04(t,J＝7.39Hz,2H),3.22-3.13(m,1H), 2.61(d,J＝7.98Hz,2H),2.07-1.93(m,2H),1.29(d,J＝7.13Hz,6H).MS(ESI):m/z 563.09[M+H] + .Mp: 200-202℃.
Example 73 preparation of (3Z, 6Z) -3- (3- (4-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (3-phenyl) propylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-3-73)
1. (Z) -1-acetyl-3- ((5-isopropyl-1- (3-phenylpropyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
A50 ml dry round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.08 mmol), (3-chloropropyl) benzene (334 mg,2.16 mmol), cesium carbonate (704 mg,2.16 mmol), potassium iodide (180 mg,1.08 mmol), 4A molecular sieve (500 mg), DMF (6 ml), vented, nitrogen protected, placed in an oil bath at 70℃and stirred for 24H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure to obtain orange oily substance, re-dissolving with a mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:5), leaching a filter cake with the mixed solvent (vethanol: vdichloromethane=1:5), concentrating under reduced pressure to obtain 400mg of brown oily mixture, and directly carrying out the next step without purification.
2. (3Z, 6Z) -3- (3- (4-fluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (3-phenyl) propylimidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of a dry reaction flask, (Z) -1-acetyl-3- ((5-isopropyl-1- (3-phenylpropyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.76 mmol), 3- (4-fluorophenoxy) benzaldehyde (164 mg,0.76 mmol), cesium carbonate (371 mg,1.14 mmol), anhydrous sodium sulfate (215 mg,1.52 mmol), DMF (6 mL), displacement nitrogen protection, light shielding, and stirring reaction under 45℃oil bath for 20H. Transferring into a 100ml single-port bottle, washing with ethanol, concentrating under reduced pressure, re-dissolving with mixed solvent of ethanol and dichloromethane (vethanol: vdichloromethane=1:3), suction filtering, eluting filter cake with mixed solvent (vethanol: vdichloromethane=1:3), and concentrating under reduced pressure. Flash purification (methanol: 83%, water: 17%) afforded the product, which was concentrated under reduced pressure to afford 150mg of a pale yellow solid in 35.88% yield.
1 H NMR(500MHz,DMSO-d6)δ11.99(s,1H),10.19(s,1H),7.91(s,1H),7.41(t,J＝7.9Hz,1H),7.29 (dd,J＝15.8,8.2Hz,3H),7.22(d,J＝8.4Hz,4H),7.19(d,J＝5.5Hz,2H),7.14-7.08(m,2H),6.90(dd,J＝ 8.1,2.1Hz,1H),6.71(s,1H),6.69(s,1H),4.04(t,J＝7.3Hz,2H),3.23-3.06(m,1H),2.61(t,J＝7.5,1H), 2.06-1.95(m,2H)，1.29(d,J＝7.1Hz,3H).MS(ESI):m/z 551.4[M+H] + .Mp:161-164℃.
Effect example 1 Compounds for inhibition of cell proliferation assay
Digesting tumor cells (NCI-H460, bxPC-3, HT-29) in logarithmic growth phase, centrifuging, re-spinning fresh medium, counting with cell counting plate, adding 100 μl of medium (containing cells) into each well of 96-well plate according to 2000-6000 cells per wellAfter that, 96-well plates were placed in an incubator (37 ℃,5% co 2 ) Culturing. After the cells were fully adherent, the test samples and Plinabulin were diluted to different concentrations using fresh medium, with 4 wells per concentration. After 72h of drug treatment, 20. Mu.L of MTT with a concentration of 5mg/L is added to each well, and after 3-4h of the mixture is placed in an incubator, the culture medium and MTT are discarded, 100. Mu.L of DMSO is added to each well, and a 96-well plate is placed on a 96-well plate oscillator, so that purple formazan is completely dissolved. Absorbance (OD value) was then measured at a wavelength of 490nm using a microplate reader. The experiment also requires the setting of zeroing wells (blank medium, MTT, DMSO). Cell inhibition = 1- (dosing OD-zeroed OD)/(blank OD-zeroed OD) ×100%.
