CN117285516A - Dehydrogenated phenyl achyranthis statin compound, preparation method and application thereof - Google Patents

Dehydrogenated phenyl achyranthis statin compound, preparation method and application thereof Download PDF

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CN117285516A
CN117285516A CN202210689557.5A CN202210689557A CN117285516A CN 117285516 A CN117285516 A CN 117285516A CN 202210689557 A CN202210689557 A CN 202210689557A CN 117285516 A CN117285516 A CN 117285516A
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alkyl
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compound
substituted
methylene
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请求不公布姓名
徐赟
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Dalian Wanzhong Yisheng Health Co ltd
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Dalian Wanzhong Yisheng Health Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/18—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The invention discloses a dehydrogenated phenyl achyranthis statin compound, a preparation method and application thereof. Specifically disclosed are compounds represented by 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

Dehydrogenated phenyl achyranthis statin compound, preparation method and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a dehydrogenated phenyl achyranthis statin 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 better stability, but has poor water solubility and large toxic and side effects, and still needs to continuously develop the microtubulin inhibitor with high activity and good solubility.
Disclosure of Invention
Aiming at the defect that the structure of the existing tubulin inhibitor is single, the invention provides a dehydrogenated phenyl achyranthis statin 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 H, 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 H, 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 Or "heteroatom (S)" selected from one or more of N, O and S3-10 membered heteroaryl ";
the ring C is
R 2 Is H, halogen or benzyl;
R 3 to be covered by one or more R 3-1 Substituted C 1 -C 8 Alkyl, C 2 -C 8 Alkynyl or C 2 -C 8 Alkenyl groups;
R 3-1 independently is hydroxy, C 1 -C 8 Alkoxy, -OTBS, NR 3-1-1 R 3-1-2 、or-O-C (=o) -R 3-1-3 ；
R 3-1-1 And R is 3-1-2 H, C independently 1 -C 8 Alkyl or-C (=o) -O-R 3-1-1-1 ；R 3-1-1-1 Is C 1 -C 8 Alkyl or benzyl;
R 3-1-3 is C 1 -C 8 Alkyl or by one or more R 3-1-3-1 Substituted C 6 -C 10 An aryl group; r is R 3-1-3-1 Independently OH or benzyloxy;
R 4 is C 1 -C 8 Alkyl or C 6 -C 10 An aryl group;
R 5 and R is 6 The definition of (2) satisfies the following condition: (1) R is R 5 Is H, R 6 Is C 6 -C 10 An aryl group; or (2) R 5 Is C 6 -C 10 Aryl, R 6 Is C 1 -C 8 Alkyl or C 6 -C 10 An aryl group;
R 7 and R is 8 Is H or R 7 And R is 8 Together with the carbon atoms to which they are attached form C 6 -C 10 Aryl of (a);
R 9 is C 1 -C 8 Alkyl, C substituted by one or more halogens 1 -C 8 Alkyl, C 2 -C 8 Alkenyl or benzyl;
R 10 、R 11 、R 12 and R is 13 Independently H, halogen, C 1 -C 8 Alkoxy, substituted by one or more R 11-1 Substituted C 1 -C 8 Alkoxy or C 1 -C 8 Alkyl, R 10 、R 11 、R 12 And R is 13 Not simultaneously H, or R 10 、R 11 Together with the carbon atoms to which they are attached form C 6 -C 10 Aryl, or R 11 、R 12 Together with the carbon atoms to which they are attached form C 6 -C 10 Aryl, or R 12 、R 13 Together with the carbon atoms to which they are attached form C 6 -C 10 An aryl group;
R 11-1 independently C 3 -C 10 Cycloalkyl;
R 14 is C 1 -C 8 Alkyl, C substituted by one or more halogens 1 -C 8 Alkyl, C 2 -C 8 Alkenyl or benzyl;
R 15 、R 16 and R is 17 Independently H, halogen, C 1 -C 8 Alkoxy, substituted by one or more R 11-1 Substituted C 1 -C 8 Alkoxy or C 1 - C 8 An alkyl group.
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 scheme of the invention"), when R 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 With itThe carbon atoms to which they are attached together 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 In the case of halogen, the halogen is chlorine, bromine or iodine.
In one embodiment of the invention, when R 3 To be covered by one or more R 3-1 Substituted C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 Alkyl groups such as ethyl or n-propyl.
In one embodiment of the invention, when R 3 Is C 2 -C 8 In the case of alkynyl, the said C 2 -C 8 Alkynyl is C 2 -C 4 Alkynyl radicals, e.g. propargyl
In one embodiment of the invention, when R 3 Is C 2 -C 8 Alkenyl, the C 2 -C 8 Alkenyl group is C 2 -C 4 Alkenyl radicals, e.g. allyl
In one embodiment of the invention, when R 3-1 Independently C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is C 1 -C 4 Alkoxy, such as methoxy or ethoxy.
In one embodiment of the invention, when R 3-1-1 And R is 3-1-2 Independent and independentThe ground 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 3-1-1-1 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 3-1-3 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 Alkyl groups such as t-butyl.
In one embodiment of the invention, when R 3-1-3 To be covered by one or more R 3-1-3-1 Substituted C 6 -C 10 Aryl, the C 6 -C 10 Aryl is phenyl.
In one embodiment of the invention, when R 4 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 Alkyl groups such as isopropyl or tert-butyl.
In one embodiment of the invention, when R 4 Is C 6 -C 10 Aryl, the C 6 -C 10 Aryl is phenyl.
In one embodiment of the invention, when R 7 And R is 8 Together with the carbon atoms to which they are attached form C 6 -C 10 The C is aryl 6 -C 10 Aryl is phenyl.
In one embodiment of the invention, when R 9 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 Alkyl, for example methyl, ethyl, n-propyl, isopropyl or n-butyl, and also for example methyl, ethyl or isopropyl.
In one embodiment of the invention, when R 9 For C substituted by one or more halogens 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 Alkyl groups such as methyl.
At the bookIn one embodiment of the invention, when R 9 Is C 2 -C 8 Alkenyl, the C 2 -C 8 Alkenyl group is C 2 -C 4 Alkenyl radicals, e.g. allyl
In one embodiment of the invention, when R 10 、R 11 、R 12 And R is 13 When independently halogen, the halogen is bromine.
In one embodiment of the invention, when R 10 、R 11 、R 12 And R is 13 Independently C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is C 1 - C 4 Alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy or n-butoxy.
In one embodiment of the invention, when R 10 、R 11 、R 12 And R is 13 Independently is one or more R 11-1 Substituted C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is C 1 -C 4 Alkoxy, such as methoxy, ethoxy or n-propoxy.
In one embodiment of the invention, when R 10 、R 11 、R 12 And R is 13 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 10 、R 11 Together with the carbon atoms to which they are attached form C 6 -C 10 Aryl, the C 6 -C 10 Aryl is phenyl.
In one embodiment of the invention, when R 11 、R 12 Together with the carbon atoms to which they are attached form C 6 -C 10 Aryl, the C 6 -C 10 Aryl is phenyl.
In one embodiment of the invention, when R 12 、R 13 To which they are connectedTogether form C 6 -C 10 Aryl, the C 6 -C 10 Aryl is phenyl.
In one embodiment of the invention, when R 11-1 Independently C 3 -C 10 In the case of cycloalkyl, the C 3 -C 10 Cycloalkyl radicals are C 5 -C 6 Cycloalkyl groups such as cyclohexenyl.
In one embodiment of the invention, when R 14 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, R 1 Is H, benzoyl substituted with one or more halogens, phenoxy or "phenoxy substituted with one or more halogens", preferably R 1 Is benzoyl, benzoyl substituted with one or more halogens, or "phenoxy substituted with one or more halogens".
In one embodiment of the invention, R 1a 、R 1b And R is 1c Independently H.
In one embodiment of the invention, R 2 Is H or halogen.
In one embodiment of the invention, R 3-1 Independently is hydroxy, C 1 -C 8 Alkoxy, NR 3-1-1 R 3-1-2 、or-O-C (=o) -R 3-1-3 。
In one embodiment of the invention, R 3-1-3 Is C 1 -C 8 An alkyl group.
In one embodiment of the invention, R 3-1-1 And R is 3-1-2 Independently H or-C (=O) -O-R 3-1-1-1 。
In one embodiment of the invention, R 4 Is C 1 -C 8 An alkyl group.
In one embodiment of the invention, R 7 And R is 8 H.
In the present inventionIn one embodiment, R 9 Is C 1 -C 8 An alkyl group.
In one embodiment of the invention, R 10 Is H or C 1 -C 8 An alkyl group.
In one embodiment of the invention, R 11 H, C of a shape of H, C 1 -C 8 Alkoxy or C 1 -C 8 Alkyl, or R 11 、R 12 Together with the carbon atoms to which they are attached form C 6 -C 10 Aryl groups.
In one embodiment of the invention, R 12 H, C of a shape of H, C 1 -C 8 Alkoxy or C 1 -C 8 Alkyl, or R 11 、R 12 Together with the carbon atoms to which they are attached form C 6 -C 10 Aryl groups.
In one embodiment of the invention, R 13 Is H, methoxy or C 1 -C 8 An alkyl group.
In one embodiment of the invention, R 14 Is C 1 -C 8 An alkyl group.
In one embodiment of the invention, R 15 、R 16 And R is 17 Independently H.
In one aspect of the present invention,is->
In one aspect of the present invention,is->In one aspect of the present invention,
is->
In one aspect of the present invention,is->
In one aspect of the present invention,is->
The present invention also provides a compound as shown below, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing (referring to a compound as shown below, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof):
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the pharmaceutically acceptable salt of the compound shown in the formula (I) can be a salt prepared by the compound shown in the formula (I) and a pharmaceutically acceptable acid, wherein the pharmaceutically acceptable acid can be an acid conventional in the art, such as an inorganic acid or an organic acid, the inorganic acid is preferably hydrochloric acid, and the organic acid is preferably methanesulfonic acid. Preferably, the pharmaceutically acceptable acid is hydrochloric acid. More preferably, the pharmaceutically acceptable salt of the compound shown in the formula (I) is a salt formed by the compound shown in the formula (I) and hydrochloric acid in a molar ratio of 1:2.
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);
wherein the ring C, R 1 、R 1a 、R 1b And R is 1c Is as defined in any one of the preceding claims.
The invention also provides a compound shown as a formula (II):
wherein ring C is as defined in any one of the preceding claims.
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: performing condensation reaction of 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 ring C is as defined in any one of the preceding claims.
The invention also provides a pharmaceutical composition comprising the above compound, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate of any of the foregoing, and a pharmaceutical adjuvant.
In certain embodiments, the pharmaceutical excipients do not comprise a cosolvent.
The invention also provides application of the compound, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate of any of the foregoing, or a pharmaceutical composition in preparing medicines. Preferably, the medicament is for the prevention and/or treatment of cancer. The cancer is preferably one or more of lung cancer, pancreatic cancer and colon 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, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate of any of the foregoing, 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 comprising administering to a patient a therapeutically effective amount of a compound as described above, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing, or a pharmaceutical composition as described above.
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 or therapeutically effective amount is that which will trigger the tissue, system, or other interrogation by a researcher, veterinarian, medical doctor or other clinicianAn amount of a biologically or medically responsive compound or pharmaceutical composition of an animal or human. 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. The "solvate of a pharmaceutically acceptable salt" includes, but is not limited to, the hydrochloride monohydrate of the compound of the invention.
When any variable (e.g. R 3-1 ) 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 3-1 The radical is substituted, that is to say, it may be substituted by up to 3R 3-1 Substituted, at position R 3-1 Definition of (d) and the remaining position R 3-1 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 "alkoxy" refers to a 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 "alkynyl" refers to a straight or branched hydrocarbon group (e.g., C 2 -C 8 Alkynyl radicals, also e.g. C 2 -C 4 Alkynyl). The one or more carbon-carbon triple bonds may be internal or terminal, e.g. a triple bond internal to propynyl groupOr the triple bond is at the terminal propynyl +.>Etc.
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 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 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 dehydrogenated phenyl-achyranthis 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 preparation of (3Z, 6Z) -3- ((5-phenyl-1H-imidazol-4-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-1)
1) Synthesis of ethyl 2-chloro-3-oxo-3-phenylpropionate 6
A100 mL dry round bottom flask was taken, ethyl benzoylacetate (10.0 g,52.1 mmol) was dissolved in dry DCM (20 mL), placed in a cold well at 0deg.C and stirred for 15min, then sulfonyl chloride (7.72 g,57.2 mmol) was slowly added dropwise, after which the flask was moved to room temperature and stirred, the reaction solution was allowed to warm to room temperature, the round bottom flask was transferred to an oil bath and reacted at 35deg.C under reflux for 6h. After the reaction was completed, the LC-MS monitored, 200mL of methylene chloride was added to the reaction solution, and the solution was transferred to a separatory funnel, and the organic phase was washed with saturated aqueous sodium carbonate (30 mL), water (30 mL) and saturated brine (30 mL) in this order, the aqueous phase was combined, the aqueous phase was back-extracted 3 times with methylene chloride (100 ml×3), the organic phase was combined, and dried by adding anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to obtain 11.6g of reddish brown clear liquid with the yield of 99.0%. 1 H NMR(500MHz,DMSO-d 6 )δ8.03(d,J＝7.3Hz,2H),7.74(t,J＝7.4Hz,1H),7.60(t,J＝7.9Hz,1H),6.63 (s,1H),4.20(q,J＝7.1Hz,2H),1.14(t,J＝7.1Hz,3H).MS(ESI)m/z:[M+Na] + Calculated value C 11 H 11 ClNaO 3 249.03, found 248.85.
2) Synthesis of 5-phenyl-1H-imidazole-4-carboxylic acid ethyl ester 11b
A100 mL dry round bottom flask was taken, ethyl 2-chloro-3-oxo-3-phenylpropionate 6 (11.6 g,51.5 mmol), formamide (23.2 g,515 mmol) and water (1.85 g,103 mmol) were added sequentially and the mixture was placed in an oil bath at 180deg.C for reflux reaction for 14h. After the reaction, cooling the reaction solution to room temperature, adding water (150 mL) into the reaction solution to generate brown solid, adding ethyl acetate (200 mL x 3) for extraction for 3 times, combining organic phases, washing the organic phases with saturated saline (200 mL x 3), back-extracting the aqueous phases with ethyl acetate (200 mL x 3) for 3 times, combining the organic phases, and adding anhydrous sodium sulfate for drying. Filtering, concentrating the filtrate under reduced pressure to solid, adding a proper amount of water into the crude product, pulping and purifying, filtering, washing a filter cake with water (100 mL 3), and vacuum drying the filter cake at 50 ℃ to obtain brown solid 5.08g with a yield of 45.6%. 1 H NMR(400 MHz,DMSO-d 6 )δ7.85(s,1H),7.77(s,1H),7.39(dt,J＝13.3,6.9Hz,4H),4.21(q,J＝6.8Hz,2H),1.22(t, J＝9.4Hz,3H).MS(ESI)m/z:[M+H] + Calculated value C 12 H 13 N 2 O 2 217.10, found 216.88.
3) Synthesis of 5-phenyl-1H-imidazole-4-methanol 12b
Ethyl 5-phenyl-1H-imidazole-4-carboxylate 11b (5.08 g,23.5 mmol) was taken as the starting material for this step of reaction, and compound 12b was synthesized according to the procedure for preparation of compound 12a, giving 5.00g of tan solid with a yield of 99.9%. MS (ESI) M/z: [ M+H ]] + Calculated value C 10 H 11 N 2 O175.09, found 174.72.
4) Synthesis of 5-phenyl-1H-imidazole-4-carbaldehyde 13b
5-phenyl-1H-imidazole-4-methanol 12b (5.00 g,28.7 mmol) was taken as a starting material for the reaction in this step, and compound 13b was synthesized according to the preparation method of compound 13a to give 3.51g of a tan solid in a yield of 71.1%. 1 H NMR(400MHz,DMSO-d 6 )δ9.86(s,1H), 8.03(s,1H),7.82(d,J＝7.0Hz,2H),7.51-7.44(m,3H).MS(ESI)m/z:[M+H] + Calculated value C 10 H 9 N 2 O173.07, found 172.74.
5) Synthesis of (Z) -1-acetyl-3- ((5-phenyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione 15b
5-phenyl-1H-imidazole-4-carbaldehyde 13b (280 mg,1.63 mmol) and 1, 4-diacetylpiperazine-2, 5-dione 14 (969 mg, 4.89 mmol) were used as starting materials for the reaction, and compound 15b was synthesized according to the preparation method of compound 15a to give orange-red solid 240 mg in a yield of 47.5%. 1 H NMR(500MHz,DMSO-d 6 )δ13.14(s,1H),11.84(s,1H),8.12(s,1H),7.56(q,J＝7.5Hz,4H),7.46(t,J＝6.8Hz,1H),6.90(s,1H),4.33(s,2H),2.49(d,J＝8.2Hz,3H).MS(ESI)m/z:[M+ H] + Calculated value C 16 H 15 N 4 O 3 311.11, found 310.81.
6) Synthesis of (3Z, 6Z) -3- ((5-phenyl-1H-imidazol-4-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione PLN-1-1
A25 mL dry brown round bottom flask was charged with (Z) -1-acetyl-3- ((5-phenyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (80.0 mg,0.26 mmol) and 3- (4-fluorobenzoyl) benzaldehyde 4 (88.2 mg,0.39 mmol), DMF (4 mL), sparged with nitrogen 3 times, cesium carbonate (143.0 mg,0.39 mmol), anhydrous sodium sulfate (74.0 mg,0.52 mmol) again sparged with nitrogen 3 times and stirred at 45℃for 24H. After LC-MS detection reaction is completed, the reaction liquid is droppedAdding into cold water, precipitating a large amount of light yellow solid, suction filtering, washing the filter cake with water, re-dissolving the filter cake with mixed solvent of methanol and dichloromethane (VMeOH: VDCM=1:3), suction filtering, concentrating the filtrate under reduced pressure to solid, adding appropriate amount of methanol, ultrasonic pulping for purification, freeze preserving in a refrigerator, suction filtering, washing the filter cake with methanol, and drying the filter cake in a vacuum drying oven at 50deg.C to obtain 58.0mg of orange-red product (PLN-1-1) with a yield of 47.0%. mp 248-250 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ13.10(s,1H),12.10(s,1H),10.41(s,1H),8.12(s,1H),7.91(dd,J＝8.4, 5.7Hz,2H),7.83(s,1H),7.76(d,J＝7.6Hz,1H),7.64(d,J＝7.6Hz,1H),7.60-7.55(m,5H),7.45(dd,J＝ 7.3,4.7Hz,1H),7.40(t,J＝8.7Hz,2H),6.84(s,1H),6.73(s,1H). 13 C NMR(125MHz,DMSO-d 6 )δ194.2, 164.8,157.5,156.1,137.3,136.8,133.5*2,133.4,132.8*2,132.7,132.0,130.1,129.3,129.2*2,128.9, 128.8,128.3,127.7*2,127.6,125.8,115.8,115.6,113.1,103.6.HRMS(ESI)m/z:[M+Na] + Calculated value C 28 H 19 FN 4 NaO 3 501.1333, found 501.1336.
Example 2 preparation of (3Z, 6Z) -3- ((5-tert-butyl-2-iodo-1H-imidazol-4-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-2)
1) Synthesis of 5-tert-butyl-2-iodo-1H-imidazole-4-carbaldehyde 13g
A100 mL dry brown round bottom flask was taken and 5- (tert-butyl) -1H-imidazole-4-carbaldehyde 13a (3.00 g,19.7 mmol) and N-iodosuccinimide (4.44 g,19.7 mmol) were used as starting materials for this reaction, and compound 13g was synthesized according to the preparation method of compound PLN-1-3 to give 4.74g as a white solid with a yield of 86.5%. 1 H NMR(600MHz,DMSO-d 6 )δ13.47(s,1H),9.80(s,1H),1.35 (s,9H).MS(ESI)m/z:[M+H] + Calculated value C 8 H 12I N 2 O279.00, found 278.71.
2) Synthesis of (Z) -1-acetyl-3- ((5-tert-butyl-2-iodo-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione 15g
5-tert-butyl-2-iodo-1H-imidazole-4-carbaldehyde 13g (1.00 g,3.60 mmol) and 1, 4-diacetylpiperazine-2, 5-dione 14 (1.43 g,7.19 mmol) were taken as starting materials for the reaction, and compound 15g was synthesized according to the preparation method of compound 15a to give 280mg of yellow solid in 18.7% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.44(s,1H),6.95(s,1H),4.30(s,2H),2.49(s,3H),1.36(s, 9H).MS(ESI)m/z:[M+H] + Calculated value C 14 H 18 IN 4 O 3 417.04, found 416.87.
3) Synthesis of (3Z, 6Z) -3- ((5-tert-butyl-2-iodo-1H-imidazol-4-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione PLN-1-2
15g (140 mg,0.34 mmol) of (Z) -1-acetyl-3- ((5-tert-butyl-2-iodo-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione and 4 (115 mg,0.50 mmol) of 3- (4-fluorobenzoyl) benzaldehyde were taken as starting materials for the reaction, and compound PLN-1-2 was synthesized according to the preparation method of compound PLN-1-1 to give 75.0mg as a pale yellow solid with a yield of 38.2%. mp.171-173 ℃. 1 H NMR(600MHz, DMSO-d 6 )δ12.69(s,1H),11.67(s,1H),10.38(s,1H),7.91(dd,J＝8.0,5.7Hz,2H),7.82(s,1H),7.76(d, J＝7.5Hz,1H),7.64(d,J＝7.6Hz,1H),7.59(t,J＝7.6Hz,1H),7.40(t,J＝8.6Hz,2H),6.81(s,1H),6.78 (s,1H),1.36(s,9H). 13 C NMR(150MHz,DMSO-d 6 )δ194.2,164.8,157.6,156.2,145.1,137.3,134.4,133.5, 133.4,132.9,132.8,130.2,129.7,128.9,128.8,127.6,124.2,115.8,115.7,113.0,104.1,86.9,32.3,30.6*3. HRMS(ESI)m/z:[M+Na] + Calculated value C 26 H 22 FIN 4 NaO 3 607.0613, found 607.0620.
Example 3 preparation of (3Z, 6Z) -3- ((2-bromo-5-tert-butyl-1H-imidazol-4-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-3)
A50 mL dry round bottom flask was taken and (3Z, 6Z) -3- ((5-tert-butyl-1H-imidazol-4-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione 1 (70.0 mg,0.15 mmol) was dissolved in dry tetrahydrofuran (8 mL) and stirred at room temperature for 2min. N-bromosuccinimide (27.2 mg,0.15 mmol) was then added to the round bottom flask, warmed to 70℃and refluxed for 24h. After the reaction is finished, the LC-MS monitors that the reaction liquid is cooled to room temperature, and saturated sodium thiosulfate aqueous solution is added into the reaction liquid dropwise until the reaction liquid becomes light yellow. The organic phases were then combined, washed with saturated brine (100 mL), the aqueous phases combined, the aqueous phases back extracted 3 times with ethyl acetate (50 mL x 3), the organic phases combined and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate under reduced pressure, reverse phase column chromatography purification (methanol: water=0:100, 5:95,10:90,15:85,20:80,25:75,30:70,35:65,40:60,45:55,50:50,55:45, 60:40) gave 29.1mg of pale yellow solid in 27.1% yield. mp 156-158 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ12.92 (s,1H),11.47(s,1H),10.37(s,1H),7.91(dd,J＝8.8,5.6Hz,2H),7.82(s,1H),7.76(d,J＝7.7Hz,1H),7.64 (d,J＝7.6Hz,1H),7.58(t,J＝7.6Hz,1H),7.40(t,J＝8.8Hz,2H),6.81(s,1H),6.79(s,1H),1.36(s,9H). 13 C NMR(125MHz,DMSO-d 6 )δ194.2,164.8,157.5,156.1,137.3,133.5,133.4*2,132.8*2,132.3,130.1, 129.6,128.9,128.8,127.5,124.1,116.1,115.8,115.6,113.1,104.5,32.5,30.5*3.HRMS(ESI)m/z:[M+ Na] + Calculated value C 26 H 22 BrFN 4 NaO 3 559.0752, found 559.0751.
Example 4 preparation of (3Z, 6Z) -3- ((5-tert-butyl-2-chloro-1H-imidazol-4-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-4)
1) Synthesis of (Z) -1-acetyl-3- ((5-tert-butyl-2-chloro-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione 15f
(Z) -1-acetyl-3- ((5- (tert-butyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione 15a (300 mg,1.03 mmol) and N-chlorosuccinimide (138 mg,1.03 mmol) were taken as starting materials for this reaction, and compound 15f was synthesized according to the preparation method of compound PLN-1-3 to give 116mg as a pale yellow solid with a yield of 34.6%. 1 H NMR(400MHz,DMSO-d 6 )δ13.00(s,1H),11.11(s, 1H),6.96(s,1H),4.30(s,2H),2.49(s,3H),1.37(s,9H).MS(ESI)m/z:[M+H] + Calculated value C 14 H 18 ClN 4 O 3 325.11, found 324.85.
2) Synthesis of (3Z, 6Z) -3- ((5-tert-butyl-2-chloro-1H-imidazol-4-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione PLN-1-4
(Z) -1-acetyl-3- ((5- (tert-butyl) -3-chloro-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione 15f (91.6 mg,0.28 mmol) and 3- (4-fluorobenzoyl) benzaldehyde 4 (96.5 mg,0.42 mmol) were taken as starting materials for this reaction, and compound PLN-1-4 was synthesized according to the preparation method of compound PLN-1-1 (reaction temperature was adjusted to 70 ℃ C.) to give 31.8mg of orange-yellow solid in 22.9% yield. mp.158-160 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ11.41(s,1H),10.37(s,1H),7.91(dd,J＝8.8,5.5Hz,2H),7.82 (s,1H),7.75(d,J＝7.7Hz,1H),7.64(d,J＝7.7Hz,1H),7.58(t,J＝7.6Hz,1H),7.40(t,J＝8.8Hz,2H), 6.81(s,1H),6.79(s,1H),1.37(s,9H). 13 C NMR(125MHz,DMSO-d 6 )δ194.2,165.8,163.8,157.5,156.1, 137.3,133.5*2,133.4*2,132.8*2,132.3,130.1,128.9,128.8,127.5,124.0,115.8,115.6,113.1,104.2, 32.5,30.5*3.HRMS(ESI)m/z:[M+Na] + Calculated value C 26 H 22 ClFN 4 NaO 3 515.1257, found 515.1253.
Example 5 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-3-benzyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-1-5)
1) Compound 1 (4.75 g,30 mmol) was dissolved in acetic acid (19.4 mL) at zero, and NaNO was added dropwise at zero 2 (5.18 g,75 mmol) in water (16.5 mL). Stirring for 2h at zero, heating to room temperature and stirring for 2.5h. LC-MS was used to detect the end point of the reaction, extracted three times with diethyl ether (50 mL. Times.3), the organic phases combined and extracted with NaHCO 3 Washed, dried over anhydrous sodium sulfate, suction filtered and distilled under reduced pressure to give 2 (4.83 g,25.82 mmol) as a pale yellow oil.
2) A100 mL reaction flask was dried, compound 2 (4.83 g,25.82 mmol) was added, dissolved in absolute ethanol (20 mL), 10% Pd/C (1.59 g) was added, degassed, HCl-EtOH (2M) solution (6.7 mL) was added dropwise, degassed, stirred at room temperature for 24h, and suction filtered to spin dry to give a tan slurry 3 (3.5 g,18.70 mmol).
