CN113956236A - Phthalimide compound and application thereof - Google Patents

Phthalimide compound and application thereof Download PDF

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CN113956236A
CN113956236A CN202111121331.7A CN202111121331A CN113956236A CN 113956236 A CN113956236 A CN 113956236A CN 202111121331 A CN202111121331 A CN 202111121331A CN 113956236 A CN113956236 A CN 113956236A
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CN113956236B (en
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吴松
张文轩
吴骏
武红娜
周琪
郝捷
王柳
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Abstract

The invention belongs to the technical field of medicines, and particularly relates to an amide compound for regulating a WNT signal pathway and application thereof. The compounds according to the invention have the structure shown in formula I:

Description

Phthalimide compound and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an amide compound for regulating a WNT signal pathway and application thereof.
Background
The Wnt signaling pathway is a complex network of protein action, the function of which is most common in embryonic development and cancer, but is also involved in the normal physiological processes in adult animals. The Wnt secretory protein family plays a decisive role in the differentiation of cells during the development of embryos, and plays a crucial role in the microenvironment for the survival of adult stem cells (adult stem cells). Wnt proteins are involved in a variety of physiological processes and can play a decisive role in guiding more complex physiological activities, including control of body morphology (body plane determination) and tissue morphology (tissue patterning). If the Wnt signaling pathway is abnormal, various diseases such as various dysplasias and cancers can be caused.
Wnt is known as Wg (wiggless) and Int. The Wingress gene was first discovered in Drosophila and acts on embryonic development, as well as limb formation in adult animals. The INT gene was first found in vertebrates, in the vicinity of the integration site of the Mouse Mammary Tumor Virus (MMTV). The Int-1 gene has homology with the wingless gene. Wingless gene mutations in Drosophila can lead to wingless malformations, while replication and integration of MMTV into the genome in mouse mammary tumors can lead to increased synthesis of one or several Wnt genes.
Since the discovery of the first Wnt gene by nusse et al in 1982, 19 members of the Wnt gene family have been discovered to date in humans, and the signaling pathway mediated by the Wnt gene to conduct signaling molecules from outside the cell to inside the cell through the cell membrane receptor has been termed the Wnt signaling pathway. The Wnt signaling pathway includes a number of proteins that regulate the synthesis of Wnt signaling molecules, which interact with receptors on target cells whose physiological responses result from the interaction of the cell with extracellular Wnt ligands. Although the occurrence, absence and magnitude of the response vary depending on the Wnt ligand, cell type and body itself, some components of the signaling pathway, from nematodes to humans, share high homology. Protein homology indicates that a variety of different Wnt ligands originate from a common ancestor of various organisms.
The opening and closing of the Wnt signaling pathway directly controls the expression of a number of genes associated with growth and metabolism, while this signaling pathway is connected to other signaling pathways (e.g., TGFbeta/BMP, Hedgehog, PI)3K. RTKs, etc.) indirectly affect genes downstream of these pathways. Thus, the Wnt signaling pathway is involved in the regulation of a variety of biological processes, including embryonic growth and morphological development, tissue stabilization, balance of energy metabolism, and stem cellsAnd (4) maintaining the cells.
The canonical Wnt pathway describes a series of responses when Wnt proteins bind to the cell surface Frizzled receptor family, including activation of the Dishevelled receptor family proteins and ultimately changes in the nuclear β -catenin levels. Dishevelled (DSH) is a key component of the cell membrane-associated Wnt receptor complex, which is activated upon binding to Wnt and inhibits downstream protein complexes, including axin, GSK-3, and APC protein. The axin/GSK-3/APC complex can promote the degradation of an intracellular signal molecule beta-catenin. When the 'beta-catenin degradation compound' is inhibited, the beta-catenin in cytoplasm exists stably, and part of the beta-catenin enters the nucleus to act with a TCF/LEF transcription factor family and promote the expression of a specific gene.
The Wnt pathway comprises 3 pathways: Wnt/Ca2+The PCP pathway and the canonical Wnt pathway. The canonical Wnt signaling pathway consists of four parts: extracellular Wnt ligand proteins, receptors on cell membranes, signaling moieties within the cytoplasm, and transcriptional regulatory moieties within the nucleus. This pathway regulates cell behavior primarily through the transcriptional properties of the TCF/LEF family of DNA binding proteins, the most critical of which is the stabilization of intracytoplasmic β -catenin, when β -catenin levels are low, the Wnt pathway is closed; otherwise, the Wnt pathway is open.
Wnt signal transduction pathways are highly conserved signal transduction pathways in the process of organism evolution, and regulate and control a plurality of life activity processes. Its abnormal activation is closely related to the occurrence and development of cancer, and in the last 90 th generation of hereditary Familial Adenomatous Polyposis (FAP) and spontaneously formed colon cancer, the involvement of Wnt pathway is found, and thus, the Wnt signaling pathway is related to tumorigenesis. Meanwhile, studies show that abnormal activation of the Wnt pathway is related to self-renewal and proliferation of tumor stem cells (CSCs), and Wnt signaling contributes to maintenance of the dryness of tumor stem cells. In other diseases, such as familial exudative vitreoretinopathy, neurodegenerative diseases, osteoporosis, etc., the Wnt signaling pathway is often found to exhibit down-regulation. In addition, it has been found that abnormal expression of the Wnt pathway is also associated with cardiovascular and cerebrovascular diseases and metabolic diseases.
Porcupine Protein (PORCN) is a multi-channel transmembrane O-acyltransferase that is essential for palmitoylation and secretion of Wnt proteins in Wnt cells. Deletion of PORCN results in retention of Wnt3A in cells, leading to developmental disorders; in turn, overexpression of PORCN is often associated with the growth of cancerous cells.
Therefore, the development of small molecules for regulating the Wnt signaling pathway is of great significance, and the inhibition of the Wnt signaling pathway activity can treat diseases such as tumors, myocardial hypertrophy, hyperosteogeny and the like, while the activation of the Wnt signaling pathway activity can treat neurodegenerative diseases, exudative vitreoretinopathy, osteoporosis, diabetes, cardiovascular and cerebrovascular diseases and the like.
Disclosure of Invention
Therefore, the invention provides an amide compound for regulating WNT signal pathway and application thereof.
According to a first aspect of the present invention, there is provided an amide compound that modulates WNT signaling pathway, and pharmaceutically acceptable salts thereof, having a structure represented by general formula I:
Figure BDA0003277129830000021
wherein R is1Selected from unsubstituted or substituted by 1-4R2Substituted succinimides, unsubstituted or substituted by 1 to 4R2Substituted maleimides, unsubstituted or substituted by 1-4R2Substituted phthalimides, unsubstituted or substituted by 1 to 4R2Substituted cycloalkylsuccinimide, unsubstituted or substituted by 1-4R2Substituted cycloalkenyl-succinimides;
the R is2Selected from substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms3-C8Heterocycloalkyl, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C6-C12Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms2-C12Heteroaryl group, C1-C8Amide group, C1-C8Ester group, carboxyl group, cyano group, halogen, hydroxyl group, amino group or nitro group;
x is selected from unsubstituted or substituted by 1-3R3Substituted C1-C6Alkylene, unsubstituted or substituted by 1 to 3R3Substituted C2-C6Alkenyl, unsubstituted or substituted by 1-3R3Substituted C2-C6Alkynyl, unsubstituted or substituted by 1-3R3Substituted C3-C6Cycloalkyl, unsubstituted or substituted by 1-3R3Substituted C3-C6Cycloalkyl monoalkyl radicals, unsubstituted or substituted by 1-3R3Substituted C3-C6Cycloalkyldialkyl, unsubstituted or substituted by 1-3R3Substituted aryl, unsubstituted or substituted by 1 to 3R3Substituted aryl monoalkyl radicals, unsubstituted or substituted by 1 to 3R3Substituted aryl dialkyl;
the R is3Selected from substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms3-C8Heterocycloalkyl, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C6-C12Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms2-C12Heteroaryl group, C1-C8Amide group, C1-C8Ester group, carboxyl group, cyano group, halogen, hydroxyl group, amino group or nitro group;
a is selected from unsubstituted or substituted by 1-3R4Substituted phenyl or heteroaryl, B is selected from unsubstituted or substituted by 1-3R5Substituted phenyl or heteroaryl, and A and B form a bi-aromatic structure;
in group A, B, the heteroaryl is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, indolyl, benzofuranyl, dibenzopyranyl, benzothienyl, dibenzothienyl;
the R is4Selected from substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms3-C8Heterocycloalkyl, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C6-C12Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms2-C12Heteroaryl group, C1-C8Amide group, C1-C8Ester group, carboxyl group, cyano group, halogen, hydroxyl group, amino group or nitro group;
the R is5Selected from substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms3-C8Heterocycloalkyl, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C6-C12Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms2-C12Heteroaryl group, C1-C8Amide group, C1-C8Ester group, carboxyl group, cyano group, halogen, hydroxyl group, amino group or nitro group;
the above substituents are independently selected from C1-C3Alkyl, halogen substituted C1-C3Alkyl radical, C1-C4Alkoxy, carboxyl, cyano, halogen, hydroxyl and nitro, wherein the halogen is selected from F, Cl, Br and I, and the heteroatom is selected from N, O, S and P.
According to one embodiment of the invention, a is selected from:
Figure BDA0003277129830000031
a is connected with B through a carbon-carbon single bond, wherein a dotted line represents connection with an amide nitrogen atom, a wavy line represents connection with B, and R4Selected from substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms3-C8Heterocycloalkyl, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C6-C12Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms2-C12Heteroaryl group, C1-C8Amide group, C1-C8Ester group, carboxyl, cyano, halogen, hydroxyl, amino or nitro, and the substituents are independently selected from C1-C3Alkyl, halogen substituted C1-C3Alkyl radical, C1-C4Alkoxy, carboxyl, cyano, halogen, hydroxyl and nitro, wherein the halogen is selected from F, Cl, Br and I, and the heteroatom is selected from N, O, S and P;
(R4)nrepresents n numbers of R4And n is selected from 1 or 2.
According to one embodiment of the invention, B is selected from:
Figure BDA0003277129830000041
the R is5Selected from substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms3-C8Heterocycloalkyl, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C6-C12Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms2-C12Heteroaryl group, C1-C8Amide group, C1-C8Ester group, carboxyl, cyano, halogen, hydroxyl, amino or nitro, and the substituents are independently selected from C1-C3Alkyl, halogen substituted C1-C3Alkyl radical, C1-C4Alkoxy, carboxyl, cyano, halogen, hydroxyl and nitro, wherein the halogen is selected from F, Cl, Br and I, and the heteroatom is selected from N, O, S and P;
(R5)nrepresents n numbers of R5And n is selected from 1,2 or 3.
According to one embodiment of the invention, the compound has the structure shown in formula IA:
Figure BDA0003277129830000051
wherein R is1Selected from unsubstituted or substituted by 1-4R2Substituted succinimides, unsubstituted or substituted by 1 to 4R2Substituted maleimide, substituted with 1-4R2Substituted phthalimides, unsubstituted or substituted by 1 to 4R2Substituted cycloalkylsuccinimide, unsubstituted or substituted by 1-4R2Substituted cycloalkenyl-succinimides;
the R is2Selected from substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms3-C8Heterocycloalkyl, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C6-C12Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms2-C12Heteroaryl radical、C1-C8Amide group, C1-C8Ester group, carboxyl group, cyano group, halogen, hydroxyl group, amino group or nitro group;
x is selected from unsubstituted or substituted by 1-3R3Substituted C1-C6Alkyl, unsubstituted or substituted by 1-3R3Substituted C2-C6Alkenyl, unsubstituted or substituted by 1-3R3Substituted C2-C6Alkynyl, unsubstituted or substituted by 1-3R3Substituted C3-C6Cycloalkyl, unsubstituted or substituted by 1-3R3Substituted C3-C6Cycloalkyl monoalkyl radicals, unsubstituted or substituted by 1-3R3Substituted C3-C6Cycloalkyldialkyl, unsubstituted or substituted by 1-3R3Substituted aryl, unsubstituted or substituted by 1 to 3R3Substituted aryl monoalkyl radicals, unsubstituted or substituted by 1 to 3R3Substituted aryl dialkyl;
the R is3Selected from substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms3-C8Heterocycloalkyl, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C6-C12Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms2-C12Heteroaryl group, C1-C8Amide group, C1-C8Ester group, carboxyl group, cyano group, halogen, hydroxyl group, amino group or nitro group;
the substituents are independently selected from C1-C3Alkyl, halogen substituted C1-C3Alkyl radical, C1-C4Alkoxy, carboxyl, cyano, halogen, hydroxyl and nitro, wherein the halogen is selected from F, Cl, Br or I, and the heteroatom is selected from N, O, S and P.
Preferably the compounds of the present invention have the structure shown in IA-1:
Figure BDA0003277129830000052
preferred compounds of the present invention have the structure shown in IA-2:
Figure BDA0003277129830000053
preferred compounds of the present invention have the structure shown in IA-3:
Figure BDA0003277129830000061
preferred compounds of the present invention have the structure shown in IA-4:
Figure BDA0003277129830000062
preferred compounds of the present invention have the structure shown in IA-5:
Figure BDA0003277129830000063
preferred compounds of the present invention have the structure shown in IA-6:
Figure BDA0003277129830000064
preferred compounds of the present invention have the structure shown in IA-7:
Figure BDA0003277129830000065
preferred compounds of the present invention have the structure shown in IA-8:
Figure BDA0003277129830000066
in the above formulae IA-1 to IA-8, R1Selected from unsubstituted or substituted by 1-4R2Substituted succinimides, unsubstituted or substituted by 1 to 4R2Substituted maleimide, substituted with 1-4R2Substituted phthalimides, unsubstituted or substituted by 1 to 4R2Substituted cycloalkylsuccinimide, unsubstituted or substituted by 1-4R2Substituted cycloalkenyl-succinimides;
the R is2Selected from substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms3-C8Heterocycloalkyl, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C6-C12Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms2-C12Heteroaryl, alkylene bridge, oxygen bridge, nitrogen bridge, C1-C8Amide group, C1-C8Ester group, carboxyl group, cyano group, halogen, hydroxyl group, amino group or nitro group, wherein the halogen is selected from F, Cl, Br or I, and the heteroatom is selected from N, O, S and P;
more preferably, R1Selected from the following structures:
Figure BDA0003277129830000071
the R is2Selected from substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms3-C8Heterocycloalkyl, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C6-C12Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms2-C12Heteroaryl group, C1-C8Amide group, C1-C8Ester group, carboxyl, cyano, halogen, hydroxyl, amino or nitro, and the substituents are independently selected from C1-C3Alkyl, halogen substituted C1-C3Alkyl radical, C1-C4Alkoxy, carboxyl, cyano, halogen, hydroxyl and nitro, wherein the halogen is selected from F, Cl, Br or I, and the heteroatom is selected from N, O, S and P;
(R2)nrepresents n numbers of R2And n is selected from 1,2 or 3.