The results of the cell proliferation inhibition assay of the compounds of the present invention are shown in Table 1, wherein "A" represents the calculated IC 50 Less than 1nM; "B" means the calculated IC 50 1nM to less than 10nM; "C" means the calculated IC 50 10nM to less than 100nM; "D" means the calculated IC 50 Is greater than or equal to 100nM.
TABLE 1 test for inhibition of cell proliferation by the compounds of the present invention
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Note that: NCI-H460 is a human non-small cell lung cancer tumor cell strain, BXPC-3 is a human pancreatic cancer tumor cell strain, and HT-29 is a human colon cancer cell strain. Plinabulin was the positive control. The control group was DMSO without added sample.
Effect example 2 compound solubility experiments
1) Experimental method
About 1mg of the compound was weighed out into a 1.5mL brown EP tube, and 1mL of ultrapure water was added thereto. Vortex shaking, sonication until the compound is no longer dissolved (the solution is cloudy or has suspended particles). Placing into an incubation oscillator, maintaining the temperature (37+ -1deg.C), shaking for 24h at 100r/min, and allowing to reach sufficient dissolution balance. After 24h, the supernatant was rapidly filtered through a 0.45 μm microporous membrane, the primary filtrate was discarded, 200. Mu.L of the subsequent filtrate was taken and diluted with 200. Mu.L of methanol. The assay was repeated at least three times. The peak area was determined by LC-MS sampling according to chromatographic conditions and the equilibrium solubility of each 2, 5-diketopiperazine-imidazole compound in pure water was calculated.
2) Experimental results
The results of the solubility experiments for the compounds are shown in table 2 below:
TABLE 2
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Effect example 3 immunofluorescence experiment
1) Experimental method
1. Preparation of cell climbing tablet: in a super clean bench, laying sterile round cover glass on twelve-hole plate, digesting NPI-H460 cells in logarithmic phase with pancreatin, centrifuging to collect cells, and re-suspending with fresh culture medium to obtain 1×10 5 Cells were added to each well containing sterile coverslips and after cell attachment (about 24 hours), plinabulin (10 nM), PLN-3-28 (2 nM) and PLN-3-41 (2 nM) were added for further incubation for 24 hours.
2. Fixing and sealing the cell climbing sheet: immersing the cell climbing sheet in PBS for 3 times for 3min each time; fixing the slide with 4% paraformaldehyde for 15min, and soaking and washing the slide with PBS for 3min each time; adding 0.5% Triton X-100 prepared with PBS, standing for 20 min, and soaking and washing the slide with PBS for 3 times each for 3min; PBS was discarded, and a 5% cover slip was dipped in normal goat serum and blocked at room temperature.
3. Adding an antibody: the blocking solution was sucked off by the absorbent paper, a sufficient amount of primary antibody (prepared in a certain proportion using PBS) was added dropwise to the dipsticks, and incubated overnight at 4℃in a wet box.
4. Adding a fluorescent secondary antibody: adding PBS to soak and wash the climbing slices for 3 times for 3min each time; after PBS is discarded, diluted fluorescent secondary antibody is added, the mixture is kept stand and incubated for 1h at 37 ℃ in a wet box, and the PBS is slowly shaken to soak and wash the climbing slices for 3 times for 3min each time. (after the addition of the fluorescent secondary antibody, each step is performed in dark place in a dark place)
Dapi counterstained nuclei: the slide was washed 3 times with shaking in PBS (pH 7.4) on a decolorizing shaker for 5min each. And (3) dripping DAPI dye solution into the ring after the slices are slightly dried, and incubating for 10min at room temperature in a dark place.
6. Sealing piece: the slide was washed 3 times with shaking in PBS (pH 7.4) on a decolorizing shaker for 5min each. After the water absorbing paper absorbs the climbing slices, the climbing slices are sealed by anti-fluorescence quenching sealing tablets.
7. And (5) microscopic examination and photographing: the slide was observed under a fluorescence microscope and images were collected. (DAPI ultraviolet excitation wavelength 330-380nm, emission wavelength 420nm, blue light emission, FITC excitation wavelength 465-495nm, emission wavelength 515-555nm, green light emission, CY3 excitation wavelength 510-560, emission wavelength 590nm, red light emission).
