CN113929662B - Succinimide or maleimide compound and use thereof - Google Patents

Succinimide or maleimide compound and use thereof Download PDF

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CN113929662B
CN113929662B CN202111123042.0A CN202111123042A CN113929662B CN 113929662 B CN113929662 B CN 113929662B CN 202111123042 A CN202111123042 A CN 202111123042A CN 113929662 B CN113929662 B CN 113929662B
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CN113929662A (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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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a succinimide or maleimide compound and application thereof. The compounds according to the invention have the structure shown in formula I.

Description

Succinimide or maleimide compounds and uses thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a succinimide or maleimide compound and application thereof.
Background
The Wnt signaling pathway is a complex network of protein actions whose function is most common in embryonic development and cancer, but also involved in 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 (winless) 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 wigless gene. A mutation in the wingless gene in Drosophila could lead to a wingless abnormality, while replication and integration of MMTV into the genome in mouse mammary tumors could 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, and at the same time, this signaling pathway is connected to other signaling pathways (e.g., TGFbeta/BMP, hedgehog, PI) 3 K. RTK, 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 maintenance of stem 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 complex' is inhibited, the beta-catenin in cytoplasm stably exists, and part of the beta-catenin enters into nucleus to act with TCF/LEF transcription factor family and promote the expression of specific gene.
The Wnt pathway includes 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 in the cytoplasm, and transcriptional regulatory moieties in the nucleus. This pathway regulates cellular behavior primarily through the DNA-binding protein transcriptional properties of the TCF/LEF family, where the most critical is the stabilization of the 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 century, the involvement of the Wnt pathway was found in hereditary Familial Adenomatous Polyposis (FAP) and spontaneously formed colon cancer, thereby linking the Wnt signaling pathway with 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 sternness 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 BDA0003277713460000021
wherein R is 1 Selected from unsubstituted or substituted by 1-4R 2 Substituted succinimides, unsubstituted or substituted by 1 to 4R 2 Substituted maleimides, unsubstituted or substituted by 1-4R 2 Substituted phthalimides, unsubstituted or substituted with 1 to 4R 2 Substituted cycloalkylsuccinimide, unsubstituted or substituted by 1-4R 2 Substituted cycloalkenyl-succinimides;
the R is 2 Selected from substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 2 -C 8 Alkenyl, substituted or unsubstituted C 2 -C 8 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms 3 -C 8 Heterocycloalkyl, substituted or unsubstituted C 1 -C 8 Alkoxy, substituted or unsubstituted C 6 -C 12 Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms 2 -C 12 Heteroaromatic compoundsBase, C 1 -C 8 Amide group, C 1 -C 8 Ester group, carboxyl group, cyano group, halogen, hydroxyl group, amino group or nitro group;
x is selected from unsubstituted or substituted by 1-3R 3 Substituted C 1 -C 6 Alkylene, unsubstituted or substituted by 1 to 3R 3 Substituted C 2 -C 6 Alkenyl, unsubstituted or substituted by 1-3R 3 Substituted C 2 -C 6 Alkynyl, unsubstituted or substituted by 1-3R 3 Substituted C 3 -C 6 Cycloalkyl, unsubstituted or substituted by 1-3R 3 Substituted C 3 -C 6 Cycloalkyl monoalkyl radicals, unsubstituted or substituted by 1-3R 3 Substituted C 3 -C 6 Cycloalkyldialkyl, unsubstituted or substituted by 1-3R 3 Substituted aryl, unsubstituted or substituted by 1-3R 3 Substituted aryl monoalkyl, unsubstituted or substituted by 1-3R 3 Substituted aryl dialkyl;
said R is 3 Selected from substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 2 -C 8 Alkenyl, substituted or unsubstituted C 2 -C 8 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms 3 -C 8 Heterocycloalkyl, substituted or unsubstituted C 1 -C 8 Alkoxy, substituted or unsubstituted C 6 -C 12 Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms 2 -C 12 Heteroaryl group, C 1 -C 8 Amide group, C 1 -C 8 Ester group, carboxyl group, cyano group, halogen, hydroxyl group, amino group or nitro group;
a is selected from unsubstituted or substituted by 1-3R 4 Substituted phenyl or heteroaryl, B is selected from unsubstituted or substituted by 1-3R 5 Substituted phenyl or heteroaryl, and A and B form a bi-aromatic structure;
in groups a, B, the heteroaryl group is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, indolyl, benzofuranyl, dibenzopyranyl, benzothienyl, dibenzothienyl;
said R is 4 Selected from substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 2 -C 8 Alkenyl, substituted or unsubstituted C 2 -C 8 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C containing 1 to 2 hetero atoms 3 -C 8 Heterocycloalkyl, substituted or unsubstituted C 1 -C 8 Alkoxy, substituted or unsubstituted C 6 -C 12 Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms 2 -C 12 Heteroaryl group, C 1 -C 8 Amide group, C 1 -C 8 Ester group, carboxyl group, cyano group, halogen, hydroxyl group, amino group or nitro group;
said R is 5 Selected from substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 2 -C 8 Alkenyl, substituted or unsubstituted C 2 -C 8 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C containing 1 to 2 hetero atoms 3 -C 8 Heterocycloalkyl, substituted or unsubstituted C 1 -C 8 Alkoxy, substituted or unsubstituted C 6 -C 12 Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms 2 -C 12 Heteroaryl group, C 1 -C 8 Amide group, C 1 -C 8 Ester group, carboxyl group, cyano group, halogen, hydroxyl group, amino group or nitro group;
the above substituents are independently selected from C 1 -C 3 Alkyl, halogen substituted C 1 -C 3 Alkyl radical, C 1 -C 4 Alkoxy, 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 BDA0003277713460000031
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 R 4 Selected from substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 2 -C 8 Alkenyl, substituted or unsubstituted C 2 -C 8 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms 3 -C 8 Heterocycloalkyl, substituted or unsubstituted C 1 -C 8 Alkoxy, substituted or unsubstituted C 6 -C 12 Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms 2 -C 12 Heteroaryl group, C 1 -C 8 Amide group, C 1 -C 8 Ester group, carboxyl, cyano, halogen, hydroxyl, amino or nitro, and the substituents are independently selected from C 1 -C 3 Alkyl, halogen substituted C 1 -C 3 Alkyl radical, C 1 -C 4 Alkoxy, 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;
(R 4 ) n represents n numbers of R 4 And n is selected from 1 or 2.
According to one embodiment of the invention, B is selected from:
Figure BDA0003277713460000041
the R is 5 Selected from substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 2 -C 8 Alkenyl, substituted or unsubstituted C 2 -C 8 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C containing 1 to 2 hetero atoms 3 -C 8 Heterocycloalkyl, substituted or unsubstituted C 1 -C 8 Alkoxy, substituted or unsubstituted C 6 -C 12 Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms 2 -C 12 Heteroaryl group, C 1 -C 8 Amide group, C 1 -C 8 Ester group, carboxyl, cyano, halogen, hydroxyl, amino or nitro, and the substituents are independently selected from C 1 -C 3 Alkyl, halogen substituted C 1 -C 3 Alkyl radical, C 1 -C 4 Alkoxy, 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;
(R 5 ) n represents n numbers of R 5 And 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 BDA0003277713460000051
wherein R is 1 Selected from unsubstituted or substituted by 1-4R 2 Substituted succinimides, unsubstituted or substituted by 1 to 4R 2 Substituted maleimide, substituted with 1-4R 2 Substituted phthalimides, unsubstituted or substituted with 1 to 4R 2 Substituted cycloalkylsuccinimide, unsubstituted or substituted by 1-4R 2 Substituted cycloalkenyl-succinimides;
the R is 2 Selected from substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 2 -C 8 Alkenyl, substituted or unsubstituted C 2 -C 8 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms 3 -C 8 Heterocycloalkyl, substituted or unsubstituted C 1 -C 8 Alkoxy, substituted or unsubstituted C 6 -C 12 Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms 2 -C 12 Heteroaryl group, C 1 -C 8 Amide group, C 1 -C 8 Ester, carboxyl, cyano, halogen, hydroxyl, amino or nitro;
x is selected from unsubstituted or substituted by 1-3R 3 Substituted C 1 -C 6 Alkyl, unsubstituted or substituted by 1-3R 3 Substituted C 2 -C 6 Alkenyl, unsubstituted or substituted by 1-3R 3 Substituted C 2 -C 6 Alkynyl, unsubstituted or substituted by 1-3R 3 Substituted C 3 -C 6 Cycloalkyl, unsubstituted or substituted by 1-3R 3 Substituted C 3 -C 6 Cycloalkyl monoalkyl radicals, unsubstituted or substituted by 1-3R 3 Substituted C 3 -C 6 Cycloalkyldialkyl, unsubstituted or substituted by 1-3R 3 Substituted aryl, unsubstituted or substituted by 1-3R 3 Substituted aryl monoalkyl radicals, unsubstituted or substituted by 1 to 3R 3 Substituted aryl dialkyl;