3) Raw material 3 (2.0 g,9.54 mmol) was dissolved in dry DCM, triethylamine (3.98 mL,28.62 mmol) was added, stirring, phenylacetyl chloride (1.9 mL,14.31 mmol) was added dropwise, stirring overnight at room temperature, and the reaction endpoint was detected by LC-MS to give compound 4 (2.22 g, 7.63 mmol).
4) Raw material 4 (2.22 g,7.63 mmol) was dissolved in glacial acetic acid (30 mL), ammonium acetate (2.94 g,38.16 mmol) was added and the reaction was refluxed overnight at 120 ℃. The solvent was completely dried by spin-drying, neutralized with saturated sodium bicarbonate, and purified by column chromatography on petroleum ether: ethyl acetate=10:1, giving closed ring compound 5 (289 mg,1.06 mmol).
5) Dissolution of LiAlH at zero degree 4 (122 mg,3.22 mmol) in dry THF (5 mL),raw material 5 (289 mg,1.06 mmol) was dissolved in dry THF (5 mL), added dropwise to the reaction system and allowed to react overnight at room temperature. TLC detection was complete, quenched with water, extracted with EA and column chromatographed to give compound 6 (223 mg,0.97 mmol).
6) Raw material 6 (223 mg,0.97 mmol) was dissolved in DCM (5 mL), manganese dioxide (842 mg,9.68 mmol) was added, stirred at room temperature for 48h, the reaction was detected by TLC and the compound 7 (15 mg,0.066 mmol) was isolated by column chromatography.
7) A second batch of prepared compound 7 (716 mg,3.14 mmol) was dissolved in dry DMF (20 mL), acetylated DKP (2.49 g,12.56 mmol) was added, potassium carbonate (651 mg,4.71 mmol) was added, reaction was carried out at 50℃for 24h, LC-MS detection reaction, suction filtration, reverse column chromatography gave compound 8 (166 mg,0.45 mmol).
8) 400mg of 4A molecular sieve was dried, compound 8 (166 mg,0.45 mmol) was dissolved in dry DMF (4 mL), parafluorobenzaldehyde (156 mg,0.68 mmol) was added, cesium carbonate (222 mg,0.68 mmol) was added, the reaction was carried out at 80℃in the absence of light for 48h, LC-MS detection gave the final product B-1, which was recrystallized from ethanol, suction filtered and dried to give yellow powder A (10 mg,0.019 mmol).
Example 6 preparation of (3Z, 6Z) -3- ((5-tert-butyloxazol-4-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-6)
1) Synthesis of 5-tert-butyloxazole-4-methanol 12c
A1L dry round bottom flask was placed in a-60℃well and dried tetrahydrofuran (250 mL) was added followed by lithium aluminum hydride (20.2 g, 552 mmol) and a solution of ethyl 5-tert-butyl-1, 3-oxazole-4-carboxylate 10a (35.0 g,178 mmol) dissolved in tetrahydrofuran (200 mL) was slowly added dropwise to the suspension of lithium aluminum hydride. After the dripping, the temperature is gradually increased to-40 ℃,the reaction was stirred for 4h. LC-MS monitors the reaction, and the reaction liquid is slowly dripped into ice water to quench the reaction. Suction filtration, filter cake washing with water (200 ml x 2) 2 times, absolute ethanol (500 ml x 2) 2 times, decompression concentration filtrate to obtain light yellow oily matter 29.1g, yield 99.9%. MS (ESI) M/z: [ M+Na ]] + Calculated value C 8 H 12 NNaO 2 178.08, found 177.77.
2) Synthesis of 5-tert-butyloxazole-4-carbaldehyde 13c
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5-tert-butyloxazole-4-methanol 12c (29.1 g,187 mmol) was taken as a starting material for the reaction in this step, and compound 13c was synthesized according to the preparation method of compound 13a to give 6.65g of an orange-yellow oil in 23.2% yield. 1 H NMR(400MHz,CDCl 3 )δ10.09(s,1H), 7.76(s,1H),1.46(s,9H).MS(ESI)m/z:[M+H] + Calculated value C 8 H 12 NO 2 154.09, found 153.68.
3) Synthesis of (Z) -1-acetyl-3- ((5-tert-butyloxazol-4-yl) methylene) piperazine-2, 5-dione 15c
5-tert-butyl-1, 3-oxazole-4-carbaldehyde 13c (1.00 g,6.53 mmol) and 1, 4-diacetylpiperazine-2, 5-dione 14 (2.59 g, 13.1 mmol) were taken as starting materials for this reaction, and compound 15c was synthesized in accordance with the preparation method of compound 15a (reaction temperature was adjusted to 45 ℃) to give 850mg of a white solid with a yield of 44.7%. 1 H NMR(400MHz,CDCl 3 )δ11.22(s,1H),7.83(s,1H),7.08 (s,1H),4.47(s,2H),2.64(s,3H),1.44(s,9H).MS(ESI)m/z:[M+Na] + Calculated value C 14 H 17 N 3 NaO 4 314.11, found 313.84.
4) Synthesis of (3Z, 6Z) -3- ((5-tert-butyloxazol-4-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione PLN-1-6
(Z) -1-acetyl-3- ((5-tert-butyloxazol-4-yl) methylene) piperazine-2, 5-dione 15c (200 mg,0.687 mmol) and 3- (4-fluorobenzoyl) benzaldehyde 4 (235 mg,1.03 mmol) were taken as the starting materials for this step of reaction, and compound PLN-1-6 was synthesized according to the preparation method of compound PLN-1-1 to give 244mg as pale yellow solid with a yield of 77.4%. mp 238-240 ℃. 1 H NMR(500MHz,DMSO- d 6 )δ11.12(s,1H),10.55(s,1H),8.60(s,1H),7.91(dd,J＝8.8,5.5Hz,2H),7.82(s,1H),7.76(d,J＝7.7Hz, 1H),7.64(s,1H),7.60(d,J＝7.6Hz,1H),7.40(t,J＝8.8Hz,2H),6.86(s,1H),6.72(s,1H),1.39(s,9H). 13 C NMR(100MHz,DMSO-d 6 )δ194.2,164.8,158.0,157.0,156.3,150.2,137.3,133.5,133.4,133.3,132.9, 132.8,130.2,129.0,128.9,128.2,127.2,126.8,115.9,115.7,114.1,100.8,33.1,29.1*3.HRMS(ESI)m/z: [M+H] + Calculated value C 26 H 23 FN 3 O 4 482.1487, found 482.1485.
Example 7 preparation of (3Z, 6Z) -3- ((5-tert-butyl-2-phenyloxazol-4-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-7)
1) Synthesis of 5-tert-butyl-2-phenyloxazole-4-carboxylic acid ethyl ester for 10h
A100 mL dry round bottom flask was taken, ethyl pivaloylacetate (5.00 g,29.0 mmol), benzylamine (7.78 g,72.6 mmol) and sodium bicarbonate (18.4 g,72.6 mmol) were added in sequence, iodine (18.4 g,72.6 mmol) and water (50 mL) were added after stirring, and the temperature was raised to 80℃and the reaction was refluxed for 2h. After the reaction is monitored by thin layer chromatography, stopping heating, and cooling at normal temperature. Stirring at room temperature, adding saturated sodium thiosulfate until the solution is clear, and adding Ethyl acetate (150 ml x 3) was added to the reaction solution and extracted three times, the organic phases were combined, the organic phases were washed with saturated brine, the aqueous phases were combined, the ethyl acetate (150 ml x 2) back-extracted the aqueous phases 2 times, the organic phases were combined, and dried by adding anhydrous sodium sulfate. Suction filtration, concentration of the filtrate under reduced pressure, column chromatography purification (PE: ea=40:1, 30:1,20:1,15:1, 10:1) afforded 5.29g of a pale yellow oil in 66.6% yield. 1 H NMR(400MHz,DMSO-d 6 )δ7.98-7.96(m,2H),7.60-7.53(m,3H),4.32(q,J＝7.1Hz,2H),1.47(s,9H), 1.32(t,J＝7.1Hz,3H).MS(ESI)m/z:[M+H] + Calculated value C 16 H 20 NO 3 274.14, found 273.85.
2) Synthesis of 5-tert-butyl-2-phenyloxazole-4-methanol for 12h
5-tert-butyl-2-phenyloxazole-4-carboxylic acid ethyl ester (3.59 g,13.1 mmol) was taken as a starting material for the reaction in this step, and compound 12h was synthesized according to the preparation method of compound 12c to give 3.43g of pale yellow oily substance with a yield of 99.9%. MS (ESI) M/z: [ M+H ]] + Calculated value C 14 H 18 NO 2 232.13, found 231.88.
3) Synthesis of 5-tert-butyl-2-phenyloxazole-4-carbaldehyde 13h
Taking 5-tert-butyl-2-phenyl oxazole-4-methanol (3.43 g,14.8 mmol) as a raw material for the reaction, and synthesizing a compound 13h according to the preparation method of the compound 13a to obtain 1.37g of orange yellow solid with a yield of 40.3%. 1 H NMR(400MHz,DMSO-d 6 )δ10.09 (s,1H),8.02-8.00(m,2H),7.58-7.56(m,3H),1.49(s,9H).MS(ESI)m/z:[M+Na] + Calculated value C 14 H 15 NNaO 2 252.10, found 251.85.
4) Synthesis of (Z) -1-acetyl-3- ((5-tert-butyl-2-phenyloxazol-4-yl) methylene) piperazine-2, 5-dione for 15h
5-tert-butyl-2-phenyloxazole-4-carbaldehyde 13h (500 mg,2.18 mmol) and 1, 4-diacetylpiperazine-2, 5-dione 14 (865 mg,4.36 mmol) were taken as starting materials for this reaction, and the compound was synthesized according to the preparation method of the compound 15a (reaction temperature was adjusted to 45 ℃) for 15h to give 591mg as a brown solid in 73.8% yield. 1 H NMR(400MHz,CDCl 3 )δ11.42(s,1H),8.05-8.03(m, 2H),7.51-7.49(m,3H),7.12(s,1H),4.51(s,1H),2.66(s,3H),1.51(s,9H).MS(ESI)m/z:[M+Na] + Calculated value C 20 H 21 N 3 NaO 4 390.14, found 390.03.
5) Preparation of (3Z, 6Z) -3- ((5-tert-butyl-2-phenyloxazol-4-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione PLN-1-7
A25 mL dry round bottom flask was charged with (Z) -1-acetyl-3- ((5-tert-butyl-2-phenyloxazol-4-yl) methylene) piperazine-2, 5-dione 15h (100 mg,0.27 mmol) and 3- (4-fluorobenzoyl) benzaldehyde 4 (93.1 mg,0.41 mmol) as starting materials for this step, compound PLN-1-7 was synthesized according to the preparation method of compound PLN-1-1 (reaction temperature adjusted to 70 ℃ C.) to give a pale yellow solid 118, mg in a yield of 81.2%. mp 259-261 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ11.21(s,1H),10.57(s,1H),8.00 (dd,J＝7.4,2.1Hz,2H),7.92(dd,J＝8.7,5.6Hz,1H),7.84(s,1H),7.77(d,J＝7.7Hz,1H),7.66(d,J＝7.7 Hz,1H),7.62-7.58(m,4H),7.41(t,J＝8.8Hz,2H),6.88(s,1H),6.75(s,1H),1.46(s,9H). 13 C NMR(125 MHz,DMSO-d 6 )δ194.1,164.8,158.6,158.0,157.0,156.2,137.3,133.5,133.4,133.3,132.8*2,131.3, 130.2,130.1,129.4*2,128.9*2,127.2,126.9,126.0*2,125.5,115.8,115.6,114.0,100.8,33.3,29.2*3. HRMS(ESI)m/z:[M+Na] + Calculated value C 32 H 26 FN 3 NaO 4 558.1800, found 558.1797.
Example 8 preparation of (3Z, 6Z) -3- ((5-phenyloxazol-4-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-8)
1) Synthesis of 5-phenyloxazole-4-carboxylic acid ethyl ester 10d
Ethyl isocyanate 7 (10.0 g,88.4 mmol) and benzoic anhydride 8d (24.0 g,106 mmol) were taken as starting materials for this reaction, and compound 16d was synthesized according to the preparation method of compound 10a to give 7.83g of a yellow oil in 40.8% yield. 1 H NMR(500MHz, DMSO-d 6 )δ8.57(s,1H),7.95(dd,J＝6.8,3.0Hz,2H),7.54-7.48(m,3H),4.29(q,J＝7.1Hz,2H),1.26(t, J＝7.1Hz,3H).MS(ESI)m/z:[M+Na] + Calculated value C 12 H 11 NNaO 3 240.06, found 239.85.
2) Synthesis of 5-phenyloxazole-4-methanol 12d
Taking 5-phenyl-1, 3-oxazole-4-ethyl formate 10d (7.20 g,33.2 mmol) as the raw material for the reaction, synthesizing compound 12d according to the preparation method of compound 12c to obtain yellow brown solid 6.57g, with a yield of 99.9%. MS (ESI) M/z: [ M+Na ]] + Calculated value C 10 H 9 NNaO 2 198.05, found 197.78.
3) Synthesis of 5-phenyloxazole-4-carbaldehyde 13d
As the solvent, 5-phenyloxazole-4-methanol 12d (6.57 g,37.5 mmol) was usedThe starting material for the step reaction, compound 13d was synthesized according to the preparation method of compound 12a, to give 1.36g of orange-yellow solid with a yield of 21.0%. 1 H NMR(400MHz,DMSO-d 6 )δ10.04(s,1H), 8.65(s,1H),8.08-8.05(m,2H),7.61-7.58(m,3H).MS(ESI)m/z:[M+H] + Calculated value C 10 H 8 NO 2 174.05, found 173.71.
4) Synthesis of (Z) -1-acetyl-3- ((5-phenyloxazol-4-yl) methylene) piperazine-2, 5-dione 15d
5-phenyl-oxazole-4-carbaldehyde 13d (500 mg,2.89 mmol) and 1, 4-diacetylpiperazine-2, 5-dione 14 (1.14 g,5.77 mmol) were taken as starting materials for this step, and compound 15d was synthesized according to the preparation method of compound 15a (reaction temperature was adjusted to 45 ℃) to give 689mg as a brown solid with a yield of 76.6%. 1 H NMR(400MHz,DMSO-d 6 )δ10.84(s,1H),8.83(s,1H),7.71(dd, J＝7.3,1.3Hz,3H),7.62(m,3H),7.54(d,J＝7.4Hz,1H),4.36(s,2H),2.51(s,5H).MS(ESI)m/z:[M+ Na] + Calculated value C 16 H 13 N 3 NaO 4 334.08, found 333.85.
5) Synthesis of (3Z, 6Z) -3- ((5-phenyloxazol-4-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione PLN-1-8
(Z) -1-acetyl-3- ((5-phenyl oxazol-4-yl) methylene) piperazine-2, 5-dione 15d (100 mg,0.32 mmol) and 3- (4-fluorobenzoyl) benzaldehyde 4 (110 mg,0.48 mmol) were taken as raw materials for the reaction, and compound PLN-1-8 was synthesized according to the preparation method of compound PLN-1-1 to give 69.4mg as pale yellow solid with a yield of 45.1%. mp 228-230 ℃. 1 H NMR(500MHz,DMSO-d 6 ) δ11.06(s,1H),10.63(s,1H),8.82(s,1H),7.91(dd,J＝8.7,5.6Hz,2H),7.84(s,1H),7.77(d,J＝7.6Hz, 1H),7.71(d,J＝7.6Hz,2H),7.66(d,J＝7.7Hz,1H),7.60(m,3H),7.51(t,J＝7.4Hz,1H),7.40(t,J＝8.8 Hz,1H),6.89(s,1H),6.75(s,1H). 13 C NMR(125MHz,DMSO-d 6 )δ194.1,164.8,156.8,156.2,151.8,148.3, 137.3,133.5,133.4,133.2,132.8*2,130.3,130.2,129.7,129.5*2,129.0,128.9,128.6,127.1,126.9,126.4 *2,115.8,115.6,114.4,99.6.HRMS(ESI)m/z:[M+Na] + Calculated value C 28 H 18 FN 3 NaO 4 502.1174, found 502.1174.
Example 9 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((1-methylimidazole) -2-methylene) piperazine-2, 5-dione (PLN-1-9)
A10 mL dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((3-p-fluorophenoxyphenyl) methylene) piperazine-2, 5-dione (100 mg,0.28 mmol), 1-methylimidazole-2-carbaldehyde (46.6 mg,0.42 mmol), cesium carbonate (137.9 mg,0.42 mmol), anhydrous sodium sulfate (80.2 mg,0.56 mmol), DMF (3 mL), vented, nitrogen protected, placed in an oil bath at 45℃and stirred for reaction 22 h. LC-MS monitored the reaction and the starting material point disappeared. After the reaction, the reaction mixture was added dropwise to cold water (30 mL) at 4 ℃ without precipitation of solids, extracted with DCM (100 ml×3) and EA (100 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried. Pulping methanol by ultrasonic, standing in a refrigerator at 0 ℃, carrying out suction filtration, washing a filter cake by using methanol with cold temperature, and drying in a vacuum drying oven at 50 ℃ to obtain yellow solid 78.2 mg with the yield of 69%.
1 H NMR(500MHz,DMSO-d 6 )δ12.23(s,1H),10.44(s,1H),7.42(t,J＝7.9Hz,1H),7.36(d,J＝0.7 Hz,1H),7.28(d,J＝7.7Hz,1H),7.24(dd,J＝11.6,4.8Hz,3H),7.19(s,1H),7.14–7.10(m,2H),6.92(dd, J＝8.1,2.2Hz,1H),6.80(s,1H),6.59(s,1H),3.77(s,3H). 13 C NMR((125MHz,DMSO-d 6 )δ159.14, 157.24,157.05,156.72,156.66,152.56,152.54,143.49,134.91,130.28,128.46,128.28,126.82,124.59, 123.00,120.60,120.53,119.02,117.98,116.63,116.44,114.55,95.92,32.49.MS(ESI)m/z:[M+H] + Calculated value C 22 H 18 FN 4 O 3 405.1357, found 405.1352. Melting point: 238-240 ℃.
Example 10 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((1-ethylimidazole) -2-methylene) piperazine-2, 5-dione (PLN-1-10)
1) Preparation of 1-ethylimidazole-2-carbaldehyde (14 o)
A25 mL dry round bottom flask was taken, imidazole-2-carbaldehyde (200 mg,2.08 mmol), DMF (3 mL), potassium carbonate (345.2 mg,2.50 mmol), iodoethane (389.6 mg,2.50 mmol) in DMF was added sequentially and the mixture was stirred in an oil bath at 50deg.C for 6h. Suction filtration, dilution with water, EA extraction, washing of the organic phase with saturated brine, drying over anhydrous sodium sulfate, and concentration under reduced pressure, yielding a brown oil 180.9. 180.9 mg in 70% yield. 1 H NMR(400MHz,CDCl 3 )δ9.81(s,1H),7.28(s,1H),7.17(s,1H),4.43(q,J＝7.3Hz, 2H),1.43(t,J＝7.3Hz,3H).MS(ESI)m/z:[M+H] + Calculated value C 6 H 9 N 2 O125.0709, found 124.69.
2) Synthesis of the end product PLN-1-10
The preparation is carried out according to the synthesis method of the compound PLN-1-9. Starting from (Z) -1-acetyl-3- ((3-p-fluorophenoxyphenyl) methylene) piperazine-2, 5-dione (100 mg,0.28 mmol), 1-ethylimidazole-2-carbaldehyde (52.5 mg,0.42 mmol), cesium carbonate (137.9mg,0.42 mmol) and anhydrous sodium sulfate (80.2 mg,0.56 mmol), DMF (3 mL) was stirred in an oil bath at 45℃to give 101.3mg of a yellow solid in 86% yield.
1 H NMR(500MHz,DMSO-d 6 )δ12.29(s,1H),10.44(s,1H),7.44–7.39(m,2H),7.28(d,J＝7.8Hz, 1H),7.23(dt,J＝6.1,4.4Hz,3H),7.20(s,1H),7.16–7.09(m,2H),6.92(dd,J＝8.1,2.1Hz,1H),6.80(s, 1H),6.59(s,1H),4.17(q,J＝7.2Hz,2H),1.32(t,J＝7.2Hz,3H). 13 C NMR(125MHz,DMSO-d 6 )δ159.14, 157.23,157.03,156.76,156.68,152.57,152.55,142.57,134.93,130.28,128.68,128.55,126.82,124.60, 121.30,120.59,120.52,119.03,117.98,116.63,116.44,114.56,95.69,16.38.MS(ESI)m/z:[M+Na] + Calculated value C 23 H 19 FN 4 O 3 Na 441.1339, found 441.1332 melting point: 214-216 ℃.
Example 11 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((1-propylimidazole) -2-methylene) piperazine-2, 5-dione (PLN-1-11)
1) Synthesis of 1-propylimidazole-2-carbaldehyde (14 p)
Prepared according to the synthesis method of compound 14 o. Imidazole-2-carbaldehyde (400 mg,4.16 mmol), potassium carbonate (690.4 mg,5.00 mmol) and 1-iodopropane (849.2 mg,5.00 mmol) were used as raw materials, and DMF (10 mL) was stirred in an oil bath at 50℃for 6h. 373.9mg of oily liquid was obtained in 65% yield. 1 H NMR(500MHz,CDCl 3 )δ9.85(s,1H),7.31(s,1H),7.15(s,1H), 4.39–4.33(m,2H),1.82(dd,J＝14.6,7.3Hz,2H),0.94(dt,J＝13.4,7.4Hz,5H).MS(ESI)m/z:[M+H] + Calculated value C 7 H 11 N 2 O139.0866, found 138.64.
2) Synthesis of the end product PLN-1-11
Is prepared by a synthetic method of a compound PLN-1-9. Starting from (Z) -1-acetyl-3- ((3-p-fluorophenoxyphenyl) methylene) piperazine-2, 5-dione (100 mg,0.28 mmol), 1-propylimidazole-2-carbaldehyde (58.5 mg,0.42 mmol), cesium carbonate (137.9mg,0.42 mmol) and anhydrous sodium sulfate (80.2 mg,0.56 mmol), DMF (3 mL) was stirred in an oil bath at 50℃for 25h. 59.5mg of yellow solid was obtained in 49% yield.
1 H NMR(500MHz,DMSO-d 6 )δ12.32(s,1H),10.44(s,1H),7.44–7.38(m,2H),7.28(d,J＝7.8Hz, 1H),7.26–7.22(m,3H),7.19(s,1H),7.14–7.09(m,2H),6.92(dd,J＝8.1,2.1Hz,1H),6.80(s,1H),6.59 (s,1H),4.11(t,J＝7.1Hz,2H),1.75–1.64(m,2H),0.84(t,J＝7.4Hz,3H). 13 C NMR(125MHz,DMSO- d 6 )δ159.14,157.23,157.03,156.76,156.68,152.57,152.55,142.93,134.93,130.27,128.68,128.42,126.82, 124.60,121.99,120.58,120.51,119.02,117.97,116.62,116.44,114.54,95.77,46.77,24.02,10.80.MS(ESI) m/z:[M+Na] + Calculated value C 24 H 21 FN 4 O 3 Na 455.1495, found 455.1507 melting point: 168-170 ℃.
Example 12 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((1-butylimidazole) -2-methylene) piperazine-2, 5-dione (PLN-1-12)
1) Synthesis of 1-butylimidazole-2-carbaldehyde (14 q)
Prepared according to the synthesis method of compound 14 o. Imidazole-2-carbaldehyde (400 mg,4.16 mmol), DMF (10 mL), potassium carbonate (690.4 mg,5.00 mmol) and 1-iodobutane (849.2 mg,5.00 mmol) were used as starting materials, DMF (10 mL) was stirred in an oil bath at 50℃for 6h. 362.4mg of oily liquid was obtained in 63% yield. 1 H NMR(500MHz,CDCl 3 )δ9.81(s,1H),7.26 (s,1H),7.13(s,1H),4.44–4.30(m,2H),1.72(ddd,J＝15.0,11.2,7.5Hz,2H),1.30(dd,J＝15.2,7.5Hz, 2H),0.90(t,J＝7.4Hz,3H).MS(ESI)m/z:[M+H] + Calculated value C 8 H 13 N 2 O153.1022, found 152.73.
2) Synthesis of the end product PLN-1-12
The preparation is carried out according to the synthesis method of the compound PLN-1-9. Starting from (Z) -1-acetyl-3- ((3-p-fluorophenoxyphenyl) methylene) piperazine-2, 5-dione (100 mg,0.28 mmol), 1-butylimidazole-2-carbaldehyde (64.4 mg,0.42 mmol), cesium carbonate (137.9mg,0.42 mmol) and anhydrous sodium sulfate (80.2 mg,0.56 mmol), DMF (3 mL) was stirred in an oil bath at 50℃for 24h. 77.3mg of yellow solid was obtained in 61% yield.
1 H NMR(500MHz,DMSO-d 6 )δ12.31(s,1H),10.44(s,1H),7.45–7.39(m,2H),7.28(d,J＝7.8Hz, 1H),7.26–7.21(m,3H),7.19(s,1H),7.14–7.10(m,2H),6.92(dd,J＝8.1,2.2Hz,1H),6.80(s,1H),6.59 (s,1H),4.14(t,J＝7.1Hz,2H),1.73–1.59(m,2H),1.25(dq,J＝14.7,7.3Hz,2H),0.88(t,J＝7.4Hz,3H). 13 C NMR(125MHz,DMSO-d 6 )δ159.14,157.23,157.03,156.76,156.68,152.55,142.88,134.93,130.28, 128.68,128.43,126.82,124.60,121.96,120.58,120.51,119.03,117.97,116.62,116.44,114.55,95.74,45.05, 32.75,19.17,13.43.MS(ESI)m/z:[M+H] + Calculated value C 25 H 24 FN 4 O 3 447.1827, found 447.1819. Melting point: 158-160 ℃.
Example 13 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((1-isopropylimidazole) -2-methylene) piperazine-2, 5-dione (PLN-1-13)
Synthesis of 1-isopropylimidazole-2-carbaldehyde (14 r)
Prepared according to the synthesis method of compound 14 o. Starting from imidazole-2-carbaldehyde (400 mg,4.16 mmol), potassium carbonate (690.4 mg,5.00 mmol) and 2-iodopropane (849.2 mg,5.00 mmol), DMF (10 mL) was reacted in an oil bath at 50℃with stirring for 6h. 74.0mg of oily liquid was obtained in 61% yield. 1 H NMR(500MHz,CDCl 3 )δ9.82(s,1H),7.32(s,1H),7.30(s,1H), 5.46(dt,J＝13.4,6.7Hz,1H),1.46(d,J＝6.7Hz,6H).MS(ESI)m/z:[M+H] + Calculated value C 7 H 11 N 2 O139.0866, found 139.04.