2) Experimental results
The IOD values were calculated using software Image Pro Plus 6.0 and the results are shown in table 3 and fig. 1:
TABLE 3 Table 3
Experiments show that: in the blank control group, untreated cells were morphologically normal, microtubule scaffolds were intact, and had regular network filaments. After 24h of compound treatment microtubules were atrophic and even broken. And compared by beta-tubulin fluorescence values, the compounds PLN-3-28 and PLN-3-41 have better microtubule effect than that of Plinablin.
Effect example 4 Western Blot experiment
1) Experimental method
(1) Extraction of cell total protein
NCI-H460 cells in logarithmic growth phase were grown at 1X 10 6 The density of each hole is inoculated into a 6-hole plate, after cells are subjected to wall-attached culture for 24 hours, plinabulin (10 nM), PLN-3-41 (5 nM) and PLN-3-41 (10 nM) are respectively added for treatment, the cells are placed into an incubator for continuous incubation for 24 hours, the culture solution is sucked and washed twice by PBS, RIPA lysate containing protease and phosphatase inhibitor is added on ice for cell lysis, the cells are placed on ice for 30 minutes and then collected in a 1.5ml EP tube, the temperature is 4 ℃, the speed is 12000rpm, the centrifugation is carried out for 10 minutes, and the supernatant is sucked to obtain the total protein of the cells.
(2) Protein concentration determination by BCA method
BSA stock at a concentration of 2mg/ml was diluted to 2, 1, 0.5, 0.25, 0.125, 0.0625mg/ml with distilled water, with a further tube of blank (distilled water). The protein solution after the lysis and centrifugation is diluted with distilled water in a ratio of 1:8. The protein content in a series of BSA solutions with different concentrations and sample protein solutions is determined by the following specific method:
firstly, 25 mu l A solution (prepared by mixing S solution and A solution in a volume of 1:50) is added into each sample tube, then 5 mu l of BSA solution and protein solution with different concentrations are added, after slight shaking and mixing, 200 mu l B solution is quickly added, and the mixture is placed for 15min at room temperature in a dark place. And (3) reading the absorbance value at the wavelength of 562nm by using a spectrophotometer, and carrying out regression curve on the absorbance value of the BSA solution obtained by diluting the standard substance and calculating the protein concentration of the sample to be detected by using the OD value of the sample to be detected.
(3) Glue filling
(1) And (5) cleaning the glue-filled glass plate by distilled water, and vertically airing.
(2) 10ml of 15% separating gel is prepared according to the method, 10 mu l of TEMED and 100 mu l of 10% ammonium persulfate are added, the gel is immediately poured after uniform mixing, the liquid surface is sealed by isopropanol to remove bubbles and isolate air until the separating gel is completely solidified after 2-3 mm of the lower edge of the comb, and the mixture is left standing for 45 minutes at room temperature.
(3) After the gel was completely coagulated, the top isopropanol was decanted, washed three times with deionized water, and the water was sucked dry with filter paper.
(4) 5ml of 5% concentrated gel is prepared, 5 μl of TEMED and 50 μl of 10% APS are added, the gel is immediately poured in after mixing, the gel is poured to the top, a Teflon comb is vertically inserted, and the gel is left to stand for 20 minutes at room temperature until the concentrated gel is solidified.
(5) After the concentrated gel is completely solidified, the comb is pulled out, the gel is placed in an electrophoresis tank, electrophoresis buffer solution is added, and the sample loading hole is washed by the electrophoresis buffer solution to remove bubbles.
(4) Electrophoresis
(1) And (3) taking each treatment histone extracting solution, adjusting the protein concentration, and mixing with an equal volume of 1X loading buffer solution to obtain the loading solution.
(2) Boiling the sample in 100deg.C boiling water for 5min to denature protein, quenching on ice, and centrifuging at 3000 rpm for 1min.
(3) 50. Mu.g of sample solution was applied to each well, leaving one well with 5. Mu.l of pre-stained Marker. Filling up electrophoresis buffer, covering a tank cover, switching on a power supply, performing constant voltage electrophoresis with 80v for about 15min, performing constant voltage electrophoresis with 120v when the indicator bromine Finnish enters the separation gel, and turning off the power supply when the indicator reaches a position about 0.5cm from the lower end of the gel, and taking out the gel plate.