the R is 3 Selected from substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 2 -C 8 Alkenyl, substituted or unsubstituted C 2 -C 8 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms 3 -C 8 Heterocycloalkyl, substituted or unsubstituted C 1 -C 8 Alkoxy, substituted or unsubstituted C 6 -C 12 Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms 2 -C 12 Heteroaryl group, C 1 -C 8 Amide group, C 1 -C 8 Ester group, carboxyl group, cyano group, halogen, hydroxyl group, amino group or nitro group;
the substituents are independently selected from C 1 -C 3 Alkyl, halogen substituted C 1 -C 3 Alkyl radical, C 1 -C 4 Alkoxy, 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 BDA0003277713460000052
preferred compounds of the present invention have the structure shown in IA-2:
Figure BDA0003277713460000053
preferred compounds of the present invention have the structure shown in IA-3:
Figure BDA0003277713460000061
preferred compounds of the present invention have the structure shown in IA-4:
Figure BDA0003277713460000062
preferred compounds of the present invention have the structure IA-5:
Figure BDA0003277713460000063
preferred compounds of the present invention have the structure shown in IA-6:
Figure BDA0003277713460000064
preferred compounds of the present invention have the structure IA-7:
Figure BDA0003277713460000065
preferred compounds of the present invention have the structure shown in IA-8:
Figure BDA0003277713460000066
in the above formulae IA-1 to IA-8, R 1 Selected from unsubstituted or substituted by 1-4R 2 Substituted succinimides, unsubstituted or substituted by 1 to 4R 2 Substituted maleimide, substituted with 1-4R 2 Substituted phthalimides, unsubstituted or substituted by 1 to 4R 2 Substituted cycloalkylsuccinimide, unsubstituted or substituted by 1-4R 2 Substituted cycloalkenyl-succinimides;
the R is 2 Selected from substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 2 -C 8 Alkenyl, substituted or unsubstituted C 2 -C 8 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms 3 -C 8 Heterocycloalkyl, substituted or unsubstituted C 1 -C 8 Alkoxy, substituted or unsubstituted C 6 -C 12 Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms 2 -C 12 Heteroaryl, alkylene bridge, oxygen bridge, nitrogen bridge, C 1 -C 8 Amide group, C 1 -C 8 Ester group, carboxyl, cyano-group, halogen, hydroxyl, amino or nitro, wherein the halogen is selected from F, cl, br or I, and the heteroatom is selected from N, O, S and P;
more preferably, R 1 Selected from the following structures:
Figure BDA0003277713460000071
the R is 2 Selected from substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 2 -C 8 Alkenyl, substituted or unsubstituted C 2 -C 8 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms 3 -C 8 Heterocycloalkyl, substituted or unsubstituted C 1 -C 8 Alkoxy, substituted or unsubstituted C 6 -C 12 Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms 2 -C 12 Heteroaryl group, C 1 -C 8 Amide group, C 1 -C 8 Ester group, carboxyl, cyano, halogen, hydroxyl, amino or nitro, and the substituent is independently selected from C 1 -C 3 Alkyl, halogen substituted C 1 -C 3 Alkyl radical, C 1 -C 4 Alkoxy, 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 ) n represents by n R 2 And 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 BDA0003277713460000072
Figure BDA0003277713460000081
Figure BDA0003277713460000091
Figure BDA0003277713460000101
Figure BDA0003277713460000111
Figure BDA0003277713460000121
Figure BDA0003277713460000131
Figure BDA0003277713460000141
Figure BDA0003277713460000151
Figure BDA0003277713460000161
Figure BDA0003277713460000171
Figure BDA0003277713460000181
Figure BDA0003277713460000191
Figure BDA0003277713460000201
Figure BDA0003277713460000211
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 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, solid or 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, 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 as coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layered and multi-layered tablets.
To encapsulate the administration units, the active ingredient compounds of the invention can be mixed with diluents and cosolvents and the mixture placed directly into hard or soft capsules. 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 diluent, adhesive, wetting agent, disintegrating agent and cosolvent used for preparing the compound tablet can also be used for preparing capsules of the compound.
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, in the preparation of lyophilized powder for injection, mannitol and glucose can also be added as proppant.
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 doses 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 has a synergistic effect with other therapeutic agents, its dosage 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 an intermediate connecting chain (NH in the figure) 2 linker-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 products, where the substituted benzidine compounds can be prepared from the corresponding halogenated compounds and borate compounds by metal-catalyzed coupling reactions.
Figure BDA0003277713460000231
The A is selected from:
Figure BDA0003277713460000232
a is connected to B through a carbon-carbon single bond, wherein the dotted line represents the connection to the amide nitrogen atom, the wavy line represents the connection to B, and R 4 Selected from substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 2 -C 8 Alkenyl, substituted or unsubstituted C 2 -C 8 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C containing 1-2 heteroatoms 3 -C 8 A heterocycloalkyl group,Substituted or unsubstituted C 1 -C 8 Alkoxy, substituted or unsubstituted C 6 -C 12 Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms 2 -C 12 Heteroaryl group, C 1 -C 8 Amide group, C 1 -C 8 Ester group, carboxyl, cyano, halogen, hydroxyl, amino or nitro, and the substituent is independently selected from C 1 -C 3 Alkyl, halogen substituted C 1 -C 3 Alkyl radical, C 1 -C 4 Alkoxy, 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;
(R 4 ) n represents by n R 4 And n is selected from 1 or 2.
According to one embodiment of the invention, B is selected from:
Figure BDA0003277713460000241
the R is 5 Selected from substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 2 -C 8 Alkenyl, substituted or unsubstituted C 2 -C 8 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C containing 1 to 2 hetero atoms 3 -C 8 Heterocycloalkyl, substituted or unsubstituted C 1 -C 8 Alkoxy, substituted or unsubstituted C 6 -C 12 Aryl, substituted or unsubstituted C containing 1 to 4 hetero atoms 2 -C 12 Heteroaryl group, C 1 -C 8 Amide group, C 1 -C 8 Ester group, carboxyl, cyano, halogen, hydroxyl, amino or nitro, and the substituents are independently selected from C 1 -C 3 Alkyl, halogen substituted C 1 -C 3 Alkyl radical, C 1 -C 4 Alkoxy, 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;
(R 5 ) n to representIs covered by n R 5 And n is selected from 1,2 or 3.
In the fourth aspect of the invention, the amide-type compound for regulating WNT signal pathway and the pharmaceutically acceptable salt thereof are provided for use in preparing a medicament for preventing or treating related diseases caused by WNT signal pathway dysregulation.
The WNT signaling pathway disorder is selected from the group consisting of 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 1 The radical R in the formula I
“R 1 Selected from the group consisting of 1-4R 2 Substituted succinimides, maleimides, phthalimides, cycloalkyldisuccinimides, cycloalkenyldisuccinimides "are intended to denote R 1 Can be substituted by 1-4R 2 Substituted, and when substituted by more than 2R 2 When substituted, the 2 or more R 2 May be identical, completely different or partially identical to each other. For example, R 1 Is selected from 3R 2 In the case of substituted phthalimides, the three R' s 2 May each be selected, for example, from methyl, for example Cl, or from the group in which two R are present 2 Selected from, for example, ethyl, another R 2 Selected from, for example, nitro, and also the three R 2 Are respectively selected from nitro, methyl and Cl.
"X is selected from the group consisting of 1-3R 3 Substituted 8230, A is selected from the group consisting of substituted R1-3 4 Substituted phenyl or heteroaryl "," B is selected from the group consisting of substituted phenyl or heteroaryl groups substituted with 1-3R 5 Substituted phenyl or heteroaryl groups "are also to be understood identically.
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.
“C 1 -C 8 The "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.
“C 2 -C 8 The "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.
“C 2 -C 8 Alkynyl "means a straight or branched chain alkynyl group of 2, 3, 4,5, 6, 7, 8 carbon atoms, the unsaturated triple bond may be at any position, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynylHeptynyl, octynyl, and the like.
“C 3 -C 8 The 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.
“C 2 -C 8 The 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.
“C 1 -C 8 Alkoxy "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.
“C 6 -C 12 Aryl "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.
“C 3 -C 8 Heteroaryl "refers to a cyclic aromatic hydrocarbon group having 3, 4,5, 6, 7, 8 carbon atoms and substituted with N, O, S, P, si, B, the number of heteroatoms being 1,2, 3, 4,5, wherein the heterocyclic group includes monocyclic and fused ring structures, furan, thiophene, pyrrole, pyrazine, thiazole, imidazole, oxazole, pyrazole, pyridine, pyrimidine, indole, benzofuran, benzothiophene, benzimidazole, purine and mixtures thereofSubstituted radicals, e.g. furylmethyl, furylethyl, etc
When R is 2 Selected from substituted C 1 -C 8 Alkyl radical, C 2 -C 8 Alkenyl of 8230am, when refers to R 2 May be C substituted by halogen (F, cl, br or I), hydroxyl, mercapto, amino, nitro, etc 1 -C 8 Alkyl radical, C 1 -C 8 Alkenyl group 8230; and can be used as carrier.