According to one embodiment of the invention, the compounds include, but are not limited to, the following compounds:
Figure BDA0003277129830000072
Figure BDA0003277129830000081
Figure BDA0003277129830000091
Figure BDA0003277129830000101
Figure BDA0003277129830000111
Figure BDA0003277129830000121
Figure BDA0003277129830000131
Figure BDA0003277129830000141
Figure BDA0003277129830000151
Figure BDA0003277129830000161
Figure BDA0003277129830000171
Figure BDA0003277129830000181
Figure BDA0003277129830000191
Figure BDA0003277129830000201
Figure BDA0003277129830000211
according to a second aspect of the present invention, there is provided a pharmaceutical composition comprising an amide compound that modulates WNT signaling pathway as described above, and pharmaceutically acceptable salts, isotopes, isomers and crystal forms thereof.
According to one embodiment of the invention, the pharmaceutical composition according to the invention further comprises one or more pharmaceutically acceptable carriers or excipients.
The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are generally present in the pharmaceutical compositions in an amount of from 0.1 to 95% by weight.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ophthalmic, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.
For tableting the compound of the present invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, and solubilizers. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and cosolvent may be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
To encapsulate the administration unit, the active ingredient of the compound of the present invention may be mixed with a diluent and a cosolvent, and the mixture may be directly placed in a hard capsule or soft capsule. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The diluents, binders, wetting agents, disintegrants, and cosolvents used to prepare the compound tablets of the present invention can also be used to prepare capsules of the compounds of the present invention.
For preparing the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixture can be used as solvent, and appropriate amount of solubilizer, cosolvent, pH regulator, and osmotic pressure regulator commonly used in the art can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable daily dosage range for a compound of the invention is 0.001-5mg/Kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.
The third aspect of the present invention provides a method for preparing the amide compound for modulating WNT signaling pathway and the pharmaceutically acceptable salt thereof, wherein the reaction scheme is as follows: using corresponding succinic anhydride, maleic anhydride, phthalic anhydride, cycloalkyldisuccinic anhydride and cycloalkenyldisuccinic anhydride as starting materials (R1 in the figure), and connecting chain (NH in the figure)2linker-COOH) and then the carboxyl groups of the intermediate linking chain with the corresponding benzidine (A-B-NH in the figure)2) The condensation reaction gives the target product, where the substituted benzidine compounds can be prepared from the corresponding halogenated compounds and borate compounds by metal-catalyzed coupling reactions.
Figure BDA0003277129830000231
The A is selected from:
Figure BDA0003277129830000232
a is connected with B through a carbon-carbon single bond, wherein a dotted line represents connection with an amide nitrogen atom, a wavy line represents connection with B, and R4Selected from substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms3-C8Heterocycloalkyl, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C6-C12Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms2-C12Heteroaryl group, C1-C8Amide group, C1-C8Ester group, carboxyl, cyano, halogen, hydroxyl, amino or nitro, and the substituents are independently selected from C1-C3Alkyl, halogen substituted C1-C3Alkyl radical, C1-C4Alkoxy, carboxyl, cyano, halogen, hydroxyl and nitro, wherein the halogen is selected from F, Cl, Br and I, and the heteroatom is selected from N, O, S and P;
(R4)nrepresents n numbers of R4And n is selected from 1 or 2.
According to one embodiment of the invention, B is selected from:
Figure BDA0003277129830000241
the R is5Selected from substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms3-C8Heterocycloalkyl, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C6-C12Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms2-C12Heteroaryl group, C1-C8Amide group, C1-C8Ester group, carboxyl, cyano, halogen, hydroxyl, amino or nitro, and the substituents are independently selected from C1-C3Alkyl, halogen substituted C1-C3Alkyl radical, C1-C4Alkoxy, carboxyl, cyano, halogen, hydroxyNitro, wherein the halogen is selected from F, Cl, Br and I, and the heteroatom is selected from N, O, S and P;
(R5)nrepresents n numbers of R5And n is selected from 1,2 or 3.
In a fourth aspect of the invention, the invention provides an application of the amide compound for regulating WNT signal pathway and the pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating related diseases caused by WNT signal pathway dysregulation.
The WNT signaling pathway disorder is selected from porcupine protein secretion disorders.
The disease may be selected from, but is not limited to: tumor, cardiovascular and cerebrovascular diseases, metabolic diseases, or neurodegenerative diseases.
The tumor may be selected from, but is not limited to: colon cancer, rectal cancer, pancreatic cancer, gastric cancer, renal cancer, breast cancer, ovarian cancer, lung cancer, prostate cancer, bladder cancer, epithelial cancer, esophageal cancer, cervical cancer, endometrial cancer, adrenal cortical cancer, basal cell carcinoma, adenocarcinoma, bronchial cancer, hepatoma, cholangiocarcinoma, choriocarcinoma, embryonic cancer, leukemia, melanoma, glioma, astrocytoma, medulloblastoma, hodgkin's lymphoma, non-hodgkin's lymphoma, multiple myeloma, or primary brain tumor.
The neurodegenerative disease is selected from, but not limited to: alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, cerebellar atrophy, Huntington's disease, spinal muscular atrophy, Creutzfeldt-Jakob disease.
The metabolic disease is selected from, but not limited to: osteoporosis, diabetes, cystoid macular edema, uveitis-related cystoid macular edema, retinopathy, diabetic retinopathy and retinopathy of prematurity.
The cardiovascular and cerebrovascular diseases are selected from but not limited to: myocardial ischemia, myocardial hypertrophy, heart failure, or ischemic stroke.
The beneficial technical effects are as follows: finds a small molecular compound with positive and negative regulation of WNT signal path, and has the potential function of preventing or treating related diseases caused by abnormal expression of the Wnt signal path, such as tumor, cardiovascular and cerebrovascular diseases, neurodegenerative diseases and metabolic diseases.
Detailed Description 1The radical R in the formula I
“R1Selected from the group consisting of 1-4R2Substituted succinimides, maleimides, phthalimides, cycloalkyldisuccinimides, cycloalkenyldisuccinimides "are intended to denote R1Can be substituted by 1-4R2Substituted, and when substituted by more than 2R2When substituted, the 2 or more R2May be identical, completely different or partially identical to each other. For example, R1Is selected from 3R2In the case of substituted phthalimides, the three R' s2May each be selected, for example, from methyl, for example Cl, or from the group in which two R are present2Selected from, for example, ethyl, another R2Selected from, for example, nitro, and also the three R2Are respectively selected from nitro, methyl and Cl.
"X is selected from the group consisting of 1-3R3Substituted … "" A is selected from the group consisting of substituted by 1-3R4Substituted phenyl or heteroaryl "," B is selected from the group consisting of substituted phenyl or heteroaryl groups substituted with 1-3R5Substituted phenyl or heteroaryl groups "are also to be understood in the same way.
In the present invention, the term "alkyl" refers to a group consisting of carbon hydrogen atoms having the specified number of carbon atoms, which may be a straight-chain or branched alkyl group.
“C1-C8The "alkyl group" refers to a straight-chain or branched alkyl group having 1,2, 3, 4,5, 6, 7, or 8 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, or the like.
“C2-C8The "alkenyl group" means a straight-chain or branched alkenyl group having 2, 3, 4,5, 6, 7, 8 carbon atoms, and the unsaturated double bond may be in any position, for example, an ethenyl group, an ethynyl group, a propenyl group, a propynyl group, a butenyl group, a butynyl group, an isobutenyl group, a pentenyl group, an isopentenyl group, a hexenyl group, a heptenyl group, an octenyl group and the like.
“C2-C8Alkynyl "means a carbon atom number of2.3, 4,5, 6, 7, 8, the unsaturated triple bond may be in any position, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, and the like.
“C3-C8The cycloalkyl group "means a cycloalkyl group having 3, 4,5, 6, 7, 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloalkenyl group or cycloalkynyl group having an unsaturated double bond or triple bond in the above cycloalkyl group.
“C2-C8The heterocyclic hydrocarbon group "means a cyclic hydrocarbon group having 2, 3, 4,5, 6, 7, 8 carbon atoms and substituted with N, O, S, P, Si, B, and includes alkyl, alkenyl or alkynyl groups, the number of heteroatoms is 1,2, 3, 4,5, and the heterocyclic group includes monocyclic and fused ring structures, such as ethylene oxide, azacyclohexane, dihydrofuran, dihydrothiophene, dihydropyrrole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, thiazolidine, piperidine, morpholine, pyran, dihydropyran, tetrahydropyran, dioxane, and groups substituted with the above-mentioned heterocyclic rings, such as tetrahydrofuranyl methyl, dihydrofuranethyl, and the like.
“C1-C8Alkoxy "means a group containing 1,2, 3, 4,5, 6, 7, 8 carbon atoms and substituted by an oxygen atom, such as methoxy, ethoxy, propoxy, isopropoxy, butyloxy, isobutyloxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyloxy, cyclobutyloxy.
“C6-C12Aryl "refers to phenyl, naphthyl and substituted groups at any position of the above groups, such as alkyl-substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenyl, nitro-substituted phenyl, carboxy-substituted phenyl and the corresponding substituted naphthyl.
“C3-C8Heteroaryl "refers to a cyclic aromatic hydrocarbon group having 3, 4,5, 6, 7, 8 carbon atoms and substituted by N, O, S, P, Si, B, the number of heteroatoms is 1,2, 3, 4,5, wherein the heterocyclic group includes monocyclic and fused ring structures, furan, thiophene, pyrrolePyrazine, thiazole, imidazole, oxazole, pyrazole, pyridine, pyrimidine, indole, benzofuran, benzothiophene, benzimidazole, purine and substituted heterocyclic rings, e.g. furylmethyl, furylethyl and the like
When R is2Selected from substituted C1-C8Alkyl radical, C2-C8When alkenyl …, refers to R2May be C substituted by halogen (F, Cl, Br or I), hydroxyl, mercapto, amino, nitro, etc1-C8Alkyl radical, C1-C8Alkenyl ….
For R3、R4、R5Selected from substituted C1-C8Alkyl radical, C1-C8Alkenyl …, also to be reacted with R2The same is understood.
Group X in the formula I
"Arylmethylalkyl" refers to an aryl group substituted with one alkyl group, which may be, for example, C6-C12Aryl radical C1-C6Alkyl, that is, aryl having 6, 7, 8, 9, 10, 11, or 12 carbon atoms substituted with an alkyl having 1,2, 3, 4,5, or 6 carbon atoms, such as benzyl, phenethyl, phenylpropyl, phenylisopropyl, phenylbutyl, phenylpentyl, phenylhexyl, naphthylbenzyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphthylhexyl, and the like.
"Aryldialkyl" refers to an aryl group substituted with two alkyl groups, which may be, for example, C1-C6Alkyl radical C6-C12Aryl radical C1-C6Alkyl, i.e. aryl having 6, 7, 8, 9, 10, 11 or 12 carbon atoms substituted with two alkyl groups having 1,2, 3, 4,5 or 6 carbon atoms, such as phenyl-1, 2 dimethyl, phenyl-1, 3 dimethyl, phenyl-1, 4 dimethyl, phenyl-1-methyl-2-benzyl, phenyl-1-methyl-4-ethyl and the like.
When X is selected from aryl, the aryl group may be ortho to R1The amide group may be bonded to each other in a meta-position or a para-position. The same should be understood when X is selected from aryl monoalkyl or from aryl dialkyl.
"cycloalkyl-monoalkyl" refers to a cycloalkyl group substituted with one alkyl group, which can be, for example, C3-C6Cycloalkyl radical C1-C6Alkyl, i.e. cycloalkyl having 3, 4,5 or 6 carbon atoms substituted by alkyl having 1,2, 3, 4,5 or 6 carbon atoms, and may be, for example, C3-C6Cycloalkyl radical C1-C3Alkyl radicals, e.g. by C1-C6Alkyl-substituted cyclohexyl radical, substituted by C1-C3Alkyl-substituted cyclohexyl groups such as methylcyclohexane, ethylcyclohexane, propylcyclohexane, methylcyclopentane, and the like.
"cycloalkyldialkyl" refers to a cycloalkyl group substituted with two alkyl groups, which may be, for example, C1-C6Alkyl radical C3-C6Cycloalkyl radical C1-C6Alkyl, i.e. cycloalkyl having 3, 4,5 or 6 carbon atoms substituted by two alkyl groups having 1,2, 3, 4,5 or 6 carbon atoms, e.g. may be C1-C3Alkyl radical C3-C6Cycloalkyl radical C1-C3Alkyl radicals, e.g. by two C1-C6Cyclohexyl substituted by alkyl, by two C1-C3Alkyl-substituted cyclohexyl groups such as methylethylcyclohexane, diethylcyclohexane, methylpropylcyclohexane, dimethylcyclopentane and the like.
When the group X is selected from unsubstituted or substituted by 1 to 3R3Substituted C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6When a cycloalkyl group is present, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6The cycloalkyl group should be as defined in [ alpha ], [ alpha ] and [ alpha ], [ alpha ] and [ alpha ] an 1The radical R in the formula I]Similar/identical terms in parts are understood similarly/identically.
When X is selected from cycloalkyl, the cycloalkyl may be ortho to R1The amide group may be bonded to each other in a meta-position or a para-position. The same should be understood when X is selected from cycloalkylmonoalkyl or from cycloalkyldialkyl. Likewise, for R2、R3、R4And R5The specification of a specific group selected from the group consisting of 1The radical R in the formula I]Similar/identical terms in parts are understood similarly/identically.
Group A, B in formula I
"A and B constitute a bi-aromatic or fused ring structure" is understood in the present invention as follows: a.A and B are directly linked by one atom in each structure to form a bi-aromatic structure, b.A and B are bonded by one carbon-carbon bond in each structure to form a fused ring structure, and c. further linked by an alkylene bridge (e.g., methylene bridge, ethylene bridge, propylene bridge, etc.), oxygen bridge, nitrogen bridge, sulfur bridge, carbonyl bridge, etc. in the case of a or B to form a fused ring structure comprising at least three rings. The "alkylene bridge" may be, for example, a methylene bridge, an ethylene bridge, a propylene bridge or the like.
Examples of the type of case a are: a is selected from phenyl, B is selected from phenyl, and finally a biphenyl structure is formed; a is selected from pyridine, B is selected from phenyl, and finally forms a structure of pyridyl biphenyl (pyridine can be connected with phenyl at 2 position, 3 position or 4 position); b is selected from pyridine, A is selected from phenyl, and finally the structure of phenyl bipyridyl is formed.
Examples of the type of case b: a is selected from triazolyl, B is selected from pyridyl, and finally the structure of the triazole pyridine is formed.
Examples of the type of case c: a is selected from phenyl and B is selected from phenyl, which are further connected through a methylene bridge, a carbonyl bridge or an ethylene bridge on the basis of the biphenyl structure type forming the situation a to obtain C6-C5-C6Or C6-C6-C6Such a structure.
For R4、R5The specification of a specific group selected from the group consisting of 1The radical R in the formula I]Similar/identical terms in parts are understood similarly/identically.
“(R2)nRepresents n numbers of R2Substituted, n is selected from 1,2 or 3' and means that 1 in the compound,2 or 3 substituents R2And when there are more than 2R in the compound2When the number of R is 2 or more2May be identical, completely different or partially identical to each other.
For (R)4)n、(R5)nShould also be taken as being (R)2)nThe same is understood.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention.
Example 1:
Figure BDA0003277129830000271
succinic anhydride (200mg, 2.0mmol) and 4-aminobutyric acid (206mg, 2.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for reaction for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 400mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 95.5%.