(5) Transfer protein and immunoassay
(1) Immediately before the end of electrophoresis, PVDF membrane was immersed in methanol for 15s in advance, then rinsed with transfer buffer for 2min, left to stand for 5min and then subjected to subsequent operations.
(2) And (3) prying the glue in water, and soaking the glue in a transfer film buffer solution for 15min after repairing the glue.
(3) The method comprises the steps of preparing a transfer film sandwich according to the sequence of black surface (negative electrode), sponge, filter paper, glue, PVDF film, filter paper, sponge and red surface (positive electrode), and spreading the transfer film sandwich after spreading each layer, and removing bubbles and spreading the other layer. The preparation of sandwiches in transfer buffer avoids the generation of bubbles.
(4) Connecting the positive electrode and the negative electrode, putting the transfer box into an electrotransfer instrument according to the direction from the film to the positive electrode, and adding a film transfer buffer solution.
(5) The electrotransport device was placed in ice water and 100mA was constantly flowing through the membrane for 90min.
(6) After the transfer, the PVDF membrane was rapidly removed and blocked with 5% BSA for 2h at room temperature.
(7) The membrane was removed and washed 5min X3 times with TBST on a shaker.
(8) TBST diluted caspase-3 (diluted antibodies according to the brand instructions) and GAPDH (diluted antibodies according to the brand instructions) were added to the incubation bags and incubated overnight at 4 ℃.
(9) TBST was washed 5min X3 times and incubated with horseradish peroxidase (HRP) -labeled goat anti-rabbit secondary antibody (Biyun brand, 1:7000) or horseradish peroxidase (HRP) -labeled goat anti-mouse secondary antibody (Biyun brand, 1:7000) for 2h at room temperature.
The membrane was washed 5min X3 times with TBST. The film was reacted with a chemiluminescent detection reagent (reagent a: reagent b=1:1) for 2min and developed by exposure to light in a chemiluminescent developer.
2) Experimental results
The results are shown in Table 4 below:
TABLE 4 Table 4
Experimental results: after 24H of treatment of each sample, the relative gray scale values of Caspase-3/GAPDH proteins were compared, and PLN-3-41 showed a stronger effect in promoting apoptosis of NCI-H460 cell line than Plinabulin.

Claims (14)

1. A compound as shown in formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing:
wherein,
R 1 is hydrogen, deuterium, halogen, C 1 -C 8 Alkyl, C substituted by one or more halogens 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C substituted by one or more halogens 1 -C 8 Alkoxy, C 2 -C 8 Alkenyl, benzoyl substituted with one or more halogens, phenoxy, or "phenoxy substituted with one or more halogens";
R 1a 、R 1b and R is 1c Independently hydrogen, deuterium, halogen or C 1 -C 8 An alkyl group;
alternatively, R 1 、R 1a Together with the carbon atoms to which they are attached form C 6 -C 10 Is selected from one or more of N, O and S, 3-10 membered heteroaryl with 1-5 heteroatoms;
alternatively, R 1 、R 1b Together with the carbon atoms to which they are attached form C 6 -C 10 Is selected from one or more of N, O and S, 3-10 membered heteroaryl with 1-5 heteroatoms;
alternatively, R 1b 、R 1c Together with the carbon atoms to which they are attached form C 6 -C 10 Is selected from one or more of N, O and S, 3-10 membered heteroaryl with 1-5 heteroatoms;
R 2 is hydrogen, deuterium, C substituted by one or more halogens 1 -C 8 Alkyl, C 1 -C 8 Alkyl or C 3 -C 10 Cycloalkyl;