For R 3 、R 4 、R 5 Selected from substituted C 1 -C 8 Alkyl radical, C 1 -C 8 Alkenyl groups of 823060, also to R 2 The 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, C 6 -C 12 Aryl radical C 1 -C 6 Alkyl, 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, C 1 -C 6 Alkyl radical C 6 -C 12 Aryl radical C 1 -C 6 Alkyl, 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 R 1 The 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, C 3 -C 6 Cycloalkyl radical C 1 -C 6 Alkyl, i.e. cycloalkyl having 3, 4,5 or 6 carbon atoms substituted by alkyl having 1,2, 3, 4,5 or 6 carbon atoms, e.g. may be C 3 -C 6 Cycloalkyl radical C 1 -C 3 Alkyl radicals, e.g. by C 1 -C 6 Cyclohexyl substituted by alkyl, by C 1 -C 3 Alkyl-substituted cyclohexyl 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, C 1 -C 6 Alkyl radical C 3 -C 6 Cycloalkyl radical C 1 -C 6 Alkyl, 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 C 1 -C 3 Alkyl radical C 3 -C 6 Cycloalkyl radical C 1 -C 3 Alkyl radicals, e.g. by two C 1 -C 6 Cyclohexyl substituted by alkyl, by two C 1 -C 3 Alkyl-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 3R 3 Substituted C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 3 -C 6 When a cycloalkyl group is present, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl radicals are to the term- 1 The 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 R 1 The 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. Similarly, for R 2 、R 3 、R 4 And R 5 The description of a specific group selected from the group consisting of 1 The radical R in the formula I]Partial phase ofSimilar/identical terms are to be understood.
Groups A, B in the general 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, 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 C 6 -C 5 -C 6 Or C 6 -C 6 -C 6 Such a structure.
For R 4 、R 5 The specification of a specific group selected from the group consisting of 1 The radical R in the formula I]Similar/identical terms in parts are understood similarly/identically.
“(R 2 ) n Represents n numbers of R 2 Substituted, n is selected from 1,2 or 3' and means that there are 1,2 or 3 substituents R in the compound 2 And when there are more than 2R in the compound 2 When the number of R is 2 or more 2 May be identical to each other,Completely different or partially identical.
For (R) 4 ) n 、(R 5 ) n Should also be taken as being (R) 2 ) n The 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 BDA0003277713460000271
succinic anhydride (200mg, 2.0 mmol) and 4-aminobutyric acid (206mg, 2.0 mmol) were added to glacial acetic acid (10 mL), and heated to 100 ℃ for reaction for 3 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, mixing the organic phases, drying over anhydrous sodium sulfate to obtain a yellow solid 400mg 1 H-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 (10 ml), triethylamine (394. Mu.L, 2.92 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (330mg, 1.94mmol) was added, and the reaction was carried out at room temperature for 24 hours. After filtration, inorganic salt filter residues are removed, and the filtrate is stirred with 60-100 mesh silica gel and separated and purified by silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is performed in 1-10), 510mg of white solid is obtained, and the yield is 68.1%. HR ESI-MS (m/z): 338.1505 2M + H] + 。
Example 2
Figure BDA0003277713460000281
3-Fluorophthalic anhydride (332mg, 2.0 m)mol) and 4-aminobutyric acid (206mg, 2.0 mmol) were added to glacial acetic acid (10 mL) and heated to 100 ℃ for reaction for 3h. The reaction was quenched with water (10 mL) and adjusted to pH 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. Times.3), saturated NaHCO 3 Washing the solution with water, combining the organic phases, drying over anhydrous sodium sulfate to obtain a yellow solid 370mg 1 H-NMR confirmed that it 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 (10 ml), triethylamine (300. Mu.L, 2.22 mmol) 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 hours. The mixture was filtered to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 245mg of white solid with a yield of 40.5%.
HR ESI-MS(m/z)：404.1399[M+H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000282
4-Fluorophthalic anhydride (332mg, 2.0 mmol) and 4-aminobutyric acid (206mg, 2.0 mmol) were added to glacial acetic acid (10 mL), and heated to 100 ℃ for reaction for 3h. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, combining the organic phases, drying over anhydrous sodium sulfate to obtain a yellow solid 370mg 1 H-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 di-ethanolTo methyl chloride (10 ml), triethylamine (300. Mu.L, 2.22 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminophenylpyridine (251mg, 1.47mmol) was added and reacted at room temperature for 24 hours. After filtration, inorganic salt filter residues are removed, and the filtrate is stirred with 60-100 mesh silica gel and separated and purified by silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is performed in 1-10). HR ESI-MS (m/z): 404.1399[ M ] +H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000291
4-chlorophthalic anhydride (362mg, 2.0 mmol) and 4-aminobutyric acid (206mg, 2.0 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ for reaction for 3 hours. The reaction was quenched with water (10 mL) and adjusted to pH 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. Times.3), saturated NaHCO 3 Washing the solution with water, combining the organic phases, drying over anhydrous sodium sulfate to obtain a yellow solid 460mg 1 H-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 (10 ml), triethylamine (360. Mu.L, 2.58 mmol) was added dropwise, stirring was carried out at room temperature for 10min, then 2-aminopyridine (293mg, 1.72mmol) was added, and reaction was carried out at room temperature for 24h. 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; 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 400mg, yield 55.1%.
HR ESI-MS(m/z)：420.1104[M+H] + ， 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000292
4-Bromophthalic anhydride (450mg, 2.0 mmol) and 4-aminobutyric acid (206mg, 2.0 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ for reaction for 3 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, mixing the organic phases, drying over anhydrous sodium sulfate to obtain a yellow solid 600mg 1 H-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 (10 ml), triethylamine (405. Mu.L, 2.90 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (328mg, 1.93mmol) was added and reacted at room temperature for 24h. 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, heat dissolve with ethyl acetate, cool for 2h with low temperature, suction filter to give a pale yellow solid, dry weigh about 495mg, yield 55.1% HR ESI-MS (m/z): 464.0606[ M ] +H] + 。
1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000301
4-nitro-phthalic acid diFormic anhydride (386mg, 2.0 mmol) and 4-aminobutyric acid (206mg, 2.0 mmol) were added to glacial acetic acid (10 mL) and heated to 100 ℃ for 3h. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 572mg 1 H-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 (10 ml), triethylamine (405. Mu.L, 2.90 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (328mg, 1.93mmol) was added and reacted at room temperature for 24h. 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 500mg, yield 58.4%. HR ESI-MS (m/z): 431.1310[ M ] +H] + 。
1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000302
4, 5-dichlorophthalic anhydride (430mg, 2.0 mmol) and 4-aminobutyric acid (206mg, 2.0 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ for reaction for 3 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 576mg, mixing with LC-MS and LC-MS, and drying to obtain white solid 1 H-NMR confirmed that it was the expected intermediate compound in a yield of 96.0%.
The intermediate compound (576mg, 1.92 mmol) and HATU (950mg, 2.50mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (400. Mu.L, 2.89 mmol) 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 hours. 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 under suction to give a pale yellow solid, dried and weighed at 594mg, with a yield of 68.2%. HR ESI-MS (m/z): 454.0695[ M ] +H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000311
Tetrachlorophthalic anhydride (566 mg,2.0 mmol) and 4-aminobutyric acid (206mg, 2.0 mmol) were added to glacial acetic acid (10 mL), and heated to 100 ℃ for reaction for 3h. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 726mg 1 H-NMR confirmed that it was the expected intermediate compound in a yield of 98.7%.
The intermediate compound (726 mg, 1.97mmol) and HATU (975mg, 2.57mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (400. Mu.L, 2.96 mmol) 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 hours. 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 718mg, yield 69.0%. HR ESI-MS (m/z): 524.1623[ M ] +H] + 。 1 H NMR(400MHz,DMSO-d 6 )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 BDA0003277713460000312
4-Methylphthalic anhydride (490mg, 3.0 mmol) and 4-aminobutyric acid (320mg, 3.1mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ to react for 3 hours. The reaction was quenched with water (10 mL) and adjusted to pH 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. Times.3), saturated NaHCO 3 Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 700mg 1 H-NMR confirmed that it was the expected intermediate compound in 93.7% yield. The intermediate compound (700mg, 2.81mmol) and HATU (1.4g, 3.65mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (580. Mu.L, 4.22 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (484mg, 2.81mmol) was added and reacted at room temperature for 24h. The mixture was filtered to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 573mg of a white solid with a yield of 50.5%.
HR ESI-MS(m/z)：400.1665[M+H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000321
4-Isobutylphthalic anhydride (500mg, 2.45mmol) and 4-aminobutyric acid (260mg, 2.5 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ to react for 3 hours. The reaction was quenched with water (10 mL), NThe solution pH of the solution is adjusted to 6-8 by the aOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. Times.3), saturated NaHCO 3 Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 620mg 1 H-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 (10 ml), triethylamine (470. Mu.L, 3.21 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (370mg, 2.15mmol) was added and reacted at room temperature for 24h. The mixture was filtered to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 573mg of a white solid with a yield of 50.5%.