The intermediate compound (400mg, 1.93mmol) and HATU (960mg, 2.52mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (394. mu.L, 2.92mmol) was added dropwise, stirring was continued for 10min at room temperature, 2-aminopyridine (330mg, 1.94mmol) was added, and the reaction was carried out at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate 20:1-10:1 gradient elution) to obtain 510mg of white solid with yield of 68.1%. HR ESI-MS (m/z): 338.1505[ M + H]+。
Example 2
Figure BDA0003277129830000281
3-Fluorophthalic anhydride (332mg, 2.0mmol) and 4-aminobutyric acid (206mg, 2.0mmol) were added to glacial acetic acid (10mL), and heated to 100 ℃ for reaction for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 370mg, LC-MS and1H-NMR confirmed it to be the expected intermediate compound in 73.5% yield.
The intermediate compound (370mg, 1.47mmol) and HATU (730mg, 1.92mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (300. mu.L, 2.22mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (251mg, 1.47mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at 20:1-10: 1) to obtain white solid 245mg with yield of 40.5%.
HR ESI-MS(m/z)：404.1399[M+H]+。1H NMR(500MHz,DMSO-d6)δ10.53(s,1H),8.60(dd,J＝2.2,1.1Hz,1H),8.10–7.99(m,2H),7.92(dd,J＝8.2,4.5Hz,1H),7.74(dd,J＝7.5,2.3Hz,1H),7.71–7.67(m,2H),7.63(ddd,J＝9.4,8.2,2.4Hz,1H),7.47(t,J＝7.7Hz,2H),7.42–7.32(m,1H),3.64(t,J＝6.7Hz,2H),2.45(t,J＝7.3Hz,2H),1.94(p,J＝7.0Hz,2H).
Example 3
Figure BDA0003277129830000282
4-Fluorophthalic anhydride (332mg, 2.0mmol) and 4-aminobutyric acid (206mg, 2.0mmol) were added to glacial acetic acid (10mL), and heated to 100 ℃ for reaction for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 370mg, LC-MS and1H-NMR confirmationIt was the expected intermediate compound in 73.5% yield.
The intermediate compound (370mg, 1.47mmol) and HATU (730mg, 1.92mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (300. mu.L, 2.22mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (251mg, 1.47mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (gradient elution with mobile phase petroleum ether/ethyl acetate of 20:1-10: 1) to obtain white solid 240mg with yield of 40.3%. HR ESI-MS (m/z): 404.1399[ M + H]+。1H NMR(500MHz,DMSO-d6)δ10.53(s,1H),8.60(dd,J＝2.2,1.1Hz,1H),8.10–7.99(m,2H),7.92(dd,J＝8.2,4.5Hz,1H),7.74(dd,J＝7.5,2.3Hz,1H),7.71–7.67(m,2H),7.63(ddd,J＝9.4,8.2,2.4Hz,1H),7.47(t,J＝7.7Hz,2H),7.42–7.32(m,1H),3.64(t,J＝6.7Hz,2H),2.45(t,J＝7.3Hz,2H),1.94(p,J＝7.0Hz,2H).
Example 4
Figure BDA0003277129830000291
4-chlorophthalic anhydride (362mg, 2.0mmol) and 4-aminobutyric acid (206mg, 2.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 460mg, LC-MS and1H-NMR confirmed it to be the expected intermediate compound in 86.4% yield.
The intermediate compound (460mg, 1.72mmol) and HATU (854mg, 2.25mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (360. mu.L, 2.58mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (293mg, 1.72mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, and spin-drying the filtrate to obtain brown oily substance; dissolving a small amount of dichloromethane, and filtering to obtain a white solid; and (3) spin-drying the filtrate again, dissolving the filtrate in ethyl acetate, cooling the solution for 2 hours at low temperature, and performing suction filtration to obtain a light yellow solid, wherein the weight of the light yellow solid is about 400mg after drying, and the yield is 55.1%.
HR ESI-MS(m/z)：420.1104[M+H]+，1H NMR(500MHz,DMSO-d6)δ10.52(s,1H),8.66–8.55(m,1H),8.08–7.98(m,2H),7.91(t,J＝1.2Hz,1H),7.85(d,J＝1.2Hz,2H),7.72–7.66(m,2H),7.47(t,J＝7.7Hz,2H),7.42–7.35(m,1H),3.64(t,J＝6.7Hz,2H),2.45(t,J＝7.3Hz,2H),1.94(p,J＝7.0Hz,2H).
Example 5
Figure BDA0003277129830000292
4-Bromophthalic anhydride (450mg, 2.0mmol) and 4-aminobutyric acid (206mg, 2.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 600mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 96.7%.
The intermediate compound (600mg, 1.93mmol) and HATU (954mg, 2.51mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (405. mu.L, 2.90mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (328mg, 1.93mmol) was added, and the reaction was carried out at room temperature for 24 h. Filtering, removing inorganic salt filter residue, and spin-drying the filtrate to obtain brown oily substance; dissolving a small amount of dichloromethane, and filtering; spin-dry the filtrate again, hot-dissolve with ethyl acetate, cool for 2h at low temperature, suction filter to obtain a pale yellow solid, dry weigh about 495mg, yield 55.1% HR ESI-MS (m/z): 464.0606[ M + H]+。
1H NMR(500MHz,DMSO-d6)δ10.51(s,1H),8.60(t,J＝1.7Hz,1H),8.04–8.01(m,3h),7.99(dd,J＝7.9,1.7Hz,1H),7.77(d,J＝7.9Hz,1H),7.73–7.64(m,2H),7.47(t,J＝7.7Hz,2H),7.41–7.35(m，1H),3.64(t，J＝6.7Hz,2H),2.45(t,J＝7.3Hz,2H),1.94(p,J＝7.0Hz,2H).
Example 6
Figure BDA0003277129830000301
4-Nitrophthalic anhydride (386mg, 2.0mmol) and 4-aminobutyric acid (206mg, 2.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for reaction for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 572mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 96.7%.
The intermediate compound (572mg, 1.93mmol) and HATU (954mg, 2.51mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (405. mu.L, 2.90mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (328mg, 1.93mmol) was added, and the reaction was carried out at room temperature for 24 h. Filtering, removing inorganic salt filter residue, and spin-drying the filtrate to obtain brown oily substance; dissolving a small amount of dichloromethane, and filtering; and (3) spin-drying the filtrate again, dissolving the filtrate in ethyl acetate, cooling the solution for 2 hours at low temperature, and performing suction filtration to obtain a light yellow solid, wherein the weight of the light yellow solid is about 500mg after drying, and the yield is 58.4%. HR ESI-MS (m/z): 431.1310[ M + H]+。
1H NMR(500MHz,DMSO-d6)δ10.52(s,1H),8.63–8.55(m,2H),8.44(d,J＝2.0Hz,1H),8.09(d，J＝8.1Hz,1H),7.99(d,J＝1.7Hz,2H),7.67(dd,J＝7.5，1.7Hz,2H),7.47(t,J＝7.7Hz，2H),7.38(t,J＝7.3Hz,1H),3.69(t,J＝6.7Hz,2H),2.46(d,J＝7.2Hz,2H),1.98(p,J＝7.0Hz,2H).
Example 7
Figure BDA0003277129830000302
4, 5-Dichlorophthalic anhydride (430mg, 2.0mmol) and 4-aminobutyric acid (206mg, 2.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for reaction for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate, and dryingThis gave 576mg of a yellow solid, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 96.0%.
The intermediate compound (576mg, 1.92mmol) and HATU (950mg, 2.50mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (400. mu.L, 2.89mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (324mg, 1.92mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, and spin-drying the filtrate to obtain brown oily substance; dissolving a small amount of dichloromethane, and filtering; the filtrate was again spin dried, hot dissolved in ethyl acetate, cooled for 2h at low temperature, filtered to give a pale yellow solid, dried and weighed about 594mg, with a yield of 68.2%. HR ESI-MS (m/z): 454.0695[ M + H]+。1H NMR(500MHz,DMSO-d6)δ10.51(s,1H),8.60(t,J＝1.7Hz,1H),8.13(s,2H),8.00(d,J＝2.1Hz,2H),7.72–7.65(m,2H),7.47(dd,J＝8.4,7.0Hz,2H),7.43–7.34(m,1H),3.65(t,J＝6.7Hz,2H),2.45(t,J＝7.2Hz,2H),1.95(p,J＝7.0Hz,2H).
Example 8
Figure BDA0003277129830000311
Tetrachlorophthalic anhydride (566mg, 2.0mmol) and 4-aminobutyric acid (206mg, 2.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for reaction for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 726mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 98.7%.
The intermediate compound (726mg, 1.97mmol) and HATU (975mg, 2.57mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (400. mu.L, 2.96mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (335mg, 1.97mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, and spin-drying the filtrate to obtain brown oily substance; dissolving a small amount of dichloromethane, and filtering; spin-drying the filtrate again, dissolving with ethyl acetate, cooling for 2 hr, and vacuum filtering to obtain light yellow solidThe dry weight of the product was 718mg, yielding 69.0%. HR ESI-MS (m/z): 524.1623[ M + H]+。1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.59(s,1H),7.99(s,2H),7.68(d,J＝7.6Hz,2H),7.47(t,J＝7.6Hz,2H),7.38(q,J＝7.5Hz,1H),3.66(t,J＝6.6Hz,2H),1.76(p,J＝7.3Hz,2H).
Example 9
Figure BDA0003277129830000312
4-Methylphthalic anhydride (490mg, 3.0mmol) and 4-aminobutyric acid (320mg, 3.1mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 700mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 93.7%. The intermediate compound (700mg, 2.81mmol) and HATU (1.4g, 3.65mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (580. mu.L, 4.22mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (484mg, 2.81mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at 20:1-10: 1) to obtain 573mg of white solid with yield of 50.5%.
HR ESI-MS(m/z)：400.1665[M+H]+。1H NMR(500MHz,DMSO-d6)δ10.52(s,1H),8.60(dd,J＝2.2,1.0Hz,1H),8.09–7.98(m,2H),7.73(d,J＝7.6Hz,1H),7.71–7.67(m,2H),7.67–7.65(m,1H),7.60(dt,J＝7.6,1.1Hz,1H),7.47(dd,J＝8.4,7.0Hz,2H),7.41–7.34(m,1H),3.62(t,J＝6.7Hz,2H),2.45(s,3H),2.43(d,J＝7.3Hz,2H),1.93(p,J＝7.0Hz,2H).
Example 10
Figure BDA0003277129830000321
4-Isobutylphthalic anhydride (500mg, 2.45mmol) and 4-aminobutyric acid (260mg, 2.5mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for reaction for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 620mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in 87.5% yield.
The intermediate compound (620mg, 2.14mmol) and HATU (1.178g, 2.79mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (470. mu.L, 3.21mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (370mg, 2.15mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at 20:1-10: 1) to obtain 573mg of white solid with yield of 50.5%.
HR ESI-MS(m/z)：442.2141[M+H]+1H NMR(500MHz,DMSO-d6)δ10.53(d,J＝15.1Hz,1H),8.63–8.56(m,1H),8.07–7.96(m,2H),7.86–7.75(m,2H),7.71–7.65(m,2H),7.47(td,J＝7.8,2.2Hz,2H),7.37(tt,J＝6.7,1.4Hz,1H),3.65(dt,J＝13.0,6.6Hz,2H),2.48–2.39(m,2H),2.02–1.89(m,2H),1.32(s,6H).
Example 11
Figure BDA0003277129830000322
4-Alkynylphenylphthalic anhydride (500mg, 2.0mmol) and 4-aminobutyric acid (206mg, 2.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 608mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 91.2%.
The intermediate compound (608mg, 1.82mmol) and HATU (907mg, 2.37mmol) were dissolvedTriethylamine (373. mu.L, 2.73mmol) was added dropwise to anhydrous dichloromethane (10ml), and after stirring at room temperature for 10min, 2-aminopyridine (313mg, 1.82mmol) was added and reacted at room temperature for 48 h. Filtering, removing inorganic salt filter residue, and spin-drying the filtrate to obtain brown oily substance; dissolving a small amount of dichloromethane, and filtering; the filtrate was again spin dried, hot dissolved in ethyl acetate, cooled for 2h at low temperature, filtered to give a pale yellow solid, dried and weighed about 304mg, yield 33.6%. HR ESI-MS (m/z): 486.1828[ M + H]+。1H NMR(500MHz,DMSO-d6)δ10.53(s,1H),8.60(t,J＝1.6Hz,1H),8.05–7.97(m,2H),7.96–7.92(m,2H),7.90–7.86(m,1H),7.71–7.66(m,2H),7.63–7.58(m,2H),7.45(dddd,J＝15.3,7.9,5.5,2.2Hz,5H),7.39–7.32(m,1H),3.66(t,J＝6.7Hz,2H),2.46(t,J＝7.2Hz,2H),1.97(q,J＝6.9Hz,2H).
Example 12
Figure BDA0003277129830000331
3-cyanophthalic anhydride (500mg, 2.0mmol) and 4-aminobutyric acid (206mg, 2.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 608mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 91.2%.
The intermediate compound (608mg, 1.82mmol) and HATU (907mg, 2.37mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (373. mu.L, 2.73mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (313mg, 1.82mmol) was added and reacted at room temperature for 48 h. Filtering, removing inorganic salt filter residue, and spin-drying the filtrate to obtain brown oily substance; dissolving a small amount of dichloromethane, and filtering; the filtrate was again spin dried, hot dissolved in ethyl acetate, cooled for 2h at low temperature, filtered to give a pale yellow solid, dried and weighed about 304mg, yield 33.6%. HR ESI-MS (m/z): 411.1457[ M + H]+。
Example 13
Figure BDA0003277129830000332
3-Nitrophthalic anhydride (386mg, 2.0mmol) and 4-aminobutyric acid (206mg, 2.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for reaction for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 570mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 96.5%.
The intermediate compound (570mg, 1.93mmol) and HATU (954mg, 2.51mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (405. mu.L, 2.90mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (328mg, 1.93mmol) was added, and the reaction was carried out at room temperature for 24 h. Filtering, removing inorganic salt filter residue, and spin-drying the filtrate to obtain brown oily substance; dissolving a small amount of dichloromethane, and filtering; the filtrate was again spin dried, hot dissolved in ethyl acetate, cooled for 2h at low temperature, filtered to give a pale yellow solid, dried and weighed about 490mg, yield 57.5%. HR ESI-MS (m/z): 431.1360[ M + H]+。1H NMR(500MHz,DMSO-d6)δ10.53(s,1H),8.60(dd,J＝2.3,1.1Hz,1H),8.25(dd,J＝8.1,0.9Hz,1H),8.15(dd,J＝7.5,0.9Hz,1H),8.08–7.96(m,3H),7.77–7.65(m,2H),7.47(t,J＝7.7Hz,2H),7.42–7.33(m,1H),3.65(t,J＝6.7Hz,2H),2.47(t,J＝7.3Hz,2H),1.95(p,J＝7.1Hz,2H).
Example 14
Figure BDA0003277129830000341
3-Methylphthalic anhydride (490mg, 3.0mmol) and 4-aminobutyric acid (320mg, 3.1mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, and drying with anhydrous sodium sulfateDrying to obtain yellow solid 686mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 91.8%.