l is a hetero atom selected from one or more of N, O, S and Se, C with 1-4 hetero atoms 1 -C 8 Alkylene ", substituted by one or more R 2-2 The substituted hetero atom is one or more of N, O, S and Se, and the hetero atom number is C of 1-4 1 -C 8 Alkylene ", C 1 -C 8 Alkylene or "by one or more R 2-1 Substituted C 1 -C 8 An alkylene group ";
R 2-1 and R is 2-2 Independently deuterium, OH, C 1 -C 8 Alkoxy or "by one or more R 2-1-1 Substituted C 1 -C 8 Alkoxy ";
R 2-1-1 independently C 3 -C 10 Cycloalkyl, C 6 -C 10 Aryl, or "heteroatom selected from one or more of N, O and S, 3-10 membered heteroaryl with 1-5 heteroatoms";
ring A is C 6 -C 10 Aryl, substituted by one or more R A-1 Substituted C 6 -C 10 Aryl, 3-10 membered heteroaryl having 1-5 heteroatoms selected from one or more of N, O and S, substituted with one or more R A-2 The substituted hetero atom is selected from one or more of N, O and S, 3-10 membered heteroaryl with 1-5 hetero atoms, C 3 -C 10 Cycloalkyl, substituted by one or more R A-3 Substituted C 3 -C 10 Cycloalkyl, 3-to 10-membered heterocycloalkyl having 1 to 5 heteroatoms selected from one or more of N, O and S, or "substituted by one or more R A-4 The substituted hetero atom is selected from one or more of N, O and S, and the hetero atom number is 3-10 membered heterocyclic alkyl';
R A-1 、R A-2 、R A-3 and R is A-4 Independently deuterium, halogen, hydroxy, cyano, nitro, C 1 -C 8 Alkyl, C substituted by one or more halogens 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C substituted by one or more halogens 1 -C 8 Alkoxy, C 3 -C 10 Cycloalkyl, C 6 -C 10 Aryl, substituted by one or more R A-1-1 Substituted C 6 -C 10 Aryl or-C (=o) -R 3-1-2 ；
R 3-1-2 Is C 1 -C 8 Alkoxy, C substituted by one or more halogens 1 -C 8 Alkoxy, C 1 -C 8 Alkyl, C substituted by one or more halogens 1 -C 8 Alkyl, C 6 -C 10 Aryl or "formed by one or more R 3-1-2-1 Substituted C 6 -C 10 Aryl ";
R A-1-1 and R is 3-1-2-1 Independently halogen, hydroxy, cyano, nitro, C 1 -C 8 Alkyl, C substituted by one or more halogens 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C substituted by one or more halogens 1 -C 8 Alkoxy or C 3 -C 10 NaphtheneA base;
the compound shown in the formula (I) is not any one of the following compounds:
2. The compound of formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing as claimed in claim 1, wherein the compound of formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing satisfies one or more of the following conditions:
(1) When R is 1 When halogen, the halogen is fluorine;
(2) When R is 1 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 An alkyl group;
(3) When R is 1 For C substituted by one or more halogens 1 -C 8 In the case of alkyl, said C substituted by one or more halogens 1 -C 8 Alkyl is C substituted by one or more halogens 1 -C 4 An alkyl group;
(4) When R is 1 Is C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is C 1 -C 4 An alkoxy group;
(5) When R is 1 For C substituted by one or more halogens 1 -C 8 Alkoxy, said C being substituted by one or more halogens 1 -C 8 Alkoxy is C substituted by one or more halogens 1 -C 4 An alkoxy group;
(6) When R is 1 In the case of benzoyl substituted with one or more halogens, the halogen is fluorine;
(7) When R is 1 In the case of phenoxy substituted with one or more halogens, the halogen is fluorine;
(8) When R is 1a 、R 1b And R is 1c When independently halogen, the halogen is fluorine;
(9) When R is 1a 、R 1b And R is 1c Independently C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 An alkyl group;
(10) When R is 1 、R 1a Together with the carbon atoms to which they are attached form C 6 -C 10 The C is aryl 6 -C 10 Aryl of (2) is phenyl;