HR ESI-MS(m/z)：442.2141[M+H] +1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000322
4-Alkynylphenylphthalic anhydride (500mg, 2.0 mmol) and 4-aminobutyric acid (206mg, 2.0 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ for reaction for 3 hours. The reaction was quenched with water (10 mL) and adjusted to pH 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. Times.3), saturated NaHCO 3 Washing with solution, water washing, combining organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 608mg 1 H-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 (10 ml), triethylamine (373. Mu.L, 2.73 mmol) was added dropwise, stirring was carried out at room temperature for 10min, and 2-aminobenzylpyridine (313mg, 1.82mmol) was added and reacted at room temperature for 48 hours. Filtering and removingFiltering inorganic salt, 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[ 2 ] M + H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000331
3-cyanophthalic anhydride (500mg, 2.0 mmol) and 4-aminobutyric acid (206mg, 2.0 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ for reaction for 3 hours. The reaction was quenched with water (10 mL) and adjusted to pH 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. Times.3), saturated NaHCO 3 Washing with solution, water washing, combining organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 608mg 1 H-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 (10 ml), triethylamine (373. Mu.L, 2.73 mmol) was added dropwise, stirring was carried out at room temperature for 10min, and 2-aminobenzylpyridine (313mg, 1.82mmol) was added and reacted at room temperature for 48 hours. 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 BDA0003277713460000332
3-Nitrophthalic anhydride (386mg, 2.0 mmol) and 4-aminobutyric acid (206mg, 2.0 mmol) were added to glacial acetic acid (10 mL), and heated to 100 ℃ for 3 hours. The reaction was quenched with water (10 mL) and adjusted to pH 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. Times.3), saturated NaHCO 3 Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 570mg, LC-MS and 1 H-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 (10 ml), triethylamine (405. Mu.L, 2.90 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (328mg, 1.93mmol) was added and reacted at room temperature for 24h. 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[ 2 ] M + H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000341
3-Methylphthalic anhydride (490 mg,3.0 mmol) and 4-aminobutyric acid (320mg, 3.1mmol) were added to glacial acetic acid (10 mL) and heated to 100 deg.C for 3h. The reaction was quenched with water (10 mL) and adjusted to pH 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. Times.3), saturated NaHCO 3 Washing the solution with water, combining the organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 686mg 1 H-NMR confirmed that it was the expected intermediate compound in a yield of 91.8%.
Intermediate compound (A), (B), (C) and (C)686mg, 2.75mmol) and HATU (1.4 g, 3.65mmol) were dissolved in dry dichloromethane (10 ml), triethylamine (580. Mu.L, 4.22 mmol) was added dropwise, after stirring at room temperature for 10min, 2-aminopyridine (484mg, 2.81mmol) was added and reacted at room temperature for 24h. After filtration, inorganic salt filter residues are removed, and the filtrate is stirred with 60-100 mesh silica gel and separated and purified by silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is carried out at 1-10), 564mg of white solid is obtained, and the yield is 50.5%. HR ESI-MS (m/z): 400.1648[ M ] +H] +1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000342
3,6-Difluorophthalic anhydride (368mg, 2.0 mmol) and 4-aminobutyric acid (210mg, 2.0 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ to react for 3 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 365mg 1 H-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 (10 ml), triethylamine (300. Mu.L, 2.18 mmol) 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 hours. After filtration, inorganic salt filter residues are removed, and the filtrate is stirred with 60-100 mesh silica gel and separated and purified by silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is performed in 1-10), 232mg of white solid is obtained, and the yield is 40.1%.
HR ESI-MS(m/z)：422.1313[M+H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000351
3,6-Difluorophthalic anhydride (368mg, 2.0 mmol) and 4-aminobutyric acid (210mg, 2.0 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ to react for 3 hours. The reaction was quenched with water (10 mL) and adjusted to pH 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. Times.3), saturated NaHCO 3 Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 365mg 1 H-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 (10 ml), triethylamine (300. Mu.L, 2.18 mmol) 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 hours. The mixture was filtered to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 232mg of white solid with a yield of 40.1%.
HR ESI-MS(m/z)：422.1293[M+H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000352
Phthalic anhydride (450mg, 3.0 mmol) and 4-aminobenzoic acid (415mg, 3.0 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ for reaction for 3 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 750mg 1 H-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 (10 ml), triethylamine (482. Mu.L, 3.57 mmol) 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 hours. 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] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000361
Phthalic anhydride (450mg, 3.0 mmol) and 3-aminobenzoic acid (415mg, 3.0 mmol) were added to glacial acetic acid (10 mL), and heated to 100 ℃ for reaction for 3h. The reaction was quenched with water (10 mL) and adjusted to pH 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. Times.3), saturated NaHCO 3 Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 746mg 1 H-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 (10 ml), triethylamine (482. Mu.L, 3.57 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (481mg, 2.83mmol) was added and reacted at room temperature for 18h. 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] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000362
Phthalic anhydride (450mg, 3.0 mmol) and 4-aminophenylacetic acid (460mg, 3.0 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ for reaction for 3 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 835mg 1 H-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 (10 ml), triethylamine (582. Mu.L, 4.46 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (505mg, 2.97mmol) was added and reacted at room temperature for 18h. 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%.
1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000371
Phenylmaleic anhydride (522mg, 3.0 mmol) and 3-aminobenzoic acid (415mg, 3.0 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ for reaction for 3 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 820mg, LC-MS and 1 H-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 (10 ml), triethylamine (482. Mu.L, 3.57 mmol) was dropwise added thereto, and after stirring at room temperature for 10min, 2-aminopyridine (481mg, 2.83mmol) was added and reacted at room temperature for 24 hours. 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, yield 46.2%. HR ESI-MS (m/z): 446.1480M + H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000372
Phenylmaleic anhydride (522mg, 3.0 mmol) and 4-aminobenzoic acid (415mg, 3.0 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ for reaction for 3 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 817mg, LC-MS and 1 H-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 (10 ml), triethylamine (482. Mu.L, 3.57 mmol) 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 hours. 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 by heating, and a white solid was precipitated by cooling, and the solution was dried and weighed 610mg, and the yield was 47.0%. HR ESI-MS (m/z): 446.1476[ M ] +H] +1 H-NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000381
Phenylmaleic anhydride (522mg, 3.0 mmol) and 4-aminophenylacetic acid (453mg, 3.0 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ for reaction for 3 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 860mg, LC-MS and 1 H-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 (10 ml), triethylamine (482. Mu.L, 3.57 mmol) 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 24h. Filtration to remove inorganic salt residues, and dressing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is carried out from 1 to 10) to obtain two white solids, wherein 496mg of the target product is expected, and the yield is 39.8%; another white solid is by-product 23.
HR ESI-MS(m/z)：460.1647[M+H] + ， 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000382
HR ESI-MS(m/z)：412.1046[M+H] + 。
Example 24
Figure BDA0003277713460000391
Phenyl maleic anhydride (520mg, 3.0 mmol) and 4-aminobutyric acid (310mg, 3.0 mmol) were added to glacial acetic acid (10 mL), and heated to 100 ℃ for reaction for 3h. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 690mg, mixing with LC-MS, and 1 H-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 (10 ml), triethylamine (482. Mu.L, 3.57 mmol) 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 hours. The mixture was filtered to remove inorganic salt residues, and the filtrate was stirred with 60-100 mesh silica gel and isolated and purified by silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is performed from 1 to 10), and after drying, 547mg of dry matter was weighed, and the yield was 47.1%. HR ESI-MS (m/z): 412.1625[ M ] +H] + ， 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000392
Succinic anhydride (200mg, 2.0mmol) and 3-aminobenzoic acid (275mg, 2.0mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ to react for 3 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 350mg 1 H-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 (10 ml), triethylamine (332. Mu.L, 2.46 mmol) 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 hours. The mixture was filtered to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 240mg of white solid with a yield of 39.4%. HR ESI-MS (m/z): 372.1331[ M ] +H] + 。 1 H NMR(400MHz,DMSO-d 6 )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 BDA0003277713460000401
Maleic anhydride (200mg, 2.0 mmol) and 4-aminobenzoic acid (275mg, 2.0 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ for reaction for 3 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 353mg, LC-MS and 1 H-NMR confirmed that it was the expected intermediate compound in 82.1% yield.
The intermediate compound (353mg, 1.64mmol) andHATU (810mg, 2.14mmol) was dissolved in anhydrous dichloromethane (10 ml), triethylamine (332. Mu.L, 2.46 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24h. The mixture was filtered to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 200mg of white solid with a yield of 32.8%. HR ESI-MS (m/z): 370.1192[ m ] +H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000402
Succinic anhydride (200mg, 2.0 mmol) and 4-aminophenylacetic acid (300mg, 2.0 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ for reaction for 3 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 373mg, mixing with LC-MS and 1 H-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 (10 ml), triethylamine (332. Mu.L, 2.46 mmol) 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 hours. Filtration was carried out to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 281mg of a white solid with a yield of 45.0%. HR ESI-MS (m/z): 386.1520[ 2 ], [ M ] +H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000411
Maleic anhydride (200mg, 2.0 mmol) and 4-aminobutyric acid (210mg, 2.0 mmol) were added to glacial acetic acid (10 mL), and heated to 100 ℃ for reaction for 3 hours. The reaction was quenched with water (10 mL) and adjusted to pH 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. Times.3), saturated NaHCO 3 Washing the solution with water, combining the organic phases, drying over anhydrous sodium sulfate to obtain a yellow solid 222mg 1 H-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 (10 ml), triethylamine (246. Mu.L, 1.83 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (210mg, 1.23mmol) was added and reacted at room temperature for 24h. After filtration, inorganic salt filter residues are removed, and the filtrate is stirred with 60-100 mesh silica gel and separated and purified by silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is carried out at 1-10) to obtain 134mg of white solid with yield of 32.8%. HR ESI-MS (m/z): 336.1340[ M ] +H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000412
maleic anhydride (200mg, 2.0 mmol) and 4-aminophenylacetic acid (300mg, 2.0 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ for reaction for 3 hours. The reaction was quenched with water (10 mL) and adjusted to pH 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. Times.3), saturated NaHCO 3 Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate, and drying to obtain yellow solid 380mg, LC-MS and 1 H-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 (10 ml), triethylamine (332. Mu.L, 2.46 mmol) 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 hours. After filtration to remove inorganic salt residue, the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 314mg of white solid with a yield of 50.0%. HR ESI-MS (m/z): 384.1334[ M ] +H] +1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000413
(3aR, 4R,7R, 7aS) -5-methyl-3a,4,7,7a-tetrahydro-4, 7-methanosorzofuran-1, 3-dione (360mg, 2.0 mmol) and 3-aminobenzoic acid (280mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing 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 1 H-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 (10 ml), triethylamine (332. Mu.L, 2.46 mmol) 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 hours. The mixture was filtered to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 226mg of white solid with a yield of 39.6%.