2) Synthesis of the end product PLN-1-13
The preparation is carried out according to the synthesis method of the compound PLN-1-9. Starting from (Z) -1-acetyl-3- ((3-p-fluorophenoxyphenyl) methylene) piperazine-2, 5-dione (100 mg,0.28 mmol), 1-isopropylimidazole-2-carbaldehyde (58.5 mg,0.42 mmol), cesium carbonate (137.9 mg,0.42 mmol) and anhydrous sodium sulfate (80.2 mg,0.56 mmol), DMF (3 mL) was stirred in an oil bath at 50℃for 22h. 78.8mg of yellow solid was obtained in 65% yield. Melting point: 198-200 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ12.36(s,1H),10.44 (s,1H),7.54(d,J＝1.0Hz,1H),7.42(t,J＝7.9Hz,1H),7.28(d,J＝7.7Hz,2H),7.26–7.21(m,2H),7.20 (s,1H),7.14–7.09(m,2H),6.92(dd,J＝8.1,2.1Hz,1H),6.80(s,1H),6.64(s,1H),4.75(dt,J＝13.2,6.6 Hz,1H),1.40(d,J＝6.6Hz,6H). 13 C NMR(125MHz,DMSO-d 6 )δ159.14,157.24,157.04,156.81,156.68, 152.55,142.22,134.93,130.28,128.83,128.77,126.82,124.60,120.59,120.52,119.02,117.98,116.63, 116.44,114.54,95.76,47.09,23.15*2.MS(ESI)m/z:[M+H] + Calculated value C 24 H 22 FN 4 O 3 433.1670, found 433.1675.
Example 14 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((1-isopropylimidazole) -2-methylene) piperazine-2, 5-dione (PLN-1-14)
The preparation is carried out according to the synthesis method of the compound PLN-1-9. Starting from (Z) -1-acetyl-3- ((3-p-fluorobenzoylphenyl) methylene) piperazine-2, 5-dione (100 mg,0.27 mmol), 1-isopropylimidazole-2-carbaldehyde (56.6 mg,0.41 mmol), cesium carbonate (133.4 mg,0.41 mmol) and anhydrous sodium sulfate (77.5 mg,0.55 mmol), DMF (3 mL) was stirred in an oil bath at 45℃for 23h. 76.6mg of yellow solid was obtained in 63% yield.
1 H NMR(500MHz,DMSO-d 6 )δ12.38(s,1H),10.63(s,1H),7.95–7.90(m,2H),7.85(s,1H),7.77 (d,J＝7.7Hz,1H),7.66(d,J＝7.7Hz,1H),7.60(t,J＝7.7Hz,1H),7.55(d,J＝1.1Hz,1H),7.41(t,J＝8.8 Hz,2H),7.28(d,J＝0.7Hz,1H),6.89(s,1H),6.64(s,1H),4.76(dt,J＝13.2,6.6Hz,1H),1.40(d,J＝6.6 Hz,6H). 13 C NMR(125MHz,DMSO-d 6 )δ194.14,165.75,163.75,156.96,156.62,142.23,137.28,133.50, 133.44,133.29,132.83,132.75,130.26,128.95,128.87,128.83,128.79,127.26,118.01,115.79,115.62, 114.15,95.80,47.08,23.16*2.MS(ESI)m/z:[M+H] + Calculated value C 25 H 22 FN 4 O 3 445.1670, found 455.1669. Melting point: 222-224 ℃.
Example 15 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((1- (2-fluoro) ethylimidazole) -2-methylene) piperazine-2, 5-dione (PLN-1-15)
1) Synthesis of 1- (2-fluoro) ethylimidazole-2-carbaldehyde (14 t)
A25 mL dry round bottom flask was taken and imidazole-2-carbaldehyde (200 mg,2.08 mmol), DMF (5 mL), potassium carbonate (345.2)mg,2.50 mmol), 1-bromo-2-fluoroethane (317.1 mg,2.50 mmol) in DMF was placed in an oil bath at 50℃and stirred for 6h. Suction filtration, dilution with water, EA extraction, washing of the organic phase with saturated brine, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain oily liquid 213.0 mg with a yield of 72%. 1 H NMR(500MHz,CDCl 3 )δ9.84(s,1H),7.32(s,1H),7.25(s,1H),4.75(s,2H),4.72– 4.68(m,1H),4.67–4.61(m,1H).MS(ESI)m/z:[M+H] + Calculated value C 6 H 8 FN 2 O143.0615, found 142.62.
2) Synthesis of end product PLN-1-15
The preparation is carried out according to the synthesis method of the compound PLN-1-9. Starting from (Z) -1-acetyl-3- ((3-p-fluorophenoxyphenyl) methylene) piperazine-2, 5-dione (100 mg,0.28 mmol), 1- (2-fluoro) ethylimidazole-2-carbaldehyde (60.2 mg,0.42 mmol), cesium carbonate (137.9 mg,0.42 mmol) and anhydrous sodium sulfate (80.2 mg,0.56 mmol), DMF (3 mL) was stirred in an oil bath at 50℃for 25h. 69.5mg of yellow solid was obtained in 56% yield.
1 H NMR(500MHz,DMSO-d 6 )δ12.29(s,1H),10.44(s,1H),7.43–7.39(m,2H),7.31–7.27(m,2H), 7.26–7.21(m,2H),7.20(s,1H),7.12(ddd,J＝10.5,5.3,3.2Hz,2H),6.92(dd,J＝8.1,2.0Hz,1H),6.80(s, 1H),6.65(s,1H),4.73(t,J＝4.5Hz,1H),4.64(t,J＝4.5Hz,1H),4.55(t,J＝4.5Hz,1H),4.49(t,J＝4.5 Hz,1H). 13 C NMR(125MHz,DMSO-d 6 )δ159.14,157.24,157.04,156.74,156.70,152.55,143.59,134.92, 130.28,128.86,128.65,126.80,124.60,122.04,120.59,120.53,119.03,117.98,116.63,116.44,114.57,95.95, 83.64,82.30,45.90,45.75.MS(ESI)m/z:[M+H] + Calculated value C 23 H 19 F 2 N 4 O 3 437.1420, found 437.1424. Melting point: 245-247 ℃.
Example 16 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((1-propenylimidazole) -2-methylene) piperazine-2, 5-dione (PLN-1-16)
1) Synthesis of 1-propenylimidazole-2-carbaldehyde (14 u)
Prepared according to the method for the synthesis of compound 14 t. Starting from imidazole-2-carbaldehyde (200 mg,2.08 mmol), DMF (5 mL), potassium carbonate (345.2 mg,2.50 mmol) and 3-bromo-propene (302.2 mg,2.50 mmol), DMF (5 mL) was stirred in an oil bath at 50℃for 6h. 158.7mg of oily liquid was obtained in 56% yield. 1 H NMR(500MHz,CDCl 3 )δ9.82(s,1H),7.30(s, 1H),7.16(s,1H),5.95(ddt,J＝16.1,10.4,5.8Hz,1H),5.24(dd,J＝10.2,0.8Hz,1H),5.10(dd,J＝17.0, 0.7Hz,1H),5.02(d,J＝5.8Hz,2H).MS(ESI)m/z:[M+H] + Calculated value C 7 H 9 N 2 O137.0709, found 136.65.
2) Synthesis of end product PLN-1-16
Is prepared by a synthetic method of a compound PLN-1-9. The reaction was stirred with (Z) -1-acetyl-3- ((3-p-fluorophenoxyphenyl) methylene) piperazine-2, 5-dione (100 mg,0.28 mmol), 1-propenyl imidazole-2-carbaldehyde (57.6 mg,0.42 mmol), cesium carbonate (137.9mg,0.42 mmol) and anhydrous sodium sulfate (80.2 mg,0.56 mmol), DMF (3 mL) in an oil bath at 50℃for 22h. 68.6mg of yellow solid was obtained in 56% yield.
1 H NMR(500MHz,DMSO-d 6 )δ12.26(s,1H),10.44(s,1H),7.42(t,J＝7.9Hz,1H),7.39(d,J＝0.8 Hz,1H),7.28(d,J＝4.9Hz,2H),7.26–7.21(m,2H),7.19(s,1H),7.16–7.09(m,2H),6.92(dd,J＝8.1,2.2 Hz,1H),6.80(s,1H),6.54(s,1H),6.01(ddd,J＝22.1,10.2,5.0Hz,1H),5.20(dd,J＝10.3,1.2Hz,1H),4.90 (dd,J＝17.1,1.3Hz,1H),4.85(d,J＝4.9Hz,2H). 13 C NMR(125MHz,DMSO-d 6 )δ159.14,157.23,157.03, 156.69，152.56，143.18，134.92，134.03，130.27，128.76，128.53，126.80，124.59，122.13，120.58，120.52，119.03,117.98,116.76,116.62,116.44,114.59,95.89,47.56.MS(ESI)m/z:[M+Na] + Calculated value C 24 H 19 FN 4 O 3 Na 453.1339, found 453.1335 melting point: 206-208 ℃.
Example 17 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((1-benzylimidazole) -2-methylene) piperazine-2, 5-dione (PLN-1-17)
1) Synthesis of 1-benzylimidazole-2-carbaldehyde (14 v)
Prepared according to the method for the synthesis of compound 14 t. Imidazole-2-carbaldehyde (200 mg,2.08 mmol), potassium carbonate (575.3 mg,4.16 mmol) and benzyl bromide (302.4 mg,1.87 mmol) were used as starting materials, DMF (10 mL) was stirred in an oil bath at 50℃for 6h. Thin layer chromatography gave 166.5mg of oily liquid in 43% yield. 1 H NMR(500MHz,CDCl 3 )δ9.86(s,1H),7.37–7.29(m, 4H),7.20(d,J＝6.9Hz,2H),7.13(s,1H),5.61(s,2H).MS(ESI)m/z:[M+H] + Calculated value C 11 H 11 N 2 O187.0866, found 186.72.
2) Synthesis of end product PLN-1-17
The preparation is carried out according to the synthesis method of the compound PLN-1-9. Starting from (Z) -1-acetyl-3- ((3-p-fluorophenoxyphenyl) methylene) piperazine-2, 5-dione (100 mg,0.28 mmol), 1-benzylimidazole-2-carbaldehyde (78.8 mg,0.42 mmol), cesium carbonate (137.9mg,0.42 mmol) and anhydrous sodium sulfate (80.2 mg,0.56 mmol), DMF (3 mL) was stirred in an oil bath at 45℃for 24h. 123.0mg of yellow solid was obtained in 91% yield.
1 H NMR(500MHz,DMSO-d 6 )δ12.26(s,1H),10.41(s,1H),7.53(d,J＝0.8Hz,1H),7.41(t,J＝7.9 Hz,1H),7.36(t,J＝7.5Hz,2H),7.32–7.21(m,5H),7.18(s,1H),7.16–7.09(m,4H),6.91(dd,J＝8.2,2.1 Hz,1H),6.78(s,1H),6.59(s,1H),5.46(s,2H). 13 C NMR(125MHz,DMSO-d 6 )δ159.13,157.22,157.01, 156.69,156.62,152.56,152.54,143.28,137.20,134.92,130.26,128.96,128.80,128.73,127.71,126.78, 126.64,124.59,122.53,120.57,120.50,119.03,117.98,116.62,116.43,114.60,95.73,48.52.MS(ESI)m/z: [M+H] + Calculated value C 28 H 22 FN 4 O 3 481.1670, found 481.1660. Melting point: 206-208 ℃.
Example 18 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((1-isopropylphenyl-imidazole) -2-methylene) piperazine-2, 5-dione (PLN-1-18)
1) Synthesis of 1-isopropyl-2-formylbenzimidazole (14 y)
Prepared according to the synthesis method of compound 14 o. Starting from 2-formylbenzimidazole (100 mg,0.68 mmol), potassium carbonate (114.6 mg,0.82mmol) and 2-iodopropane (139.6 mg,0.82 mmol), DMF (3 mL) was stirred in an oil bath at 50℃for 6h. 86.3mg of oily liquid was obtained in 67% yield. 1 H NMR(400MHz,CDCl 3 )δ10.11(s,1H),7.93(d,J＝7.7Hz, 1H),7.67(d,J＝8.3Hz,1H),7.47–7.41(m,1H),7.37(dd,J＝11.0,4.0Hz,1H),5.88(dt,J＝13.9,7.0Hz, 1H),5.88(dt,J＝13.9,7.0Hz,1H),1.67(d,J＝7.0Hz,6H).MS(ESI)m/z:[M+H] + Calculated value C 11 H 13 N 2 O189.1022, found 189.24.
2) Synthesis of end product (PLN-1-18)
The preparation is carried out according to the synthesis method of the compound PLN-1-9. Starting from (Z) -1-acetyl-3- ((3-p-fluorophenoxyphenyl) methylene) piperazine-2, 5-dione (100 mg,0.28 mmol), 1-isopropyl-2-formylbenzimidazole (79.7 mg,0.42 mmol), cesium carbonate (137.9 mg,0.42 mmol) and anhydrous sodium sulfate (80.2 mg,0.56 mmol), DMF (3 mL) was stirred in an oil bath at 50℃for 24h. 126.3mg of yellow solid was obtained in 93% yield.
1 H NMR(500MHz,DMSO-d 6 )δ12.61(s,1H),10.64(s,1H),7.84–7.80(m,1H),7.78(dd,J＝6.3, 2.8Hz,1H),7.43(t,J＝7.9Hz,1H),7.33–7.28(m,3H),7.25(dd,J＝12.2,5.4Hz,3H),7.16–7.09(m,2H), 6.94(dd,J＝8.1,1.9Hz,1H),6.87(s,1H),6.83(s,1H),5.11(dq,J＝13.6,6.8Hz,1H),1.62(d,J＝6.9Hz, 6H). 13 C NMR(125MHz,DMSO-d 6 )δ159.62,157.71,157.49,157.43,156.89,153.04,148.71,142.66, 135.32,133.68,132.77,130.75,125.20,123.75,123.22,121.06,120.99,119.60,119.44,118.60,117.11, 116.92,115.91,112.84,97.75,95.17,47.87,21.73*2.MS(ESI)m/z:[M+H] + Calculated value C 28 H 24 FN 4 O 3 483.1827, found 483.1820. Melting point: 263-265 ℃.
Example 19 preparation of (3Z, 6Z) -3- (pyridin-2-ylmethylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-19)
A25 mL dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (100 mg, 0).273 mmol), pyridine-2-carbaldehyde 25a (35.1 mg,0.328 mmol), cesium carbonate (134 mg,0.410 mmol), anhydrous sodium sulfate (77.6 mg,0.546 mmol) and DMF (2.5 mL) were stirred at 45℃under nitrogen blanket 3 times for 24 h. After the reaction is finished, the LC-MS monitors, the reaction liquid is dripped into cold water, a large amount of solids are separated out, suction filtration is carried out, and a filter cake is washed by water. The filter cake was redissolved with a mixed solvent of methanol and dichloromethane (V Methanol ：V Dichloromethane (dichloromethane) =1:3), suction filtration, vacuum concentration of the filtrate to solid, ultrasonic pulping with a proper amount of methanol, freezing overnight in a refrigerator, suction filtration, methanol washing of filter cake, and drying of the filter cake in a vacuum drying oven at 50 ℃ to obtain 80.0mg of pale yellow solid with a yield of 70.9%. mp 259-261 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ12.60(s,1H),10.63(s, 1H),8.73(d,J＝4.1Hz,1H),7.93-7.89(m,3H),7.85(s,1H),7.78(d,J＝7.7Hz,1H),7.67(dd,J＝7.8,5.2 Hz,2H),7.60(t,J＝7.6Hz,1H),7.42-7.36(m,3H),6.90(s,1H),6.73(s,1H).HRMS(ESI)m/z:[M+Na] + Calculated value C 24 H 16 FN 3 NaO 3 436.1068, found 436.1062.
EXAMPLE 20 preparation of (3Z, 6Z) -3- ((6-methoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-20)
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (50.0 mg,0.14 mmol) and 6-methoxypyridine-2-carbaldehyde (22.5 mg,0.16 mmol) were taken as starting materials for this reaction, and compound PLN-1-20 was synthesized according to the preparation method of compound PLN-1-19 to give 39.0mg of a pale yellow solid with a yield of 64.4%. mp 216-218 ℃. 1 H NMR(500MHz,DMSO-d 6 ) δ12.32(s,1H),10.61(s,1H),7.92(dd,J＝8.8,5.5Hz,2H),7.85(s,1H),7.82-7.77(m,2H),7.66(d,J＝7.7 Hz,1H),7.60(t,J＝7.7Hz,1H),7.40(t,J＝8.8Hz,2H),7.27(d,J＝7.3Hz,1H),6.87(s,1H),6.84(d,J＝ 8.2Hz,1H),6.66(s,1H),3.99(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ194.2,164.8,162.5,157.0,156.4, 151.9,140.5,137.3,133.6,133.5,133.3,132.9,132.8,130.5,130.4,129.1,128.9,127.3,119.8,115.9,115.7, 114.3,110.0,108.1,53.7.HRMS(ESI)m/z:[M+Na] + Calculated value C 25 H 18 FN 3 NaO 4 466.1174, found 466.1170.
Example 21 preparation of (3Z, 6Z) -3- ((5-methoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-21)
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (50.0 mg,0.14 mmol) and 5-methoxypyridine-2-carbaldehyde (22.5 mg,0.16 mmol) were taken as starting materials for this reaction, and compound PLN-1-21 was synthesized according to the preparation method of compound PLN-1-19 to give 42.3mg of pale yellow solid with a yield of 69.9%. mp 237-239 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ 12.34(s,1H),10.54(s,1H),8.48(d,J＝3.0Hz,1H),7.92(dd,J＝8.8,5.5Hz,2H),7.85(s,1H),7.78(d,J＝ 7.7Hz,1H),7.66(dd,J＝8.2,5.0Hz,2H),7.59(t,J＝7.7Hz,1H),7.53(dd,J＝8.8,3.0Hz,1H),7.40(t,J ＝8.8Hz,2H),6.87(s,1H),6.72(s,1H),3.89(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ194.2,164.8,157.2, 156.6,154.5,147.1,137.3,136.7,133.6,133.5,133.4,132.9,132.8,130.4,129.0,128.9,128.7,127.7,127.3, 122.1,115.9,115.7,114.0,108.2,55.9.HRMS(ESI)m/z:[M+Na] + Calculated value C 25 H 18 FN 3 NaO 4 466.1174, found 466.1167.
Example 22 preparation of (3Z, 6Z) -3- ((4-methoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-22)
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (50.0 mg,0.14 mmol) and 4-methoxypyridine-2-carbaldehyde (22.5 mg,0.16 mmol) were taken as the reaction mixture The starting material for the step reaction, compound PLN-1-22 was synthesized according to the preparation method of compound PLN-1-19, to give 41.4mg of pale yellow solid with a yield of 68.4%. mp 253-255 ℃. 1 H NMR(500MHz,CDCl 3 )δ13.06 (s,1H),8.47(d,J＝5.8Hz,1H),8.25(s,1H),7.86(dd,J＝8.9,5.4Hz,2H),7.77-7.75(m,2H),7.63-7.58(m, 2H),7.19(t,J＝8.6Hz,2H),7.09(s,1H),6.87(s,1H),6.68(s,1H),3.88(s,3H). 13 C NMR(125MHz, Pyridine-d 5 )δ194.5,167.0,165.0,158.4,157.8,157.5,138.8,135.5,135.2,134.4,133.8,133.5,133.4,132.8, 131.6,130.0,129.8,129.2,116.4,116.2,115.3,112.3,109.6,109.3,55.8.HRMS(ESI)m/z:[M+Na] + Calculated value C 25 H 18 FN 3 NaO 4 466.1174, found 466.1165.
Example 23 preparation of (3Z, 6Z) -3- ((3-methoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-23)
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (50.0 mg,0.14 mmol) and 3-methoxypyridine-2-carbaldehyde (22.5 mg,0.16 mmol) were taken as starting materials for this reaction, and compound PLN-1-23 was synthesized according to the preparation method of compound PLN-1-19 to give 35.6mg of pale yellow solid with a yield of 58.8%. mp 274-276 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ 12.57(s,1H),10.62(s,1H),8.32(d,J＝4.8Hz,1H),7.92(dd,J＝8.8,5.5Hz,2H),7.85(s,1H),7.78(d,J＝ 7.6Hz,1H),7.66(d,J＝7.7Hz,1H),7.61-7.58(m,2H),7.43-7.39(m,3H),7.00(s,1H),6.90(s,1H),3.92 (s,3H).HRMS(ESI)m/z:[M+Na] + Calculated value C 25 H 18 FN 3 NaO 4 466.1174, found 466.1171.
Example 24 preparation of (3Z, 6Z) -3- ((5-hydroxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-24)
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (100 mg,0.27 mmol) and 5-hydroxypyridine-2-carbaldehyde 25k (40.3 mg,0.33 mmol) were taken as starting materials for this reaction, and compound PLN-1-24 was synthesized according to the preparation method of compound PLN-1-19 to give 40.1mg as a pale yellow solid with a yield of 34.2%. mp 243-245 ℃. 1 H NMR(500MHz,DMSO-d 6 ) δ12.35(s,1H),8.28(d,J＝2.7Hz,1H),7.92(dd,J＝8.7,5.6Hz,2H),7.84(s,1H),7.78(d,J＝7.7Hz,1H), 7.65(d,J＝7.7Hz,1H),7.59(t,J＝7.7Hz,1H),7.52(d,J＝8.6Hz,1H),7.40(t,J＝8.8Hz,2H),7.26(dd, J＝8.5,2.8Hz,1H),6.86(s,1H),6.66(s,1H). 13 C NMR(100MHz,DMSO-d 6 )δ194.3,164.8,157.3,156.5, 140.1,138.5,137.3*2,133.6,133.5*2,132.9,132.8,130.4,128.9,128.1,127.9,127.5,127.4,123.7,115.9, 115.7,113.7,108.8.HRMS(ESI)m/z:[M+H] + Calculated value C 24 H 17 FN 3 O 4 430.1198, found 430.1195.
Example 25 preparation of (3Z, 6Z) -3- ((3-hydroxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-25)
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(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (100 mg,0.27 mmol) and 3-hydroxypyridine-2-carbaldehyde 25j (40.3 mg,0.33 mmol) were taken as the starting materials for this reaction, and compound PLN-1-25 was synthesized according to the preparation method of compound PLN-1-19 to give 47.7mg as a pale yellow solid with a yield of 40.8%. mp 260-262 ℃. 1 H NMR(500MHz,DMSO-d 6 ) δ12.61(s,1H),10.73(s,1H),10.56(s,1H),8.21(d,J＝3.4Hz,1H),7.92(dd,J＝8.8,5.5Hz,2H),7.85(s, 1H),7.78(d,J＝7.7Hz,1H),7.66(d,J＝7.7Hz,1H),7.60(t,J＝7.6Hz,1H),7.41(t,J＝8.8Hz,2H),7.34 (d,J＝7.0Hz,1H),7.25(dd,J＝8.3,4.6Hz,1H),7.02(s,1H),6.88(s,1H). 13 C NMR(100MHz,DMSO-d 6 ) δ194.2,164.8,157.2,156.6,152.8,142.8,139.3,137.3,133.6,133.5,133.4,132.9,132.8,130.4,129.6,129.0, 128.9,127.3,124.0,123.1,115.9,115.7,114.1,102.4.HRMS(ESI)m/z:[M+H] + Calculated value C 24 H 17 FN 3 O 4 430.1198, found 430.1196.
EXAMPLE 26 preparation of (3Z, 6Z) -3- (3- (p-fluorophenoxy) benzene) methylene-6- ((N-methylpyrrole) -2-methylene) piperazine-2, 5-dione (PLN-1-26)
A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((3-p-fluorophenoxyphenyl) methylene) piperazine-2, 5-dione (100 mg,0.28 mmol), N-methyl-2-pyrrole-carbaldehyde (46.19 mg,0.34 mmol), cesium carbonate (137.9 mg,0.42 mmol), anhydrous sodium sulfate (80.2 mg,0.56 mmol), DMF (3 ml), vented, nitrogen blanket, placed in an oil bath at 45℃and stirred for reaction 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, filter cake cold water washing, vacuum drying oven drying at 50 ℃, methanol ultrasonic beating, standing in a refrigerator at 0 ℃, suction filtration, filter cake cold methanol washing, large plate chromatography (MeOH: dcm=1:200), short column filtration (MeOH: dcm=1:10), vacuum concentration, methanol ultrasonic beating, standing in a refrigerator at 0 ℃, suction filtration, filter cake cold methanol washing, vacuum drying oven drying at 50 ℃ to obtain yellow solid 4.5mg, yield 3.95%. Starting from Z) -1-acetyl-3- ((3-p-fluorophenoxyphenyl) methylene) piperazine-2, 5-dione (100 mg,0.28 mmol), N-methyl-2-pyrrole-carbaldehyde (46.2 mg,0.34 mmol), cesium carbonate (137.9 mg,0.42 mmol) and anhydrous sodium sulfate (80.2 mg,0.56 mmol), DMF (3 mL) was stirred in an oil bath at 45℃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, filter cake cold water washing, vacuum drying oven drying at 50 ℃, methanol ultrasonic beating, standing in a refrigerator at 0 ℃, suction filtration, filter cake cold methanol washing, large plate chromatography (MeOH: dcm=1:200), short column filtration (MeOH: dcm=1:10), vacuum concentration, methanol ultrasonic beating, standing in a refrigerator at 0 ℃, suction filtration, filter cake cold methanol washing, vacuum drying oven drying at 50 ℃ to obtain yellow solid 4.5mg, yield 4%.
1 H NMR(500MHz,DMSO-d 6 )δ10.27(s,1H),9.56(s,1H),7.41(t,J＝8.0Hz,1H),7.28(d,J＝7.7 Hz,1H),7.23(d,J＝8.6Hz,2H),7.19(s,1H),7.12(dd,J＝9.0,4.5Hz,2H),6.99(s,1H),6.91(dd,J＝8.1, 1.9Hz,1H),6.80(d,J＝3.4Hz,1H),6.75(s,1H),6.72(s,1H),6.20–6.13(m,1H),3.66(s,3H). 13 C NMR (125MHz，DMSO-d 6 )δ157.03，135.18，130.26，127.24，126.05，124.46，120.57，120.50，118.88，117.79，116.63,116.44,113.48,112.18,108.86,104.73,33.75.MS(ESI)m/z:[M+Na] + Calculated value C 23 H 18 FN 3 O 3 Na 426.1224, found 426.1219 melting point: 211-213 ℃.
EXAMPLE 27 preparation of (3Z, 6Z) -3- ((3-methylpyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-27)
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (80.0 mg,0.22 mmol) and 3-methylpyridine-2-carbaldehyde 25f (31.7 mg,0.26 mmol) were taken as the starting materials for this reaction, and compound PLN-1-27 was synthesized according to the preparation method of compound PLN-1-19 to give 80.6mg as a pale yellow solid with a yield of 86.4%. MP 244-247 ℃. 1 H NMR(400MHz,DMSO-d 6 ) δ10.69(s,1H),8.56(s,1H),7.92(t,J＝5.7Hz,2H),7.85(s,1H),7.77(t,J＝9.2Hz,2H),7.66(d,J＝7.5 Hz,1H),7.60(t,J＝7.6Hz,1H),7.41(t,J＝8.7Hz,2H),7.29(dd,J＝7.5,5.0Hz,1H),6.90(s,1H),6.76(s, 1H),2.42(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ194.3,163.6,157.1,156.8,153.0,146.0,139.0,137.3, 133.7,133.6,133.5*2,133.3,132.9,132.8,131.2,130.4,129.1,128.9,122.5,115.9,115.7,114.5,103.7, 18.4.HRMS(ESI)m/z:[M+H] + Calculation ofValue C 25 H 19 FN 3 O 3 428.1405, found 428.1402.