(11) When R is 1 、R 1a When "heteroatom selected from one or more of N, O and S, 3-to 10-membered heteroaryl having 1 to 5 heteroatoms" is formed together with the carbon atom to which they are attached, the "heteroatom selected from one or more of N, O and S, 3-to 10-membered heteroaryl having 1 to 5 heteroatoms" is "heteroatom selected from one or more of N, O and S, 5-to 6-membered heteroaryl having 1 to 2 heteroatoms";
(12) When R is 2 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 An alkyl group;
(13) When R is 2 Is C 3 -C 10 In the case of cycloalkyl, the C 3 -C 10 Cycloalkyl radicals are C 3 -C 6 Cycloalkyl;
(14) When L is "hetero atom selected from one or more of N, O, S and Se, the hetero atom number is 1-4C of each 1 -C 8 When the hetero alkyl is, the hetero atom is one or more of N, O, S and Se, and the hetero atom number is C of 1-4 1 -C 8 The hetero-alkyl group is C with hetero atoms of 1-2 and is one or more selected from O and S 1 -C 5 An alkylene group ";
(15) When L is C 1 -C 8 In the case of alkylene, the C 1 -C 8 Alkylene is C 1 -C 5 An alkylene group;
(16) When ring A is C 6 -C 10 Aryl or "formed by one or more R A-1 Substituted C 6 -C 10 Aryl ", the C 6 -C 10 Aryl is phenyl or naphthyl;
(17) When ring A is "heteroatom selected from one or more of N, O and S, 3-to 10-membered heteroaryl having 1-5 heteroatoms" or "substituted with one or more R A-2 When the substituted hetero atom is selected from one or more of N, O and S and 3-10 membered heteroaryl with 1-5 hetero atoms is selected from one or more of N, O and S, the 3-10 membered heteroaryl with 1-5 hetero atoms is selected from one or more of N, O and S and 5-10 membered heteroaryl with 1-2 hetero atoms is selected from "substituted hetero atoms;
(18) When ring A is C 3 -C 10 Cycloalkyl or "substituted by one or more R A-3 Substituted C 3 -C 10 Cycloalkyl ", C 3 -C 10 Cycloalkyl radicals are C 3 -C 6 Cycloalkyl;
(19) When ring A is "heteroatom selected from one or more of N, O and S, 3-10 membered heterocycloalkyl having 1-5 heteroatoms" or "substituted with one or more R A-4 A substituted heteroatom selected from one or more of N, O and S, a 3-to 10-membered heterocycloalkyl group having 1 to 5 heteroatoms selected from one or more of N, O and S, 3-10 membered heterocycloalkyl having 1 to 5 heteroatoms "is" a 5-6 membered heterocycloalkyl having 1 to 2 heteroatoms "selected from one or more of N, O and S;
(20) When R is A-1 、R A-2 、R A-3 And R is A-4 When independently halogen, the halogen is fluorine, chlorine or bromine;
(21) When R is A-1 、R A-2 、R A-3 And R is A-4 Independently C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 An alkyl group;
(22) When R is A-1 、R A-2 、R A-3 And R is A-4 Independently C substituted by one or more halogens 1 -C 8 In the case of alkyl, said C substituted by one or more halogens 1 -C 8 Alkyl is C substituted by one or more halogens 1 -C 4 An alkyl group;
(23) When R is A-1 、R A-2 、R A-3 And R is A-4 Independently C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is C 1 -C 4 An alkoxy group;
(24) When R is A-1 、R A-2 、R A-3 And R is A-4 Independently C substituted by one or more halogens 1 -C 8 Alkoxy, said C being substituted by one or more halogens 1 -C 8 Alkoxy is C substituted by one or more halogens 1 -C 4 An alkoxy group;
(25) When R is A-1 、R A-2 、R A-3 And R is A-4 Independently C 6 -C 10 Aryl or "formed by one or more R A-1-1 Substituted C 6 -C 10 Aryl ", the C 6 -C 10 Aryl is phenyl;
(26) When R is 3-1-2 Is C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is C 1 -C 4 An alkoxy group;
(27) When R is 3-1-2 Is C 6 -C 10 Aryl or "formed by one or more R 3-1-2-1 Substituted C 6 -C 10 Aryl ", the C 6 -C 10 Aryl is phenyl.