HR ESI-MS(m/z)：450.1818[M+H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000421
(3aR, 4R,7R, 7aS) -5-methyl-3a,4, 7a-tetrahydro-4, 7-methanobenzofurans-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 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing 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 392mg 1 H-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 (10 ml), triethylamine (332. Mu.L, 2.46 mmol) was added dropwise, stirring was carried out at room temperature for 10min, 2-aminopyridine (300mg, 2.24mmol) was added, and the reaction was carried out at room temperature for 24h. The mixture was filtered to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 240mg of white solid with a yield of 38.5%. HR ESI-MS (m/z): 415.1896[ m ] +H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000431
Hexahydrophthalic anhydride (310mg, 2.0 mmol) and 3-aminobenzoic acid (280mg, 2.0 mmol) were dissolved in 10mL glacial acetic acid and heated to 120 ℃ for 2h. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution and water, combining organic phases, drying by anhydrous sodium sulfate, separating and purifying by silica gel column to obtain 454mg yellow oily matter 1 H-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 (10 ml), triethylamine (370. Mu.L, 2.75 mmol) 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 hours. The mixture was filtered to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 393mg of white solid with a yield of 50.6%. HR ESI-MS (m/z): 426.1812[ 2 ] M + H] + 。
1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000432
(3aR, 4S,7R, 7aS) -hexahydro-4,7-epoxyisobenzofuran-1,3-dione (336 mg,2.0 mmol) and 3-aminobenzoic acid (280mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with solution, water, combining organic phases,drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 416mg 1 H-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 (10 ml), triethylamine (332. Mu.L, 2.46 mmol) was added dropwise, stirring was performed at room temperature for 10min, and after that, 2-aminopyridine (280mg, 1.64mmol) was added, and the reaction was carried out at room temperature for 24h. After filtration, inorganic salt filter residues are removed, and the filtrate is stirred with 60-100 mesh silica gel and separated and purified by silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is performed in 1-10) to obtain 316mg of white solid with yield of 45.0%. HR ESI-MS (m/z): 440.1615[ M ] C +H] +1 H 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 BDA0003277713460000441
(3aR, 4S,7R, 7aS) -hexahydro-4,7-epoxyisobenzofuran-1,3-dione (336 mg,2.0 mmol) and 4-aminobenzoic acid (280mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, mixing the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 420mg 1 H-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 (10 ml), triethylamine (332. Mu.L, 2.46 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24h. Filtering, removing inorganic salt residue, mixing the filtrate with 60-100 mesh silica gel, separating and purifying with silica gel column(mobile phase: petroleum ether/ethyl acetate =20 gradient elution from 1 to 10) to give 317mg of white solid in 45.1% yield. HR ESI-MS (m/z): 440.1579[ M ] +H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000442
(3aR, 4S,7R, 7aS) -hexahydro-4,7-epoxyisobenzofuran-1,3-dione (336 mg,2.0 mmol) and 4-aminophenylacetic acid (300mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for reaction for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, combining the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 440mg 1 H-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 (10 ml), triethylamine (318. Mu.L, 2.36 mmol) 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 hours. After filtration to remove inorganic salt residue, the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 331mg of white solid with a yield of 46.5%. HR ESI-MS (m/z): 454.1764[ M + H ]] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000451
(3aR, 4S,7R, 7aS) -hexahydro-4,7-epoxyisobenzofuran-1,3-dione (336 mg,2.0 mmol) and 4-aminobutyric acid (210mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for reaction for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, combining organic phases, drying the organic phases with anhydrous sodium sulfate, separating and purifying the organic phases with a silica gel column to obtain 403mg of yellow oil, LC-MS and 1 H-NMR confirmed that it was the expected intermediate compound in 80.5% yield.
The intermediate compound (403mg, 1.61mmol) and HATU (800mg, 2.1 mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (332. Mu.L, 2.46 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added, and reacted at room temperature for 24h. The mixture was filtered to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 292mg of white solid with a yield of 44.8%. HR ESI-MS (m/z): 406.1772[ M ] +H] + 。 1 H 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 BDA0003277713460000452
(3aR, 4S,7R, 7aS) -hexahydro-4,7-epoxyisobenzofuran-1,3-dione (336 mg,2.0 mmol) and aminopropionic acid (180mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and reacted at 80 ℃ for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow extractOil 346mg, LC-MS and 1 H-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 (10 ml), triethylamine (225. Mu.L, 2.16 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (24557 mg, 1.44mmol) was added and reacted at room temperature for 24h. The mixture was filtered to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 213mg of white solid with a yield of 37.9%.
1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000461
(3aR, 4S,7R, 7aS) -hexahydro-4,7-epoxyisobenzofuran-1,3-dione (336 mg,2.0 mmol) and glycine (152mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for reaction for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oily matter 325mg 1 H-NMR confirmed it to be the expected intermediate compound in a yield of 72.0%.
The intermediate compound (340mg, 1.4 mmol) and HATU (710mg, 1.87mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (225. Mu.L, 2.16 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (2454mg, 1.44mmol) was added and reacted at room temperature for 24h. After filtration, the inorganic salt residue was removed, and the filtrate was stirred with 60-100 mesh silica gel and purified by silica gel column separation (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 263mg of white solid with a yield of 49.8%. HR ESI-MS (m/z)：378.1430[M+H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000462
(3aR, 4S,7R, 7aS) -3a,4,7,7a-tetrahydro-4, 7-ethanosobenzofuran-1, 3-dione (356 mg,2.0 mmol) and 3-aminobenzoic acid (280mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and reacted for 6 hours with heating to 80 ℃. The reaction was quenched with water (10 mL) 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 NaHCO 3 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 and 1 H-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 (10 ml), triethylamine (332. Mu.L, 2.46 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added, and the reaction was carried out at room temperature for 24 hours. After filtration to remove inorganic salt residue, the filtrate was stirred with 60-100 mesh silica gel and separated and purified by silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is performed at 1-10) to obtain 327mg of white solid with a yield of 45.0%.
1 H NMR(400MHz,DMSO-d 6 )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 BDA0003277713460000471
(3aR, 4S,7R, 7aS) -3a,4,7,7a-tetrahydro-4, 7-ethanosobenzofuranon-1, 3-dione (356 mg,2.0 mmol) and 4-aminobenzoic acid (280mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing 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 525mg 1 H-NMR confirmed that it was the expected intermediate compound in 84.9% yield.
The intermediate compound (525mg, 1.70mmol) and HATU (840mg, 2.21mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (344. Mu.L, 2.55 mmol) 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 hours. After filtration, the inorganic salt residue was removed, and the filtrate was stirred with 60-100 mesh silica gel and purified by silica gel column separation (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 378mg of white solid with a yield of 48.1%. HR ESI-MS (m/z): 464.1958[ M ] +H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000472
(3aR, 4R,7R, 7aS) -5-methyl-3a,4,7,7a-tetrahydro-4, 7-methanosorzofuran-1, 3-dione (356 mg,2.0 mmol) and 4-aminobenzoic acid (280mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with water, mixing organic phases, drying with anhydrous sodium sulfate, and separating with silica gel columnPurification to give 478mg of a yellow oil, LC-MS and 1 H-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 (10 ml), triethylamine (332. Mu.L, 2.46 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24h. The mixture was filtered to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 333mg of white solid with a yield of 46.1%. HR ESI-MS (m/z): 450.1837[ M ] +H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000481
(3aR, 4R,7R, 7aS) -5-methyl-3a,4,7,7a-tetrahydro-4, 7-methanosobenzofuran-1, 3-dione (356 mg,2.0 mmol) and 4-aminophenylacetic acid (310mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 520mg 1 H-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 (10 ml), triethylamine (344. Mu.L, 2.55 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (290mg, 1.70mmol) was added, and the reaction was carried out at room temperature for 24 hours. After filtration, the inorganic salt residue was removed, and the filtrate was stirred with 60-100 mesh silica gel and purified by silica gel column separation (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 370mg of white solid with a yield of 47.6%.