EXAMPLE 28 preparation of (3Z, 6Z) -3- ((4-methylpyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-28)
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (100 mg,0.27 mmol) and 4-methylpyridine-2-carbaldehyde 25g (39.7 mg,0.33 mmol) were taken as raw materials for this reaction, and compound PLN-1-28 was synthesized according to the preparation method of compound PLN-1-19 to give 87.2mg as a pale yellow solid with a yield of 74.7%. mp 241-243 ℃. 1 H NMR(400MHz,DMSO-d 6 ) δ10.61(s,1H),8.57(d,J＝5.1Hz,1H),7.91(dd,J＝8.9,5.5Hz,2H),7.84(s,1H),7.77(d,J＝7.6Hz,1H), 7.66(d,J＝7.8Hz,1H),7.59(t,J＝7.6Hz,1H),7.50(s,1H),7.40(t,J＝8.9Hz,2H),7.21(d,J＝5.1Hz, 1H),6.89(s,1H),6.65(s,1H),2.35(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ194.2,164.8,157.0,156.6, 154.4,148.7,148.2,137.3,133.6,133.5,133.3,132.9,132.8,131.1,130.4,129.0,128.9,127.2*2,123.5, 115.9,115.7,114.4,107.9,20.6.HRMS(ESI)m/z:[M+H] + Calculated value C 25 H 19 FN 3 O 3 428.1405, found 428.1403.
Example 29 preparation of (3Z, 6Z) -3- ((5-methylpyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-29)
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (100 mg,0.27 mmol) and 5-methylpyridine-2-carbaldehyde 25h (39.7 mg,0.33 mmol) were taken as starting materials for this reaction, and compound PLN-1-29 was synthesized according to the preparation method of compound PLN-1-19 to give 99.1mg as a pale yellow solid with a yield of 84.9%. mp 255-257 ℃. 1 H NMR(400MHz,DMSO-d 6 ) δ12.53(s,1H),10.62(s,1H),8.57(s,1H),7.92(t,J＝8.2Hz,2H),7.85(s,1H),7.75(dd,J＝17.4,7.7Hz, 2H),7.66(d,J＝7.6Hz,1H),7.59(t,J＝9.3Hz,2H),7.41(t,J＝8.7Hz,2H),6.88(s,1H),6.70(s,1H),2.35 (s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ194.2,163.6,157.1,156.6,152.0,148.8,138.2,137.3,133.6,133.5, 133.3,132.9,132.8,132.4,130.4,130.3,129.0,128.9,127.3,126.2,115.9,115.7,114.2,108.0,18.0.HRMS (ESI)m/z:[M+H] + Calculated value C 25 H 19 FN 3 O 3 428.1405, found 428.1401.
Example 30 preparation of (3Z, 6Z) -3- ((6-methylpyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-30)
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (50.0 mg,0.14 mmol) and 6-methylpyridine-2-carbaldehyde 25i (19.8 mg,0.16 mmol) were taken as the starting materials for this reaction, and compound PLN-1-30 was synthesized according to the preparation method of compound PLN-1-19 to give a pale yellow solid of 37.0mg in 63.4% yield. mp 220-223 ℃. 1 H NMR(500MHz,DMSO-d 6 ) δ12.80(s，1H)，10.61(s，1H)，7.92(dd，J＝8.8，5.6Hz，2H)，7.85(s，1H)，7.80(t，J＝7.8Hz，2H)，7.66(d，J ＝7.7Hz,1H),7.60(t,J＝7.7Hz,1H),7.47(d,J＝7.8Hz,1H),7.41(t,J＝8.8Hz,2H),7.25(d,J＝7.7Hz, 1H),6.89(s,1H),6.68(s,1H),2.58(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ194.2,163.6,157.1,157.0, 156.6,154.0,138.1,137.3,133.6,133.5,133.3,132.9,132.8,130.9,130.4,129.0,128.9,127.3,123.8,122.2, 115.9,115.7,114.2,107.8,24.1.HRMS(ESI)m/z:[M+Na] + Calculated value C 25 H 18 FN 3 NaO 3 450.1224, found 450.1222.
Example 31 preparation of (3Z, 6Z) -3- ((5-bromopyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-31)
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (100 mg,0.27 mmol) and 5-bromopyridine-2-carbaldehyde 25l (61.0 mg,0.33 mmol) were taken as starting materials for this reaction, and compound PLN-1-31 was synthesized according to the preparation method of compound PLN-1-19 to give 65.3mg as a tan solid in 48.6% yield. mp 256-259 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ 12.11(s,1H),10.69(s,1H),8.87(s,1H),8.15(d,J＝8.4Hz,1H),7.91(t,J＝7.9Hz,2H),7.84(s,1H),7.77 (d,J＝7.5Hz,1H),7.65(d,J＝8.3Hz,2H),7.60(t,J＝7.6Hz,1H),7.40(t,J＝8.6Hz,2H),6.90(s,1H), 6.73(s,1H). 13 C NMR(125MHz,Pyridine-d 5 )δ194.5,166.0,159.2,158.1,157.9,154.3,140.4,138.8,135.1, 134.4,133.8,133.5,133.4,133.0,131.6,130.1,129.8,129.0,127.9,119.2,116.4 116.2,115.64,107.8.HRMS (ESI)m/z:[M+H] + Calculated value C 24 H 16 BrFN 3 O 3 492.0354, found 492.0351.
Example 32 preparation of (3Z, 6Z) -3- (quinolin-2-ylmethylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-32)
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (100 mg,0.27 mmol) and quinoline-2-carbaldehyde 25m (51.6 mg,0.33 mmol) were taken as the starting materials for this reaction, and compound PLN-1-32 was synthesized according to the preparation method of compound PLN-1-19 to give 75.5mg as a tan solid with a yield of 59.7%. mp 241-243 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.74 (s,1H),8.44(d,J＝8.5Hz,1H),8.00(d,J＝8.4Hz,2H),7.92(t,J＝8.2Hz,2H),7.86(d,J＝10.9Hz,2H), 7.80(m,J＝13.0,2H),7.63(dt,J＝20.8,7.8Hz,3H),7.41(t,J＝8.7Hz,2H),6.94(s,1H),6.86(s,1H). 13 C NMR(100MHz,Pyridine-d 5 )δ194.5,166.0,158.2*2,156.3,147.4,138.7,137.7,135.1,134.4,134.1,133.9, 133.5,133.4,131.7,131.0,130.1,129.8,129.1,129.1,128.5,127.6,127.4,124.7,116.4,116.2,115.7,108.4. HRMS(ESI)m/z:[M+H] + Calculated value C 28 H 19 FN 3 O 3 464.1405, found 464.1403.
Example 33 preparation of (3Z, 6Z) -3- (isoquinolin-3-ylmethylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-33)
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (70.0 mg,0.19 mmol) and isoquinoline-3-carbaldehyde 25n (36.0 mg,0.23 mmol) were taken as starting materials for this reaction, and compound PLN-1-33 was synthesized according to the preparation method of compound PLN-1-19 to give 64.0mg as a pale yellow solid with a yield of 72.3%. mp 278-280 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ12.52 (s,1H),10.63(s,1H),9.48(s,1H),8.20(d,J＝8.2Hz,1H),8.13(s,1H),7.98(d,J＝8.0Hz,1H),7.93(dd, J＝8.9,5.5Hz,2H),7.86(t,J＝7.0Hz,2H),7.80(d,J＝7.6Hz,1H),7.74(t,J＝7.5Hz,1H),7.66(d,J＝7.7Hz,1H),7.60(t,J＝7.6Hz,1H),7.41(t,J＝8.9Hz,2H),6.89(s,1H),6.85(s,1H). 13 C NMR(100MHz, DMSO-d 6 )δ194.3,163.6,157.2,156.5,152.1,148.1,137.3,135.8,133.6,133.5*2,133.0,132.9,131.9, 130.4*2,129.9*2,129.0,128.5,128.4*2,128.3,127.0,126.8,123.2,115.9,115.7.HRMS(ESI)m/z:[M +H] + Calculated value C 28 H 19 FN 3 O 3 464.1405, found 464.1402.
Example 34 preparation of (3Z, 6Z) -3- (isoquinolin-1-ylmethylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-34)
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (70.0 mg,0.19 mmol) and isoquinoline-1-carbaldehyde 25o (36.0 mg,0.23 mmol) were taken as starting materials for this reaction, and compound PLN-1-34 was synthesized according to the preparation method of compound PLN-1-19 to give 67.2mg as a pale yellow solid with a yield of 75.9%. MP 274-276 ℃, HRMS (ESI) M/z: [ M+H ]] + Calculated value C 28 H 19 FN 3 O 3 464.1405, found 464.1403.
Example 35 preparation of (3Z, 6Z) -3- ((5-ethoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-35)
1) Synthesis of 5-ethoxypyridine-2-aldehyde 25p
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A25 mL dry round bottom flask was taken, 5-hydroxypyridine-2-carbaldehyde 20 (25.0 mg,0.20 mmol), bromoethane (22.1 mg,0.20 mmol), potassium carbonate (28.1 mg,0.20 mmol) and DMF (1.5 mL) were added sequentially, nitrogen was replaced 3 times, and the mixture was placed in an oil bath at 100deg.C and stirred for 1h. After the reaction was completed, LC-MS was monitored, and after the reaction solution cooled to room temperature, excess water (10 mL) was added to the reaction solution, ethyl acetate (50 ml×3) was extracted 3 times, the organic phases were combined, saturated brine (50 mL) was used to wash the organic phases, the aqueous phases were combined, ethyl acetate (50 ml×3) was used to strip the aqueous phases three times, the organic phases were combined, and anhydrous sodium sulfate was added to dry. Suction filtration, concentration of the filtrate under reduced pressure, column chromatography purification (PE: ea=1:1) gave 14.3mg of pale yellow oil, yield 53.1%. 1 H NMR(400MHz,CDCl 3 )δ9.98(s,1H), 8.41(s,1H),7.95(d,J＝8.6Hz,1H),7.27(dd,J＝2.7,2.8Hz,1H),4.30(t,J＝6.7Hz,2H),4.13(t,J＝6.6 Hz,3H).MS(ESI)m/z:[M+H] + Calculated value C 8 H 10 NO 2 152.07, found 151.57.
2) Synthesis of (3Z, 6Z) -3- ((5-ethoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione PLN-1-35
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (56.4 mg,0.15 mmol) and 5-ethoxypyridine-2-aldehyde 25p (28.0 mg,0.19 mmol) were taken as starting materials for this reaction, and compound PLN-1-35 was synthesized according to the preparation method of compound PLN-1-19 to give 47.3mg as a pale yellow solid with a yield of 67.1%. mp.229-231 ℃. 1 H NMR(500MHz,DMSO-d 6 ) δ12.33(s,1H),10.53(s,1H),8.46(d,J＝3.0Hz,1H),7.92(dd,J＝8.8,5.5Hz,2H),7.84(s,1H),7.77(d,J ＝7.7Hz，1H)，7.65(dd，J＝8.2，3.4Hz，2H)，7.59(t，J＝7.7Hz，1H)，7.51(dd，J＝8.8，3.0Hz，1H)，7.40(t，J＝8.8Hz,2H),6.87(s,1H),6.72(s,1H),4.17(q,J＝7.0Hz,2H),1.37(t,J＝7.0Hz,3H). 13 C NMR(100 MHz,DMSO-d 6 )δ194.2,163.6,157.2,156.6,153.8,146.9,137.3,136.9,133.6,133.5,133.4,132.9,132.8, 130.4,129.0,128.9,128.7,127.8,127.3,122.5,115.9,115.7,113.9,108.3,64.1,14.5.HRMS(ESI)m/z:[M +H] + Calculated value C 26 H 21 FN 3 O 4 458.1511, found 458.1507.
Example 36 preparation of (3Z, 6Z) -3- ((5-propoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-36)
1) Synthesis of 5-propoxypyridine-2-carbaldehyde 25q
As the solvent, 5-hydroxypyridine-2-carbaldehyde 20 (50.0 mg,0.41 mmol) and n-iodo-propane (69.0 mg,0.41 mmol) were takenThe starting material for the step reaction, compound 25q was synthesized according to the preparation method of compound 25p to give 48.1mg of pale yellow oil in 71.7% yield. 1 H NMR(400MHz,CDCl 3 )δ9.99(s,1H),8.43(s,1H),7.95(d,J＝8.6Hz,1H),7.29(d,J＝2.8Hz,1H),4.06 (t,J＝6.5Hz,2H),1.88(h,J＝7.0Hz,2H),1.07(t,J＝7.4Hz,3H).MS(ESI)m/z:[M+H] + Calculated value C 9 H 12 NO 2 166.09, found 165.67.
2) Synthesis of (3Z, 6Z) -3- ((5-ethoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione PLN-1-36
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (79.1 mg,0.22 mmol) and 5-propoxypyridine-2-carbaldehyde 25q (42.7 mg,0.26 mmol) were taken as starting materials for this reaction, and Compound PLN-1-36 was synthesized according to the preparation method of Compound PLN-1-19 to give 65.8mg as a pale yellow solid with a yield of 64.6%. mp 223-225 ℃. 1 H NMR(500MHz,DMSO- d 6 )δ12.33(s,1H),10.53(s,1H),8.47(d,J＝2.8Hz,1H),7.92(dd,J＝8.5,5.6Hz,2H),7.84(s,1H),7.77 (d,J＝7.7Hz,1H),7.65(dd,J＝8.0,5.4Hz,2H),7.59(t,J＝7.6Hz,1H),7.52(dd,J＝8.7,2.9Hz,1H),7.40 (t,J＝8.7Hz,2H),6.87(s,1H),6.71(s,1H),4.08(t,J＝6.5Hz,2H),1.80-1.73(m,2H),0.99(t,J＝7.4Hz, 3H). 13 C NMR(100MHz,DMSO-d 6 )δ194.2,164.8,157.2,156.6,153.9,146.9,137.3,136.9,133.6,133.5, 133.4,132.9,132.8,130.4,129.0,128.9,128.7,127.7,127.3,122.5,115.9,115.7,113.9,108.3,69.8,21.9, 10.3.HRMS(ESI)m/z:[M+H] + Calculated value C 27 H 23 FN 3 O 4 472.1667, found 472.1664.
Example 37 preparation of (3Z, 6Z) -3- ((5-Butoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-37)
1) Synthesis of 5-butoxypyridine-2-carbaldehyde 25r
5-hydroxypyridine-2-carbaldehyde 20 (50.0 mg,0.41 mmol) and n-iodo-butane (74.7 mg,0.41 mmol) were taken as raw materials for this reaction, and compound 25r was synthesized according to the preparation method of compound 25p to give 43.5mg of colorless transparent oil in 59.8% yield. 1 H NMR(400MHz,CDCl 3 )δ9.99(s,1H),8.42(d,J＝2.8Hz,1H),7.95(d,J＝8.1Hz,1H),7.28(dd,J＝8.7, 2.8Hz,1H),4.10(t,J＝6.4Hz,2H),1.86-1.79(m,2H),1.57-1.47(m,2H),1.00(t,J＝7.4Hz,3H).MS(ESI) m/z:[M+H] + Calculated value C 10 H 14 NO 2 180.10, found 179.68.
2) Synthesis of (3Z, 6Z) -3- ((5-butoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione PLN-1-37
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (64.9 mg,0.18 mmol) and 5-butoxypyridine-2-carbaldehyde 25r (38.1 mg,0.21 mmol) were taken as starting materials for this reaction, and compound PLN-1-37 was synthesized according to the preparation method of compound PLN-1-19 to give 67.0mg as a pale yellow solid with a yield of 77.9%. mp 224-226 ℃. 1 H NMR(400MHz,DMSO- d 6 )δ12.33(s,1H),10.56(s,1H),8.46(s,1H),7.91(t,J＝8.7Hz,2H),7.84(s,1H),7.77(d,J＝7.5Hz,1H), 7.65(dd,J＝7.9,4.8Hz,2H),7.59(t,J＝7.6Hz,1H),7.51(d,J＝8.7Hz,1H),7.40(t,J＝8.7Hz,2H),6.87 (s,1H),6.71(s,1H),4.10(t,J＝6.4Hz,2H),1.72(p,J＝6.5Hz,2H),1.44(h,J＝7.3Hz,2H),0.94(t,J＝ 7.4Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ194.2,163.6,157.2,156.5,153.9,146.9,137.3,136.9,133.5 *2,133.4 132.9,132.8,130.4,129.0,128.9,128.6,127.7,127.3,122.5,115.9,115.7,113.9,108.3,68.0,30.6, 18.7,13.7.HRMS(ESI)m/z:[M+H] + Calculated value C 28 H 25 FN 3 O 4 486.1824, found 486.1819.
Example 38 preparation of (3Z, 6Z) -3- ((5-isopropoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-38)
1) Synthesis of 5-hydroxy-N-methoxy-N-methylpyridine amide 22
A100 mL dry round bottom flask was taken, 5-hydroxypicolinic acid 21 (1.00 g,7.19 mmol) was dissolved in DMF and stirred at room temperature for 1min, then N-methyl-N-methoxyamine hydrochloride (1.05 g,10.8 mmol), EDCI (2.07 g,10.8 mmol), HOBT (1.65 g,12.2 mmol) and triethylamine (2.91 g,28.8 mmol) were added sequentially and the reaction was stirred at room temperature for 6.5h. After the reaction is finished, LC-MS monitors, and a proper amount of saturated ammonium chloride aqueous solution is added into the reaction solution until the solution becomes clear. Ethyl acetate (100 mL x 3) was added to extract 3 times, the organic phases were combined, the organic phases were washed with saturated brine (100 mL), the aqueous phases were combined, the aqueous phases were back-extracted 3 times with ethyl acetate (80 mL x 3), the organic phases were combined, and dried with anhydrous sodium sulfate. Suction filtration, concentration of the filtrate under reduced pressure, column chromatography purification (PE: ea=1:1) gave 860mg of a tan oil with a yield of 65.7%. 1 H NMR(400MHz,CDCl 3 )δ8.16(s,1H),7.60(d,J＝8.6Hz,1H),7.19(dd,J ＝8.6,2.7Hz,1H),3.72(s,3H),3.44(s,3H).MS(ESI)m/z:[M+H] + Calculated value C 8 H 11 FN 2 O 3 183.08, found 182.71.
2) Synthesis of 5-isopropoxy-N-methoxy-N-methylpyridine amide 24s
A100 mL dry round bottom flask was taken, 5-hydroxy-N-methoxy-N-methylpyridine amide 22 (300 mg,1.65 mmol) was dissolved in dry DCM (10 mL), stirred at room temperature for 1min, isopropanol (149 mg,2.47 mmol), triphenylphosphine (562 mg,2.14 mmol) and diisopropyl azodicarboxylate (433 mg,2.14 mmol) were added sequentially and the reaction was stirred at room temperature for 30min. After completion of the reaction, LC-MS was monitored, water (50 mL) was added to the reaction solution, DCM (100 ml×3) was extracted 3 times, the organic phases were combined, the saturated brine (100 mL) was washed, the aqueous phase was combined, the aqueous phase was back-extracted 3 times with DCM (80 ml×3), the organic phases were combined, and anhydrous sodium sulfate was added to dry. The filtrate was concentrated under suction and purified by column chromatography (PE: ea=10:1, 8:1,5:1, 2:1) to give 223mg of a pale yellow oil in 45.4% yield. 1 H NMR(400MHz,CDCl 3 )δ8.23(s,1H),7.70(d,J＝8.6Hz,1H),7.20(dd,J＝8.7,2.9Hz,1H),4.62(hept, J＝6.0Hz,1H),3.76(s,3H),3.41(s,3H),1.36(d,J＝8.1Hz,6H).MS(ESI)m/z:[M+H] + Calculated value C 11 H 17 FN 2 O 3 225.12, found 224.83.
3) Synthesis of 5-isopropoxypyridine-2-carbaldehyde 25s
50mL of a dry and sealed round-bottomed flask was taken, nitrogen was purged 3 times, diisobutylaluminum hydride (199mg, 1.40 mmol) was dissolved in THF (5 mL), and after stirring at-78℃for 10min, a solution of 5-isopropoxy-N-methoxy-N-methylpyridine amide 24s (209 mg,0.93 mmol) in THF (2 mL) was slowly added dropwise, and the mixture was stirred at-78℃for 1.5h. LC-MS monitoring the completion of the reaction, a saturated aqueous solution (20 mL) of potassium sodium tartrate was added to the reaction mixture, and the reaction flask was stirred at room temperature for 1 hour. Ethyl acetate (50 mL x 3) was added to extract 3 times, the organic phases were combined, the organic phases were washed with saturated brine (50 mL), the aqueous phases were combined, the aqueous phases were back-extracted 3 times with ethyl acetate (40 mL x 3), the organic phases were combined, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate under reduced pressure, column chromatography purification (PE: ea=10:1, 8:1) gave 109.4mg of a pale yellow oil in 71.0% yield. 1 H NMR(400MHz,CDCl 3 )δ9.97(s,1H),8.39(s,1H), 7.94(d,J＝8.7Hz,1H),7.27-7.25(m,1H),4.71(hept,J＝5.8Hz,1H),1.40(d,J＝6.1Hz,6H).MS(ESI) m/z:[M+H] + Calculated value C 9 H 12 NO 2 166.09, found 165.65.
4) Synthesis of (3Z, 6Z) -3- ((5-isopropoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione PLN-1-38
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (121 mg,0.33 mmol) and 5-isopropoxypyridine-2-carbaldehyde 25s (65.2 mg,0.40 mmol) were taken as starting materials for this reaction, and compound PLN-1-38 was synthesized according to the preparation method of compound PLN-1-19 to give 131mg of pale yellow solid with a yield of 84.3%. mp 234-236 ℃. 1 H NMR(500MHz,DMSO- d 6 )δ12.33(s,1H),10.53(s,1H),8.44(d,J＝2.9Hz,1H),7.92(dd,J＝8.7,5.6Hz,2H),7.84(s,1H),7.77 (d,J＝7.7Hz,1H),7.62(dt,J＝15.3,8.0Hz,3H),7.51(dd,J＝8.8,2.9Hz,1H),7.40(t,J＝8.8Hz,2H), 6.87(s,1H),6.71(s,1H),4.83-4.75(m,1H),1.31(d,J＝6.0Hz,6H). 13 C NMR(100MHz,DMSO-d 6 )δ 194.2,164.8,157.2,156.6,152.8,146.7,137.8,137.3,133.6,133.5,133.4,132.9,132.8,130.4,129.0*2, 128.6,127.8,127.4,123.4,115.9,115.7,113.9,108.3,70.4,21.6*2.HRMS(ESI)m/z:[M+H] + Calculated value C 27 H 23 FN 3 O 4 472.1667, found 472.1663.
Example 39 preparation of (3Z, 6Z) -3- ((5- (2-cyclohexylethoxy) pyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-39)
1) Synthesis of 5- (2-cyclohexylethoxy) pyridine-2-aldehyde 25t
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5-hydroxypyridine-2-carbaldehyde 20 (50.0 mg,0.41 mmol) and 2-bromoethylcyclohexane (77.6 mg,0.41 mmol) were taken as starting materials for this reaction, and compound 25t was synthesized according to the preparation method of compound 25p to give 74.5mg of a pale yellow oily substance in 78.6% yield. 1 H NMR(400MHz,CDCl 3 )δ9.99(s,1H),8.42(s,1H),7.95(dd,J＝8.6,0.5Hz,1H),7.28(dd,J＝5.2,4.2 Hz,1H),4.32-4.28(m,10H),4.21-4.15(m,3H),3.74-3.69(m,2H).MS(ESI)m/z:[M+H] + Calculated value C 14 H 20 NO 2 234.15, found 233.84.
2) Synthesis of (3Z, 6Z) -3- ((5- (2-cyclohexylethoxy) pyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione PLN-1-39
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (87.0 mg,0.24 mmol) and 5- (2-cyclohexylethoxy) pyridine-2-carbaldehyde 25t (66.5 mg,0.29 mmol) were taken as starting materials for this reaction, and Compound PLN-1-39 was synthesized according to the preparation method of Compound PLN-1-19 to give 115mg as a pale yellow solid with a yield of 89.6%. mp 217-219 ℃. 1 H NMR(500MHz, DMSO-d 6 )δ12.62(s,1H),8.34(s,1H),8.25(s,1H),7.86(dd,J＝8.5,5.5Hz,2H),7.75(t,J＝7.4Hz,2H), 7.63-7.57(m,2H),7.30(d,J＝8.7Hz,1H),7.24-7.17(m,3H),7.07(s,1H),6.72(s,1H),4.09(t,J＝6.6Hz, 2H),1.78-1.63(m,7H),1.31-1.17(m,4H),0.99(dd,J＝22.7,10.8Hz,2H). 13 C NMR(100MHz,Pyridine- d 5 )δ194.8,166.0,158.6,157.9,154.8,148.2,138.7,137.3,135.3,134.4,133.8,133.5,133.4,131.6,130.3, 129.9,129.8,129.4,127.9,122.9,116.4,116.2,114.8,109.4,67.3,36.9,35.0,33.6*2,27.0,26.8*2.HRMS (ESI)m/z:[M+H] + Calculated value C 32 H 31 FN 3 O 4 540.2293, found 540.2291.
Example 40 preparation of (3Z, 6Z) -3- ((5-Benzyloxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-40)
1) Synthesis of 5-benzyloxy-N-methoxy-N-methylpyridine amide 24u
5-hydroxy-N-methoxy-N-methylpyridinamide 22 (300 mg,1.65 mmol) and benzyl alcohol (267 mg,2.47 mmol) were taken as starting materials for this reaction, and 24u was synthesized according to the preparation method of 24s to give 169mg as pale yellow oily substance in 37.8% yield. 1 H NMR(400MHz,DMSO-d 6 )δ8.36(s,1H),7.62-7.54(m,2H),7.48(d,J＝7.2Hz,2H),7.39(dt,J＝15.8, 7.1Hz,3H),5.24(s,2H),3.67(s,3H),3.27(s,3H).MS(ESI)m/z:[M+H] + Calculated value C 15 H 17 N 2 O 3 273.12, found 272.79.
2) Synthesis of 5-benzyloxypyridine-2-carbaldehyde 25u
5-benzyloxy-N-methoxy-N-methylpyridine amide 24u (169 mg,0.62 mmol) was taken as a raw material for the reaction, and compound 25u was synthesized according to the preparation method of compound 25s to obtain 109mg of pale yellow oil with a yield of 82%. 1 H NMR(400MHz,CDCl 3 ) δ9.99(s,1H),8.51(d,J＝2.3Hz,1H),7.95(d,J＝8.7Hz,1H),7.43-7.42(m,3H),7.40-7.35(m,3H),5.21 (s,2H).MS(ESI)m/z:[M+H] + Calculated value C 13 H 12 NO 2 214.09, found 213.79.