The intermediate compound (686mg, 2.75mmol) and HATU (1.4g, 3.65mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (580. mu.L, 4.22mmol) was added dropwise, stirring was carried out at room temperature for 10min, 2-aminopyridine (484mg, 2.81mmol) was added, and the reaction was carried out at room temperature for 24 h. Filtering, removing inorganic salt residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase petroleum ether/ethyl acetate of 20:1-10: 1) to obtain white solid 564mg with yield of 50.5%. HR ESI-MS (m/z): 400.1648[ M + H]+1H NMR(500MHz,DMSO-d6)δ10.53(s,1H),8.60(dd,J＝2.3,1.0Hz,1H),8.13–7.98(m,2H),7.73–7.63(m,4H),7.61–7.54(m,1H),7.47(t,J＝7.7Hz,2H),7.41–7.35(m,1H),3.62(t,J＝6.7Hz,2H),2.45(t,J＝7.3Hz,2H),1.93(p,J＝7.0Hz,2H).
Example 15
Figure BDA0003277129830000342
3, 6-Difluorophthalic anhydride (368mg, 2.0mmol) and 4-aminobutyric acid (210mg, 2.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 365mg, LC-MS and1H-NMR confirmed it to be the expected intermediate compound in a yield of 72.6%.
The intermediate compound (365mg, 1.45mmol) and HATU (720mg, 1.89mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (300. mu.L, 2.18mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (250mg, 1.45mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at 20:1-10: 1) to obtain white solid 232mg with yield of 40.1%.
HR ESI-MS(m/z)：422.1313[M+H]+。1H NMR(500MHz,DMSO-d6)δ10.54(s,1H),8.60(dd,J＝2.4,1.0Hz,1H),8.12–7.99(m,2H),7.76–7.64(m,4H),7.47(t,J＝7.7Hz,2H),7.42–7.33(m,1H),3.60(t,J＝6.7Hz,2H),2.46(t,J＝7.3Hz,2H),1.93(p,J＝7.0Hz,2H).
Example 16
Figure BDA0003277129830000351
3, 6-Difluorophthalic anhydride (368mg, 2.0mmol) and 4-aminobutyric acid (210mg, 2.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 365mg, LC-MS and1H-NMR confirmed it to be the expected intermediate compound in a yield of 72.6%.
The intermediate compound (365mg, 1.45mmol) and HATU (720mg, 1.89mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (300. mu.L, 2.18mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (250mg, 1.45mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at 20:1-10: 1) to obtain white solid 232mg with yield of 40.1%.
HR ESI-MS(m/z)：422.1293[M+H]+。1H NMR(500MHz,DMSO-d6)δ10.53(s,1H),8.60(t,J＝1.6Hz,1H),8.14–7.97(m,4H),7.75–7.63(m,2H),7.48(t,J＝7.7Hz,2H),7.42–7.33(m,1H),3.64(t,J＝6.7Hz,2H),2.45(t,J＝7.2Hz,2H),1.95(q,J＝7.0Hz,2H).
Example 17
Figure BDA0003277129830000352
Phthalic anhydride (450mg, 3.0mmol) and4-Aminobenzoic acid (415mg, 3.0mmol) was added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 750mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 94.3%.
The intermediate compound (750mg, 2.83mmol) and HATU (1180mg, 3.68mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (482. mu.L, 3.57mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (481mg, 2.83mmol) was added, and the reaction was carried out at room temperature for 18 h. Filtering, removing inorganic salt filter residue, spin-drying the filtrate to obtain an oily substance, dissolving with dichloromethane, filtering, and spin-drying the filtrate to obtain an oily substance; ethyl acetate is dissolved thermally, cooled for 2h at low temperature and filtered to obtain white solid, which is dried and weighed to be 560mg, and the yield is 47.3%.
HR ESI-MS(m/z)：420.1339[M+H]+。1H NMR(500MHz,DMSO-d6)δ11.07(s,1H),8.75(dd,J＝2.6,0.8Hz,1H),8.33(dd,J＝8.6,0.8Hz,1H),8.22–8.15(m,3H),8.01(dd,J＝5.4,3.0Hz,2H),7.94(td,J＝5.2,2.1Hz,2H),7.83–7.73(m,2H),7.67–7.59(m,2H),7.51(t,J＝7.7Hz,2H),7.47–7.38(m,1H).
Example 18
Figure BDA0003277129830000361
Phthalic anhydride (450mg, 3.0mmol) and 3-aminobenzoic acid (415mg, 3.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 746mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 94.3%.
The intermediate compound (746mg, 2.83mmol) and HATU (1180mg, 3.68mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (482. mu.L, 3.57mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (481mg, 2.83mmol) was added, and the reaction was carried out at room temperature for 18 h. Filtering, removing inorganic salt filter residue, spin-drying the filtrate to obtain an oily substance, dissolving with dichloromethane, filtering, and spin-drying the filtrate to obtain an oily substance; ethyl acetate is dissolved thermally, cooled for 2h at low temperature and filtered to obtain white solid, which is weighed as 547mg after being dried, and the yield is 46.7%.
HR ESI-MS(m/z)：420.1317[M+H]+。1H NMR(500MHz,DMSO-d6)δ11.04(s,1H),8.74(dd,J＝2.5，0.8Hz,1H),8.30(dd,J＝8.6,0.8Hz,1H),8.22–8.10(m,3H),8.01(dd,J＝5.5,3.1Hz,2H),7.96–7.90(m,2H),7.80–7.73(m,2H),7.72–7.64(m,2H),7.50(dd,J＝8.4,7.0Hz,2H),7.44–7.37(m,1H).
Example 19
Figure BDA0003277129830000362
Phthalic anhydride (450mg, 3.0mmol) and 4-aminophenylacetic acid (460mg, 3.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 835mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 99.0%.
The intermediate compound (835mg, 2.97mmol) and HATU (1391mg, 3.86mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (582. mu.L, 4.46mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (505mg, 2.97mmol) was added and reacted at room temperature for 18 h. Filtering, removing inorganic salt filter residue, spin-drying the filtrate to obtain an oily substance, dissolving with dichloromethane, filtering, and spin-drying the filtrate to obtain an oily substance; ethyl acetate was dissolved hot and cooled to precipitate a white solid, which was dried and weighed 600mg, giving a yield of 47.4%.
1H NMR(500MHz,DMSO-d6)δ10.91(s,1H),8.67(dd,J＝2.4,0.9Hz,1H),8.16(d,J＝8.7Hz,1H),8.10(dd,J＝8.7,2.5Hz,1H),8.08–8.04(m,2H),7.73–7.69(m,2H),7.54(dd,J＝3.0,1.7Hz,2H),7.48(d,J＝3.2Hz,2H),7.47(d,J＝2.6Hz,2H),7.40–7.38(m,1H),7.36(dd,J＝8.7,2.2Hz,2H),3.82(s,2H).
Example 20
Figure BDA0003277129830000371
Phenylmaleic anhydride (522mg, 3.0mmol) and 3-aminobenzoic acid (415mg, 3.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 820mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 93.2%. The intermediate compound (820mg, 2.80mmol) and HATU (1180mg, 3.64mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (482. mu.L, 3.57mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (481mg, 2.83mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, spin-drying the filtrate to obtain an oily substance, dissolving with dichloromethane, filtering, and spin-drying the filtrate to obtain an oily substance; ethyl acetate was dissolved hot and cooled to precipitate a white solid, which was dried and weighed 600mg, with a yield of 46.2%. HR ESI-MS (m/z): 446.1480[ M + H]+。1H NMR(500MHz,DMSO-d6)δ11.01(s,1H),8.74(s,1H),8.32(d,J＝8.6Hz,1H),8.18(t,J＝7.2Hz,3H),8.08(d,J＝6.4Hz,2H),7.76(d,J＝7.5Hz,2H),7.61–7.47(m,8H),7.41(t,J＝7.6Hz,1H).
Example 21
Figure BDA0003277129830000372
Phenylmaleic anhydride (522mg, 3.0mmol) and 4-aminobenzoic acid (415mg, 3.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, water and thenAnd the organic phase was dried over anhydrous sodium sulfate to give 817mg of a yellow solid, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 93.0%.
The intermediate compound (817mg, 2.80mmol) and HATU (1180mg, 3.64mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (482. mu.L, 3.57mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (481mg, 2.83mmol) was added, and the reaction was carried out at room temperature for 24 h. Filtering, removing inorganic salt filter residue, spin-drying the filtrate to obtain an oily substance, dissolving with dichloromethane, filtering, and spin-drying the filtrate to obtain an oily substance; ethyl acetate was dissolved hot and cooled to precipitate a white solid, which was dried and weighed 610mg, giving a yield of 47.0%. HR ESI-MS (m/z): 446.1476[ M + H]+1H-NMR(500MHz,DMSO-d6)δ11.01(s，1H),8.73(s,1H),8.31(d,J＝8.6Hz,1H),8.18(t,J＝7.6Hz,3H),8.08(s,2H),7.76(d,J＝7.6Hz,2H),7.57(d，J＝18.7Hz,5H),7.50(d,J＝5.0Hz，3H),7.41(t,J＝7.4Hz,1H).
Example 22
Figure BDA0003277129830000381
Phenylmaleic anhydride (522mg, 3.0mmol) and 4-aminophenylacetic acid (453mg, 3.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 860mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 93.3%.
The intermediate compound (860mg, 2.80mmol) and HATU (1180mg, 3.64mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (482. mu.L, 3.57mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (481mg, 2.83mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (gradient elution with mobile phase petroleum ether/ethyl acetate of 20:1-10: 1) to obtain two white solids, wherein desired target product is 496mg, and yield is 39.8%; another white solid is byproduct 23.
HR ESI-MS(m/z)：460.1647[M+H]+，1H NMR(500MHz,DMSO-d6)δ10.88(s,1H),8.66(s,1H),8.16(d,J＝8.7Hz,1H),8.10(d,J＝8.6Hz,1H),8.06(d,J＝5.6Hz,2H),7.71(d,J＝7.8Hz,2H),7.56–7.52(m,3H),7.47(dd,J＝10.9,7.0Hz,5H),7.37(dd,J＝16.8,7.9Hz,3H),3.83(s,2H).
Example 23
Figure BDA0003277129830000382
HR ESI-MS(m/z)：412.1046[M+H]+。
Example 24
Figure BDA0003277129830000391
Phenylmaleic anhydride (520mg, 3.0mmol) and 4-aminobutyric acid (310mg, 3.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for reaction for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain a yellow solid 690mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 94.8%.
The intermediate compound (690mg, 2.83mmol) and HATU (1180mg, 3.64mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (482. mu.L, 3.57mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (481mg, 2.83mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate gradient elution at 20:1-10: 1), drying, weighing 547mg, and obtaining 47.1% yield. HR ESI-MS (m/z): 412.1625[ M + H]+，1H NMR(500MHz,DMSO-d6)δ10.68(s,1H),8.47(d,J＝2.5Hz,1H),7.97(d,J＝8.6Hz,1H),7.90(dd,J＝8.8,2.5Hz,1H),7.52(d，J＝7.7Hz,2H),7.30–7.25(m,4H),7.19(q,J＝7.3,6.8Hz,3H),7.02(dd，J＝12.6,7.7Hz,4H),3.44(d,J＝3.0Hz,2H),2.31(s,4H).
Example 25
Figure BDA0003277129830000392
Succinic anhydride (200mg, 2.0mmol) and 3-aminobenzoic acid (275mg, 2.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 350mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 82.1%.
The intermediate compound (350mg, 1.64mmol) and HATU (810mg, 2.14mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (332. mu.L, 2.46mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate 20:1-10:1 gradient elution) to obtain white solid 240mg, and obtaining yield 39.4%. HR ESI-MS (m/z): 372.1331[ M + H]+。1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),8.73(s,1H),8.32–8.23(m,3H),8.21–8.11(m,2H),7.65(d,J＝7.8Hz,3H),7.50(d,J＝7.7Hz,4H),7.41(d,J＝7.4Hz,2H),7.03(d,J＝9.7Hz,1H).
Example 26
Figure BDA0003277129830000401
Maleic anhydride (200mg, 2.0mmol) and 4-aminobenzoic acid (275mg, 2.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate, and dryingThen 353mg of yellow solid, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 82.1%.
The intermediate compound (353mg, 1.64mmol) and HATU (810mg, 2.14mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (332. mu.L, 2.46mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at 20:1-10: 1) to obtain white solid 200mg with yield of 32.8%. HR ESI-MS (m/z): 370.1192[ M + H]+。1H NMR(500MHz,DMSO-d6)δ11.05(s,1H),8.77–8.71(m,1H),8.34–8.27(m,1H),8.18(dd,J＝8.7,2.5Hz,1H),8.13(dt,J＝7.9,1.3Hz,1H),7.96(t,J＝1.9Hz,1H),7.78–7.72(m,3H),7.70–7.62(m,2H),7.53–7.48(m,3H),7.44–7.38(m,1H).
Example 27
Figure BDA0003277129830000402
Succinic anhydride (200mg, 2.0mmol) and 4-aminophenylacetic acid (300mg, 2.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 373mg, LC-MS and1H-NMR confirmed it to be the expected intermediate compound in 81.1% yield.
The intermediate compound (373mg, 1.62mmol) and HATU (810mg, 2.14mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (332. mu.L, 2.46mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate 20:1-10:1 gradient elution) to obtain 281mg of white solid with yield of 45.0%. HR ESI-MS (m/z): 386.1520[ M + H]+。1H NMR(500MHz,DMSO-d6)δ10.90(s,1H),8.66(dd,J＝2.5,0.8Hz,1H),8.20–8.05(m,2H),7.76–7.66(m,2H),7.50–7.44(m,4H),7.41–7.34(m,3H),7.24–7.17(m,3H),3.81(s,2H).
Example 28
Figure BDA0003277129830000411
Maleic anhydride (200mg, 2.0mmol) and 4-aminobutyric acid (210mg, 2.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for reaction for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 222mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 61.0%.
The intermediate compound (222mg, 1.22mmol) and HATU (605mg, 1.59mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (246. mu.L, 1.83mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (210mg, 1.23mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (gradient elution with mobile phase petroleum ether/ethyl acetate of 20:1-10: 1) to obtain white solid 134mg with yield of 32.8%. HR ESI-MS (m/z): 336.1340[ M + H]+。1H NMR(500MHz,DMSO-d6)δ10.55(s,1H),8.62(dd,J＝2.5,0.8Hz,1H),8.19–8.04(m,2H),7.72–7.63(m,2H),7.48(t,J＝7.7Hz,2H),7.38(t,J＝7.4Hz,1H),7.01(d,J＝9.1Hz,2H),3.46(t,J＝6.9Hz,2H),2.40(t,J＝7.4Hz,2H),1.82(p,J＝7.1Hz,2H).
Example 29:
Figure BDA0003277129830000412
maleic anhydride (200mg, 2.0mmol) and 4-aminophenylacetic acid (300mg, 2.0mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL),NaOH solution (0.1mol/L) is used for adjusting the pH value of the solution to 6-8. Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 380mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 82.0%.