HR ESI-MS(m/z)：464.19769[M+H] + 。 1 H NMR(400MHz,DMSO-d 6 )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 BDA0003277713460000482
Hexahydrophthalic anhydride (310mg, 2.0 mmol) and 4-aminophenylacetic acid (300mg, 2.0 mmol) were dissolved in 10mL glacial acetic acid and heated to 120 ℃ for 2h. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, mixing the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 525mg 1 H-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 (10 ml), triethylamine (370. Mu.L, 2.75 mmol) 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 hours. After filtration to remove inorganic salt residue, the filtrate was stirred with 60-100 mesh silica gel and purified by silica gel column separation (mobile phase: petroleum ether/ethyl acetate =20 gradient elution from 1 to 10) to obtain 396mg of white solid with a yield of 49.3%. HR ESI-MS (m/z): 440.1974[ M ] +H] +1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000491
Tetrahydrophthalic anhydride (310mg, 2.0 mmol) and 4-aminophenylacetic acid (300mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid, and heated to 120 ℃ for reaction for 2 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing 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 525mg 1 H-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 (10 ml), triethylamine (370. Mu.L, 2.75 mmol) 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 hours. After filtration to remove inorganic salt residue, the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 396mg of white solid with a yield of 49.3%. HR ESI-MS (m/z): 438.1818[ 2 ] M + H] + 。
Example 47
Figure BDA0003277713460000492
(3aR, 4R,7R, 7aS) -5-methyl-3a,4,7,7a-tetrahydro-4, 7-methanosobenzo-furan-1, 3-dione (356mg, 2.0 mmol) and glycine (150mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, mixing the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 376mg 1 H-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 (10 ml), triethylamine (332. Mu.L, 2.46 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24h. The mixture was filtered to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 333mg of white solid with a yield of 46.1%.
HR ESI-MS(m/z)：388.1697[M+H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000501
(3aR, 4R,7R, 7aS) -5-methyl-3a,4,7,7a-tetrahydro-4, 7-methanosobenzo-furan-1, 3-dione (356 mg,2.0 mmol) and aminopropionic acid (180mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, mixing the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 400mg 1 H-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 (10 ml), triethylamine (332. Mu.L, 2.46 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added, and reacted at room temperature for 24h. After filtration to remove inorganic salt residue, the filtrate was mixed with 60-100 mesh silica gel and purified by silica gel column separation (mobile phase: petroleum ether/ethyl acetate =20 gradient elution from 1 to 10) to obtain 313mg of white solid with a yield of 52.1％。HR ESI-MS(m/z)：402.1818[M+H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000502
(3aR, 4R,7R, 7aS) -5-methyl-3a,4,7,7a-tetrahydro-4, 7-methanosobenzo-furan-1, 3-dione (356 mg,2.0 mmol) and aminopropionic acid (180mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and reacted for 6 hours by heating to 80 ℃. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, mixing the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 400mg 1 H-NMR confirmed that it was the expected intermediate compound in 80.5% yield.
The intermediate compound (400mg, 1.61mmol) and HATU (800mg, 2.1mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (332. Mu.L, 2.46 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added, and reacted at room temperature for 24h. After filtration, inorganic salt filter residues are removed, and the filtrate is stirred with 60-100 mesh silica gel and separated and purified by silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is performed in 1-10), 313mg of white solid is obtained, and the yield is 52.1%. HR ESI-MS (m/z): 402.1871[ M ] C +H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000511
(3aR, 4S,7R, 7aS) -3a,4,7,7a-tetrahydro-4, 7-methanosozofuran-1, 3-dione (326mg, 2.0 mmol) and glycine (150mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, combining the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 354mg 1 H-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 (10 ml), triethylamine (332. Mu.L, 2.46 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24h. After filtration, the inorganic salt residue was removed, and the filtrate was stirred with 60-100 mesh silica gel and purified by silica gel column separation (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 238mg of white solid with a yield of 39.8%. HR ESI-MS (m/z): 374.1520[ mu ] M ] +H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000512
(3aR, 4S,7R, 7aS) -3a,4,7,7a-tetrahydro-4, 7-methanosobenzofuran-1, 3-dione (328mg, 2.0mmol) and alanine (180mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ to react for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, combining organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain 375mg of yellow oily matter,LC-MS and 1 H-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 (10 ml), triethylamine (332. Mu.L, 2.46 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24h. The mixture was filtered to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 186mg of white solid with a yield of 30.2%. HR ESI-MS (m/z): 388.1661[ M ] C + H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000521
(3aR, 4S,7R, 7aS) -3a,4,7,7a-tetrahydro-4, 7-methanosobenzofuran-1, 3-dione (328mg, 2.0mmol) and aminopropionic acid (180mg, 2.0mmol) were dissolved in 10mL of glacial acetic acid and reacted at 80 ℃ for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing 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 385mg 1 H-NMR confirmed that it was the expected intermediate compound in 80.2% yield.
The intermediate compound (385mg, 1.6 mmol) and HATU (800mg, 2.1mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (332. Mu.L, 2.46 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24h. And (3) filtering to remove inorganic salt filter residues, mixing the filtrate with 60-100-mesh silica gel, and separating and purifying the mixture by using a silica gel column (mobile phase: petroleum ether/ethyl acetate =20Dearsenification) to give 320mg of a white solid in 50.2% yield. HR ESI-MS (m/z): 388.1676[ 2 ] M + H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000522
(3aR, 4S,7R, 7aS) -3a,4,7,7a-tetrahydro-4, 7-methanosobenzofuran-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 ℃ to react for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, combining organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 420mg 1 H-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 (10 ml), triethylamine (345. Mu.L, 2.54 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminobenzpyridine (288mg, 1.69mmol) was added and reacted at room temperature for 24h. After filtration, inorganic salt filter residues are removed, and the filtrate is stirred with 60-100 mesh silica gel and separated and purified by silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is performed in 1-10) to obtain 360mg of white solid with the yield of 53.3%. HR ESI-MS (m/z): 402.1828[ M ] +H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000531
(3aR, 4S,7R, 7aS) -3a,4,7,7a-tetrahydro-4, 7-ethanosoxazofuran-1, 3-dione (356 mg,2.0 mmol) and glycine (1506 mg,2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, mixing the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 400mg 1 H-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 (10 ml), triethylamine (345. Mu.L, 2.54 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (295mg, 1.72mmol) was added and reacted at room temperature for 24h. After filtration to remove inorganic salt residue, the filtrate was stirred with 60-100 mesh silica gel and separated and purified by silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is performed at 1-10) to obtain 336mg of white solid with a yield of 51.2%. HR ESI-MS (m/z): 388.1660[ M ] +H] + 。 1 H NMR(400MHz,DMSO-d 6 )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 BDA0003277713460000532
(3aR, 4S,7R, 7aS) -3a,4,7,7a-tetrahydro-4, 7-ethanosobenzofuran-1, 3-dione (356 mg,2.0 mmol) and alanine (180mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and reacted at 80 ℃ for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oily substance 400mg, LC-MS and 1 H-NMR confirmed that it was the expected intermediate compound in a yield of 80.1%.
The intermediate compound (400mg, 1.6 mmol) and HATU (800mg, 2.1mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (332. Mu.L, 2.46 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24h. The mixture was filtered to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 264mg of white solid with a yield of 40.0%. ESI-MS (m/z): 402.1630[ M ] +H] + 。 1 H NMR(400MHz,DMSO-d 6 )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 BDA0003277713460000541
(3aR, 4S,7R, 7aS) -3a,4,7,7a-tetrahydro-4, 7-ethanosobenzofuran-1, 3-dione (356 mg,2.0 mmol) and aminopropionic acid (180mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and reacted at 80 ℃ for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, mixing the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 400mg 1 H-NMR confirmed that it was the expected intermediate compound in a yield of 80.0%.