3) Synthesis of (3Z, 6Z) -3- ((5-benzyloxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione PLN-1-40
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (102 mg,0.28 mmol) and 5-benzyloxypyridine-2-carbaldehyde 25u (71.0 mg,0.33 mmol) were taken as the starting materials for this reaction, and compound PLN-1-40 was synthesized according to the preparation method of compound PLN-1-19 to give 121mg as a yellowish white solid in 84.1% yield. mp 220-223 ℃. 1 H NMR(500MHz,DMSO-d 6 ) δ12.32(s,1H),10.54(s,1H),8.54(d,J＝2.8Hz,1H),7.92(dd,J＝8.6,5.6Hz,2H),7.84(s,1H),7.77(d,J ＝7.6Hz,1H),7.66(t,J＝8.6Hz,2H),7.60(t,J＝8.6Hz,2H),7.49(d,J＝7.3Hz,2H),7.43-7.35(m,5H), 6.88(s,1H),6.71(s,1H),5.26(s,2H). 13 C NMR(100MHz,DMSO-d 6 )δ194.3,164.9,157.2,156.6,153.6, 147.3,137.3,137.2,136.2,133.6,133.5,133.4,133.0,132.9,130.4,129.1,129.0,128.9,128.7*2,128.3, 128.1*2,127.7,127.4,123.1,115.9,115.7,114.0,108.2,70.0.HRMS(ESI)m/z:[M+H] + Calculated value C 31 H 23 FN 3 O 4 520.1667, found 520.1663.
Example 41 preparation of (3Z, 6Z) -3- ((5-phenethyloxy-pyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-41)
1) Synthesis of 5-phenethyl-N-methoxy-N-methylpyridine amide 24v
5-hydroxy-N-methoxy-N-methylpyridine amide 22 (300 mg,1.65 mmol) and phenethyl alcohol (302 mg,2.47 mmol) were taken as starting materials for this reaction, and 24v was synthesized according to the preparation method of 24s to give 291mg of pale yellow oil in 46.2% yield. 1 H NMR(400MHz,CDCl 3 )δ8.24(s,1H),7.67(d,J＝8.5Hz,1H),7.32-7.18(m,6H),4.23(t,J＝7.0Hz, 2H),3.73(s,3H),3.38(s,3H),3.10(t,J＝7.0Hz,2H).MS(ESI)m/z:[M+H] + Calculated value C 16 H 19 N 2 O 3 287.14, found 286.80.
2) Synthesis of 5-phenethyloxy pyridine-2-carbaldehyde 25v
5-phenethyl-N-methoxy-N-methylpyridine amide 24v (281mg, 0.98 mmol) was taken as a starting material for this step of reaction, and compound 25v was synthesized according to the preparation method of compound 25s to give 178mg of colorless transparent oil with a yield of 80.1%. 1 H NMR(400MHz, CDCl 3 )δ9.98(s,1H),8.42(d,J＝2.8Hz,1H),7.94(d,J＝8.7Hz,1H),7.36-7.26(m,6H),4.31(t,J＝6.9 Hz,2H),3.16(t,J＝6.9Hz,2H).MS(ESI)m/z:[M+H] + Calculated value C 14 H 14 NO 2 228.10, found 227.77.
3) Synthesis of (3Z, 6Z) -3- ((5-phenethoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione 26v
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (79.5 mg,0.22 mmol) and 5-phenethyloxy pyridine-2-carbaldehyde 25v (59.0 mg,0.26 mmol) were taken as starting materials for this reaction, and Compound PLN-1-41 was synthesized according to the preparation method of Compound PLN-1-19 to give 98.7mg as a pale yellow solid with a yield of 85.2%. mp 175-178 ℃. 1 H NMR(500MHz,DMSO- d 6 )δ12.32(s,1H),10.53(s,1H),8.47(d,J＝2.9Hz,1H),7.91(dd,J＝8.7,5.6Hz,2H),7.84(s,1H),7.77 (d,J＝7.7Hz,1H),7.62(dt,J＝15.3,8.2Hz,3H),7.53(dd,J＝8.8,2.9Hz,1H),7.40(t,J＝8.8Hz,2H), 7.35-7.30(m,4H),7.23(t,J＝6.8Hz,1H),6.87(s,1H),6.71(s,1H),4.35(t,J＝6.9Hz,2H),3.08(t,J＝6.9 Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ194.2,163.6,157.2,156.6,153.7,147.1,137.9,137.3,136.9, 133.6,133.5*2,133.4,132.9,132.8,130.4,129.1,129.0*2,128.9,128.7,128.4,127.7,127.4,126.5,122.7, 115.9,115.7,113.9,108.2,68.9,34.7.HRMS(ESI)m/z:[M+H] + Calculated value C 32 H 25 FN 3 O 4 534.1824, found 534.1823.
Example 42 preparation of (3Z, 6Z) -3- ((3-ethoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-42)
1) Synthesis of 3-ethoxypyridine-2-carbaldehyde 25w
3-hydroxypyridine-2-carbaldehyde 18 (50.0 mg,0.41 mmol) and bromoethane (44.2 mg,0.41 mmol) were taken as starting materials for this reaction, and compound 25w was synthesized according to the preparation method of compound 25p to give 32.8mg of a pale yellow solid in 53.4% yield. 1 H NMR (400MHz,DMSO-d 6 )δ10.21(s,1H),8.34(d,J＝4.3Hz,1H),7.73(d,J＝8.6Hz,1H),7.63(dd,J＝8.6,4.3 Hz,1H),4.21(q,J＝7.0Hz,2H),1.38(t,J＝7.0Hz,3H).MS(ESI)m/z:[M+H] + Calculated value C 8 H 10 NO 2 152.07, found 151.65.
2) Synthesis of (3Z, 6Z) -3- ((3-ethoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione 26w
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (56.1 mg,0.15 mmol) and 3-ethoxypyridine-2-carbaldehyde 25w (27.6 mg,0.18 mmol) were taken as the starting materials for this reaction, and Compound PLN-1-42 was synthesized in accordance with the preparation method of Compound PLN-1-19 to give a pale yellow solid of 33.6mg, which was collectedThe rate was 48.0%. mp 225-227 ℃. 1 H NMR(500MHz,DMSO- d 6 )δ12.63(s,1H),10.61(s,1H),8.30(d,J＝4.7Hz,1H),7.92(dd,J＝8.7,5.5Hz,2H),7.84(s,1H),7.78 (d,J＝7.6Hz,1H),7.66(d,J＝7.7Hz,1H),7.61-7.56(m,2H),7.39(dt,J＝8.5,6.8Hz,3H),7.01(s,1H), 6.89(s,1H),4.18(q,J＝6.9Hz,2H),1.41(t,J＝6.9Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ194.2,157.1, 156.7,153.1,144.0,139.8,137.3,133.6,133.5,133.4,133.3,132.9,132.8,130.5,130.3,129.0,128.9,127.2, 123.8,119.9,115.9,115.6,114.3,101.4,64.2,14.5.HRMS(ESI)m/z:[M+H] + Calculated value C 26 H 21 FN 3 O 4 458.1511, found 458.1505.
Example 43 preparation of (3Z, 6Z) -3- ((3-propoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-43)
1) Synthesis of 3-propoxypyridine-2-carbaldehyde 25x
3-hydroxypyridine-2-carbaldehyde 18 (50.0 mg,0.41 mmol) and n-iodo-propane (69.0 mg,0.41 mmol) were taken as raw materials for this reaction, and compound 25x was synthesized according to the preparation method of compound 25p to give 67.1mg of pale yellow oily substance in 70.6% yield. 1 H NMR(400MHz,CDCl 3 )δ10.43(s,1H),8.38(d,J＝4.3Hz,1H),7.45(dd,J＝8.6,4.3Hz,1H),7.39(d,J＝ 8.6Hz,1H),4.07(t,J＝6.1Hz,2H),1.91(h,J＝7.4Hz,2H),1.09(t,J＝7.4Hz,3H).MS(ESI)m/z:[M+ H] + Calculated value C 9 H 12 NO 2 166.09, found 165.67.
2) Synthesis of (3Z, 6Z) -3- ((3-propoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione 26x
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(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (38.1 mg,0.10 mmol) and 3-propoxypyridine-2-carbaldehyde 25x (20.5 mg,0.12 mmol) were taken as starting materials for this reaction, and Compound PLN-1-43 was synthesized according to the preparation method of Compound PLN-1-19 to give 41.2mg as a pale yellow solid with a yield of 83.4%. mp 188-191 ℃. 1 H NMR(500MHz,DMSO- d 6 )δ(s,1H),10.61(s,1H),8.30(d,J＝4.6Hz,1H),7.92(dd,J＝8.7,5.6Hz,2H),7.85(s,1H),7.78(d,J＝ 7.6Hz,1H),7.66(d,J＝7.7Hz,1H),7.59(dd,J＝15.6,7.9Hz,2H),7.42-7.36(m,3H),7.02(s,1H),6.89(s, 1H),4.09(t,J＝6.5Hz,2H),1.81(m,2H),1.02(t,J＝7.4Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ194.6, 163.6,157.1,156.8,153.3,144.2,139.9,137.4,133.7,133.6,133.4,132.9,132.9,130.7,130.5,129.1,129.0, 127.4,123.9,120.0,116.0,115.8,114.4,101.3,68.2,19.0,13.8.HRMS(ESI)m/z:[M+H] + Calculated value C 27 H 23 FN 3 O 4 472.1667, found 472.1662.
Example 44 preparation of (3Z, 6Z) -3- ((3-Butoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-44)
1) Synthesis of 3-butoxypyridine-2-carbaldehyde 25y
3-hydroxypyridine-2-carbaldehyde 18 (50.0 mg,0.41 mmol) and n-iodo-butane (74.7 mg,0.41 mmol) were taken as raw materials for this reaction, and compound 25y was synthesized according to the preparation method of compound 25p to give 54.9mg of orange-yellow oil in 75.4% yield. 1 H NMR(400MHz,CDCl 3 )δ10.42(s,1H),8.38(d,J＝2.9Hz,1H),7.45(dd,J＝8.6,4.3Hz,1H),7.40(d,J＝ 7.3Hz,1H),4.11t,J＝6.5Hz,2H),1.90-1.83(m,2H),1.59-1.49(m,2H),1.00(t,J＝7.4Hz,3H).MS(ESI) m/z:[M+H] + Calculated value C 10 H 14 NO 2 180.10, found 179.69.
2) Synthesis of (3Z, 6Z) -3- ((3-butoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione PLN-1-44
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (84.6 mg,0.23 mmol) and 3-butoxypyridine-2-carbaldehyde 25y (49.6 mg,0.28 mmol) were taken as starting materials for this reaction, and compound PLN-1-44 was synthesized according to the preparation method of compound PLN-1-19 to give 71.0mg as a pale yellow solid with a yield of 63.3%. mp 188-191 ℃. 1 H NMR(400MHz,DMSO- d 6 )δ10.63(s,1H),8.28(s,1H),7.91(t,J＝5.64Hz 2H),7.84(s,1H),7.78(d,J＝7.5Hz,1H),7.66(d,J＝ 7.6Hz,1H),7.59(dd,J＝12.4,8.0Hz,2H),7.43-7.35(m,3H),7.00(s,1H),6.88(s,1H),4.11(t,J＝6.4Hz, 2H),1.77(p,J＝6.6Hz,2H),1.47(h,J＝7.4Hz,2H),0.95(t,J＝7.4Hz,3H). 13 C NMR(100MHz,DMSO- d 6 )δ194.2,164.8,157.1,156.7,153.2,144.1,139.9,137.3,133.6,133.5,133.3,132.9,132.8,130.6,130.4, 129.0,128.9,127.3,123.8,120.0,115.9,115.7,114.3,101.3,68.1,30.5,18.8,13.7.HRMS(ESI)m/z:[M+ H] + Calculated value C 28 H 25 FN 3 O 4 486.1824, found 486.1822.
Example 45 preparation of (3Z, 6Z) -3- ((3-isopropoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-45)
1) Synthesis of 3-isopropoxypyridine-2-carbaldehyde 25z
3-hydroxypyridine-2-carbaldehyde 18 (50.0 mg,0.41 mmol) and 2-bromopropane (49.9 mg,0.41 mmol) were taken as starting materials for this reaction, and compound 25z was synthesized according to the preparation method of compound 25p to give 21.6mg as a pale yellow oily substance in 32.2% yield. 1 H NMR (400MHz,CDCl 3 )δ10.44(s,1H),8.38(s,1H),7.71(dd,J＝5.8,3.3Hz,1H),7.52(dd,J＝5.8,3.3Hz,1H), 4.68(hept,J＝6.0Hz,1H),1.43(d,J＝6.0Hz,6H).MS(ESI)m/z:[M+H] + Calculated value C 9 H 12 NO 2 166.09, found 165.65.
2) Synthesis of (3Z, 6Z) -3- ((3-isopropoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione 26z
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (39.9 mg,0.11 mmol) and 3-isopropoxypyridine-2-aldehyde 25Z (21.6 mg,0.13 mmol) were taken as starting materials for this step of reaction, and compound PLN-1-45 was synthesized according to the preparation method of compound PLN-1-19 to give 42.7mg as a pale yellow solid with a yield of 83.2%. mp 179-181 ℃. 1 H NMR(400MHz,DMSO- d 6 )δ10.64(s,1H),8.28(d,J＝3.6Hz,1H),7.91(dd,J＝8.9,5.5Hz,2H),7.84(s,1H),7.77(d,J＝7.6Hz, 2H),7.66(d,J＝7.8Hz,2H),7.59(t,J＝7.7Hz,1H),7.41(t,J＝8.9Hz,1H),7.36(dd,J＝8.5,4.7Hz,1H), 6.99(s,1H),6.89(s,1H),4.77(hept,J＝5.9Hz,1H),1.33(d,J＝6.0Hz,6H). 13 C NMR(100MHz,DMSO- d 6 )δ194.2,164.8,157.1,156.7,152.2,144.7,139.8,137.3,133.6,133.5,133.3,132.9,132.8,130.5,130.4, 129.0,128.9,127.2,123.8,121.2,115.9,115.7,114.3,101.6,70.7,21.6*2.HRMS(ESI)m/z:[M+H] + Calculated value C 27 H 23 FN 3 O 4 472.1667, found 472.1663.
Example 46 preparation of (3Z, 6Z) -3- ((3-cyclohexylmethoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-46)
1) Synthesis of 3-cyclohexylmethoxypyridine-2-carbaldehyde 25aa
3-hydroxypyridine-2-carbaldehyde 18 (50.0 mg,0.41 mmol) and bromomethylcyclohexane (71.9 mg,0.41 mmol) were taken as starting materials for this reaction, and compound 25aa was synthesized according to the preparation method of compound 25p to give 46.2mg as a pale yellow oil, yield 51.9%. 1 H NMR(400MHz,DMSO-d 6 )δ10.20(s,1H),8.33(dd,J＝4.4,1.2Hz,1H),7.73(d,J＝7.6Hz,1H),7.62 (dd,J＝8.6,4.4Hz,1H),3.95(d,J＝6.2Hz,2H),1.85-1.64(m,6H),1.31-1.03(m,4H).MS(ESI)m/z:[M+ H] + Calculated value C 13 H 18 NO 2 220.13, found 219.80.
2) Synthesis of (3Z, 6Z) -3- ((3-cyclohexylmethoxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione 26aa
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (56.4 mg,0.15 mmol) and 3-cyclohexylmethoxypyridine-2-carbaldehyde 25aa (40.4 mg,0.18 mmol) were taken as starting materials for this reaction, and compound PLN-1-46 was synthesized according to the preparation method of compound PLN-1-19 to give 65.5mg as a pale yellow solid with a yield of 80.9%. mp.171-173 ℃. 1 H NMR(400MHz, DMSO-d 6 )δ10.64(s,1H),8.29(d,J＝3.6Hz,1H),7.91(dd,J＝8.9,5.5Hz,2H),7.84(s,1H),7.78(d,J＝ 7.6Hz,1H),7.66(d,J＝7.8Hz,1H),7.59(dd,J＝15.1,7.5Hz,2H),7.41(t,J＝8.9Hz,2H),7.36(dd,J＝8.5,4.7Hz,1H),7.01(s,1H),6.88(s,4H),3.92(d,J＝6.1Hz,2H),1.83-1.65(m,6H),1.32-1.03(m,5H). 13 C NMR(100MHz,DMSO-d 6 )δ194.2,164.8,157.0,156.7,153.3,144.1,139.9,137.3,133.6,133.5,133.4, 132.9,132.8,130.7,130.4,129.0,128.9,127.3,123.8,120.0,115.9,115.7,114.3,101.2,73.4,36.8,29.2*2, 26.1,25.2*2.HRMS(ESI)m/z:[M+H] + Calculated value C 31 H 29 FN 3 O 4 526.2137, found 526.2132.
Example 47 preparation of (3Z, 6Z) -3- ((3- (2-cyclohexylethoxy) pyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-47)
1) Synthesis of 3-cyclohexylmethoxypyridine-2-carbaldehyde 25ab
3-hydroxypyridine-2-carbaldehyde 18 (50.0 mg,0.41 mmol) and 2-bromoethylcyclohexane (77.6 mg,0.41 mmol) were taken as starting materials for this reaction, and compound 25ab was synthesized according to the preparation method of compound 25p to give 69.1mg of a pale yellow oily substance in a yield of 72.9%. 1 H NMR(400MHz,CDCl 3 )δ10.42(s,1H),8.38(dd,J＝4.2,1.2Hz,2H),7.46-7.39(m,2H),4.14(t,J＝6.7 Hz,2H),1.78-1.65(m,7H),1.31-1.15(m,4H),1.04-0.94(m,3H).MS(ESI)m/z:[M+H] + Calculated value C 14 H 20 NO 2 234.15, found 233.84.
2) Synthesis of (3Z, 6Z) -3- ((3- (2-cyclohexylethoxy) pyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione 26ab
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (87.0 mg,0.24 mmol) and 3-cyclohexylmethoxypyridine-2-carbaldehyde 25ab (66.5 mg,0.29 mmol) were taken as starting materials for this step of the reaction according toCompound PLN-1-47 was synthesized by a preparation method of compound PLN-1-19, 115mg of pale yellow solid was obtained, and the yield was 89.6%. mp 195-197 ℃. 1 H NMR(500MHz, DMSO-d 6 )δ12.59(s,1H),10.59(s,1H),8.29(d,J＝4.7Hz,1H),7.92(dd,J＝8.7,5.6Hz,2H),7.86(s,1H), 7.79(d,J＝7.6Hz,1H),7.66(d,J＝7.7Hz,1H),7.59(t,J＝7.8Hz,2H),7.42-7.35(m,3H),7.02(s,1H), 6.88(s,1H),4.15(t,J＝6.7Hz,2H),1.74-1.60(m,7H),1.26-1.13(m,4H),0.98(dd,J＝23.9,12.1Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ194.2,157.0,156.7,153.2,144.1,139.9,137.3,133.5*2,133.4,133.3, 132.9,132.8,130.5,130.4,129.0,128.9,127.2,123.8,120.1,115.9,115.6,114.3,101.4,66.7,35.8,34.3,32.7 *2,26.0,25.8*2.HRMS(ESI)m/z:[M+H] + Calculated value C 32 H 31 FN 3 O 4 540.2293, found 540.2288.
Example 48 preparation of (3Z, 6Z) -3- ((3-Benzyloxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione (PLN-1-48)
1) Synthesis of 3-benzyloxypyridine-2-carbaldehyde 25ac
3-hydroxypyridine-2-carbaldehyde 18 (50.0 mg,0.41 mmol) and benzyl bromide (69.4 mg,0.41 mmol) were taken as starting materials for this reaction, and compound 25ac was synthesized according to the preparation method of compound 25p to give 48.2mg of a pale yellow oily substance, yield 55.7%. 1 H NMR (400MHz,DMSO-d 6 )δ10.22(s,1H),8.37(d,J＝5.4Hz,1H),7.82(d,J＝8.6Hz,1H),7.65(dd,J＝8.6,4.4 Hz,1H),7.52(d,J＝7.4Hz,2H),7.41(t,J＝7.4Hz,2H),7.34(t,J＝7.2Hz,1H),5.32(s,2H).MS(ESI) m/z:[M+H] + Calculated value C 13 H 12 NO 2 214.09, found 213.79.
2) Synthesis of (3Z, 6Z) -3- ((3-benzyloxypyridin-2-yl) methylene) -6- (3- (4-fluorobenzoyl) benzylidene) piperazine-2, 5-dione 26ac
(Z) -1-acetyl-3- (3- (4-fluorobenzoyl) methylene) piperazine-2, 5-dione 17 (62.7 mg,0.17 mmol) and 3-benzyloxypyridine-2-carbaldehyde 25ac (43.8 mg,0.21 mmol) were taken as starting materials for this reaction, and Compound PLN-1-48 was synthesized according to the preparation method of Compound PLN-1-19 to give 59.2mg as a pale yellow solid with a yield of 66.6%. mp is 192-194 ℃. 1 H NMR(500MHz,DMSO- d 6 )δ12.62(s,1H),10.62(s,1H),8.32(d,J＝4.6Hz,1H),7.91(dd,J＝8.6,5.6Hz,2H),7.84(s,1H),7.77 (d,J＝7.6Hz,1H),7.66(dd,J＝8.2,3.1Hz,2H),7.59(t,J＝7.6Hz,1H),7.48(d,J＝7.3Hz,2H),7.44-7.37 (m,6H),7.03(s,1H),6.89(s,1H),5.28(s,2H). 13 C NMR(100MHz,DMSO-d 6 )δ194.2,164.8,157.0,156.7, 152.8,144.3,140.2,137.3,136.2,133.6,133.5,133.3,132.9,132.8,130.8,130.4,129.1,128.9,128.7*2, 128.3,128.0*2,127.2,123.7,120.5,115.9,115.7,114.4,101.2,69.9.HRMS(ESI)m/z:[M+H] + Calculated value C 31 H 23 FN 3 O 4 520.1667, found 520.1664.
EXAMPLE 49 Synthesis of (3Z, 6Z) -3- (3-p-fluorobenzylmethoxy) benzylidene-6- ((1-methyl-5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-1)
1) Synthesis of (Z) -1-acetyl-3- ((1-methyl-5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (18 b)
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 (100 mg, 0). 36 mmol), DMF (2.5 mL), cesium carbonate (353.8 mg,1.09 mmol), and iodomethane (513.7 mg,3.62 mmol) were added dropwise in a cold trap at-30℃for 20min, and the reaction was continued with stirring at room temperature for 2h. LC-MS monitored the reaction and the starting material was complete. The reaction solution was dropped into cold water at 4℃and stirred for 20min, suction-filtered, and the cake was washed with water. Drying in a vacuum drying oven at 50 ℃ to obtain 60.0mg of earthy yellow solid with a yield of 57%. 1 H NMR(500MHz,CDCl 3 )δ11.98(s,1H),7.39(s,1H),7.02(s,1H),4.46(s,2H), 3.67(s,3H),3.31–3.16(m,1H),2.64(s,3H),1.39(d,J＝7.2Hz,6H).MS(ESI)m/z:[M+H] + Calculated value C 14 H 19 N 4 O 3 291.1452, found 290.75.
2) Synthesis of the end product (PLN-5-1)
The preparation is carried out according to the synthesis method of the compound PLN-1-1. Starting from (Z) -1-acetyl-3- ((1-methyl-5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (30 mg,0.10 mmol), p-fluorobenzenemethoxybenzaldehyde (27 mg,0.12 mmol), cesium carbonate (51 mg, 0.16 mmol) and anhydrous sodium sulfate (30 mg,0.21 mmol), DMF (3 mL) was stirred in an oil bath at 55deg.C for 24H. 17mg of pale yellow solid was obtained in 37% yield. Melting point: 218-219 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ11.98(s,1H),10.12 (s,1H),7.84(s,1H),7.41(t,J＝7.9Hz,1H),7.29-7.20(m,3H),7.17(s,1H),7.12(dd,J＝8.9,4.5Hz,2H), 6.90(d,J＝6.6Hz,1H),6.70(d,J＝13.7Hz,2H),3.68(s,3H),3.31-3.23(m,1H),1.32(d,J＝7.1Hz,6H). 13 C NMR(125MHz,DMSO-d 6 )δ159.1,157.2,157.0,156.8(J C-F ＝155.7Hz),152.6,138.6,138.1,135.2, 132.2,130.3,127.3,124.4,123.8,120.5*2(J C-F ＝8.4Hz),118.9,117.7,116.6*2(J C-F ＝23.2Hz),113.1,104.1, 32.2,23.8,21.9*2.MS(ESI):m/z 447.1825[M+H] + .Mp:218-219℃℃.
Example 50 preparation of (3Z, 6Z) -3- (3-p-fluorobenzylmethoxy) benzylidene-6- ((1-ethyl-5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-2)
1) Synthesis of (Z) -1-acetyl-3- ((1-ethyl-5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (18 d)
Prepared according to the synthetic method of compound 18 b. Starting from (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.54 mmol), cesium carbonate (530.7 mg,1.63 mmol) and iodoethane (846.8 mg,5.43 mmol), DMF (4 mL) was reacted with stirring at 0℃for 1.5H. 111.8mg of a earthy yellow solid was obtained in a yield of 68%. 1 H NMR(500MHz, CDCl 3 )δ12.02(s,1H),7.45(s,1H),7.05(s,1H),4.46(s,2H),3.99(q,J＝7.3Hz,2H),3.16(dt,J＝14.4, 7.2Hz,1H),2.64(s,3H),1.45(t,J＝7.3Hz,3H),1.41(d,J＝7.2Hz,6H).MS(ESI)m/z:[M+H] + Calculated value C 15 H 21 N 4 O 3 305.1608, found 304.82.
2) Synthesis of end product (PLN-5-2)
The preparation is carried out according to the synthesis method of the compound PLN-1-1. Starting from (Z) -1-acetyl-3- ((1-ethyl-5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (152.2 mg,0.50 mmol), p-fluorobenzenemethoxybenzaldehyde (130 mg,0.60 mmol) and cesium carbonate (244 mg,0.75 mmol), DMF (2 mL) was stirred in an oil bath at 55deg.C for 24H. 70.0mg of pale yellow solid was obtained in 30% yield. Melting point: 195-198 deg.c. 1 H NMR(500MHz,DMSO-d 6 )δ12.02(s,1H),10.13(s,1H),7.92(s,1H),7.42 (t,J＝7.9Hz,1H),7.31-7.22(m,3H),7.18(s,1H),7.15-7.11(m,2H),6.92(dd,J＝8.1,2.1Hz,1H),6.72(d, J＝9.5Hz,2H),4.07(q,J＝7.2Hz,2H),3.32-3.22(m,1H),1.34(d,J＝7.0Hz,9H). 13 C NMR(125MHz, DMSO-d 6 )δ159.1,157.2,157.0,156.8(J C-F ＝154.2Hz),152.6,138.3,136.7,135.2,132.1,130.3,127.2, 124.4,123.7,120.5*2(J C-F ＝8.4Hz),118.9,117.7,116.5*2(J C-F ＝23.2Hz),113.1,104.2,39.7,23.7,22.5*2, 16.5.MS(ESI):m/z 461.1973[M+H] + .Mp:195-198℃.
EXAMPLE 51 Synthesis of (3Z, 6Z) -3- (3-p-fluorobenzylmethoxy) benzylidene-6- ((1-n-propyl-5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-3)
1) Synthesis of (Z) -1-acetyl-3- ((1-n-propyl-5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (18 f)
Prepared according to the synthetic method of compound 18 b. Starting from (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.54 mmol), cesium carbonate (530.7 mg,1.63 mmol) and iodopropane (922.9 mg,5.43 mmol), DMF (4 mL) was stirred at room temperature for 2H. A yellowish brown solid 74mg was obtained in 43% yield. 1 H NMR(500MHz, CDCl 3 )δ12.02(s,1H),7.42(s,1H),7.06(s,1H),4.46(s,2H),4.01–3.80(m,2H),3.24–2.99(m,1H),2.64 (s,3H),1.79(dd,J＝14.8,7.4Hz,2H),1.41(d,J＝7.2Hz,6H),0.98(t,J＝7.4Hz,3H).MS(ESI)m/z:[M +H] + Calculated value C 16 H 23 N 4 O 3 319.1765, found 319.23.