3. The compound of formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing as claimed in claim 1, wherein the compound of formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing satisfies one or more of the following conditions:
(1) When R is 1 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is methyl;
(2) When R is 1 For C substituted by one or more halogens 1 -C 8 In the case of alkyl, said C substituted by one or more halogens 1 -C 8 Alkyl is trifluoromethyl;
(3) When R is 1 Is C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is methoxy;
(4) When R is 1 For C substituted by one or more halogens 1 -C 8 Alkoxy, said C being substituted by one or more halogens 1 -C 8 Alkoxy is trifluoromethoxy;
(5) When R is 1 In the case of benzoyl substituted by one or more halogens, the benzoyl substituted by one or more halogens is
(6) When R is 1 In the case of a phenoxy group substituted by one or more halogens, the phenoxy group substituted by one or more halogens is
(7) When R is 1a 、R 1b And R is 1c Independently C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is methyl;
(8) When R is 1 、R 1a Together with the carbon atoms to which they are attached form a "hetero atomWhen the heteroatom is 3-10 membered heteroaryl with 1-5 heteroatoms selected from one or more of N, O and S, the heteroatom is 3-10 membered heteroaryl with 1-5 heteroatoms selected from one or more of N, O and S, and is pyridyl;
(9) When R is 2 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is methyl, ethyl, isopropyl or tert-butyl;
(10) When R is 2 Is C 3 -C 10 In the case of cycloalkyl, the C 3 -C 10 Cycloalkyl is cyclopropyl;
(11) When L is "hetero atom(s) selected from one or more of N, O, S and Se, C having 1-4 hetero atoms 1 -C 8 When the hetero alkyl is, the hetero atom is one or more of N, O, S and Se, and the hetero atom number is C of 1-4 1 -C 8 Alkylene "is
(12) When L is C 1 -C 8 In the case of alkylene, the C 1 -C 8 Alkylene is methylene,
(13) When ring A is C 6 -C 10 Aryl or "formed by one or more R A-1 Substituted C 6 -C 10 Aryl ", the C 6 -C 10 Aryl is phenyl;
(14) When ring A is "heteroatom selected from one or more of N, O and S, 3-to 10-membered heteroaryl having 1-5 heteroatoms" or "substituted with one or more R A-2 When the substituted hetero atom is selected from one or more of N, O and S and 3-10 membered heteroaryl with 1-5 hetero atoms is selected from one or more of N, O and S, the 3-10 membered heteroaryl with 1-5 hetero atoms is pyridyl, indolyl, indolinyl, pyrrolyl or tetrahydroquinolinyl;
(15) When ring A is C 3 -C 10 NaphtheneRadicals or "by one or more R A-3 Substituted C 3 -C 10 Cycloalkyl ", C 3 -C 10 Cycloalkyl is cyclopentylalkyl;
(16) When ring A is "heteroatom selected from one or more of N, O and S, 3-10 membered heterocycloalkyl having 1-5 heteroatoms" or "substituted with one or more R A-4 When the substituted heteroatom is selected from one or more of N, O and S and 3-10 membered heterocyclic alkyl with 1-5 heteroatoms, the heteroatom is selected from one or more of N, O and S, and the 3-10 membered heterocyclic alkyl with 1-5 heteroatoms is pyrrolidinyl or piperidinyl;
(17) When R is A-1 、R A-2 、R A-3 And R is A-4 Independently C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is methyl;
(18) When R is A-1 、R A-2 、R A-3 And R is A-4 Independently C substituted by one or more halogens 1 -C 8 In the case of alkyl, said C substituted by one or more halogens 1 -C 8 Alkyl is trifluoromethyl;
(19) When R is A-1 、R A-2 、R A-3 And R is A-4 Independently C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is methoxy;
(20) When R is A-1 、R A-2 、R A-3 And R is A-4 Independently C substituted by one or more halogens 1 -C 8 Alkoxy, said C being substituted by one or more halogens 1 -C 8 Alkoxy is trifluoromethoxy;
(21) When R is 3-1-2 Is C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is methoxy.