The intermediate compound (400mg, 1.6 mmol) and HATU (800mg, 2.1mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (332. Mu.L, 2.46 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (280mg, 1.64mmol) was added and reacted at room temperature for 24h. And (2) filtering to remove inorganic salt filter residues, mixing the filtrate with 60-100-mesh silica gel, separating and purifying the mixture by using a silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is carried out by 1-10), and the white solid is obtained by 304mg, and the yield is as follows44.8％。ESI-MS(m/z)：402.1798[M+H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000542
(3aR, 4S,7R, 7aS) -3a,4,7,7a-tetrahydro-4, 7-ethanosbenzuran-1, 3-dione (356 mg,2.0 mmol) and 4-aminobutyric acid (210mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ to react for 6 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, mixing the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain 473mg of yellow oil 1 H-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 (10 ml), triethylamine (370. Mu.L, 2.75 mmol) 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 hours. The mixture was filtered to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain 370mg of white solid with a yield of 51.8%. ESI-MS (m/z): 416.2012[ M ] +H] +1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000551
3-Methylphthalic anhydride (490mg, 3.0 mmol) and glycine (230mg, 3.1 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ to react for 3 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 420mg 1 H-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 (10 ml), triethylamine (580. Mu.L, 4.22 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (488mg, 2.87mmol) was added and reacted at room temperature for 24h. After filtration, inorganic salt filter residues are removed, and the filtrate is stirred with 60-100 mesh silica gel and separated and purified by silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is carried out at 1-10) to obtain 370mg of white solid with yield of 52.3%. ESI-MS (m/z): 372.1361[ M ] +H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000552
3-Methylphthalic anhydride (490 mg,3.0 mmol) and alanine (270mg, 3.1mmol) were added to glacial acetic acid (10 mL) and heated to 100 deg.C for 3h. The reaction was quenched with water (10 mL) and adjusted to pH 6-8 with NaOH solution (0.1 mol/L). Extraction with dichloromethane (10 mL. Times.3), saturated NaHCO 3 Washing with water, mixing organic phases, drying with anhydrous sodium sulfate to obtain yellow solid 420mg 1 H-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 (10 ml), triethylamine (550. Mu.L, 4.09 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (464mg, 2.72mmol) was added and reacted at room temperature for 24h. Filtration to remove 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, gradient elution 1-10) to obtain 388mg of white solid, yield 48.0% esi-MS (m/z): 386.1493[ M ] +H] + 。
1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000561
3-Methylphthalic anhydride (490 mg,3.0 mmol) and aminopropionic acid (270mg, 3.1mmol) were added to glacial acetic acid (10 mL) and heated to 100 ℃ for 3h. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with solution, water washing, mixing organic phases, drying with anhydrous sodium sulfate to obtain 445mg yellow solid, LC-MS and 1 H-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 (10 ml), triethylamine (580. Mu.L, 4.22 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (488mg, 2.87mmol) was added and reacted at room temperature for 24h. After filtration, inorganic salt filter residues are removed, and the filtrate is mixed with 60-100 mesh silica gel and separated and purified by silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is carried out in 1-10), 400mg of white solid is obtained, and the yield is 54.4%. ESI-MS (m/z): 386.1538[ mu ] M +H] + 。 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000562
3-chlorophthalic anhydride (365mg, 2.0 mmol) and glycine (155mg, 2.1mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ to react for 3 hours. The reaction was quenched with water (10 mL) and adjusted to pH 6-8 with NaOH solution (0.1 mol/L). Filtering, drying to obtain yellow solid 400mg 1 H-NMR confirmed that it was the expected intermediate compound in a yield of 96.1%.
The intermediate compound (400mg, 1.92mmol) and HATU (950mg, 2.5 mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (390. Mu.L, 2.88 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminophenylpyridine (327mg, 1.92mmol) was added and reacted at room temperature for 24 hours. 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[ 2 ], M + H] + 。
1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000571
3-chlorophthalic anhydride (365mg, 2.0 mmol) and alanine (190mg, 2.1mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ to react for 3 hours. The reaction was quenched with water (10 mL) and adjusted to pH 6-8 with NaOH solution (0.1 mol/L). Filtering, drying to obtain yellow solid 430mg, LC-MS and 1 H-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 (10 ml), triethylamine (390. Mu.L, 2.88 mmol) 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 hours. 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] + 。
1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000572
3-chlorophthalic anhydride (365mg, 2.0 mmol) and aminopropionic acid (190mg, 2.1mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 ℃ to react for 3 hours. The reaction was quenched with water (10 mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Filtering, drying to obtain 425mg of yellow solid 1 H-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 (10 ml), triethylamine (390. Mu.L, 2.88 mmol) was dropwise added thereto, and after stirring at room temperature for 10min, 2-aminopyridine (330mg, 1.92mmol) was added and reacted at room temperature for 24 hours. 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] + 。
1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000581
3-chlorophthalic anhydride (365mg, 2.0 mmol) and 4-aminobutyric acid (190mg, 2.1mmol) were added to glacial acetic acid (10 mL), and heated to 100 ℃ for reaction for 3h. The reaction was quenched with water (10 mL) and the pH of the solution was adjusted to 6-8 with NaOH solution (0.1 mol/L). Filtering, drying to obtain 444mg yellow solid 1 H-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 (10 ml), triethylamine (390. Mu.L, 2.88 mmol) was dropwise added thereto, and after stirring at room temperature for 10min, 2-aminopyridine (330mg, 1.92mmol) was added and reacted at room temperature for 24 hours. Filtering, removing inorganic salt filter residue, spin-drying the filtrate, dissolving with ethyl acetate under heating, 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] + 。
1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000582
3-Bromophthalic anhydride (380mg, 2.0 mmol) and 4-aminobutyric acid (190mg, 2.1mmol) were added to glacial acetic acid (10 mL), and heated to 100 ℃ for reaction for 3h. The reaction was quenched with water (10 mL) and adjusted to pH 6-8 with NaOH solution (0.1 mol/L). Filtered and dried to obtain 460mg of yellow solid, LC-MS and 1 H-NMR confirmed that it was the expected intermediate compound in 95.5% yield.
The intermediate compound (460mg, 1.92mmol) and HATU (950mg, 2.5 mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (390. Mu.L, 2.88 mmol) 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 hours. 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 BDA0003277713460000583
(3aR, 7aS) -3a,4,7, 7a-5-methyl-tetrahydrobenozuran-1, 3-dione (310mg, 2.0 mmol) and 4-aminobutyric acid (210mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 4 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing 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 450mg 1 H-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 (10 ml), triethylamine (385. Mu.L, 2.85 mmol) 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 hours. Filtration was carried out to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain a white solid, which was dried and weighed about 415mg, and the yield was 56.1%.
ESI-MS(m/z)：404.1974[M+H] + 。
Example 67
Figure BDA0003277713460000591
(3aR,7aS) -3a,4,7,7a-4-methyl-tetrahydrobifuran-1, 3-dione (310)mg,2.0 mmol) and 4-aminobutyric acid (210mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 4h. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 460mg, LC-MS and 1 H-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 (10 ml), triethylamine (385. Mu.L, 2.85 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminobenzpyridine (323mg, 1.9mmol) was added, and the reaction was carried out at room temperature for 24 hours. Filtration was carried out to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution of 1-10) to obtain a white solid, which was dried and weighed to be about 485mg, and the yield was 66.1%. ESI-MS (m/z): 404.1974[ M ] +H] + 。
Example 68
Figure BDA0003277713460000592
(3aR, 7aS) -5-methyl-3a,4,5,7a-tetrahydroisobenzofuran-1,3-dione (310mg, 2.0 mmol) and 4-aminobutyric acid (210mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 4h. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 460mg, LC-MS and 1 H-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 (10 ml), triethylamine (385. Mu.L, 2.85 mmol) 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 hours. Filtering, removing inorganic salt residue, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (mobile phase: stone)Oil ether/ethyl acetate =20 gradient elution) to give a white solid weighing about 485mg dry, 66.1% yield. ESI-MS (m/z): 404.1974[ M ] +H] + 。
Example 69
Figure BDA0003277713460000601
(3aR, 7aS) -3a,4,7,7a-4-methyl-tetrahydroisobenzofuran-1,3-dione (310mg, 2.0 mmol) and glycine (150mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 4h. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, mixing the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain 410mg yellow oil 1 H-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 (10 ml), triethylamine (385. Mu.L, 2.85 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminobenzopyridine (323mg, 1.9mmol) was added, and the reaction was carried out at room temperature for 24 hours. Filtration to remove inorganic salt residues, mixing the filtrate with 60-100 mesh silica gel, and separating and purifying with silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is performed from 1 to 10) to obtain white solid, which is dried and weighed about 455mg, and the yield is 56.1%. ESI-MS (m/z): 376.1661[ M ] +H] + 。
Example 70
Figure BDA0003277713460000602
(3aR, 7aS) -3a,4,7, 7a-tetrahydrodibenzofuran-1, 3-dione (304mg, 2.0 mmol) and alanine (180mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid, and the mixture was heated to 80 ℃ to react for 4 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, combining the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column400mg of a yellow oil was obtained, LC-MS and 1 H-NMR confirmed that it was the expected intermediate compound in 89.9% yield.
The intermediate compound (400mg, 1.8 mmol) and HATU (925mg, 2.43mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (378. Mu.L, 2.81 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminobenzpyridine (310mg, 1.8 mmol) was added and reacted at room temperature for 24 hours. The inorganic salt residue is removed by filtration, and the filtrate is stirred with 60-100 mesh silica gel and separated and purified by silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is from 1 to 10) to obtain white solid, which is dried and weighed about 328mg, and the yield is 48.7%.
ESI-MS(m/z)：376.1678[M+H] + ， 1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000611
(3aR, 7aS) -3a,4,7, 7a-tetrahydrodibenzofuran-1, 3-dione (304mg, 2.0 mmol) and aminopropionic acid (180mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid, and reacted at 80 ℃ for 4 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing with solution, washing with water, mixing organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 401mg 1 H-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 (10 ml), triethylamine (378. Mu.L, 2.81 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (310mg, 1.8mmol) was added and reacted at room temperature for 24h. 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, gradient elution from 1 to 10) to give a white solid weighing about 363mg dry, yield 54.0%. ESI-MS (m/z): 376.1660[ M ] +H] + 。
1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000612
(3aR, 7aS) -3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione (304mg, 2.0 mmol) and 4-aminobutanoic acid (210mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and heated to 80 ℃ for 4 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, mixing the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain yellow oil 450mg 1 H-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 (10 ml), triethylamine (385. Mu.L, 2.85 mmol) 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 hours. Filtration was carried out to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain a white solid, which was dried and weighed to about 414mg, and the yield was 56.1%.