2) Synthesis of end product (PLN-5-3)
The preparation is carried out according to the synthesis method of the compound PLN-1-1. In (Z) -1-acetyl1-3- ((1-n-propyl-5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (75 mg,0.24 mmol), p-fluorobenzenemethoxybenzaldehyde (62 mg,0.28 mmol) and cesium carbonate (116 mg,0.35 mmol) were used as starting materials and DMF (6 mL) was stirred in an oil bath at 55deg.C for 24H. 75mg of pale yellow solid was obtained in 67% yield. Melting point: 201-203 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ12.00(s,1H),10.12(s,1H),7.89(s,1H),7.41(t,J＝ 7.9Hz,1H),7.30-7.20(m,3H),7.17(s,1H),7.12(dd,J＝9.0,4.5Hz,2H),6.94-6.87(m,1H),6.71(d,J＝ 8.0Hz,2H),3.97(t,J＝7.3Hz,2H),3.31-3.18(m,1H),1.71-1.67(m,2H),1.32(d,J＝7.1Hz,6H),0.87(t, J＝7.3Hz,3H). 13 C NMR(125MHz,DMSO-d 6 )δ159.1,157.2,157.0,156.8(J C-F ＝152.6Hz),152.6,138.5, 137.2,135.2,132.1,130.3,127.2,124.4,123.7,120.5*2(J C-F ＝8.5Hz),118.9,117.7,116.5*2(J C-F ＝23.2 Hz),113.1,104.2,46.08,24.0,23.6,22.6*2,10.7.MS(ESI):m/z 475.2133[M+H] + .Mp:201-203℃.
EXAMPLE 52 Synthesis of (3Z, 6Z) -3- (3-p-fluorophenoxy) benzylidene-6- ((1-n-butyl-5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-4)
1) Synthesis of (Z) -1-acetyl-3- ((1-n-butyl-5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (18 g)
Prepared according to the synthetic method of compound 18 b. Starting from (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,1.09 mmol), cesium carbonate (1.1 g,3.26 mmol) and n-iodo butane (2.0 g,10.86 mmol). DMF (5 mL) solution was stirred at room temperature for 4h. A tan solid 148.0mg was obtained in 41% yield. 1 H NMR(400MHz, CDCl 3 )δ12.03(s,1H),7.42(s,1H),7.05(s,1H),4.45(s,2H),3.90(t,J＝7.4Hz,2H),3.13(dt,J＝14.3,7.1 Hz,1H),2.64(s,3H),1.80–1.67(m,2H),1.46–1.25(m,8H),0.97(t,J＝7.4Hz,3H).MS(ESI)m/z:[M+ H] + Calculated value C 17 H 25 N 4 O 3 333.1921, found 332.86.
2) Synthesis of end product (PLN-5-4)
The preparation is carried out according to the synthesis method of the compound PLN-1-1. Starting from (Z) -1-acetyl-3- ((1-n-butyl-5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (100 mg,0.31 mmol), p-fluorophenoxybenzaldehyde (78.1 mg,0.36 mmol), cesium carbonate (147.0 mg,0.45mmol) and anhydrous sodium sulfate (85.5 mg,0.60 mmol), DMF (3.5 mL) was stirred in an oil bath at 50℃for 25H. 90.3mg of pale yellow solid was obtained in 61% yield. Melting point: 203-204 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ12.01 (s,1H),10.16(s,1H),7.90(s,1H),7.41(t,J＝7.9Hz,1H),7.24(ddd,J＝8.6,7.3,5.4Hz,3H),7.17(s,1H), 7.14–7.09(m,2H),6.90(dd,J＝8.1,2.0Hz,1H),6.71(s,1H),6.69(s,1H),4.00(t,J＝7.4Hz,2H),3.21 (dt,J＝14.2,7.1Hz,1H),1.69–1.58(m,2H),1.34–1.24(m,8H),0.90(t,J＝7.4Hz,3H). 13 C NMR(125 MHz,DMSO-d 6 )δ159.13,157.38,157.23,157.04,156.16,152.59,138.44,137.17,135.20,132.09,130.28, 127.23,124.42,123.68,120.57,120.50,118.89,117.74,116.63,116.44,113.16,104.23,44.38,32.71,23.67, 22.63*2,19.18,13.47.MS(ESI):m/z 489.01[M+H] + .Mp:203-204℃.
EXAMPLE 53 (3Z, 6Z) -3- (3- (benzoyl) benzene) methylene-6- ((5-isopropyl-1-ethylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-5) Synthesis
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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 (150 mg,0.54 mmol), DMF (4 ml), cesium carbonate (530.65 mg,1.63 mmol) was placed in a cold trap at 0deg.C for 20 min, ethyl iodide (846.75 mg,5.43 mmol) was added dropwise and the reaction was continued with stirring for 1.5H. LC-MS detection reaction, complete reaction of raw materials. The reaction solution is dripped into cold water with the temperature of 0 ℃, stirred for 10min, filtered by suction, and the filter cake is washed by water. Vacuum drying at 50 ℃ gave 101mg of a earthy yellow solid in 61.12% yield.
2) A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1-ethylimidazol-4-yl) methylene) piperazine-2, 5-dione (95 mg,0.31 mmol), DMF (2 ml), 1-2 (85.49 mg,0.37 mmol), cesium carbonate (152.55 mg,0.47mmol), anhydrous sodium sulfate (88.67 mg,0.62 mmol), vented, nitrogen protected, placed in an oil bath at 55deg.C and stirred for 24h. After the reaction, the reaction solution was dropped into cold water (50 ml) at 4℃and was suction-filtered, methanol and methylene chloride (50 ml:20 ml) were dissolved, filtered, concentrated under reduced pressure, and EA was slurried, and the mixture was left overnight at-30℃and suction-filtered, and the cake was washed with EA and dried under vacuum at 50℃to give 82mg of pale yellow solid in 55.60% yield.
1 H NMR(500MHz,DMSO-d 6 )δ12.02(s,1H),10.35(s,1H),7.91(s,1H),7.84-7.80(m,3H),7.75(d, J＝7.6Hz,1H),7.69(t,J＝7.4Hz,1H),7.63(d,J＝7.7Hz,1H),7.58(t,J＝7.7Hz,3H),6.80(s,1H),6.69 (s,1H),4.05(q,J＝7.2Hz,2H),3.27-3.17(m,1H),1.33(dd,J＝7.0,5.5Hz,9H).MS(ESI):m/z 455.14 [M+H] + .Mp:214-216℃.
Example 54 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-allylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-6)
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,0.73 mmol), potassium carbonate (300.1 mg,2.17 mmol) and bromopropene (175.2 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 ℃ 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 135.5mg of brown yellow solid with a yield of 59.17%.
2) 10ml of dry brown round bottom flask was taken, and (Z) -1-acetyl-3- ((5-isopropyl-1- (propenyl imidazol-4-yl) methylene) piperazine-2, 5-dione (100 mg,0.32 mmol), 3-p-fluorobenzoyl benzaldehyde (118.95 mg,0.52 mmol), cesium carbonate (154.67 mg,0.47 mmol), anhydrous sodium sulfate (89.90 mg,0.63 mmol), DMF (4 ml), air exhaust, nitrogen protection, 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 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 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 114.5mg with yield of 74.67%.
1 H NMR(500MHz,DMSO-d 6 )δ11.99(s,1H),10.36(s,1H),7.94-7.89(m,2H),7.88(s,1H),7.82(s, 1H),7.75(d,J＝7.52Hz,1H),7.64(d,J＝7.63Hz,1H),7.59(t,J＝7.63Hz,1H),7.40(t,J＝8.74Hz,2H), 6.81(s,1H),6.71(s,1H),6.01(ddd,J＝4.97,10.23,15.29Hz,1H),5.22(d,J＝10.32Hz,1H),4.94(d,J＝ 17.16Hz,1H),4.73(s,2H),3.15(dt,J＝7.05,14.20Hz,1H),1.30(d,J＝7.07Hz,6H).MS(ESI):m/z 485.14[M+H] + .Mp:200-202℃.
Example 55 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-propargylimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-7)
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,1.08 mmol), potassium carbonate (450.16 mg,3.26 mmol) and bromopropyne (258.33 mg,2.17 mmol) in DMF (6 ml) was added dropwise and the reaction 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 a tan solid 232.0mg with a yield of 67.97%.
2) A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (propenyl imidazol-4-yl) methylene) piperazine-2, 5-dione (150 mg,0.48 mmol), 3-p-fluorobenzoyl benzaldehyde (130.82 mg,0.57 mmol), cesium carbonate (233.48 mg,0.72 mmol), anhydrous sodium sulfate (135.71 mg,0.96 mmol), DMF (5 ml), vented, nitrogen protection, placed in 45℃oil bath and stirred for 17h. 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, the filter cake is dissolved in a mixed solution of methanol and dichloromethane (1:3), filtration is carried out, and vacuum concentration is carried out. Pulping with methanol by ultrasonic, standing in a refrigerator at-30deg.C, filtering, washing with filter cake with cold methanol, and vacuum drying at 50deg.C to obtain yellow solid 166.0mg with a yield of 72.02%.
1 H NMR(500MHz,DMSO-d 6 )δ11.90(s,1H),10.38(s,1H),7.92(dd,J＝9.14,17.20Hz,3H),7.82(s, 1H),7.76(d,J＝7.43Hz,1H),7.64(d,J＝7.54Hz,1H),7.59(t,J＝7.58Hz,1H),7.40(t,J＝8.70Hz,2H), 6.82(s,1H),6.69(s,1H),5.02(s,2H),3.58(s,1H),3.37-3.25(m,1H),1.35(d,J＝7.03Hz,6H).MS(ESI): m/z 483.10[M+H] + .Mp:150-152℃.
Example 56 preparation of (3Z, 6Z) -3- (4-p-fluorobenzoyl) benzylidene-6- ((1- (2-methoxyethyl) -5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-8)
1. (Z) -1-acetyl-3- ((5-isopropyl-1- (2-methoxyethyl) -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-bromo-2-methoxyethane (300 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- (4-p-fluorobenzoyl) benzylidene-6- ((1- (2-methoxyethyl) -5-isopropyl-1H-)
Imidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of a dry reaction flask, (Z) -1-acetyl-3- ((5-isopropyl-1- (2-methoxyethyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.90 mmol), 3- (4-fluorobenzoyl) benzaldehyde (246 mg,1.08 mmol), cesium carbonate (438 mg, 1.35 mmol), anhydrous sodium sulfate (255 mg,1.80 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, filtering at-20deg.C, and oven drying to obtain 160mg pale yellow solid with yield of 29.52%. 1 H NMR(500MHz,DMSO- d6)δ12.00(s,1H),10.34(s,1H),7.93–7.89(m,2H),7.85(s,1H),7.82(s,1H),7.75(d,J＝7.5Hz,1H),7.64 (d,J＝7.5Hz,2H),7.59(t,J＝7.6Hz,1H),7.40(t,J＝8.5Hz,1H),6.81(s,1H),6.71(s,1H),4.20(t,J＝4.8 Hz,2H),3.58(t,J＝4.9Hz,2H),3.29–3.17(m,4H),1.31(d,J＝7.0Hz,6H).MS(ESI):m/z 503.17[M+ H] + .Mp:209-211℃.
Example 57 preparation of (3Z, 6Z) -3- (4-p-fluorobenzoyl) benzylidene-6- ((1- (2-ethoxyethyl) -5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-9)
1. (Z) -1-acetyl-3- ((1- (2-ethoxyethyl) -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-bromo-2-ethoxyethane (330 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- (4-p-fluorobenzoyl) benzylidene-6- ((1- (2-ethoxyethyl) -5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of dry reaction flask, (Z) -1-acetyl-3- ((1- (2-ethoxyethyl) -5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.86 mmol), 3- (4-fluorobenzoyl) benzaldehyde (224 mg,1.03 mmol), cesium carbonate (419 mg, 1.29 mmol), anhydrous sodium sulfate (244 mg,1.72 mmol), DMF (6 mL), nitrogen protection, light shielding, and 45℃under an oil bath were takenThe reaction was 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. Pulping with methanol, filtering at-20deg.C, and oven drying to obtain 100mg pale yellow solid with yield of 17.95%. 1 H NMR(500MHz,DMSO- d6)δ12.01(s,1H),10.34(s,1H),7.96–7.89(m,2H),7.85(s,1H),7.82(s,1H),7.75(d,J＝7.5Hz,1H), 7.64(d,J＝7.6Hz,1H),7.58(t,J＝7.7Hz,1H),7.40(t,J＝8.2Hz,2H),6.81(s,1H),6.71(s,1H),4.18(d, J＝4.3Hz,2H),3.61(t,J＝4.5Hz,2H),3.42(q,J＝6.9Hz,2H),3.25(dt,J＝13.4,6.7Hz,1H),1.32(d,J＝ 7.1Hz,6H),1.08(t,J＝6.9Hz,3H).MS(ESI):m/z 517.15[M+H] + .Mp:205-207℃.
Example 58 preparation of (3Z, 6Z) -3- (3- (4-fluorophenoxy) benzene) methylene) -6- ((5-isopropyl-1- (2-methoxyethyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-10)
1) (Z) -1-acetyl-3- ((5-isopropyl-1- (2-methoxyethyl) -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-bromo-2-methoxyethane (300 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) benzylidene) -6- ((5-isopropyl-1- (2-methoxyethyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
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25mL of a dry reaction flask was taken, (Z) -1-acetyl-3- ((5-isopropyl-1- (2-methoxyethyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.90 mmol), 3- (4-fluorophenoxy) benzaldehyde (233 mg,1.08 mmol), cesium carbonate (438 mg,1.35 mmol), anhydrous sodium sulfate (255 mg,1.80 mmol), DMF (6 mL), nitrogen-protected, protected from light, and placed in an oil bath at 45℃for stirring 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. Pulping with methanol, standing at-20deg.C for 2 hr, filtering, and oven drying to obtain 145mg pale yellow solid with yield of 27.25%.
1 H NMR(500MHz,dmso)δ11.78(s,1H),10.14(s,1H),7.77(s,1H),7.59(s,1H),7.44(d,J＝7.5Hz, 1H),7.33(t,J＝7.9Hz,1H),7.21(t,J＝8.7Hz,2H),7.13-7.02(m,2H),6.78(d,J＝7.9Hz,1H),6.56(s, 1H),6.51(s,1H),4.17(t,J＝4.9Hz,2H),3.57(t,J＝5.0Hz,2H),3.25(s,3H),3.24-3.16(m,1H),1.31(d,J ＝7.1Hz,6H).MS(ESI):m/z 491.06[M+H] + .Mp:159-162℃.
Example 59 preparation of (3Z, 6Z) -3- (-3- (4-fluorophenoxy) benzene) methylene) -6- ((5-isopropyl-1- (2-ethoxyethyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-11)
1) (Z) -1-acetyl-3- ((1- (2-ethoxyethyl) -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-bromo-2-ethoxyethane (330 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-ethoxyethyl) -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-ethoxyethyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.86 mmol), 3- (4-fluorophenoxy) benzaldehyde (222 mg,1.03 mmol), cesium carbonate (419 mg,1.29 mmol), anhydrous sodium sulfate (244 mg,1.72 mmol), DMF (6 mL), nitrogen-protected, protected from light, and placed in an oil bath at 45℃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. Pulping with methanol, standing at-20deg.C for 2 hr, filtering, and oven drying to obtain 95mg pale yellow solid with yield of 17.33%.
1 H NMR(500MHz,dmso)δ11.99(s,1H),10.15(s,1H),7.85(s,1H),7.41(t,J＝7.7Hz,1H),7.26(d, J＝10.1Hz,1H),7.23(d,J＝8.3Hz,2H),7.17(s,1H),7.12(dd,J＝6.9,4.4Hz,2H),6.90(d,J＝8.1Hz, 1H),6.72(s,1H),6.71(s,1H),4.19(s,2H),3.61(s,2H),3.42(q,J＝6.7Hz,2H),3.28-3.22(m,1H),1.31(d, J＝6.8Hz,6H),1.07(t,J＝6.8Hz,3H).MS(ESI):m/z 505.26[M+H] + .Mp:177-180℃.
Example 60 preparation of (3Z, 6Z) -3- (3- (4-fluorophenoxy) benzene) methylene) -6- ((5-isopropyl-1- (3-methoxypropyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-12)
1) (Z) -1-acetyl-3- ((5-isopropyl-1- (3-methoxypropyl) -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-bromo-3-methoxypropane (330 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- (3-methoxypropyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of a dry reaction flask was taken, (Z) -1-acetyl-3- ((5-isopropyl-1- (3-methoxypropyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.86 mmol), 3- (4-fluorophenoxy) benzaldehyde (222 mg,1.03 mmol), cesium carbonate (419 mg,1.29 mmol), anhydrous sodium sulfate (244 mg,1.72 mmol), DMF (6 mL), nitrogen-protected, protected from light, and placed in an oil bath at 45℃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. Pulping with methanol, standing at-20deg.C for 2 hr, filtering, and oven drying to obtain 90mg pale yellow solid with yield of 16.42%.
1 H NMR(500MHz,dmso)δ11.99(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＝8.6Hz,2H),7.17(s,1H),7.15-7.08(m,2H),6.90(d,J＝8.1Hz,1H),6.71(s, 1H),6.70(s,1H),4.06(t,J＝7.2Hz,2H),3.35-3.28(m,2H),3.25(s,2H),3.23-3.18(m,1H),2.00–1.81(m, 3H),1.32(d,J＝7.1Hz,6H).MS(ESI):m/z 505.12[M+H] + .Mp:194-196℃.
Example 61 preparation of (3Z, 6Z) -3- (3- (4-fluorophenoxy) benzene) methylene) -6- ((5-isopropyl-1- (3, 3-dimethoxypropyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-13)
1) (Z) -1-acetyl-3- ((1- (3, 3-dimethoxypropyl) -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-bromo-1, 1-dimethoxypropane (390 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) Preparation of (3Z, 6Z) -3- (3- (4-fluorophenoxy) benzene) methylene) -6- ((5-isopropyl-1- (3, 3-dimethoxypropyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of a dry reaction flask was taken, (Z) -1-acetyl-3- ((1- (3, 3-dimethoxypropyl) -5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.79 mmol), 3- (4-fluorophenoxy) benzaldehyde (205 mg,0.95 mmol), cesium carbonate (385 mg,1.18 mmol), anhydrous sodium sulfate (224 mg,1.58 mmol), DMF (6 mL), nitrogen-protected, protected from light, and placed in an oil bath at 45℃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. Pulping with methanol, standing at-20deg.C for 2 hr, filtering, and oven drying to obtain 80mg pale yellow solid with yield of 13.79%.
1 H NMR(500MHz,DMSO-d 6 )δ11.99(s,1H),10.08(s,1H),7.90(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),7.14-7.09(m,2H),6.90(d,J＝8.1Hz,1H),6.72(s, 1H),6.70(s,1H),4.39(t,J＝5.3Hz,1H),4.04(t,J＝7.3Hz,2H),3.26(s,6H),3.23-3.17(m,1H),1.97(dd, J＝13.0,6.6Hz,2H),1.33(d,J＝7.0Hz,6H).MS(ESI):m/z 535.00[M+H] + .Mp:176-178℃.
Example 62 preparation of (3Z, 6Z) -3- (3-Parafluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (hydroxyethyl ethyl acetate) -imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-14)
1) (Z) -2- (4- ((4-acetyl-3, 6-dioxopiperazin-2-ylidene) methyl) -5-isopropyl-1H-imidazolyl) acetic acid ethyl ester
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), ethyl 2-bromo-acetate (360 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-Parafluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (hydroxyethyl ethyl acetate) -imidazol-4-yl) methylene) piperazine-2, 5-dione
25mL of ethyl (Z) -2- (4- ((4-acetyl-3, 6-dioxopiperazin-2-ylidene) methyl) -5-isopropyl-1H-imidazol-1-yl) acetate (300 mg,0.83 mmol), 3- (4-fluorophenoxy) benzaldehyde (215 mg,0.99 mmol), cesium carbonate (405 mg,1.24 mmol), anhydrous sodium sulfate (236 mg,1.66 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. Flash purification, methanol: 76%, water: the product was obtained at 24% and concentrated under reduced pressure to give 90mg of pale yellow solid in 16.10% yield.
1 H NMR(500MHz,dmso)δ11.96(s,1H),10.12(s,1H),7.91(s,1H),7.41(t,J＝7.9Hz,1H),7.27(d, J＝7.7Hz,1H),7.23(t,J＝8.6Hz,2H),7.17(s,1H),7.16–7.08(m,2H),6.91(d,J＝8.1Hz,1H),6.72(s, 1H),6.70(s,1H),4.30(d,J＝4.4Hz,2H),4.27(d,J＝4.1Hz,2H),3.25–3.18(m,1H),2.01(s,3H),1.33 (d,J＝7.0Hz,6H).MS(ESI):m/z 519.19[M+H] + .Mp:185-187℃.
EXAMPLE 63 Synthesis of (3Z, 6Z) -3- (2- (p-fluorobenzoyl) benzene) methylene-6- ((5-methyl-1- (N-t-butoxycarbonyl) ethanamino-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-15)
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 (300 mg,1.21 mmol), N-t-butoxycarbonyl-3-bromoethylamine (541.65 mg,2.42 mmol), cesium carbonate (787.50 mg,2.42 mmol), sodium iodide (181.14 mg,1.21 mmol), 4A molecular sieve (500 mg), DMF (5 ml), vented, nitrogen blanket, placed in an oil bath at 70℃and stirred for 4H. After the reaction, the mixture was concentrated under reduced pressure and dried, then dissolved in methanol and methylene chloride (1:3), filtered, concentrated under reduced pressure and dried to give 378.43mg of a pale tan crude solid, yield 80.0%. The mixture was directly taken to the next step without purification.
2) 25mL of a dry brown round bottom flask was taken, Z) -1-acetyl-3- ((5-methyl-1- (N-t-butoxycarbonyl) ethanaminoimidazol-4-yl) methylene) piperazine-2, 5-dione (378.43 mg,0.97 mmol), 2-p-fluorobenzoyl benzaldehyde (264.75 mg,1.16 mmol), cesium carbonate (472.50 mg,1.45 mmol), anhydrous sodium sulfate (274.65 mg,1.93 mmol), DMF (6 mL) was added sequentially, the mixture was vented, nitrogen protected, placed in an oil bath at 55deg.C and stirred for 24h. LC-MS monitors the reaction, after the reaction, the mixture was concentrated under reduced pressure and dried, then methanol and methylene chloride (1:3) were dissolved, filtered, concentrated under reduced pressure, dried, eluted with a gradient, and concentrated under reduced pressure to give 52.8mg of pale yellow solid, yield 7.81%.
1 H NMR(500MHz,DMSO-d 6 )δ＝11.84(s,1H),10.34(s,1H),7.95-7.88(m,3H),7.85(d,J＝6.0,1H), 7.82(s,1H),7.57(dt,J＝15.1,7.6,2H),7.40(t,J＝8.8,2H),7.00(t,J＝5.7,1H),6.74(s,1H),6.53(s,1H),4.01 (t,J＝5.8,2H),3.22(d,J＝5.9,2H),2.29(s,3H),1.37(s,9H).MS(ESI):m/z 560.16[M+H] + .Mp:189-191 ℃.
EXAMPLE 64 Synthesis of (3Z, 6Z) -3- (2- (p-fluorobenzoyl) benzene) methylene-6- ((5-methyl-1-ethylaminoimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-16)
A100 ml dry round bottom flask was taken and was charged with (3Z, 6Z) -3- (2- (p-fluorobenzoyl) benzene) methylene-6- ((5-methyl-1- (N-t-butoxycarbonyl) ethylamino-imidazol-4-yl) methylene) piperazine-2, 5-dione synthesis (35.1 mg,0.063 mmol), methanol (5 ml), hydrochloric acid (0.5 ml) and placed in an oil bath at 40℃and stirred for reaction for 12h. LC-MS monitoring reaction, concentrating under reduced pressure, drying, adding 0.5. 0.5ml methanol dropwise into acetone (2 ml), precipitating solid, standing in a refrigerator at-20deg.C for more than 2 hr, vacuum filtering, washing filter cake with acetone, and vacuum drying at 50deg.C to obtain brown yellow solid 14mg with yield of 44.96%.
1 H NMR(500MHz,DMSO-d 6 )δ＝11.70(s,1H),10.38(s,1H),8.36(s,3H),8.17(s,1H),7.94-7.88(m, 2H),7.82(s,1H),7.75(d,J＝7.4,1H),7.64(d,J＝7.5,1H),7.59(t,J＝7.6,1H),7.40(t,J＝8.6,2H),6.82(s,1H), 6.58(s,1H),4.32(t,J＝6.3,2H),3.20(d,J＝5.6,2H),2.34(s,3H).MS(ESI):m/z 460.15[M+H] + .Mp:180- 182℃.
EXAMPLE 65 Synthesis of (3Z, 6Z) -3- (2- (p-fluorobenzoyl) benzene) methylene-6- ((5-methyl-1- (N-t-butoxycarbonyl) propylamino-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-17)
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 (300 mg,1.21 mmol), N-t-butoxycarbonyl-3-bromopropylamine (575.54 mg,2.42 mmol), cesium carbonate (787.50 mg,2.42 mmol), sodium iodide (181.14 mg,1.21 mmol), 4A molecular sieve (500 mg), DMF (6 ml), vented, nitrogen blanket, placed in an oil bath at 70℃and stirred for 3H. After the reaction, the reaction solution is dripped into cold water at the temperature of 4 ℃ to precipitate solids, the solid is filtered, a filter cake is washed with water, then methanol and dichloromethane are dissolved, filtered, concentrated under reduced pressure and dried, and 367mg of light brown solid is obtained, and the yield is 74.90%. The mixture was directly taken to the next step without purification.
2) A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-methyl-1- (N-t-butoxycarbonyl) propylaminoimidazol-4-yl) methylene) piperazine-2, 5-dione (367 mg,0.90 mmol), 2-p-fluorobenzoyl benzaldehyde (247.89 mg,1.09 mmol), cesium carbonate (442.37 mg,1.36 mmol), anhydrous sodium sulfate (257.13 mg,1.81 mmol), DMF (5 ml), vented, nitrogen-protected, placed in an oil bath at 60℃and stirred for 21h. LC-MS monitors the reaction, after the reaction, the reaction liquid is dripped into cold water at 4 ℃, solid is separated out, suction filtration is carried out, a filter cake is washed by cold water, then methanol and dichloromethane are dissolved, filtration is carried out, and vacuum concentration is carried out. The aqueous phase EA was extracted to clear, the organic phases were combined and concentrated under reduced pressure. The filter cake and the organic phase sample are combined and eluted in gradient to obtain 260mg of pale yellow solid with the yield of 50.10%.
1 H NMR(500MHz,DMSO-d 6 )δ＝11.87(s,1H),10.37(s,1H),7.97-7.88(m,3H),7.86(s,1H),7.82 (d,J＝7.2,1H),7.62(d,J＝7.5,1H),7.57(t,J＝7.6,1H),7.40(t,J＝8.7,2H),6.95(s,1H),6.77(s,1H),6.56(s, 1H),3.97(t,J＝6.8,2H),2.93(d,J＝5.8,2H),2.30(s,3H),1.90-1.70(m,2H),1.39(s,9H).MS(ESI):m/z 574.23[M+H] + .Mp:206-208℃.