The intermediate compound (380mg, 1.64mmol) and HATU (810mg, 2.14mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (332. mu.L, 2.46mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at 20:1-10: 1) to obtain white solid 314mg with yield of 50.0%. HR ESI-MS (m/z): 384.1334[ M + H]+1H NMR(500MHz,DMSO-d6)δ10.90(s,1H),8.66(d,J＝2.6Hz,1H),8.17–8.13(m,1H),8.09(dt,J＝8.7,2.7Hz,1H),7.75–7.68(m,3H),7.50–7.43(m,4H),7.38(t,J＝7.4Hz,1H),7.32–7.26(m,2H),7.18(s,2H),3.81(s,2H).
Example 30
Figure BDA0003277129830000413
(3aR,4R,7R,7aS) -5-methyl-3a,4,7,7a-tetrahydro-4,7-methano benzofuranone-1, 3-dione (360mg, 2.0mmol) and 3-aminobenzoic acid (280mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for reaction for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing the solution with water, mixing the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 487mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 82.1%.
The intermediate compound (365mg, 1.64mmol) and HATU (810mg, 2.14mmol) were dissolved in anhydrous dichloromethane (10ml) and triethylamine (332. mu.L, 2.46mmol) was added dropwise, followed by stirring at room temperature for 10min, followed by addition of 2-aminopyridine (280mg, 1.64mmol) and reaction at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase petroleum ether/ethyl acetate of 20:1-10: 1) to obtain white solid 226mg with yield of 39.6%.
HR ESI-MS(m/z)：450.1818[M+H]+。1H NMR(500MHz,DMSO-d6)δ11.01(s,1H),8.74(d,J＝2.5Hz,1H),8.30(d,J＝8.7Hz,1H),8.24–8.09(m,2H),8.04–7.96(m,1H),7.76(d,J＝7.5Hz,2H),7.66(t,J＝7.8Hz,1H),7.57–7.46(m,4H),7.41(t,J＝7.3Hz,1H),3.17(t,J＝4.8Hz,2H),1.88–1.77(m,5H)，1.44(dd,J＝8.8,4.4Hz,2H).
Example 31:
Figure BDA0003277129830000421
(3aR,4R,7R,7aS) -5-methyl-3a,4,7,7a-tetrahydro-4,7-methano zofuran-1,3-dione (360mg, 2.0mmol) and 4-aminobutyric acid (210mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid, and heated to 80 ℃ for reaction for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing the solution with water, combining the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 392mg, LC-MS and1H-NMR confirmed it to be the expected intermediate compound in 74.6% yield.
The intermediate compound (392mg, 1.49mmol) and HATU (736mg, 1.94mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (332. mu.L, 2.46mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (300mg, 2.24mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (gradient elution with mobile phase petroleum ether/ethyl acetate of 20:1-10: 1) to obtain white solid 240mg with yield 38.5%. HR ESI-MS (m/z): 415.1896[ M + H]+。1H NMR(500MHz,DMSO-d6)δ10.52(s,1H),8.60(d,J＝2.5Hz,1H),8.13(d,J＝8.7Hz,1H),8.03(dd,J＝8.8,2.5Hz，1H)，7.99(dd，J＝6.9，3.0Hz，2H),7.68(d，J＝7.7Hz,2H),7.38(t,J＝7.4Hz，1H),7.27(d，J＝4.6Hz,1H),3.54(t,J＝6.8Hz,2H),2.52–2.48(m,5H),2.45(t,J＝7.3Hz,2H),1.91(s,4H),1.27–1.13(m,2H).
Example 32
Figure BDA0003277129830000431
Hexahydrophthalic anhydride (310mg, 2.0mmol) and 3-aminobenzoic acid (280mg, 2.0mmol) were dissolved in 10mL glacial acetic acid and heated to 120 ℃ for 2 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing the solution with water, combining the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain 454mg of yellow oily matter, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 91.5%.
The intermediate compound (454mg, 1.83mmol) and HATU (905mg, 2.38mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (370. mu.L, 2.75mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (311mg, 1.83mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at 20:1-10: 1) to obtain 393mg of white solid with yield of 50.6%. HR ESI-MS (m/z): 426.1812[ M + H]+。
1H NMR(500MHz,DMSO-d6)δ11.04(s,1H),8.73(d,J＝2.5Hz,1H),8.29(d,J＝8.6Hz,1H),8.19(dd,J＝8.7,2.6Hz,1H),8.12(dt,J＝7.9,1.4Hz,1H),7.99(t,J＝1.9Hz,1H),7.78–7.73(m,2H),7.65(t,J＝7.9Hz,1H),7.55–7.48(m,3H),7.43–7.38(m,1H),3.17(td,J＝4.5,2.3Hz,2H),1.87–1.76(m,4H),1.48–1.39(m,4H).
Example 33
Figure BDA0003277129830000432
(3aR,4S,7R,7aS) -hexahydro-4,7-epoxyisobenzofuran-1,3-dione (336mg, 2.0mmol) and 3-aminobenzoic acid (280mg, 2.0mmol) were dissolved in 10In mL of glacial acetic acid, the mixture is heated to 80 ℃ and reacted for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oily substance 416mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 80.0%.
The intermediate compound (416mg, 1.60mmol) and HATU (800mg, 2.1mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (332. mu.L, 2.46mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at 20:1-10: 1) to obtain white solid 316mg with yield of 45.0%. HR ESI-MS (m/z): 440.1615[ M + H]+1H NMR(500MHz,Chloroform-d)δ8.79(s,1H),8.53(d,J＝2.6Hz,1H),8.45(d,J＝8.7Hz,1H),7.98(td,J＝6.2,2.8Hz,2H),7.89(d,J＝2.4Hz,1H),7.62(t,J＝7.9Hz,1H),7.58(d,J＝7.7Hz,2H),7.51(d,J＝7.9Hz,1H),7.48(t,J＝7.6Hz,2H),7.40(d,J＝7.3Hz,1H),5.06–5.00(m,2H),3.08(s,2H),1.95–1.91(m,2H),1.69(s,2H).
Example 34
Figure BDA0003277129830000441
(3aR,4S,7R,7aS) -hexahydro-4,7-epoxyisobenzofuran-1,3-dione (336mg, 2.0mmol) and 4-aminobenzoic acid (280mg, 2.0mmol) were dissolved in 10mL glacial acetic acid and heated to 80 ℃ for reaction for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oily substance 420mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 80.1%.
The intermediate compound (420mg, 1.60mmol) and HATU (800mg, 2.1mmol) were dissolved in anhydrous dichloromethane (10ml) and added dropwiseTriethylamine (332. mu.L, 2.46mmol) was stirred at room temperature for 10min, and 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate of 20:1-10: 1) to obtain white solid 317mg with yield of 45.1%. HR ESI-MS (m/z): 440.1579[ M + H]+。1H NMR(500MHz,DMSO-d6)δ11.07(s,1H),8.74(dd,J＝2.5,0.8Hz,1H),8.30(dd,J＝8.7,0.8Hz,1H),8.19(dd,J＝8.7,2.6Hz,1H),8.16–8.11(m,2H),7.79–7.74(m,2H),7.50(dd,J＝8.4,7.1Hz,2H),7.44–7.40(m,1H),7.40–7.36(m,2H),4.83(d,J＝2.2Hz,2H),3.23(s,2H),1.71(d,J＝1.6Hz,4H).
Example 35
Figure BDA0003277129830000442
(3aR,4S,7R,7aS) -hexahydro-4, 7-epoxybenzfuran-1, 3-dione (336mg, 2.0mmol) and 4-aminophenylacetic acid (300mg, 2.0mmol) were dissolved in 10mL glacial acetic acid and heated to 80 ℃ for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 440mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in 78.5% yield.
The intermediate compound (440mg, 1.57mmol) and HATU (780mg, 2.04mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (318. mu.L, 2.36mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (272mg, 1.57mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at 20:1-10: 1) to obtain white solid 331mg with yield 46.5%. HR ESI-MS (m/z): 454.1764[ M + H]+。1H NMR(500MHz,DMSO-d6)δ8.66(d,J＝2.6Hz,1H),8.15(d,J＝8.7Hz,1H),8.09(dd,J＝8.7,2.5Hz,1H),7.47(q,J＝7.6Hz,4H),7.38(t，J＝7.4Hz,1H),7.16(d,J＝8.0Hz,2H),3.81(s，2H),3.18(s，2H)，1.69(s,4H).
Example 36
Figure BDA0003277129830000451
(3aR,4S,7R,7aS) -hexahydro-4,7-epoxyisobenzofuran-1,3-dione (336mg, 2.0mmol) and 4-aminobutyric acid (210mg, 2.0mmol) were dissolved in 10mL glacial acetic acid and heated to 80 ℃ for reaction for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 403mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 80.5%.
The intermediate compound (403mg, 1.61mmol) and HATU (800mg, 2.1mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (332. mu.L, 2.46mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at 20:1-10: 1) to obtain white solid 292mg with yield of 44.8%. HR ESI-MS (m/z): 406.1772[ M + H]+。1H NMR(500MHz,Chloroform-d)δ8.57–8.43(m,2H),8.28(d,J＝8.5Hz,1H),7.91(dd,J＝8.5,2.3Hz,1H),7.56(d,J＝7.7Hz,2H),7.46(t,J＝7.6Hz,2H),7.38(t,J＝7.3Hz,1H),4.97–4.87(m,2H),3.63(t,J＝6.4Hz,2H),2.95–2.86(m,2H),2.37(t,J＝7.1Hz,2H),2.05(t,J＝6.7Hz,2H),1.94–1.82(m,2H).
Example 37
Figure BDA0003277129830000452
(3aR,4S,7R,7aS) -hexahydro-4,7-epoxyisobenzofuran-1,3-dione (336mg, 2.0mmol) and aminopropionic acid (180mg, 2.0mmol) were dissolved in 10mL glacial acetic acid and heated to 80 ℃ for reaction for 6 h. Using water (1)0mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing the solution with water, combining organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 346mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 72.1%.
The intermediate compound (340mg, 1.44mmol) and HATU (711mg, 1.87mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (225. mu.L, 2.16mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (245mg, 1.44mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate of 20:1-10: 1) to obtain 213mg of white solid with 37.9% yield.
1H NMR(500MHz,DMSO-d6)δ10.52(s,1H),8.63(s,1H),8.10(s,2H),7.70(d,J＝7.6Hz,2H),7.47(t,J＝7.6Hz,2H),7.38(t,J＝7.3Hz,1H),4.77(q,J＝7.0Hz,1H),4.72(d,J＝13.7Hz,2H),3.13–3.02(m,2H),1.65(s,4H),1.43(d,J＝7.1Hz,3H).
Example 38
Figure BDA0003277129830000461
(3aR,4S,7R,7aS) -hexahydro-4,7-epoxyisobenzofuran-1,3-dione (336mg, 2.0mmol) and glycine (152mg, 2.0mmol) were dissolved in 10mL glacial acetic acid and heated to 80 ℃ for reaction for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 325mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 72.0%.
The intermediate compound (340mg, 1.4mmol) and HATU (710mg, 1.87mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (225. mu.L, 2.16mmol) was added dropwise, stirring was carried out at room temperature for 10min, 2-aminopyridine (245mg, 1.44mmol) was added, and the reaction was carried out at room temperatureAnd (5) 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate 20:1-10:1 gradient elution) to obtain white solid 263mg, yield 49.8%. HR ESI-MS (m/z): 378.1430[ M + H]+。1H NMR(500MHz,DMSO-d6)δ10.95(s,1H),8.67(dd,J＝2.4,0.9Hz,1H),8.11(dd,J＝8.7,2.5Hz,1H),8.06(d,J＝8.9Hz,1H),7.79–7.68(m,2H),7.48(dd,J＝8.4,7.0Hz,2H),7.41–7.34(m,1H),4.74(t,J＝2.0Hz,2H),4.28(s,2H),3.18(s,2H),1.79–1.53(m,4H).
Example 39
Figure BDA0003277129830000462
(3aR,4S,7R,7aS) -3a,4,7,7a-tetrahydro-4,7-methano zofuran-1,3-dione (356mg, 2.0mmol) and 3-aminobenzoic acid (280mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for reaction for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 480mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 81.0%.
The intermediate compound (480mg, 1.62mmol) and HATU (800mg, 2.1mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (332. mu.L, 2.46mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (gradient elution with mobile phase petroleum ether/ethyl acetate of 20:1-10: 1) to obtain white solid 327mg with yield of 45.0%.
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.73(s,1H),8.18(d,J＝11.2Hz,1H),8.14–8.09(m,1H)，7.80(s,1H),7.75(t,J＝5.9Hz,2H),7.55–7.46(m，2H),7.37(d，J＝10.2Hz,2H),6.30(s，2H),3.13(s,2H),3.08(s,2H),1.68(d，J＝8.3Hz,2H),1.30(d，J＝8.4Hz,2H).
Example 40
Figure BDA0003277129830000471
(3aR,4S,7R,7aS) -3a,4,7,7a-tetrahydro-4,7-methano zofuran-1,3-dione (356mg, 2.0mmol) and 4-aminobenzoic acid (280mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for reaction for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 525mg, LC-MS and1H-NMR confirmed it to be the expected intermediate compound in 84.9% yield.
The intermediate compound (525mg, 1.70mmol) and HATU (840mg, 2.21mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (344. mu.L, 2.55mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (290mg, 1.70mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (gradient elution with mobile phase petroleum ether/ethyl acetate of 20:1-10: 1) to obtain 378mg of white solid with yield of 48.1%. HR ESI-MS (m/z): 464.1958[ M + H]+。1H NMR(500MHz,DMSO-d6)δ10.89(s,1H),8.66(dd,J＝2.5,0.9Hz,1H),8.15(d,J＝8.7Hz,1H),8.10(dd,J＝8.7,2.5Hz,1H),7.76–7.65(m,2H),7.51–7.46(m,2H),7.46–7.42(m,2H),7.41–7.37(m,1H),7.14–7.05(m,2H),6.25(dd,J＝4.5,3.1Hz,2H),3.80(s,2H),3.08(t,J＝1.6Hz,2H),3.05(dtq,J＝4.6,3.1,1.6Hz,2H),1.66(dt,J＝8.8,2.0Hz,2H),1.36–1.22(m,2H).
EXAMPLE 41
Figure BDA0003277129830000472
(3aR,4R,7R,7aS) -5-methyl-3a,4,7,7a-tetrahydro-4, 7-methanozofuran-1, 3-dione (356mg, 2.0mmol) and 4-aminobenzoic acid (280mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid, and addedThe reaction was heated to 80 ℃ for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing the solution with water, mixing the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain 478mg of yellow oily substance, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 80.1%.
The intermediate compound (478mg, 1.61mmol) and HATU (800mg, 2.1mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (332. mu.L, 2.46mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate 20:1-10:1 gradient elution) to obtain white solid 333mg, yield 46.1%. HR ESI-MS (m/z): 450.1837[ M + H]+。1H NMR(500MHz,DMSO-d6)δ11.04(d,J＝3.0Hz,2H),8.73(dd，J＝2.5，0.8Hz,2H),8.30(dd,J＝8.6，0.8Hz,2H),8.18(dd,J＝8.7,2.6Hz,2H),8.14–8.07(m,4H),7.78–7.72(m,4H),7.50(t,J＝7.7Hz,4H),7.44–7.37(m,2H),7.32–7.21(m,4H),6.24(dd,J＝5.6,2.9Hz,1H),6.08(d,J＝5.7Hz,1H),5.79(p,J＝1.5Hz,1H),3.62(dd,J＝7.6,4.7Hz，1H),3.58–3.49(m,2H),3.32(s,1H),3.28–3.23(m,2H),3.19(d,J＝7.6Hz,1H),3.14(dt,J＝4.3,1.5Hz,1H),1.73(d，J＝1.7Hz，3H),1.65(dt，J＝8.5,1.8Hz,1H),1.63–1.56(m,2H)，1.53(s,2H),1.52–1.46(m,1H).