ESI-MS(m/z)：390.1802[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )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 BDA0003277713460000621
(3aR, 7aS) -3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione (304mg, 2.0 mmol) and 4-methylamino-cyclohexanecarboxylic acid (314mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and reacted at 80 ℃ for 4 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing 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 525mg 1 H-NMR confirmed that it was the expected intermediate compound in 89.9% yield.
The intermediate compound (400mg, 1.4 mmol) and HATU (925mg, 2.43mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (378. Mu.L, 2.81 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminopyridine (310mg, 1.8 mmol) was added and reacted at room temperature for 24h. Filtration was carried out to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution of 1-10) to obtain a white solid, which was dried and weighed about 303mg, and the yield was 54.0%. HR ESI-MS (m/z): 444.2287[ M ] +H] + 。
Example 74
Figure BDA0003277713460000622
(3aR, 4R,7R, 7aS) -5-methyl-3a,4,7,7a-tetrahydro-4, 7-methanosobenzo-furan-1, 3-dione (356 mg,2.0 mmol) and p-aminocyclohexyl formic acid (286 mg,2.0 mmol) were dissolved in 10mL of glacial acetic acid and reacted at 80 ℃ for 4 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing 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 1 H-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 (10 ml), triethylamine (378. Mu.L, 2.81 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminobenzpyridine (310mg, 1.8 mmol) was added and reacted at room temperature for 24 hours. Filtration was carried out to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain a white solid, which was dried and weighed to be about 363mg, and the yield was 60.0%. HR ESI-MS (m/z): 456.2287[ M ] +H] + 。
Example 75
Figure BDA0003277713460000631
(3aR, 4R,7R, 7aS) -5-methyl-3a,4,7,7a-tetrahydro-4, 7-methanosobenzo-furan-1, 3-dione (356mg, 2.0 mmol) and 4-methylamino-cyclohexanecarboxylic acid (314mg, 2.0 mmol) were dissolved in 10mL of glacial acetic acid and reacted at 80 ℃ for 4 hours. The reaction was quenched with water (10 mL) 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 NaHCO 3 Washing the solution with water, mixing the organic phases, drying with anhydrous sodium sulfate, separating and purifying with silica gel column to obtain 500mg yellow oil, LC-MS and 1 H-NMR confirmed that it was the expected intermediate compound in 80% yield.
The intermediate compound (400mg, 1.27mmol) and HATU (925mg, 2.43mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (378. Mu.L, 2.81 mmol) was added dropwise, and after stirring at room temperature for 10min, 2-aminobenzpyridine (310mg, 1.8 mmol) was added and reacted at room temperature for 24 hours. Filtration was carried out to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain a white solid, which was dried and weighed about 263mg, and the yield was 44.0%. HR ESI-MS (m/z): 470.2444[ M ] +H] + 。
Example 76
Figure BDA0003277713460000632
The intermediate compound (450mg, 1.9mmol) of EXAMPLE 71 and HATU (940mg, 2.47mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (385. Mu.L, 2.85 mmol) 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 hours. The inorganic salt residue is removed by filtration, and the filtrate is stirred with 60-100 mesh silica gel and separated and purified by silica gel column (mobile phase: petroleum ether/ethyl acetate =20, gradient elution is performed by 1-10) to obtain white solid, which is dried and weighed about 454mg, and the yield is 61.5%. HR ESI-MS (m/z): 391.1770[ 2 ] M + H] + 。
Example 77
Figure BDA0003277713460000633
The intermediate compound (450mg, 1.9mmol) of EXAMPLE 71 and HATU (940mg, 2.47mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (385. Mu.L, 2.85 mmol) 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 24h. Filtration was carried out to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain a white solid, which was dried and weighed about 441mg, and the yield was 59.7%. HR ESI-MS (m/z): 391.1770[ 2 ] M +H] + 。
Example 78
Figure BDA0003277713460000641
The intermediate compound (450mg, 1.9mmol) of EXAMPLE 71 and HATU (940mg, 2.47mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (385. Mu.L, 2.85 mmol) was added dropwise, and after stirring at room temperature for 10min, 5-amino-2- (4-pyridyl) pyridine (325mg, 1.9mmol) was added and reacted at room temperature for 24 hours. 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 ether)Acid ethyl ester =20, gradient elution from 1 to 10) to give a white solid weighing about 476mg dry, yield 64.5%. HR ESI-MS (m/z): 391.1770[ 2 ] M +H] + 。
Example 79
Figure BDA0003277713460000642
The intermediate compound (450mg, 1.9mmol) of EXAMPLE 71 and HATU (940mg, 2.47mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (385. Mu.L, 2.85 mmol) 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 24h. The mixture was filtered to remove inorganic salt residues, and the filtrate was stirred with 60-100 mesh silica gel and purified by silica gel column separation (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain a white solid, which was dried and weighed about 427mg, yield 57.9%. HR ESI-MS (m/z): 392.1723[ deg. ] M + H] + 。
Example 80
Figure BDA0003277713460000643
The intermediate compound (450mg, 1.9mmol) of EXAMPLE 71 and HATU (940mg, 2.47mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (385. Mu.L, 2.85 mmol) 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 24h. The inorganic salt residue is removed by filtration, and the filtrate is subjected to sample mixing with 60-100 mesh silica gel and silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain a white solid, which is dried and weighed about 484mg, and the yield is 65.6%. HR ESI-MS (m/z): 404.1974[ M ] +H] + 。
Example 81
Figure BDA0003277713460000651
Intermediate compounds from EXAMPLE 71 (450mg, 1.9mmol) and HATU (940mg, 2.47mmo)L) was dissolved in anhydrous dichloromethane (10 ml), triethylamine (385. Mu.L, 2.85 mmol) 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 24h. Filtration was carried out to remove inorganic salt residue, and the filtrate was stirred with 60-100 mesh silica gel and subjected to silica gel column separation and purification (mobile phase: petroleum ether/ethyl acetate =20, gradient elution from 1 to 10) to obtain a white solid, which was dried and weighed about 417mg, and the yield was 56.1%. 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-SV 40) vector is transfected to serve as an internal reference.
2. Experimental methods
a. Cell culture
Cells were cultured with DMEM (DMEM +10% FBS +1% double antibody +0.5mg/mL G-418). Culture conditions 37 ℃ and 5% CO 2 0.25% trypsinization passage (1 passage, 10 passage), or 5000 cells/well in 96-well plates, cultured for two days for wnt signaling pathway activity assay experiments.
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 the test compound at a given concentration and cultured for 48 hours. The DMSO content in the control and compound culture solutions was 0.1% in total.
Wnt signaling pathway modulator treatment
According to the manufacturer's instruction, the strength fluorescence intensity of firefly luciferase (Top-Flash) and Renilla luciferase (pRL-SV 40) 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 a negative value indicates that the test compound has an effect of agonizing the wnt signaling pathway and a positive value indicates that the test compound has an effect of inhibiting the wnt signaling pathway, and IC is performed on the partial compounds 50 And (4) numerical calculation.
3. Results
Wnt/beta-catenin signaling activity (Wnt/beta-catenin signaling activity) = (Top-Flash) fluorescence value/(pRL-SV 40) fluorescence value.
Screening results of Compound Activity inhibition (C = 10. Mu.M)
Figure BDA0003277713460000661
Partial compound inhibits Wnt/beta-catenin signal channel activity IC 50 (μM)
Figure BDA0003277713460000662
Figure BDA0003277713460000671
According to WNT signal pathway activity screening results, part of the compounds have obvious inhibition effects on WNT signal pathways, and have potential effects of preventing/treating diseases such as tumors, hyperosteogeny, myocardial hypertrophy and the like, and part of the compounds have obvious activation effects on the WNT signal pathways, and have potential effects of preventing/treating neurodegenerative diseases, osteoporosis, metabolic diseases and the like.

Claims (5)

1. A succinimide or maleimide compound and a pharmaceutically acceptable salt thereof, characterized by having a structure represented by general formula IA:
Figure FDA0003913869220000011
wherein, IA is:
Figure FDA0003913869220000012
R 1 selected from the following structures:
Figure FDA0003913869220000013
(R 2 ) n represents by n R 2 Substituted, n is selected from 1;
the R is 2 Selected from phenyl.
2. The succinimide or maleimide compound and pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is:
Figure FDA0003913869220000014
Figure FDA0003913869220000021
3. a pharmaceutical composition comprising the succinimide or maleimide compound of claim 1 or 2 and pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.
4. The use of a succinimide or maleimide compound according to claim 1 or 2 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 signalling pathway;
the WNT signaling pathway disorder is selected from the group consisting of porcupine protein secretion disorders;
the disease is selected from neurodegenerative diseases.
5. Use according to claim 4, characterized in that the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, cerebellar atrophy, huntington's disease, spinal muscular atrophy, creutzfeldt-Jakob disease.
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