Example 66 Synthesis of (3Z, 6Z) -3- (2- (p-fluorobenzoyl) benzene) methylene-6- ((5-methyl-1-propanamino-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-18)
A100 ml dry round bottom flask was taken and charged with (3Z, 6Z) -3- (2- (p-fluorobenzoyl) benzene) methylene-6- ((5-methyl-1- (N-t-butoxycarbonyl) propylamino-imidazol-4-yl) methylene) piperazine-2, 5-dione (100 mg,0.21 mmol), methanol (15 ml), water (1 ml), hydrochloric acid (2 ml,12 mmol/ml) and placed in a 30℃oil bath to react with stirring for 12h. After the reaction is finished, the LC-MS monitoring reaction is naturally cooled to room temperature, white solid is separated out, suction filtration is carried out, filter cakes are washed by methanol, and the white solid is obtained by drying, wherein the yield is 84.50%.
1 H NMR(500MHz,DMSO-d 6 )δ＝11.65(s,1H),10.39(s,1H),8.27(s,1H),8.20(s,3H),7.91(dd, J＝8.7,5.6,2H),7.82(s,1H),7.75(d,J＝7.7,1H),7.64(d,J＝7.7,1H),7.59(t,J＝7.6,1H),7.40(t,J＝8.8,2H), 6.82(s,1H),6.57(s,1H),4.16(t,J＝7.0,2H),2.80(dd,J＝12.9,6.6,2H),2.32(s,3H),2.08-1.98(m,2H).MS (ESI):m/z 474.16[M+H] + .Mp:247-248℃.
EXAMPLE 67 preparation of (3Z, 6Z) -3- (3-Parafluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (3- (dimethylamino) propyl) methylene) piperazine-2, 5-dione (PLN-5-19)
1. (Z) -1-acetyl-3- ((1- (3- (dimethylamino) 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), 3-chloro-N, N-dimethylpropan-1-amine (261 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 400mg of brown oily mixture, and directly carrying out the next step without purification.
2. (3Z, 6Z) -3- (3-Parafluorophenoxy) benzene) methylene-6- ((5-isopropyl-1- (3- (dimethylamino) propyl) methylene) piperazine-2, 5-dione
25mL of a dry reaction flask, (Z) -1-acetyl-3- ((1- (3- (dimethylamino) propyl) -5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.83 mmol), 3- (4-fluorophenoxy) benzaldehyde (180 mg,0.83 mmol), cesium carbonate (405 mg,1.24 mmol), anhydrous sodium sulfate (239 mg,1.66 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: 60%,0.5% formic acid water: 40% of the product was obtained and concentrated under reduced pressure to give 138mg of a pale yellow solid with a yield of 32.16%.
1 H NMR(500MHz,DMSO-d6)δ12.00(s,1H),10.13(s,1H),7.88(s,1H),7.40(t,J＝7.6Hz,1H), 7.28-7.21(m,3H),7.17(s,1H),7.12(s,2H),6.90(d,J＝7.4Hz,1H),6.71(s,2H),4.02(t,J＝6.4Hz,2H), 3.27–3.14(m,1H),2.14(s,6H),2.00(t,J＝8.0Hz,2H),1.94–1.72(m,2H),1.33(d,J＝5.9Hz,6H).MS (ESI):m/z 518.22[M+H] + .Mp:164-166℃.
Example 68 preparation of (3Z, 6Z) -3- (3-Parafluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (tert-butyldimethylsilyloxy ethyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-20)
Preparation of (Z) -1-acetyl-3- ((5- (isopropyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
A dried 250mL eggplant-shaped reaction flask was taken, 5-isopropyl-1H-imidazole-4-carbaldehyde (5.0 g,36.19 mmol) was dissolved in 120mL dry DMF, 1, 4-diacetyl-piperazine-2, 5-dione (14.34 g,72.38 mmol) was added, cesium carbonate (17.69 g,54.29 mmol) was added, the mixture was degassed, and the reaction was carried out at 25℃in the absence of light for 24H, and the reaction was detected by LC-MS. Washing with water, extracting with ethyl acetate, collecting the organic phase, drying, suction-filtering, spin-drying, beating with ethyl acetate, suction-filtering, and drying to obtain the compound (Z) -1-acetyl-3- ((5- (isopropyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (4.39 g,15.89 mmol) with a yield of 43.9%.
Preparation of (Z) -1-acetyl-3- ((5- (isopropyl) -1- (tert-butyldimethylsilyloxy ethyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione
A dried 25mL eggplant-shaped reaction flask was taken, and (Z) -1-acetyl-3- ((5- (isopropyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (50 mg,0.18 mmol) was dissolved in 4mL dry DMF, 2-iodo-tert-butyldimethylsilyl ethanol (156 mg,0.54 mmol) was added, cesium carbonate (177 mg,0.54 mmol) was added, and the reaction was degassed, protected from light at 50℃for 24H and detected by LC-MS. Washing with water, extraction with ethyl acetate, drying the organic phase, suction filtration spin drying, and methanol/water gradient separation by C18 Flash column chromatography to give the compound (Z) -1-acetyl-3- ((5- (isopropyl) -1- (tert-butyldimethylsilyloxy ethyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione (34.2 mg,0.08 mmol) in 42.3% yield as a yellow solid.
Preparation of (3Z, 6Z) -3- (3-p-fluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (t-butyldimethylsiloxy ethyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione
A dried 25mL eggplant-shaped reaction flask was taken, and (Z) -1-acetyl-3- ((5- (isopropyl) -1- (tert-butyldimethylsilyloxy ethyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione (108 mg,0.25 mmol) was dissolved in 8mL dry DMF, 3- (4-fluorophenoxy) -benzaldehyde (65 mg,0.30 mmol) was added, cesium carbonate (122 mg,0.37 mmol) was added, and the reaction was degassed at 50deg.C for 24h under light-proof conditions and detected by LC-MS. Washing with water, extraction with ethyl acetate, drying the organic phase, suction filtration spin drying, and C18 Flash column chromatography methanol/water gradient separation to give the compound dissolved (3Z, 6Z) -3- (3-p-fluorophenoxy) benzylidene-6- ((5- (isopropyl) -1- (tert-butyldimethylsilyloxy ethyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione (80 mg,0.14 mmol), yield 54.5% as a yellow solid.
Example 69 preparation of (3Z, 6Z) -3- (3-Parafluorophenoxy) benzene) methylene) -6- ((5- (isopropyl) -1- (hydroxyethyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-21)
A dried 25mL eggplant-shaped reaction flask was taken, and (3Z, 6Z) -3- (3-p-fluorophenoxy) benzylidene-6- ((5- (isopropyl) -1- (tert-butyldimethylsilyloxy ethyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione (57 mg,0.10 mmol) was dissolved in 3mL dry THF, TBAF was reacted in 1M THF (1.11 mL,0.11 mmol) at 25℃in the absence of light for 5h, and LC-MS detection was complete. Suction filtration, spin drying, water washing, ethyl acetate extraction, and beating with spin-dried methanol to obtain the compound (3Z, 6Z) -3- (3-p-fluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (hydroxyethyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione (14 mg,0.04 mmol), with a yield of 17.1% as yellow paper.
1 H NMR(500MHz,Pyridine-d5)δ11.35(s,1H),7.95(s,1H),7.44(d,J＝10.5Hz,2H),7.34(d,J＝ 15.1Hz,3H),7.17(t,J＝8.2Hz,2H),7.04(s,2H),6.95(d,J＝7.1Hz,2H),4.14(s,2H),3.99(s,2H),3.29- 3.14(m,1H),1.30(d,J＝6.9Hz,6H).
Example 70 preparation of (3Z, 6Z) -3- (3-Parafluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (hydroxypropyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-22)
Preparation of (Z) -1-acetyl-3- ((5- (isopropyl) -1- (tert-butyldimethylsiloxy propyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione
A dried 25mL eggplant-shaped reaction flask was taken, and (Z) -1-acetyl-3- ((5- (isopropyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.72 mmol) was dissolved in 4mL dry DMF, 3-iodo-tert-butyldimethylsilyl ethanol (649 mg,2.16 mmol) was added, cesium carbonate (704 mg,2.16 mmol) was added, degassed, reacted at 50℃in the absence of light for 24H, and the reaction was detected by LC-MS. Washing with water, extraction with ethyl acetate, drying the organic phase, suction filtration spin drying, and methanol/water gradient separation by C18 Flash column chromatography to give the compound (Z) -1-acetyl-3- ((5- (isopropyl) -1- (tert-butyldimethylsilyloxy propyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione (38 mg,0.08 mmol) in 11.7% yield as a yellow solid.
Preparation of (3Z, 6Z) -3- (3-p-fluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (t-butyldimethylsiloxy-propyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione
A dry 25mL eggplant-shaped reaction flask was taken, intermediate (Z) -1-acetyl-3- ((5- (isopropyl) -1- (tert-butyldimethylsilyloxy-propyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione (30 mg,0.07 mmol) was dissolved in 4mL dry DMF, 3- (4-fluorophenoxy) -benzaldehyde (18 mg,0.08 mmol) was added, cesium carbonate (33 mg,0.10 mmol) was added, degassed, and reacted at 50℃in the absence of light for 12h, and the reaction was detected by LC-MS. Washing with water, extraction with ethyl acetate, drying the collected organic phase, beating with methanol to give the compound (3Z, 6Z) -3- (3-p-fluorophenoxy) benzylidene-6- ((5- (isopropyl) -1- (tert-butyldimethylsilyloxy propyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione (30 mg,0.05 mmol) in 74.1% yield as a yellow solid.
Preparation of (3Z, 6Z) -3- (3-p-fluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (hydroxypropyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione
A dried 25mL eggplant-shaped reaction flask was taken, and (3Z, 6Z) -3- (3-p-fluorophenoxy) benzylidene-6- ((5- (isopropyl) -1- (tert-butyldimethylsilyloxy) propyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione (120 mg,0.20 mmol) was dissolved in 3mL dry THF, TBAF was reacted in 1M THF (1.11 mL,0.11 mmol) at 25℃in the absence of light for 5h, and LC-MS detection was complete. Suction filtration, spin drying, water washing, ethyl acetate extraction, and beating of the spin-dried methanol to give the compound (3Z, 6Z) -3- (3-p-fluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (hydroxypropyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione (86 mg,0.18 mmol) in a yield of 87.7% as a yellow solid.
1 H NMR(500MHz,Pyridine-d5)δ11.35(s,2H),7.87(s,1H),7.44(dd,J＝18.7,11.0Hz,2H),7.37- 7.30(m,3H),7.17(t,J＝8.6Hz,2H),7.04(dd,J＝8.9,4.4Hz,2H),6.98-6.92(m,1H),4.19(t,J＝7.1Hz, 2H),3.80(t,J＝5.7Hz,2H),3.19-3.16(m,1H),2.09-1.94(m,2H),1.32(d,J＝7.1Hz,6H). 13 C NMR(125 MHz,Pyridine-d5)δ160.7,159.0,158.5,153.5,139.3,137.8,137.2,134.2,131.3,129.5,125.7,124.8, 121.8*2,119.6,118.4,117.3*2,117.2,114.1,105.9,58.5,43.0,35.0,25.1,23.1*2.
Example 71 preparation of (3Z, 6Z) -3- (3-Parafluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (2-hydroxy-benzopropyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-23)
2-benzyloxy-benzoic acid- (3-iodo) -propyl ester
A dried 50mL eggplant-shaped reaction flask was taken, 3-iodopropanol (1 g,5.38 mmol) was dissolved in 20mL of dry DCM, 2-benzyloxy-benzoic acid (1.47 g,6.45 mmol) was added, DPTS (3.16 g,10.75 mmol) was added, DIC (1.67 mL,10.75 mmol) was added, and the reaction was allowed to proceed to completion at 25℃in the absence of light for 12h, and LC-MS detection. Washing with water, extraction with ethyl acetate, collection of the organic phase, drying over anhydrous sodium sulfate, suction filtration, spin-drying, column chromatography (P/e=20/1) to give the compound 2-benzyloxy-benzoic acid- (3-iodo) -propyl ester (2.05 g,5.17 mmol) in 96.4% yield as a colorless syrup.
Preparation of (Z) -1-acetyl-3- ((5- (isopropyl) -1- (2-benzyloxy-propyl benzoate) -imidazol-4-yl) methylene) piperazine-2, 5-dione
A dried 50mL eggplant-shaped reaction flask was taken, and (Z) -1-acetyl-3- ((5- (isopropyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (560 mg,2.03 mmol) was dissolved in 25mL dry DMF, 2-benzyloxy-benzoic acid- (3-iodo) -propyl ester (2.41 g,6.08 mmol) was added, cesium carbonate (1.98 g,6.08 mmol) was added, and the reaction was degassed and protected from light at 50℃for 24H and detected by LC-MS. Washing with water, extraction with ethyl acetate, drying the organic phase, suction filtration spin drying, and methanol/water gradient separation by C18 Flash column chromatography to give the compound (Z) -1-acetyl-3- ((5- (isopropyl) -1- (2-benzyloxy-propyl benzoate) -imidazol-4-yl) methylene) piperazine-2, 5-dione (505 mg,0.93 mmol) in 45.7% yield as a yellow solid.
Preparation of (3Z, 6Z) -3- (3-p-fluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (2-benzyloxy-propyl benzoate) -imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-2-2-73)
The compound (Z) -1-acetyl-3- ((5- (isopropyl) -1- (2-benzyloxy-propyl benzoate) -imidazol-4-yl) methylene) piperazine-2, 5-dione (1.3 g,2.39 mmol) was dissolved in 30mL dry DMF, 3- (4-fluorophenoxy) -benzaldehyde (620 mg,2.86 mmol) was added, cesium carbonate (1.17 g,3.58 mmol) was added, degassed and reacted at 50℃in the absence of light for 24h, and LC-MS detection reaction was complete. Suction filtration, spin drying, water washing, ethyl acetate extraction, methanol/water gradient separation by C18 Flash column chromatography, and methanol beating to obtain the compound (3Z, 6Z) -3- (3-p-fluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (2-benzyloxy-propyl benzoate) -imidazol-4-yl) methylene) piperazine-2, 5-dione (540 mg, 0.77 mmol), yield 32.3% as a yellow solid.
1 H NMR(500MHz,CDCl 3 )δ12.19(s,1H),8.05(s,1H),7.82(dd,J＝7.7,1.7Hz,1H),7.53-7.44(m, 3H),7.41-7.27(m,5H),7.14-6.99(m,7H),6.95(s,1H),6.93-6.89(m,2H),6.85(s,1H),5.16(s,2H),4.28(t, J＝5.7Hz,2H),3.78(t,J＝7.1Hz,2H),3.05-3.01(m,1H),2.06-2.03(m,2H),1.34(d,J＝7.2Hz,6H). 13 C NMR(125MHz,CDCl3)δ166.7,159.0,158.3,157.2,153.5,138.7,136.4,136.4,135.3,134.0,133.4,132.2, 130.9,128.8*3,128.4,127.9*3,127.4,123.8,122.6,121.3*2,120.9,120.3,117.9,117.8,116.7*2,113.9,113.5, 106.4,71.0,61.1,42.0,30.3,24.7,22.8*2.
Example 72 preparation of (3Z, 6Z) -3- (3-Parafluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (2-hydroxy-benzopropyl) -imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-24)
The compound (3Z, 6Z) -3- (3-p-fluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (2-benzyloxy-propyl benzoate) -imidazol-4-yl) methylene) piperazine-2, 5-dione (300 mg,0.43 mmol) was dissolved in 30mL methanol and 30mL ethyl acetate, 200mg Pd/C was added, degassed, and reacted under hydrogen at 25℃in the absence of light for 3h, and the reaction was detected by LC-MS. Suction filtration spin drying, and C18 Flash column chromatography methanol/water gradient separation to obtain the compound (3Z, 6Z) -3- (3-p-fluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (2-hydroxy-propyl benzoate) -imidazol-4-yl) methylene) piperazine-2, 5-dione (82 mg,0.13 mmol) with a yield of 31.2% as yellow powder.
1 H NMR(500MHz,CDCl3)δ12.15(s,1H),10.61(s,1H),8.06(s,1H),7.76(d,J＝7.5Hz,1H),7.56- 7.45(m,2H),7.39(t,J＝8.0Hz,1H),7.13-6.98(m,6H),6.98-6.83(m,5H),4.41(t,J＝5.8Hz,2H),4.13(t, J＝7.2Hz,2H),3.19-3.13(m,1H),2.28-2.23(m,2H),1.40(dd,J＝13.3,7.3Hz,6H).
Example 73 preparation of (3Z, 6Z) -3- (3-Parafluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (propylphosphite) -imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-25)
Preparation of dibutyl-3-iodopropyl phosphate
Compound 3-iodopropanol (300 mg,0.43 mmol) was dissolved in dry 10mL of dichloromethane, pyridine (0.95 mL,11.75 mmol) was added at 0deg.C, DMAP (18 mg,0.15 mmol) was added, di-tert-butyl phosphoryl chloride (1.99 g,3.72 mmol) was added dropwise, and the reaction was carried out at 25deg.C for 3h, and the reaction was detected by LC-MS. Suction filtration spin drying, column chromatography gradient separation petroleum ether: ethyl acetate = 15:1 to petroleum ether: ethyl acetate=5:1 to give the compound dibutyl-3-iodopropyl phosphate (659 mg,1.74 mmol) in 59.9% yield.
Preparation of (Z) -1-acetyl-3- ((5- (isopropyl) -1- (dibutylpropyl phosphate) -imidazol-4-yl) methylene) piperazine-2, 5-dione
A dried 50mL eggplant-shaped reaction flask was taken, and (Z) -1-acetyl-3- ((5- (isopropyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (500 mg,1.81 mmol) was dissolved in 25mL dry DMF, dibutyl-3-iodopropyl phosphate (2.05 g,5.43 mmol) was added, cesium carbonate (1.77 g,5.43 mmol) was added, degassed, and reacted at 50℃in the absence of light for 24H, and the reaction was detected by LC-MS. Washing with water, extraction with ethyl acetate, drying the organic phase, suction filtration spin drying, and methanol/water gradient separation on a C18 Flash column chromatography to give the compound (Z) -1-acetyl-3- ((5- (isopropyl) -1- (dibutylpropyl-phosphate) -imidazol-4-yl) methylene) piperazine-2, 5-dione (324 mg,0.62 mmol) in 34.0% yield as a yellow solid.
Preparation of (3Z, 6Z) -3- (3-p-fluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (dibutylpropyl-phosphate) -imidazol-4-yl) methylene) piperazine-2, 5-dione
Compound (Z) -1-acetyl-3- ((5- (isopropyl) -1- (dibutylpropyl-phosphate) -imidazol-4-yl) methylene) piperazine-2, 5-dione (289 mg,0.55 mmol) was dissolved in dry 10mL DMF, 3- (4-fluorophenoxy) -benzaldehyde (143 mg,0.66 mmol) was added, cesium carbonate (399 mg,0.82 mmol) was added, and the reaction was degassed, reacted at 50℃for 24h and detected by LC-MS. Suction filtration spin drying, C18 Flash column chromatography methanol/water gradient separation, methanol beating, obtaining the compound (3Z, 6Z) -3- (3-p-fluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (dibutyl propyl phosphate) -imidazol-4-yl) methylene) piperazine-2, 5-dione (226 mg,0.33 mmol) with a yield of 60.2%.
1 H NMR(500MHz,CDCl 3 )δ12.17(s,1H),8.04(s,1H),7.50(s,1H),7.38(t,J＝7.9Hz,1H),7.15- 6.98(m,5H),6.91(dd,J＝19.4,15.4Hz,4H),4.11-4.05(m,9H),3.16-3.11(m,1H),2.20-2.01(m,3H),1.70- 1.67(m,4H),1.43-1.39(m,8H),0.97-0.93(t,J＝7.4Hz,6H).
Preparation of (3Z, 6Z) -3- (3-p-fluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (propylphosphite) -imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-2-2-21)
The compound (3Z, 6Z) -3- (3-p-fluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (dibutylpropyl-phosphate) -imidazol-4-yl) methylene) piperazine-2, 5-dione (50 mg,0.07 mmol) was dissolved in dry 3mL DMF, TMSBr (0.48 mL,3.66 mmol) was added, degassed, sealed at 45℃for 4h and the reaction was detected by LC-MS. Suction filtration spin drying, and C18 Flash column chromatography methanol/water gradient separation to give the compound (3Z, 6Z) -3- (3-p-fluorophenoxy) benzene) methylene-6- ((5- (isopropyl) -1- (propylphosphite) -imidazol-4-yl) methylene) piperazine-2, 5-dione (20 mg,0.04 mmol) in 49.2% yield.
1 H NMR(500MHz,DMSO-d6)δ11.66(s,1H),10.25(s,1H),8.22(s,1H),7.41(t,J＝7.9Hz,1H), 7.30-7.20(m,3H),7.17(s,1H),7.15-7.09(m,2H),6.91(dd,J＝8.2,1.7Hz,1H),6.74(s,1H),6.64(s,1H), 4.18(t,J＝7.2Hz,2H),3.56(t,J＝6.4Hz,2H),3.23-3.20(m,1H),2.28-2.24(m,2H),1.32(d,J＝7.1Hz, 6H). 13 C NMR(125MHz,DMSO-d6)δ158.2,157.1,157.0,156.5,152.6,138.1,136.7,135.1,130.3,127.1, 124.5,120.6*2,118.9,117.8,116.6*2,116.5,113.8,109.5,102.9,43.6,33.3,30.9,23.6,22.2*2.
EXAMPLE 74 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (N-t-butoxycarbonyl) ethanaminoimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-26)
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 (200 mg,0.72 mmol), N-t-butoxycarbonyl-3-bromoethylamine (324.43 mg,1.45 mmol), cesium carbonate (471.69 mg,1.45 mmol), potassium iodide (120.17 mg,0.72 mmol), 4A molecular sieve (400 mg), DMF (4 ml), vented, nitrogen blanket, placed in an oil bath at 70℃and stirred for 3.5H. After the reaction, concentrating under reduced pressure, drying, dissolving methanol and dichloromethane (1:3), filtering, concentrating under reduced pressure, and drying to obtain 242.80mg of light tan crude solid, with a yield of 80.00%. The mixture was directly taken to the next step without purification.
2) A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (N-t-butoxycarbonyl) ethanaminoimidazol-4-yl) methylene) piperazine-2, 5-dione (242 mg,0.58 mmol), 2-p-fluorobenzoyl benzaldehyde (158.00 mg,0.69 mmol), cesium carbonate (281.96 mg,0.87 mmol), anhydrous sodium sulfate (163.89 mg,1.15 mmol), DMF (4 ml), vented, nitrogen protected, placed in an oil bath at 55deg.C and stirred for 24h. LC-MS monitored the reaction, after which the reaction was completed, concentrated under reduced pressure, dried, then dissolved in methanol and dichloromethane (1:3), filtered, concentrated under reduced pressure, and dried. Gradient elution and decompression concentration gave 64.4mg of pale yellow solid with a yield of 19.00%.
1 H NMR(500MHz,DMSO-d 6 )δ＝12.00(s,1H),10.35(s,1H),7.91(dt,J＝8.4,4.2,2H),7.83(s,1H), 7.77(d,J＝11.6,2H),7.63(d,J＝7.7,1H),7.58(t,J＝7.6,1H),7.40(t,J＝8.8,2H),7.03(t,J＝5.7,1H),6.79(s, 1H),6.70(s,1H),4.05(t,J＝5.8,2H),3.25–3.15(m,3H),1.38–1.27(m,15H).MS(ESI):m/z 588.25[M+ H] + .Mp:204-206℃.
Example 75 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-ethylaminoimidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-27)
A25 ml dry round bottom flask was taken and was charged with (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (N-t-butoxycarbonyl) ethanaminoimidazol-4-yl) methylene) piperazine-2, 5-dione synthesis (51.8 mg,0.088 mmol), methanol (5 ml), hydrochloric acid (1 ml,12 mmol/ml) and placed in a 40℃oil bath to stir for 4h. LC-MS monitoring reaction, concentrating under reduced pressure, drying, adding 0.5ml of methanol, dripping acetone (2 ml), precipitating solid, standing in a refrigerator at-20deg.C for more than 2 hr, vacuum filtering, washing filter cake with acetone, and vacuum drying at 50deg.C to obtain brown yellow solid 24mg with a yield of 76.92%.
1 H NMR(500MHz,DMSO-d 6 )δ＝11.89(s,1H),10.40(s,1H),8.31(s,3H),8.06(s,1H),7.91(dd, J＝8.7,5.6,2H),7.82(s,1H),7.75(d,J＝7.7,1H),7.64(d,J＝7.7,1H),7.59(t,J＝7.6,1H),7.41(t,J＝8.8,2H), 6.82(s,1H),6.70(s,1H),4.34(t,J＝6.7,2H),3.26(dt,J＝14.2,7.1,1H),3.15(dd,J＝12.0,6.0,2H),1.33(d, J＝7.1,6H).MS(ESI):m/z 488.21[M+H] + .Mp:190-192℃.
EXAMPLE 76 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (N-t-butoxycarbonyl) propylamino-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-28)
1) 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,1.09 mmol), N-t-butoxycarbonyl-3-bromopropylamine (517.09 mg,2.17 mmol), cesium carbonate (707.55 mg,2.17 mmol), sodium iodide (162.75 mg,1.09 mmol), 4A molecular sieve (500 mg), DMF (6 ml), vented, nitrogen-protected, placed in an 80℃oil bath and stirred for 4H. After the reaction, the reaction solution is dripped into cold water at the temperature of 4 ℃ to precipitate solids, the solid is filtered by suction, a filter cake is washed by water, then methanol and dichloromethane are dissolved, filtered, concentrated under reduced pressure and dried, and the light brown solid 393mg is obtained, and the yield is 83.49%. The mixture was directly taken to the next step without purification.
2) A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (N-t-butoxycarbonyl) propylaminoimidazol-4-yl) methylene) piperazine-2, 5-dione (393 mg,0.91 mmol), 3-p-fluorobenzoyl benzaldehyde (310.33 mg,1.36 mmol), cesium carbonate (443.05 mg,1.36 mmol), anhydrous sodium sulfate (257.53 mg,1.81 mmol), DMF (5 ml), vented, nitrogen protected, placed in an oil bath at 60℃and stirred for 21h. LC-MS monitors the reaction, after the reaction, the reaction liquid is dripped into cold water at 4 ℃, solid is separated out, suction filtration, sticky, filter cake cold water washing, then methanol and dichloromethane are dissolved, 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. The filter cake and the organic phase sample are combined and eluted in gradient to obtain pale yellow solid of 200mg and yield of 43.98%.
1 H NMR(500MHz,DMSO-d6)δ＝12.01(s,1H),10.35(s,1H),7.91(s,3H),7.82(s,1H),7.75(d,J＝6.5, 1H),7.66-7.56(m,2H),7.40(s,2H),6.98(s,1H),6.81(s,1H),6.69(s,1H),4.02(s,2H),3.20(s,1H),2.95 (s,2H),1.79(s,2H),1.47-1.24(m,15H).MS(ESI):m/z 602.25[M+H] + .Mp:179-180℃.