Example 42
Figure BDA0003277129830000481
(3aR,4R,7R,7aS) -5-methyl-3a,4,7,7a-tetrahydro-4,7-methano benzofuranon-1, 3-dione (356mg, 2.0mmol) and 4-aminophenylacetic acid (310mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid, and the mixture was heated to 80 ℃ to react for 6 hours. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing the solution and water, combining organic phases, drying by anhydrous sodium sulfate, separating and purifying by a silica gel column,520mg of a yellow oil, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in 84.6% yield.
The intermediate compound (520mg, 1.70mmol) and HATU (840mg, 2.21mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (344. mu.L, 2.55mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (290mg, 1.70mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate 20:1-10:1 gradient elution) to obtain white solid 370mg, yield 47.6%.
HR ESI-MS(m/z)：464.19769[M+H]+。1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.65(s,1H),8.23–8.01(m,2H),7.70(d,J＝7.6Hz,2H),7.47(t,J＝7.5Hz,2H),7.39(dd,J＝17.4,8.0Hz,3H),7.04(dd,J＝16.7，7.9Hz,2H),3.79(s，2H),3.50(d,J＝10.7Hz,1H),3.32(s,2H),1.99(s,1H),1.71(s,1H),1.66–1.49(m,3H).
Example 45
Figure BDA0003277129830000482
Hexahydrophthalic anhydride (310mg, 2.0mmol) and 4-aminophenylacetic acid (300mg, 2.0mmol) were dissolved in 10mL glacial acetic acid and heated to 120 ℃ for 2 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 525mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 91.5%.
The intermediate compound (525mg, 1.83mmol) and HATU (905mg, 2.38mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (370. mu.L, 2.75mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (311mg, 1.83mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate 20:1-10:1 gradient elution)) 396mg of a white solid was obtained in 49.3% yield. HR ESI-MS (m/z): 440.1974[ M + H]+1H NMR(500MHz,DMSO-d6)δ10.87(s,1H),8.66(s,1H),8.20–8.05(m,2H),7.71(d,J＝8.0Hz,2H),7.51–7.42(m,4H),7.39(q,J＝7.4Hz,1H),7.23(d,J＝8.0Hz,2H),3.81(s,2H),2.69(s,2H),1.85–1.70(m,4H),1.49–1.34(m,4H).
Example 46
Figure BDA0003277129830000491
Tetrahydrophthalic anhydride (310mg, 2.0mmol) and 4-aminophenylacetic acid (300mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 120 ℃ for 2 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 525mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 91.5%.
The intermediate compound (525mg, 1.83mmol) and HATU (905mg, 2.38mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (370. mu.L, 2.75mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (311mg, 1.83mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate 20:1-10:1 gradient elution) to obtain 396mg of white solid with 49.3% yield. HR ESI-MS (m/z): 438.1818[ M + H]+。
Example 47
Figure BDA0003277129830000492
(3aR,4R,7R,7aS) -5-methyl-3a,4,7,7a-tetrahydro-4, 7-methano-furan-1, 3-dione (356mg, 2.0mmol) and glycine (150mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L).Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 376mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 80.1%.
The intermediate compound (376mg, 1.61mmol) and HATU (800mg, 2.1mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (332. mu.L, 2.46mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate 20:1-10:1 gradient elution) to obtain white solid 333mg, yield 46.1%.
HR ESI-MS(m/z)：388.1697[M+H]+。1H NMR(500MHz,DMSO-d6)δ10.87(d,J＝9.4Hz,1H),8.66(dd,J＝2.4,1.0Hz,1H),8.16–8.02(m,2H),7.76–7.65(m,2H),7.52–7.44(m,2H),7.42–7.34(m,1H),5.86–5.80(m,1H),4.15(d,J＝7.2Hz,2H),3.93–3.88(m,3H),1.66(d,J＝1.7Hz,1H),1.61(d,J＝1.8Hz,2H),1.48(d,J＝8.5Hz,3H).
Example 48
Figure BDA0003277129830000501
(3aR,4R,7R,7aS) -5-methyl-3a,4,7,7a-tetrahydro-4, 7-methano-furan-1, 3-dione (356mg, 2.0mmol) and aminopropionic acid (180mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for reaction for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 400mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 80.5%.
The intermediate compound (400mg, 1.61mmol) and HATU (800mg, 2.1mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (332. mu.L, 2.46mmol) was added dropwise, stirred at room temperature for 10min and then added2-Aminophenylpyridine (280mg, 1.64mmol) was reacted at room temperature for 24 hours. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at 20:1-10: 1) to obtain 313mg of white solid with yield of 52.1%. HR ESI-MS (m/z): 402.1818[ M + H]+。1H NMR(500MHz,DMSO-d6)δ10.67(s,1H),8.63(d,J＝2.2Hz,1H),8.20–8.04(m,2H),7.71(d,J＝7.9Hz,2H),7.48(t,J＝7.6Hz,2H),7.38(t,J＝7.3Hz,1H),3.53(t,J＝7.5Hz,2H),3.32(qd,J＝7.5,4.0Hz,3H),2.56(q,J＝8.3,7.9Hz,2H),2.51(t,J＝3.9Hz,2H),1.65(s,2H),1.48(d,J＝9.1Hz,2H).
Example 49
Figure BDA0003277129830000502
(3aR,4R,7R,7aS) -5-methyl-3a,4,7,7a-tetrahydro-4, 7-methano-furan-1, 3-dione (356mg, 2.0mmol) and aminopropionic acid (180mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for reaction for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 400mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 80.5%.
The intermediate compound (400mg, 1.61mmol) and HATU (800mg, 2.1mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (332. mu.L, 2.46mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at 20:1-10: 1) to obtain 313mg of white solid with yield of 52.1%. HR ESI-MS (m/z): 402.1871[ M + H]+。1H NMR(500MHz,DMSO-d6)δ10.67(s,1H),8.63(d,J＝2.2Hz,1H),8.20–8.04(m,2H),7.71(d,J＝7.9Hz,2H),7.48(t,J＝7.6Hz,2H),7.38(t,J＝7.3Hz,1H),3.53(t,J＝7.5Hz,2H),3.32(qd,J＝7.5,4.0Hz,3H),2.56(q,J＝8.3,7.9Hz,2H),2.51(t,J＝3.9Hz,2H),1.65(s,2H),1.48(d,J＝9.1Hz,2H).
Example 50
Figure BDA0003277129830000511
(3aR,4S,7R,7aS) -3a,4,7,7a-tetrahydro-4, 7-methanosozofuran-1, 3-dione (326mg, 2.0mmol) and glycine (150mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for reaction for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing the solution with water, combining organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 354mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 80.1%.
The intermediate compound (354mg, 1.60mmol) and HATU (800mg, 2.1mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (332. mu.L, 2.46mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (gradient elution with mobile phase petroleum ether/ethyl acetate of 20:1-10: 1) to obtain white solid 238mg with yield of 39.8%. HR ESI-MS (m/z): 374.1520[ M + H]+。1H NMR(500MHz,DMSO-d6)δ10.88(s,1H),8.66(dd,J＝2.4,0.9Hz,1H),8.13–8.01(m,2H),7.73–7.69(m,2H),7.50–7.45(m,2H),7.41–7.35(m,1H),6.09(t,J＝1.9Hz,2H),4.14(s,2H),3.46(dd,J＝2.9,1.5Hz,2H),3.28(td,J＝3.3,1.7Hz,2H),1.58(q,J＝1.9Hz，2H).
Example 51
Figure BDA0003277129830000512
(3aR,4S,7R,7aS) -3a,4,7,7a-tetrahydro-4, 7-methanosorzofuran-1, 3-dione (328mg, 2.0mmol) and alanine (180mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid, heated to 80 deg.CAnd reacting for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 375mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in 79.5% yield.
The intermediate compound (375mg, 1.59mmol) and HATU (800mg, 2.1mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (332. mu.L, 2.46mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at 20:1-10: 1) to obtain white solid 186mg with yield of 30.2%. HR ESI-MS (m/z): 388.1661[ M + H]+。1H NMR(500MHz,DMSO-d6)δ10.88(s,1H),8.66(d,J＝2.5Hz,1H),8.20–7.97(m,2H)，7.72(tdd,J＝6.1,5.2,4.4,2.8Hz,2H),7.48(t,J＝7.7Hz,2H),7.39(dd,J＝8.3,6.5Hz,1H),6.09(t,J＝1.9Hz,2H),3.46(dd,J＝2.9,1.5Hz,2H),3.30–3.27(m,2H),2.68(s,1H),1.58(p,J＝1.8Hz,2H),1.55(dt,J＝3.1,1.7Hz,3H).
Example 52
Figure BDA0003277129830000521
(3aR,4S,7R,7aS) -3a,4,7,7a-tetrahydro-4, 7-methanosorzofuran-1, 3-dione (328mg, 2.0mmol) and aminopropionic acid (180mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for reaction for 6 hours. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 385mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 80.2%.
The intermediate compound (385mg, 1.6mmol) and HATU (800mg, 2.1mmol) were dissolved in anhydrous dichloromethane (10ml), and triethylamine (triethylamine) (triethylamine) was added dropwise332 μ L, 2.46mmol), stirred at room temperature for 10min, added with 2-aminopyridine (280mg, 1.64mmol), and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at 20:1-10: 1) to obtain 320mg of white solid with yield of 50.2%. HR ESI-MS (m/z): 388.1676[ M + H]+。1H NMR(500MHz,DMSO-d6)δ10.59(s,1H),8.63(d,J＝2.3Hz,1H),8.19–8.02(m,2H),7.71(d,J＝7.6Hz,2H)，7.48(t,J＝7.6Hz，2H),7.38(t,J＝7.6Hz,1H),6.02(s,2H),3.54(t,J＝7.2Hz,2H),3.08(q,J＝7.3Hz,2H),2.56(t,J＝7.2Hz,2H),1.17(t,J＝7.2Hz,4H).
Example 53
Figure BDA0003277129830000522
(3aR,4S,7R,7aS) -3a,4,7,7a-tetrahydro-4, 7-methanosozofuran-1, 3-dione (328mg, 2.0mmol) and 4-aminobutyric acid (210mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for reaction for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oily substance 420mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in 84.6% yield.
The intermediate compound (420mg, 1.69mmol) and HATU (835mg, 2.2mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (345. mu.L, 2.54mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (288mg, 1.69mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (gradient elution with mobile phase petroleum ether/ethyl acetate of 20:1-10: 1) to obtain white solid 360mg with yield 53.3%. HR ESI-MS (m/z): 402.1828[ M + H]+。1H NMR(500MHz,DMSO-d6)δ10.57(s,1H),8.66–8.60(m,1H),8.17(d,J＝8.7Hz,1H),8.09(dd,J＝8.7,2.5Hz,1H),7.77–7.66(m,2H),7.48(t,J＝7.7Hz,2H),7.42–7.34(m,1H),6.11(t,J＝1.9Hz,2H),3.27(t,J＝7.0Hz,2H),2.35(t,J＝7.4Hz,2H),1.68(q,J＝7.2Hz,2H),1.58–1.51(m,4H).
Example 54
Figure BDA0003277129830000531
(3aR,4S,7R,7aS) -3a,4,7,7a-tetrahydro-4, 7-methanosozofuran-1, 3-dione (356mg, 2.0mmol) and glycine (150mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for reaction for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 400mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in 85.1% yield.
The intermediate compound (400mg, 1.72mmol) and HATU (835mg, 2.2mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (345. mu.L, 2.54mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (295mg, 1.72mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate 20:1-10:1 gradient elution) to obtain white solid 336mg with yield 51.2%. HR ESI-MS (m/z): 388.1660[ M + H]+。1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.63(s,1H),8.08(d,J＝11.1Hz,1H),8.02(d,J＝9.0Hz,1H),7.68(t,J＝5.4Hz,2H),7.47(q,J＝7.9,7.4Hz,2H),7.41–7.31(m,1H),6.13(s,2H),4.19(s,2H),3.03(s,2H),2.99(s,2H),1.61(d,J＝8.5Hz,2H),1.24(d,J＝10.2Hz,2H).
Example 55
Figure BDA0003277129830000532
(3aR,4S,7R,7aS) -3a,4,7,7a-tetrahydro-4, 7-ethanozofuran-1, 3-dione (356mg, 2.0mmol) and alanine (180mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid, andthe reaction was heated to 80 ℃ for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 400mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 80.1%.
The intermediate compound (400mg, 1.6mmol) and HATU (800mg, 2.1mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (332. mu.L, 2.46mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at 20:1-10: 1) to obtain white solid 264mg with yield of 40.0%. ESI-MS (m/z): 402.1630[ M + H]+。1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.63(s,1H),8.16(d,J＝8.7Hz,1H),8.08(d,J＝8.7Hz,1H),7.69(s,1H),7.47(d,J＝7.5Hz,2H),7.38(d,J＝6.9Hz,2H),6.09(s,2H),4.52(m,1H),2.96(d,J＝8.6Hz,2H),2.11(s,3H),1.59(d,J＝8.2Hz,2H),1.23(d,J＝6.9Hz,4H).
Example 56
Figure BDA0003277129830000541
(3aR,4S,7R,7aS) -3a,4,7,7a-tetrahydro-4,7-methano zofuran-1,3-dione (356mg, 2.0mmol) and aminopropionic acid (180mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for reaction for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 400mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 80.0%.
The intermediate compound (400mg, 1.6mmol) and HATU (800mg, 2.1mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (332. mu.L, 2.46mmol) was added dropwise, and the mixture was stirred at room temperatureAfter 10min, 2-aminophenylpyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (gradient elution with mobile phase petroleum ether/ethyl acetate of 20:1-10: 1) to obtain 304mg of white solid with yield of 44.8%. ESI-MS (m/z): 402.1798[ M + H]+。1H NMR(500MHz,DMSO-d6)δ10.59(s,1H),8.63(s,1H),8.10(q,J＝8.8Hz,2H),7.71(d,J＝7.7Hz,2H),7.48(t,J＝7.6Hz,2H),7.38(t,J＝7.5Hz,1H),6.07(t,J＝3.8Hz,2H),3.59(t,J＝7.3Hz,2H),2.96(s,2H),2.91(s,2H),2.50(s,2H),1.59(d,J＝7.9Hz,2H),1.22(d,J＝8.7Hz,2H).
Example 57:
Figure BDA0003277129830000542
(3aR,4S,7R,7aS) -3a,4,7,7a-tetrahydro-4,7-methano sobenzofuran-1,3-dione (356mg, 2.0mmol) and 4-aminobutyric acid (210mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for reaction for 6 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 473mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in 89.9% yield.