4. The compound of formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing as claimed in claim 1, wherein the compound of formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing satisfies one or more of the following conditions:
(1) When ring A is "heteroatom selected from one or more of N, O and S, 3-to 10-membered heteroaryl having 1-5 heteroatoms" or "substituted with one or more R A-2 When the substituted hetero atom is selected from one or more of N, O and S and 3-10 membered heteroaryl with 1-5 hetero atoms is selected from one or more of N, O and S, 3-10 membered heteroaryl with 1-5 hetero atoms is
(2) When ring A is "heteroatom selected from one or more of N, O and S, 3-10 membered heterocycloalkyl having 1-5 heteroatoms" or "substituted with one or more R A-4 When the substituted hetero atom is selected from one or more of N, O and S and 3-10 membered heterocycloalkyl with 1-5 hetero atoms, the "hetero atom is selected from one or more of N, O and S and 3-10 membered heterocycloalkyl with 1-5 hetero atoms" is
5. The compound of formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing as claimed in claim 1, wherein the compound of formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing satisfies one or more of the following conditions:
(1)R 1 Is hydrogen, halogen, benzoyl substituted with one or more halogens, or "phenoxy substituted with one or more halogens";
(2)R 1a hydrogen or halogen;
(3)R 1b is hydrogen;
(4)R 1c hydrogen or halogen;
(5)R 2 is hydrogen, C substituted by one or more halogens 1 -C 8 Alkyl, C 1 -C 8 Alkyl or C 3 -C 10 Cycloalkyl;
(6) L is a hetero atom selected from one or more of N, O, S and Se, C with 1-4 hetero atoms 1 -C 8 Alkylene "or C 1 -C 8 An alkylene group;
(7) Ring A is C 6 -C 10 Aryl, substituted by one or more R A-1 Substituted C 6 -C 10 Aryl, one or more hetero atoms selected from N, O and S, 3-10 membered heteroaryl with 1-5 hetero atoms, C 3 -C 10 Cycloalkyl or "heteroatom is selected from one or more of N, O and S, 3-10 membered heterocycloalkyl having 1-5 heteroatoms";
(8)R A-1 independently halogen, cyano, nitro, C 1 -C 8 Alkyl, C substituted by one or more halogens 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C substituted by one or more halogens 1 -C 8 Alkoxy, C 6 -C 10 Aryl or-C (=o) -R 3-1-2 ；
(9)R 3-1-2 Is C 1 -C 8 Alkoxy or C 6 -C 10 Aryl groups.
6. The compound of formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing as claimed in claim 5 wherein the compound of formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing meets one or more of the following conditions:
(1)R 1 Is hydrogen, F,
(2)R 2 For C substituted by one or more halogens 1 -C 8 Alkyl, C 1 -C 8 Alkyl or C 3 -C 10 Cycloalkyl;
(3) L is C 1 -C 8 An alkylene group;
(4) Ring A is C 6 -C 10 Aryl, substituted by one or more R A-1 Substituted C 6 -C 10 Aryl or 'hetero atom is selected from one or more of N, O and S, and the hetero atom number is 1-2, namely 5-6 membered heteroaryl';
(5)R A-1 independently halogen, cyano, nitro, C 1 -C 8 Alkyl, C substituted by one or more halogens 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C substituted by one or more halogens 1 -C 8 Alkoxy or-C (=o) -R 3-1-2 ；
(6)R 3-1-2 Is C 1 -C 8 An alkoxy group.
7. The compound of formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing as claimed in claim 1, wherein the compound of formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing satisfies one or more of the following conditions:
(1)is->
(2) Ring A is
8. The compound of formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing as claimed in claim 1, wherein the compound of formula (I) is any one of the following:
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9. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 8, comprising the steps of: the compound shown in the formula (II) and the compound shown in the formula (III) undergo condensation reaction as shown below to obtain the compound shown in the formula (I);
therein, L, R 1 、R 1a 、R 1b 、R 1c 、R 2 And ring a is as defined in any one of claims 1 to 8.
10. A compound of formula (II):
therein, L, R 2 And ring a is as defined in any one of claims 1 to 8;
the compound shown in the formula (II) is not any one of the following compounds:
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11. the compound shown as the formula (II) is any one of the following compounds:
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12. a pharmaceutical composition comprising a compound of formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate of any of the foregoing as claimed in any one of claims 1 to 8, and a pharmaceutically acceptable adjuvant.
13. Use of a compound of formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate of any of the foregoing, or a pharmaceutical composition according to claim 12, according to any one of claims 18, for the manufacture of a medicament for the prophylaxis and/or treatment of cancer, preferably one or more of lung cancer, pancreatic cancer, colon cancer and liver cancer.
14. Use of a compound of formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate of any of the foregoing, according to any one of claims 1 to 8, or a pharmaceutical composition according to claim 12, for the preparation of a tubulin inhibitor.
CN202210689551.8A 2022-06-16 2022-06-16 2, 5-diketopiperazine-imidazole compound, preparation method and application thereof Pending CN117285512A (en)

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