EXAMPLE 77 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-propylamino-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-29)
A50 ml dry round bottom flask was taken and was charged with (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (N-t-butoxycarbonyl) propylamino-imidazol-4-yl) methylene) piperazine-2, 5-dione synthesis (475.8 mg,0.79 mmol), methanol (30 ml), hydrochloric acid (3.30 ml,12 mmol/ml) and placed in an oil bath at 40℃for stirring reaction for 11h. LC-MS monitoring reaction, after reaction, concentrating under reduced pressure, regulating pH to neutrality with saturated sodium bicarbonate aqueous solution, concentrating under reduced pressure, and ethanol: re-dissolving dichloromethane (1:3), filtering to remove salt, carrying out C18 reverse column chromatography, gradient eluting, and concentrating under reduced pressure to obtain yellow solid 310mg with a yield of 78.07%
1 H NMR(500MHz,DMSO-d 6 )δ＝11.82(s,1H),10.41(s,1H),8.17(s,3H),7.93–7.86(m,2H),7.81 (s,1H),7.75(d,J＝7.7,1H),7.64(d,J＝7.7,1H),7.58(t,J＝7.6,1H),7.43–7.37(m,2H),6.81(s,1H),6.67(d, J＝3.6,1H),4.19(dt,J＝14.5,7.4,2H),3.28–3.19(m,1H),2.81(dd,J＝13.3,6.5,2H),2.04–1.95(m,2H),1.32 (dd,J＝7.0,2.4,6H).MS(ESI):m/z 502.21[M+H] + .Mp:199-201℃.
EXAMPLE 78 Synthesis of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1- (3-N-benzyloxycarbonyl piperazinyl) propylamino-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-30)
A25 ml dry round bottom flask was taken and a solution of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((5-isopropyl-1-propanamino-imidazol-4-yl) methylene) piperazine-2, 5-dione (60 mg,0.12 mmol), pyridine (28.39 mg,0.36 mmol) and dichloromethane (1.5 ml) was added sequentially, stirred in a cold trap at 0deg.C for 10min, benzyloxycarbonyl chloride (30.60 mg,0.18 mmol) in dichloromethane (1.5 ml) was added dropwise, and the mixture was allowed to stand at room temperature for 1h with stirring. LC-MS monitoring reaction, complete reaction, methanol quenching, reduced pressure concentration, C18 loading, reverse column chromatography, gradient elution and reduced pressure concentration to obtain yellow solid 42mg with a yield of 55.24%.
1 H NMR(500MHz,DMSO-d 6 )δ12.01(s,1H),10.35(s,1H),7.90(s,3H),7.82(s,1H),7.75(d,J＝6.08 Hz,1H),7.69-7.55(m,2H),7.47-7.26(m,7H),6.81(s,1H),6.69(s,1H),5.03(s,2H),4.03(s,2H),3.20(s, 1H),3.04(s,2H),1.83(s,2H),1.31(d,J＝4.75Hz,6H).MS(ESI):m/z 636.33[M+H] + .Mp:175-178℃.
Example 79 Synthesis of (3Z, 6Z) -3-benzylidene-6- ((5-isopropyl-1- (N-t-butoxycarbonyl) propanamino-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-31)
1) A50 ml dry two-neck round bottom flask was taken, and (Z) -1-acetyl-3- ((5-isopropyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (200 mg,0.72 mmol), N-t-butoxycarbonyl-3-bromopropylamine (344.8 mg,1.45 mmol), cesium carbonate (471.80 mg,1.45mmol), sodium iodide (108.50 mg,0.72 mmol), 4A molecular sieve (300 mg), DMF (4 ml), exhaust gas, nitrogen protection, and placed in an oil bath at 60℃to stir for 10H. After the reaction, the reaction solution is dripped into cold water at the temperature of 4 ℃ to precipitate solids, the solid is filtered by suction, a filter cake is washed by water, then methanol and dichloromethane are dissolved, filtered, concentrated under reduced pressure and dried, and the light brown solid 256mg is obtained, and the yield is 81.57%. The mixture was directly taken to the next step without purification.
2) A25 ml dry brown round bottom flask was taken and charged with (Z) -1-acetyl-3- ((5-isopropyl-1- (N-t-butoxycarbonyl) propylaminoimidazol-4-yl) methylene) piperazine-2, 5-dione (256 mg,0.59 mmol), cesium carbonate (288.61 mg,0.89 mmol), anhydrous sodium sulfate (167.76 mg,1.18 mmol), benzaldehyde (94.00 mg,0.89 mmol), DMF (4 ml), vented, nitrogen blanket, placed in an oil bath at 60℃and stirred for 18h. LC-MS monitors the reaction, after the reaction, the reaction liquid is dripped into cold water at 4 ℃, solid is separated out, suction filtration is carried out, a filter cake is washed by cold water, then methanol and dichloromethane are dissolved, filtration is carried out, and vacuum concentration is carried out. The aqueous phase EA was extracted to clear, the organic phases were combined and concentrated under reduced pressure. And combining the filter cake with the organic phase sample, performing reverse column chromatography, and performing gradient elution to obtain light yellow solid with 99mg and the yield of 34.96%.
1 H NMR(500MHz,DMSO-d 6 )δ＝11.98(s,1H),10.04(s,1H),7.91(s,1H),7.59–7.25(m,5H),6.98 (s,1H),6.73(d,J＝29.1,2H),4.02(s,2H),3.21(s,1H),2.95(s,2H),1.80(s,2H),1.36(15H).MS(ESI):m/z 480.23[M+H] + .Mp:210-213℃.
Example 80 Synthesis of (3Z, 6Z) -3-benzylidene-6- ((5-isopropyl-1-propylamino-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-32)
A50 ml dry round bottom flask was taken and charged with the synthesis (60 mg,0.12 mmol) of (3Z, 6Z) -3-benzylidene-6- ((5-isopropyl-1- (N-t-butoxycarbonyl) propylamino-imidazol-4-yl) methylene) piperazine-2, 5-dione, methanol (10 ml), water (1 ml), hydrochloric acid (2 ml 12 mmol/ml) and placed in an oil bath at 30℃and stirred for reaction for 12h. LC-MS monitoring reaction, after reaction, regulating pH to 8 with saturated sodium hydroxide aqueous solution, concentrating under reduced pressure, redissolving methanol and dichloromethane, filtering, and concentrating under reduced pressure. Ethyl acetate and water were dissolved and extracted, and the organic phases were combined and concentrated under reduced pressure to give 30mg of a yellow solid in 63.20% yield.
1 H NMR(500MHz,DMSO-d 6 )δ＝7.88(s,1H),7.54(d,J＝7.2,2H),7.41(t,J＝7.2,2H),7.32(d,J＝7.1, 1H),6.74(s,1H),6.69(s,1H),4.06(s,2H),3.24(m,2H),2.54(s,2H),1.73(s,2H),1.33(d,J＝6.8,6H).MS (ESI):m/z 380.09[M+H] + .Mp:207-210℃.
Example 81 preparation of (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((4- (3-aminopropyl) -5-phenyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (PLN-5-33)
1) (3Z) -1-acetyl-3- ((4- (N-Boc-3-aminopropyl) -5-phenyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
A25 ml dry brown round bottom flask was taken, followed by addition of (3Z) -1-acetyl-3- ((5-phenyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (40.00 mg,0.13 mmol), N-Boc-3-aminopropyl bromide (61.43 mg,0.26 mmol), cesium carbonate (84.06mg,0.26 mmol), potassium iodide (21.41 mg,0.13 mmol), 4A molecular sieve (40 mg), DMF (2.5 ml), displacement nitrogen protection 3 times, placed in an oil bath at 75℃and stirred for 4H. After the reaction, the reaction solution is dripped into cold water, a reddish brown solid is separated out, the filter cake is washed by suction filtration, the filter cake is redissolved by methanol and dichloromethane, the suction filtration is carried out, and the filtrate is concentrated under reduced pressure to obtain 41.8mg of orange yellow solid with the yield of 69.37%.
2) (3Z, 6Z) -3- (2- (p-fluorobenzoyl) benzene) methylene-6- ((4- (N-Boc-3-aminopropyl) -5-phenyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
A25 ml dry brown round flask was taken, and (3Z) -1-acetyl-3- ((4- (N-Boc-3-aminopropyl) -5-phenyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (41.8 mg,0.090 mmol), 3- (4-fluorobenzoyl) benzaldehyde (30.55 mg,0.13 mmol), cesium carbonate (43.66 mg,0.13 mmol), anhydrous sodium sulfate (25.43 mg,0.18 mmol), DMF (2 ml) were added in sequence, placed in an oil bath at 50℃and stirred for 21H. After the reaction, the reaction mixture was added dropwise to cold water (20 ml) at 4℃to precipitate a pale yellow solid, suction filtration was carried out, 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 with cold methanol, and vacuum drying at 50deg.C to obtain orange yellow solid 34.5mg with yield 60.71%.
3) (3Z, 6Z) -3- (3- (p-fluorobenzoyl) benzene) methylene-6- ((4- (3-aminopropyl) -5-phenyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
A25 ml dry round bottom brown bottle was taken and successively charged with (3Z, 6Z) -3- (2- (p-fluorobenzoyl) benzene) methylene-6- ((4- (N-Boc-3-aminopropyl) -5-phenyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione (27 mg,0.042 mmol), concentrated hydrochloric acid (0.18 ml), methanol (3 ml), nitrogen sparged 3 times, placed in a 30℃oil bath and stirred for reaction for 12H. After the reaction, concentrating under reduced pressure to solid, redissolving with 0.5ml of methanol, dripping into a round bottom flask containing 10ml of ethyl acetate, and separating out pale yellow solid. The flask was placed in a 0℃cold well and stirred for 1h. Suction filtration, washing the filter cake with ethyl acetate, and vacuum drying at 50 ℃ to obtain light yellow solid 10.6mg. The yield thereof was found to be 48.18%.
1 H NMR(500MHz,DMSO-d 6 )δ11.83(s,1H),10.39(s,1H),8.25(s,1H),7.99(s,3H),7.90(m,2H), 7.80(s,1H),7.74(d,J＝7.5Hz,1H),7.60(m,5H),7.47(d,J＝7.0Hz,2H),7.39(t,J＝8.7Hz,2H),6.84(s, 1H),6.32(s,1H),4.13(t,J＝6.6Hz,2H),2.65(d,J＝5.6Hz,2H),1.83(m,2H).MS(ESI):m/z 536.10[M +H] + .Mp:263-265℃.
EXAMPLE 82 preparation of dehydrophenyl-achyranthis hydrochloride and hydrochloric acid content test
1) General procedure for salt formation of compounds:
the compound (1.0 eq) was taken in a dry round bottom flask, dissolved with an appropriate amount of methanol, added dropwise with concentrated hydrochloric acid (10.0 eq) and stirred at room temperature for 2h under dark conditions. After the reaction, concentrating under reduced pressure until no solvent exists, dissolving a small amount of methanol, dripping into ethyl acetate or acetone, precipitating solid, placing in a cold trap at zero ℃ for stirring for 2 hours, carrying out suction filtration, washing a filter cake with cold ethyl acetate or acetone, and carrying out vacuum drying on the filter cake at 50 ℃ to obtain white solid, wherein the white solid and hydrochloric acid are subjected to quantitative molar ratio to form salt (a compound: hydrochloric acid=1:2).
2) Dehydrophenyl-achyranthis statin hydrochloride pure hydrochloric acid content test and result analysis
1. Reagent and reagent
Sodium hydroxide (analytically pure), potassium hydrogen phthalate (reference); phenolphthalein indicator: taking 1g of phenolphthalein and adding 100ml of ethanol to obtain the final product.
2. Configuration of
Adding water into proper amount of sodium hydroxide, shaking to dissolve into saturated solution, cooling, placing into polyethylene plastic bottle, standing for several days, and clarifying.
Sodium hydroxide titration solution (0.1 mol/L): taking 5.6ml of clarified sodium hydroxide saturated solution, adding new boiled cold water to make 1000ml, and shaking.
3. Calibrating
3.1 procedure
Sodium hydroxide titration solution (0.1 mol/L) is prepared by taking about 0.6g of standard potassium hydrogen phthalate dried to constant weight at 105 ℃, precisely weighing, adding 50ml of newly boiled cold water, and shaking to dissolve as much as possible; adding 2 drops of phenolphthalein indicator solution, and titrating with the solution; near the end point, the potassium hydrogen phthalate should be completely dissolved and titrated to pink. Each 1ml of sodium hydroxide titration solution (0.1 mol/L) corresponds to 20.42mg of potassium hydrogen phthalate.
3.2 calculation formula
The concentration C (mol/L) of the sodium hydroxide titration solution is calculated according to the following formula:
C(mol/L)＝(m*1.000)/(V*204.2)
wherein: m is the weighing amount (mg) of the standard potassium hydrogen phthalate;
V is the consumption (ml) of the titration solution;
204.2 is the milligrams equivalent to potassium hydrogen phthalate per 1ml of sodium hydroxide solution (1.000 mol/L).
4. Titration
Precisely weighing test reagent (about 10 mg), adding new boiled cold water 50ml, and shaking to dissolve; adding 2 drops of phenolphthalein indicator solution, titrating with calibrated sodium hydroxide solution until the solution reaches the end point and turns pink, and recording the volume V of the sodium hydroxide solution consumed Consumption of 。
5. Analysis of results
n (sodium hydroxide) ＝C(mol/L)*V Consumption of
n (reagent) ＝m Reagent /M Reagent
The salt forming ratio is as follows: n is n (sodium hydroxide) /n (reagent)
The experimental results show that: through detection calculation, the salifying ratio of the plinabulin morpholine derivative and the hydrochloric acid is 1:2, namely one molecule of derivative is combined with two molecules of hydrochloric acid.
Effect example 1 Compounds or their hydrochloride salt for cell proliferation inhibition test
Tumor cells (NCI-H460, bxPC-3, HT-29) in logarithmic growth phase were digested, centrifuged, and after re-spinning fresh medium, counted using a cell counting plate, 100. Mu.L of medium (containing cells) was added to each well of a 96-well plate according to the standard of 2000-6000 cells per well, and the 96-well plate was 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 test of the compounds of the present invention or the hydrochloride thereof on cell proliferation inhibition are shown in Table 1.
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) Establishment of a Standard Curve
About 1mg of the compound was weighed and dissolved in DMSO to prepare a 1mg/mL mother liquor. And diluting the mother solution with methanol to working solutions with different concentrations, and taking the working solutions as standard samples for sample injection test. The concentration of the different working solutions is diluted in sequence: 100000 50000, 10000, 5000, 1000, 500, 250ng/mL.
2) Method for measuring solubility of sample
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 compound in pure water was calculated.
3) Calculation and results
The results of the solubility experiments for the compounds are shown in table 2 below:
TABLE 2
Names of Compounds Solubility of
Plinabulin <250(ng/mL)
PLN-1-13-1 <250(ng/mL)
PLN-1-14-1 <250(ng/mL)
PLN-5-29 833.10±49.65
PLN-5-6 <250
PLN-5-4 <250
PLN-5-8 <250
PLN-5-9 <250
PLN-5-10 <250
Effect example 3 solubility experiment of dehydrophenyl-achyranthis hydrochloride
1) Experimental method
About 2mg of dehydrophenyl-achyranthis hydrochloride was weighed out by taking a 0.5mL brown EP tube, and 0.2mL of ultrapure water was added thereto. Vortex shaking, placing into an incubation vibrator, maintaining the temperature (37+ -1deg.C), shaking for 24h at 100r/min, and allowing to reach full dissolution balance. The dissolution was observed.
2) Experimental results
The solubility test results of dehydrophenyl-achyranthis hydrochloride are shown in table 3 below:
TABLE 3 Table 3
Effect example 4 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-5-6 (2 nM), PLN-5-8 (2 nM) and PLN-5-9 (2 nM) were added and incubation continued 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)
5. Counterstaining the nuclei: DAPI dye solution is added dropwise, and incubated for 10min at room temperature in dark places.
6. Sealing piece: the climbing slices are placed in PBS and washed for 3 times on a decolorizing shaker for 5min each time. 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, the results are shown in table 4 below and fig. 1:
TABLE 4 Table 4
Experiments show that: the untreated control group had normal cell morphology, intact tubulin structure, and a regular fusiform structure. After 24h of compound treatment microtubules were atrophic and even broken. The immunofluorescence experimental result graph and the beta-tubulin fluorescence value show that the effect of the compound PLN-5-6 on inhibiting tubulin polymerization is superior to that of the compound Plinabulin.
Effect example 5Western 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 in a 6-hole plate, after cells are subjected to adherence culture for 24h, plinabulin (10 nM), PLN-5-4 (5 nM), PLN-5-4 (10 nM), PLN-5-6 (5 nM) and PLN-5-6 (10 nM) are respectively added for treatment, the cells are placed in an incubator for continuous incubation for 24 hours, the culture solution is sucked, PBS is used for washing twice, RIPA lysate containing protease and phosphatase inhibitor is added on ice for lysing the cells, the cells are placed on ice for 30min, and then are collected in a 1.5ml EP tube, the temperature is 4 ℃, the speed is 12000rpm, and the centrifugation is carried out for 10min, 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 2 min, 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 5 below:
TABLE 5
The experimental results show that: after 24H of treatment of each sample, the relative gray values of Caspase-3/GAPDH protein were compared, and PLN-5-4 and PLN-5-6 had better effect in promoting apoptosis of NCI-H460 cell line than Plinabulin.

Claims (12)

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 H, 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 H, 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;
the ring C is
R 2 Is H, halogen or benzyl;
R 3 to be covered by one or more R 3-1 Substituted C 1 -C 8 Alkyl, C 2 -C 8 Alkynyl or C 2 -C 8 Alkenyl groups;
R 3-1 independently is hydroxy, C 1 -C 8 Alkoxy, -OTBS, NR 3-1-1 R 3-1-2 、or-O-C (=o) -R 3-1-3 ；
R 3-1-1 And R is 3-1-2 H, C independently 1 -C 8 Alkyl or-C (=o) -O-R 3-1-1-1 ；R 3-1-1-1 Is C 1 -C 8 Alkyl or benzyl;
R 3-1-3 is C 1 -C 8 Alkyl or by one or more R 3-1-3-1 Substituted C 6 -C 10 An aryl group; r is R 3-1-3-1 Independently OH or benzyloxy;
R 4 is C 1 -C 8 Alkyl or C 6 -C 10 An aryl group;
R 5 and R is 6 The definition of (2) satisfies the following condition: (1) R is R 5 Is H, R 6 Is C 6 -C 10 An aryl group; or (2) R 5 Is C 6 -C 10 Aryl, R 6 Is C 1 -C 8 Alkyl or C 6 -C 10 An aryl group;
R 7 and R is 8 Is H or R 7 And R is 8 Together with the carbon atoms to which they are attached form C 6 -C 10 Aryl of (a);
R 9 is C 1 -C 8 Alkyl, C substituted by one or more halogens 1 -C 8 Alkyl, C 2 -C 8 Alkenyl or benzyl;
R 10 、R 11 、R 12 and R is 13 Independently H,Halogen, C 1 -C 8 Alkoxy, substituted by one or more R 11-1 Substituted C 1 -C 8 Alkoxy or C 1 -C 8 Alkyl, R 10 、R 11 、R 12 And R is 13 Not simultaneously H, or R 10 、R 11 Together with the carbon atoms to which they are attached form C 6 -C 10 Aryl, or R 11 、R 12 Together with the carbon atoms to which they are attached form C 6 -C 10 Aryl, or R 12 、R 13 Together with the carbon atoms to which they are attached form C 6 -C 10 An aryl group;
R 11-1 independently C 3 -C 10 Cycloalkyl;
R 14 is C 1 -C 8 Alkyl, C substituted by one or more halogens 1 -C 8 Alkyl, C 2 -C 8 Alkenyl or benzyl;
R 15 、R 16 and R is 17 Independently H, halogen, C 1 -C 8 Alkoxy, substituted by one or more R 11-1 Substituted C 1 -C 8 Alkoxy or C 1 -C 8 An alkyl group.
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 Alkyl, substituted by one or more halogensC of (2) 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 When halogen, the halogen is chlorine, bromine or iodine;
(13) When R is 3 To be covered by one or more R 3-1 Substituted C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 An alkyl group;
(14) When R is 3 Is C 2 -C 8 In the case of alkynyl, the said C 2 -C 8 Alkynyl is C 2 -C 4 Alkynyl;
(15) When R is 3 Is C 2 -C 8 Alkenyl, the C 2 -C 8 Alkenyl group is C 2 -C 4 Alkenyl groups;
(16) When R is 3-1 Independently C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is C 1 -C 4 An alkoxy group;
(17) When R is 3-1-1 And R is 3-1-2 Independently C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 An alkyl group;
(18) When R is 3-1-1-1 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 An alkyl group;
(19) When R is 3-1-3 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 An alkyl group;
(20) When R is 3-1-3 To be covered by one or more R 3-1-3-1 Substituted C 6 -C 10 Aryl, the C 6 -C 10 Aryl is phenyl;
(21) When R is 4 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 An alkyl group;
(22) When R is 4 Is C 6 -C 10 Aryl, the C 6 -C 10 Aryl is phenyl;
(23) When R is 7 And R is 8 Together with the carbon atoms to which they are attached form C 6 -C 10 The C is aryl 6 -C 10 Aryl is phenyl;
(24) When R is 9 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 An alkyl group;
(25) When R is 9 For C substituted by one or more halogens 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 An alkyl group;
(26) When R is 9 Is C 2 -C 8 Alkenyl, the C 2 -C 8 Alkenyl group is C 2 -C 4 Alkenyl groups;
(27) When R is 10 、R 11 、R 12 And R is 13 When independently halogen, the halogen is bromine;
(28) When R is 10 、R 11 、R 12 And R is 13 Independently C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is C 1 -C 4 An alkoxy group;
(29) When R is 10 、R 11 、R 12 And R is 13 Independently is one or more R 11-1 Substituted C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is C 1 -C 4 An alkoxy group;
(30) When R is 10 、R 11 、R 12 And R is 13 Independently C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 An alkyl group;
(31) When R is 10 、R 11 Together with the carbon atoms to which they are attached form C 6 -C 10 Aryl, the C 6 -C 10 Aryl is phenyl;
(32) When R is 11 、R 12 Together with the carbon atoms to which they are attached form C 6 -C 10 Aryl, the C 6 -C 10 Aryl is phenyl;
(33) When R is 12 、R 13 Together with the carbon atoms to which they are attached form C 6 -C 10 Aryl, the C 6 -C 10 Aryl is phenyl;
(34) When R is 11-1 Independently C 3 -C 10 Cycloalkyl radicals, when present, areC 3 -C 10 Cycloalkyl radicals are C 5 -C 6 Cycloalkyl;
(35) When R is 14 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is C 1 -C 4 An alkyl group.
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 When "heteroatom selected from one or more of N, O and S, 3-10 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, 3-10 membered heteroaryl having 1 to 5 heteroatoms" is pyridinyl;
(9) When R is 3 To be covered by one or more R 3-1 Substituted C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is ethyl or n-propyl;
(10) When R is 3 Is C 2 -C 8 In the case of alkynyl, the said C 2 -C 8 Alkynyl is propargyl;
(11) When R is 3 Is C 2 -C 8 Alkenyl, the C 2 -C 8 Alkenyl is allyl;
(12) When R is 3-1 Independently C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is methoxy or ethoxy;
(13) When R is 3-1-1 And R is 3-1-2 Independently C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is methyl;
(14) When R is 3-1-1-1 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is methyl;
(15) When R is 3-1-3 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is tert-butyl;
(16) When R is 4 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is isopropyl or tert-butyl;
(17) When R is 9 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is methyl, ethyl, n-propyl, isopropyl or n-butylA group such as methyl, ethyl or isopropyl;
(18) When R is 9 For C substituted by one or more halogens 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is methyl;
(19) When R is 9 Is C 2 -C 8 Alkenyl, the C 2 -C 8 Alkenyl is allyl;
(20) When R is 10 、R 11 、R 12 And R is 13 Independently C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy or n-butoxy;
(21) When R is 10 、R 11 、R 12 And R is 13 Independently is one or more R 11-1 Substituted C 1 -C 8 Alkoxy, the C 1 -C 8 Alkoxy is methoxy, ethoxy or n-propoxy;
(22) When R is 10 、R 11 、R 12 And R is 13 Independently C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is methyl;
(23) When R is 11-1 Independently C 3 -C 10 In the case of cycloalkyl, the C 3 -C 10 Cycloalkyl is cyclohexenyl;
(24) When R is 14 Is C 1 -C 8 When alkyl, the C 1 -C 8 Alkyl is methyl.
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)R 1 is H, benzoyl substituted by one or more halogens, benzeneOxy or "phenoxy substituted with one or more halogens"; preferably, R 1 Is benzoyl, benzoyl substituted with one or more halogens, or "phenoxy substituted with one or more halogens";
(2)R 1a 、R 1b and R is 1c Independently H;
(3)R 2 is H or halogen;
(4)R 3-1 independently is hydroxy, C 1 -C 8 Alkoxy, NR 3-1-1 R 3-1-2 、or-O-C (=o) -R 3-1-3 ；
(5)R 3-1-3 Is C 1 -C 8 An alkyl group;
(6)R 3-1-1 and R is 3-1-2 Independently H or-C (=O) -O-R 3-1-1-1 ；
(7)R 4 Is C 1 -C 8 An alkyl group;
(8)R 7 and R is 8 Is H;
(9)R 9 is C 1 -C 8 An alkyl group;
(10)R 10 is H or C 1 -C 8 An alkyl group;
(11)R 11 h, C of a shape of H, C 1 -C 8 Alkoxy or C 1 -C 8 Alkyl, or R 11 、R 12 Together with the carbon atoms to which they are attached form C 6 -C 10 An aryl group;
(12)R 12 h, C of a shape of H, C 1 -C 8 Alkoxy or C 1 -C 8 Alkyl, or R 11 、R 12 Together with the carbon atoms to which they are attached form C 6 -C 10 An aryl group;
(13)R 13 is H, methoxy or C 1 -C 8 An alkyl group;
(14)R 14 is C 1 -C 8 An alkyl group;
(15)R 15 、R 16 and R is 17 Independently H.
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)is->
(2)Is->
(3)Is->
(4)Is->
(5)Is->
6. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 5, 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);
wherein the ring C, R 1 、R 1a 、R 1b And R is 1c Is as defined in any one of claims 1 to 5.
7. A compound of formula (II):
wherein ring C is as defined in any one of claims 1 to 5.
8. A compound of any one of:
9. a compound as shown below, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing:
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10. A pharmaceutical composition comprising a compound according to any one of claims 1-5 or claim 9, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate of any one of the foregoing, and a pharmaceutically acceptable adjuvant.
11. Use of a compound according to any one of claims 1 to 5 or claim 9, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate of any one of the foregoing, or a pharmaceutical composition according to claim 10, for the manufacture of a medicament for the prophylaxis and/or treatment of cancer; the cancer is preferably one or more of lung cancer, pancreatic cancer, colon cancer and liver cancer.
12. Use of a compound according to any one of claims 1 to 5 or claim 9, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate of any one of the foregoing, or a pharmaceutical composition according to claim 10, for the preparation of a tubulin inhibitor.
CN202210689557.5A 2022-06-16 2022-06-16 Dehydrogenated phenyl achyranthis statin compound, preparation method and application thereof Pending CN117285516A (en)

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