The intermediate compound (473mg, 1.80mmol) and HATU (905mg, 2.38mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (370. mu.L, 2.75mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (311mg, 1.83mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate 20:1-10:1 gradient elution) to obtain white solid 370mg, yield 51.8%. ESI-MS (m/z): 416.2012[ M + H]+1H NMR(500MHz,DMSO-d6)δ10.56(s,1H),8.63(dd,J＝2.5,0.8Hz,1H),8.16(d,J＝8.7Hz,1H),8.09(dt,J＝8.7,2.4Hz,1H),7.72–7.69(m,2H),7.48(dd,J＝8.4,7.0Hz,2H),7.41–7.36(m,1H),6.15(dd,J＝4.5,3.1Hz,2H),3.33(t,J＝7.0Hz,2H),2.96(d,J＝1.4Hz,2H),2.90(q,J＝1.5Hz,2H),2.69(s,2H),2.34(t,J＝7.5Hz,2H),1.69(q,J＝7.3Hz,2H),1.61(s,1H),1.55(s,1H).
Example 58
Figure BDA0003277129830000551
3-Methylphthalic anhydride (490mg, 3.0mmol) and glycine (230mg, 3.1mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 420mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 95.5%.
The intermediate compound (420mg, 2.87mmol) and HATU (1.4g, 3.72mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (580. mu.L, 4.22mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (488mg, 2.87mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase petroleum ether/ethyl acetate of 20:1-10: 1) to obtain white solid 370mg with yield of 52.3%. ESI-MS (m/z): 372.1361[ M + H]+。1H NMR(500MHz,DMSO-d6)δ11.06(s,1H),8.69(d,J＝2.7Hz,1H),8.12(dd,J＝8.7,2.6Hz,1H),8.07(s,1H),7.75(d,J＝4.5Hz,2H),7.72(d,J＝7.7Hz,2H),7.68(q,J＝4.2Hz,1H),7.48(t,J＝7.6Hz,2H),7.39(t,J＝7.4Hz,1H),4.53(s,2H).
Example 59
Figure BDA0003277129830000552
3-Methylphthalic anhydride (490mg, 3.0mmol) and alanine (270mg, 3.1mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Dichloro-methylAlkane extraction (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 420mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 90.8%.
The intermediate compound (420mg, 2.72mmol) and HATU (1.34g, 3.54mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (550. mu.L, 4.09mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (464mg, 2.72mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate 20:1-10:1 gradient elution) to obtain 388mg of white solid, yield 48.0% ESI-MS (m/z): 386.1493[ M + H]+。
1H NMR(500MHz,DMSO-d6)δ10.71(s,1H),8.49(s,1H),7.99(q,J＝8.9Hz,2H),7.57(s,4H),7.50(d,J＝6.8Hz,1H),7.34(d,J＝7.7Hz,2H),7.25(d,J＝8.4Hz,1H),4.88(d,J＝8.8Hz,1H),1.51(d,J＝7.6Hz,3H).
Example 60
Figure BDA0003277129830000561
3-Methylphthalic anhydride (490mg, 3.0mmol) and aminopropionic acid (270mg, 3.1mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 445mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 95.4%.
The intermediate compound (445mg, 2.86mmol) and HATU (1.4g, 3.72mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (580. mu.L, 4.22mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (488mg, 2.87mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate)Gradient elution with 20:1-10: 1) gave 400mg of white solid in 54.4% yield. ESI-MS (m/z): 386.1538[ M + H]+。1H NMR(500MHz,DMSO-d6)δ10.69(s,1H),8.61(d,J＝2.2Hz,1H),8.15–8.01(m,2H),7.69(dd,J＝7.3,4.8Hz,4H),7.61(d,J＝6.7Hz,1H),7.47(t,J＝7.6Hz,2H),7.38(t,J＝7.4Hz,1H),3.88(t,J＝6.9Hz,2H),2.77(t,J＝7.0Hz,2H),2.61(s,3H).
Example 61
Figure BDA0003277129830000562
3-chlorophthalic anhydride (365mg, 2.0mmol) and glycine (155mg, 2.1mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Filtering, and drying to obtain yellow solid 400mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 96.1%.
The intermediate compound (400mg, 1.92mmol) and HATU (950mg, 2.5mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (390. mu.L, 2.88mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (327mg, 1.92mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, spin-drying the filtrate, dissolving with ethyl acetate, cooling at low temperature for 2h, filtering to obtain light yellow solid, drying and weighing about 411mg, and obtaining yield of 54.9%. ESI-MS (m/z): 392.0828[ M + H]+。
1H NMR(500MHz,DMSO-d6)δ11.07(s,1H),8.69(d,J＝2.4Hz,1H),8.12(dd,J＝8.5,2.6Hz,1H),8.05(d,J＝20.6Hz,1H),8.02(d,J＝4.0Hz,1H),7.96–7.85(m,3H),7.72(d,J＝7.4Hz,2H),7.49(t,J＝7.6Hz,2H),7.39(t,J＝7.4Hz,1H),4.54(s,2H).
Example 62
Figure BDA0003277129830000571
3-Chlorophthalic anhydride (365mg, 2.0mmol) and alanine (190mg, 2.1mmol) were added to glacial acetic acidIn acid (10mL), the mixture was heated to 100 ℃ and reacted for 3 hours. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Filtered and dried to obtain a yellow solid of 430mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 96.4%.
The intermediate compound (430mg, 1.93mmol) and HATU (950mg, 2.5mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (390. mu.L, 2.88mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (335mg, 1.93mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, spin-drying the filtrate, dissolving with ethyl acetate, cooling at low temperature for 2h, filtering to obtain light yellow solid, drying and weighing about 430mg, and obtaining yield of 55.0%.
ESI-MS(m/z)：406.0995[M+H]+。
1H NMR(500MHz,DMSO-d6)δ10.84(s,1H),8.61(s,1H),8.12(d,J＝3.4Hz,2H),7.87(d,J＝10.4Hz,3H),7.70(d,J＝7.6Hz,2H),7.48(t,J＝7.7Hz,2H),7.38(t,J＝7.4Hz,1H),5.01(q,J＝7.2Hz,1H),1.61(d,J＝7.1Hz,3H).
Example 63
Figure BDA0003277129830000572
3-Chlorophthalic anhydride (365mg, 2.0mmol) and aminopropionic acid (190mg, 2.1mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Filtered and dried to give 425mg of a yellow solid, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 96.0%.
The intermediate compound (425mg, 1.92mmol) and HATU (950mg, 2.5mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (390. mu.L, 2.88mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (330mg, 1.92mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, spin-drying the filtrate, dissolving with ethyl acetate, cooling at low temperature for 2h, filtering to obtain light yellow solid, drying and weighing about 450mg, and obtaining yield of 57.8%. ESI-MS (m/z): 406.1003[ M + H]+。
1H NMR(500MHz,DMSO-d6)δ10.71(s,1H),8.62(s,1H),8.10(q,J＝8.7Hz,2H),7.83(dq,J＝14.4,7.4Hz,3H),7.70(d,J＝7.6Hz,2H),7.48(t,J＝7.6Hz,2H),7.38(t,J＝7.4Hz,1H),3.90(t,J＝6.9Hz,2H),2.79(t,J＝7.0Hz,2H).
Example 64
Figure BDA0003277129830000581
3-chlorophthalic anhydride (365mg, 2.0mmol) and 4-aminobutyric acid (190mg, 2.1mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for reaction for 3 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Filtered and dried to obtain yellow solid 444mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 95.5%.
The intermediate compound (444mg, 1.92mmol) and HATU (950mg, 2.5mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (390. mu.L, 2.88mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (330mg, 1.92mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, spin-drying the filtrate, dissolving with ethyl acetate, cooling at low temperature for 2h, filtering to obtain light yellow solid, drying and weighing about 412mg, and obtaining yield of 52.3%.
420.1136[M+H]+。
1H NMR(500MHz,DMSO-d6)δ10.51(s,1H),8.60(d,J＝2.3Hz,1H),8.11–7.98(m,2H),7.81(q,J＝5.2Hz,3H),7.69(d,J＝7.6Hz,2H),7.48(t,J＝7.6Hz,2H),7.38(t,J＝7.4Hz,1H),3.64(t,J＝6.7Hz,2H),1.95(p,J＝7.0Hz,2H).
Example 65
Figure BDA0003277129830000582
3-Bromophthalic anhydride (380mg, 2.0mmol) and 4-aminobutyric acid (190mg, 2.1mmol) were added to glacial acetic acid (10mL) and heated to 100 ℃ for 3 h. The reaction was quenched with water (10mL), NaOH solution(0.1mol/L) adjusting the pH value of the solution to 6-8. Filtered and dried to give 460mg of a yellow solid, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 95.5%.
The intermediate compound (460mg, 1.92mmol) and HATU (950mg, 2.5mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (390. mu.L, 2.88mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (330mg, 1.92mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, spin-drying the filtrate, dissolving with ethyl acetate, cooling at low temperature for 2h, filtering to obtain light yellow solid, drying and weighing about 452mg, and obtaining yield of 50.3%.
ESI-MS(m/z)：464.0610[M+H]+。
Example 66
Figure BDA0003277129830000583
(3aR,7aS) -3a,4,7,7 a-5-methyl-tetrahydrobenzofuranone-1, 3-dione (310mg, 2.0mmol) and 4-aminobutyric acid (210mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 4 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 450mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 95.0%.
The intermediate compound (450mg, 1.9mmol) and HATU (940mg, 2.47mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (385. mu.L, 2.85mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (323mg, 1.9mmol) was added, and the reaction was carried out at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate gradient elution from 20:1 to 10: 1) to obtain white solid, drying and weighing 415mg, and obtaining 56.1% yield.
ESI-MS(m/z)：404.1974[M+H]+。
Example 67
Figure BDA0003277129830000591
(3aR,7aS) -3a,4,7,7 a-4-methyl-tetrahydrobenzofuranone-1, 3-dione (310mg, 2.0mmol) and 4-aminobutyric acid (210mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 4 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 460mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 95.0%.
The intermediate compound (450mg, 1.9mmol) and HATU (940mg, 2.47mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (385. mu.L, 2.85mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (323mg, 1.9mmol) was added, and the reaction was carried out at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate 20:1-10:1 gradient elution) to obtain white solid, drying and weighing about 485mg, and obtaining 66.1% yield. ESI-MS (m/z): 404.1974[ M + H]+。
Example 68
Figure BDA0003277129830000592
(3aR,7aS) -5-methyl-3a,4, 5,7 a-tetrahydrodibenzofuran-1, 3-dione (310mg, 2.0mmol) and 4-aminobutyric acid (210mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 4 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 460mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 95.0%.
The intermediate compound (450mg, 1.9mmol) and HATU (940mg, 2.47mmol) were dissolved in anhydrous waterTo dichloromethane (10ml), triethylamine (385. mu.L, 2.85mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (323mg, 1.9mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate 20:1-10:1 gradient elution) to obtain white solid, drying and weighing about 485mg, and obtaining 66.1% yield. ESI-MS (m/z): 404.1974[ M + H]+。
Example 69
Figure BDA0003277129830000601
(3aR,7aS) -3a,4,7,7 a-4-methyl-tetrahydrobenzofuranone-1, 3-dione (310mg, 2.0mmol) and glycine (150mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ to react for 4 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 410mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 95.0%.
The intermediate compound (410mg, 1.9mmol) and HATU (940mg, 2.47mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (385. mu.L, 2.85mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (323mg, 1.9mmol) was added, and the reaction was carried out at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate gradient elution from 20:1 to 10: 1) to obtain white solid, drying and weighing about 455mg, and obtaining 56.1% yield. ESI-MS (m/z): 376.1661[ M + H]+。
Example 70
Figure BDA0003277129830000602
Reacting (3aR,7aS) -3a,4,7,7 a-tetrahydrodibenzofuran-1, 3-dione (304mg, 2.0mmol) and alanine (180mg, 2.0mmol)Dissolved in 10mL of glacial acetic acid, and heated to 80 ℃ for reaction for 4 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 400mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in 89.9% yield.
The intermediate compound (400mg, 1.8mmol) and HATU (925mg, 2.43mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (378. mu.L, 2.81mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (310mg, 1.8mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at 20:1-10: 1) to obtain white solid, drying and weighing about 328mg, and obtaining 48.7% yield.
ESI-MS(m/z)：376.1678[M+H]+，1H NMR(500MHz,DMSO-d6)δ10.55(s,1H),8.63(s,1H),8.09(s,2H),7.71(d,J＝7.7Hz,2H),7.48(t,J＝7.6Hz,2H),7.39(t,J＝7.3Hz,1H),5.88(t,J＝3.3Hz,2H),4.78(q,J＝7.2Hz,1H),3.17(dtd,J＝16.7,8.9,4.6Hz,2H),2.44–2.34(m,2H),2.21(td,J＝15.0,7.2Hz,2H),1.43(d,J＝7.2Hz,3H).
Example 71
Figure BDA0003277129830000611
(3aR,7aS) -3a,4,7,7 a-tetrahydrodibenzofuran-1, 3-dione (304mg, 2.0mmol) and aminopropionic acid (180mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ to react for 4 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oily substance 401mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in 89.9% yield.
The intermediate compound (400mg, 1.8mmol) and HATU (925mg, 2.43mmol) were dissolved inTriethylamine (378. mu.L, 2.81mmol) was added dropwise to anhydrous dichloromethane (10ml), and after stirring at room temperature for 10min, 2-aminopyridine (310mg, 1.8mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate gradient elution from 20:1 to 10: 1) to obtain white solid, drying and weighing about 363mg, and obtaining 54.0% yield. ESI-MS (m/z): 376.1660[ M + H]+。
1H NMR(500MHz,DMSO-d6)δ10.61(s,1H),8.62(d,J＝2.9Hz,1H),8.15–8.04(m,2H),7.70(d,J＝7.6Hz,2H),7.48(t,J＝7.6Hz,2H),7.38(t,J＝7.4Hz,1H),5.82(q,J＝4.4,2.9Hz,2H),3.66(t,J＝7.2Hz,2H),3.11(dd,J＝8.4,5.3Hz,2H),2.63(t,J＝7.3Hz,2H),2.38–2.33(m,2H),2.18(dt,J＝14.7,4.4Hz,2H).
Example 72
Figure BDA0003277129830000612
(3aR,7aS) -3a,4,7,7 a-tetrahydrodibenzofuran-1, 3-dione (304mg, 2.0mmol) and 4-aminobutyric acid (210mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 4 hours. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 450mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 95.0%.
The intermediate compound (450mg, 1.9mmol) and HATU (940mg, 2.47mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (385. mu.L, 2.85mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (323mg, 1.9mmol) was added, and the reaction was carried out at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate gradient elution from 20:1 to 10: 1) to obtain white solid, drying and weighing about 414mg, and obtaining 56.1% yield.
ESI-MS(m/z)：390.1802[M+H]+。
1H NMR(500MHz,DMSO-d6)δ10.55(s,1H),8.62(d,J＝2.5Hz,1H),8.24–8.02(m,2H),7.75–7.63(m,2H),7.47(t,J＝7.6Hz,2H),7.38(t,J＝7.3Hz,1H),5.86(q,J＝4.1,3.6Hz,2H),3.35(d,J＝6.8Hz,2H),2.37(d,J＝6.7Hz,2H),2.21–2.09(m,4H),1.75(p,J＝7.3Hz,2H).
Example 73
Figure BDA0003277129830000621
(3aR,7aS) -3a,4,7,7 a-tetrahydrodibenzofuran-1, 3-dione (304mg, 2.0mmol) and 4-methylamino-cyclohexanecarboxylic acid (314mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ to react for 4 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 525mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in 89.9% yield.
The intermediate compound (400mg, 1.4mmol) and HATU (925mg, 2.43mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (378. mu.L, 2.81mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (310mg, 1.8mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate gradient elution from 20:1 to 10: 1) to obtain white solid, drying and weighing about 303mg, and obtaining 54.0% yield. HR ESI-MS (m/z): 444.2287[ M + H]+。
Example 74
Figure BDA0003277129830000622
(3aR,4R,7R,7aS) -5-methyl-3a,4,7,7a-tetrahydro-4, 7-methano-furan-1, 3-dione (356mg, 2.0mmol) and p-aminocyclohexyl carboxylic acid (286mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid, heated to 80 deg.CAnd reacting for 4 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 550mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in 92% yield.
The intermediate compound (400mg, 1.33mmol) and HATU (925mg, 2.43mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (378. mu.L, 2.81mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (310mg, 1.8mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate gradient elution from 20:1 to 10: 1) to obtain white solid, drying and weighing about 363mg, yield 60.0%. HR ESI-MS (m/z): 456.2287[ M + H]+。
Example 75
Figure BDA0003277129830000631
(3aR,4R,7R,7aS) -5-methyl-3a,4,7,7a-tetrahydro-4, 7-methano-furan-1, 3-dione (356mg, 2.0mmol) and 4-methylamino-cyclohexanecarboxylic acid (314mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 4 h. The reaction was quenched with water (10mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. times.3), saturated NaHCO3Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 500mg, LC-MS and1H-NMR confirmed that it was the expected intermediate compound in a yield of 80%.
The intermediate compound (400mg, 1.27mmol) and HATU (925mg, 2.43mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (378. mu.L, 2.81mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (310mg, 1.8mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate at ratio of 20:1-10: 1) to obtain the final productTo a white solid, dry weight about 263mg, yield 44.0%. HR ESI-MS (m/z): 470.2444[ M + H]+。
Example 76
Figure BDA0003277129830000632
The intermediate compound (450mg, 1.9mmol) of example 71 and HATU (940mg, 2.47mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (385. mu.L, 2.85mmol) was added dropwise, and after stirring at room temperature for 10min, 2-amino-4- (2-pyridyl) pyridine (325mg, 1.9mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate 20:1-10:1 gradient elution) to obtain white solid, drying and weighing about 454mg, and obtaining yield of 61.5%. HR ESI-MS (m/z): 391.1770[ M + H]+。
Example 77
Figure BDA0003277129830000633
The intermediate compound (450mg, 1.9mmol) of example 71 and HATU (940mg, 2.47mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (385. mu.L, 2.85mmol) was added dropwise, and after stirring at room temperature for 10min, 2-amino-4- (4-pyridyl) pyridine (325mg, 1.9mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (gradient elution with mobile phase of petroleum ether/ethyl acetate of 20:1-10: 1) to obtain white solid, drying and weighing about 441mg, and obtaining 59.7% yield. HR ESI-MS (m/z): 391.1770[ M + H]+。
Example 78
Figure BDA0003277129830000641
The intermediate compound from example 71 (450mg, 1.9mmol) and HATU (940mg, 2.47mmol) were dissolved in dry dichloromethane (10ml) and the solution was poured into dry dichloromethane (10ml) one by oneTriethylamine (385. mu.L, 2.85mmol) was added dropwise thereto, and after stirring at room temperature for 10min, 5-amino-2- (4-pyridyl) pyridine (325mg, 1.9mmol) was added thereto and reacted at room temperature for 24 hours. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate gradient elution from 20:1 to 10: 1) to obtain white solid, drying and weighing about 476mg, and obtaining 64.5% yield. HR ESI-MS (m/z): 391.1770[ M + H]+。
Example 79
Figure BDA0003277129830000642
The intermediate compound (450mg, 1.9mmol) of example 71 and HATU (940mg, 2.47mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (385. mu.L, 2.85mmol) was added dropwise, and after stirring at room temperature for 10min, 2-amino-4- (2-pyrazinyl) pyridine (327mg, 1.9mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate gradient elution from 20:1 to 10: 1) to obtain white solid, drying and weighing about 427mg, yield 57.9%. HR ESI-MS (m/z): 392.1723[ M + H]+。
Example 80
Figure BDA0003277129830000643
The intermediate compound (450mg, 1.9mmol) of example 71 and HATU (940mg, 2.47mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (385. mu.L, 2.85mmol) was added dropwise, and after stirring at room temperature for 10min, 3-amino-2-methylbenzopyridine (348mg, 1.9mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate gradient elution from 20:1 to 10: 1) to obtain white solid, drying and weighing about 484mg, and obtaining 65.6% yield. HR ESI-MS (m/z): 404.1974[ M + H]+。
Example 81
Figure BDA0003277129830000651
The intermediate compound (450mg, 1.9mmol) of example 71 and HATU (940mg, 2.47mmol) were dissolved in anhydrous dichloromethane (10ml), triethylamine (385. mu.L, 2.85mmol) was added dropwise, and after stirring at room temperature for 10min, 2-amino-3-methylbenzopyridine (348mg, 1.9mmol) was added and reacted at room temperature for 24 h. Filtering, removing inorganic salt filter residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate gradient elution from 20:1 to 10: 1) to obtain white solid, drying and weighing about 417mg, and obtaining 56.1% yield. HR ESI-MS (m/z): 404.1974[ M + H]+。
Pharmacological activity:
1. principle of experiment
Activation of the canonical Wnt signaling pathway requires β -catenin (β -catenin) to enter the nucleus, bind to the transcription factor TCF/LEF to form a complex, and together initiate transcription of downstream regulatory genes. The TOP-Flash firefly luciferase report system vector contains a plurality of copies of TCF/LEF binding sites, and the expression level of downstream firefly luciferase can be regulated and controlled according to the activity intensity of beta-catenin, so that the activation degree of the Wnt/beta-catenin signal path can be detected through the luciferase activity. Meanwhile, in order to reduce experimental error, a Renilla luciferase (pRL-SV40) vector is transfected to serve as an internal reference.
2. Experimental methods
a. Cell culture
The cells were cultured in DMEM (DMEM + 10% FBS + 1% diabody +0.5mg/mL G-418). The culture conditions were 37 ℃ and 5% CO2And (3) carrying out 0.25% pancreatin digestion passage (passage 1: 10) or inoculating 5000 cells/hole into a 96-hole plate, and culturing for two days to be used for a wnt signal path activity detection experiment.
b. Cell transfection
Transfection of the plasmid was performed with X-treme GENE 9 transfection reagent. The TOP-Flash firefly luciferase plasmid and the pRL-SV40 Renilla luciferase plasmid were transfected into L-Wnt3A cells using transfection reagents, respectively, and cultured for 24 hours.
c. Treatment of compounds
The transfected L-Wnt3A cells were treated with test compounds at a given concentration and cultured for 48 hours. The DMSO content in the control and compound cultures was 0.1% together.
Wnt signaling pathway modulator treatment
According to the manufacturer's instruction, the strength fluorescence intensity of firefly luciferase (Top-Flash) and Renilla luciferase (pRL-SV40) is detected by using a dual-luciferase detection kit, and the inhibition rate of the Wnt signal channel strength is calculated according to the formula. Wherein negative values indicate that the test compound has the function of stimulating the wnt signaling pathway, and positive values indicate that the test compound has the function of inhibiting the wnt signaling pathway, and the test compound is subjected to IC (integrated Circuit) treatment50And (4) numerical calculation.
3. Results
Wnt/β -catenin signaling activity (Wnt/β -catenin signaling activity) (Top-Flash) fluorescence value/(pRL-SV 40) fluorescence value.
Screening of inhibitory Activity of Compound (C. about.10. mu.M)
Figure BDA0003277129830000661
Partial compound inhibits Wnt/beta-catenin signal channel activity IC50(μM)
Figure BDA0003277129830000662
Figure BDA0003277129830000671
According to the screening result of WNT signal pathway activity, part of compounds have obvious inhibition effect on the WNT signal pathway and have potential effects of preventing/treating diseases such as tumor, hyperosteogeny, myocardial hypertrophy and the like, and part of compounds have obvious activation effect on the WNT signal pathway and have potential effects of preventing/treating neurodegenerative diseases, osteoporosis, metabolic diseases and the like.

Claims (16)

1. A phthalimide compound and a pharmaceutically acceptable salt thereof are characterized by having a structure shown in a general formula IA:
Figure FDA0003277129820000011
wherein R is1Selected from the group consisting of 1-4R2Substituted phthalimides;
the R is2Selected from substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms3-C8Heterocycloalkyl, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C6-C12Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms2-C12Heteroaryl group, C1-C8Amide group, C1-C8Ester group, carboxyl group, cyano group, halogen, hydroxyl group, amino group or nitro group;
x is selected from unsubstituted or substituted by 1-3R3Substituted C1-C6Alkyl, unsubstituted or substituted by 1-3R3Substituted C2-C6Alkenyl, unsubstituted or substituted by 1-3R3Substituted C2-C6Alkynyl, unsubstituted or substituted by 1-3R3Substituted C3-C6Cycloalkyl, unsubstituted or substituted by 1-3R3Substituted C3-C6Cycloalkyl monoalkyl radicals, unsubstituted or substituted by 1-3R3Substituted C3-C6Cycloalkyldialkyl, unsubstituted or substituted by 1-3R3Substituted aryl, unsubstituted or substituted by 1 to 3R3Substituted aryl monoalkyl radicals, unsubstituted or substituted by 1 to 3R3Substituted aryl dialkyl;
the R is3Is selected fromSubstituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms3-C8Heterocycloalkyl, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C6-C12Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms2-C12Heteroaryl group, C1-C8Amide group, C1-C8Ester group, carboxyl group, cyano group, halogen, hydroxyl group, amino group or nitro group;
the substituents are independently selected from C1-C3Alkyl, halogen substituted C1-C3Alkyl radical, C1-C4Alkoxy, carboxyl, cyano, halogen, hydroxyl and nitro, wherein the halogen is selected from F, Cl, Br or I, and the heteroatom is selected from N, O, S and P.
2. The amide-based compound and the pharmaceutically acceptable salt thereof for modulating the WNT signaling pathway according to claim 1, having a structure represented by IA-1:
Figure FDA0003277129820000012
wherein R is1The same as claim 1.
3. A phthalimide compound and a pharmaceutically acceptable salt thereof according to claim 1, characterized by having a structure represented by IA-2:
Figure FDA0003277129820000021
wherein R is1The same as claim 1.
4. A phthalimide compound and a pharmaceutically acceptable salt thereof according to claim 1, characterized by having a structure represented by IA-3:
Figure FDA0003277129820000022
wherein R is1The same as claim 1.
5. A phthalimide compound and a pharmaceutically acceptable salt thereof according to claim 1, characterized by having a structure represented by IA-4:
Figure FDA0003277129820000023
wherein R is1The same as claim 1.
6. A phthalimide compound and a pharmaceutically acceptable salt thereof according to claim 1, characterized by having a structure represented by IA-5:
Figure FDA0003277129820000024
wherein R is1The same as claim 1.
7. A phthalimide compound and a pharmaceutically acceptable salt thereof according to claim 1, characterized by having a structure represented by IA-6:
Figure FDA0003277129820000031
wherein R is1The same as claim 1.
8. A phthalimide compound and a pharmaceutically acceptable salt thereof according to claim 1, characterized by having a structure represented by IA-7:
Figure FDA0003277129820000032
wherein R is1The same as claim 1.
9. A phthalimide compound according to any one of claims 1 to 8, and a pharmaceutically acceptable salt thereof, R1Selected from the following structures:
Figure FDA0003277129820000033
the R is2Selected from substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms3-C8Heterocycloalkyl, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C6-C12Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms2-C12Heteroaryl group, C1-C8Amide group, C1-C8Ester group, carboxyl, cyano, halogen, hydroxyl, amino or nitro, and the substituents are independently selected from C1-C3Alkyl, halogen substituted C1-C3Alkyl radical, C1-C4Alkoxy, carboxyl, cyano, halogen, hydroxyl and nitro, wherein the halogen is selected from F, Cl, Br or I, and the heteroatom is selected from N, O, S and P; (R)2)nRepresents n numbers of R2And n is selected from 1,2 or 3.
10. According to any one of claims 1-9Phthalimide compound and pharmaceutically acceptable salt thereof, wherein R is2Selected from substituted or unsubstituted methyl, ethyl, propyl, butyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, ethylene, propenyl, butenyl, ethynyl, propynyl, butynyl, phenyl, benzyl, halogen, furan, thiophene, pyrrole, pyrazine, thiazole, imidazole, oxazole, pyrazole, pyridine, pyrimidine, indole, benzofuran, benzothiophene, benzimidazole, purine, the substituents being independently selected from C1-C3Alkyl, halogen substituted C1-C3Alkyl radical, C1-C4Alkoxy, carboxyl, cyano, halogen, hydroxyl and nitro, wherein the halogen is selected from F, Cl, Br or I.
11. The phthalimide compound and the pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, comprising the following compounds:
Figure FDA0003277129820000041
Figure FDA0003277129820000051
Figure FDA0003277129820000061
Figure FDA0003277129820000071
12. a pharmaceutical composition comprising the phthalimide compound of any of claims 1-11, and pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.
13. Use of phthalimide compounds according to any of claims 1-11, and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the prevention or treatment of a disease associated with dysregulation of the WNT signaling pathway.
14. Use according to claim 13, characterized in that the WNT signalling pathway disorder is selected from the group consisting of porcupine protein secretion disorders.
15. Use according to claim 13, characterized in that the disease is selected from the group consisting of tumors, cardiovascular diseases, metabolic diseases or neurodegenerative diseases.
16. Use according to claims 13 to 15, characterized in that the tumor is selected from colon cancer, rectal cancer, pancreatic cancer, gastric cancer, kidney cancer, breast cancer, ovarian cancer, lung cancer, prostate cancer, bladder cancer, epithelial cancer, esophageal cancer, cervical cancer, endometrial cancer, adrenocortical cancer, basal cell carcinoma, adenocarcinoma, bronchial cancer, hepatoma, cholangiocarcinoma, choriocarcinoma, embryonal carcinoma, leukemia, melanoma, glioma, astrocytoma, medulloblastoma, hodgkin's lymphoma, non-hodgkin's lymphoma, multiple myeloma or primary brain tumor; the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, cerebellar atrophy, Huntington's disease, spinal muscular atrophy, Creutzfeldt-Jakob disease; the metabolic disease is selected from osteoporosis, diabetes, cystoid macular edema, uveitis-related cystoid macular edema, retinopathy, diabetic retinopathy or retinopathy of prematurity; the cardiovascular and cerebrovascular diseases are selected from myocardial ischemia, myocardial hypertrophy, heart failure or ischemic stroke.
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