Hydroxyoxime compounds in angelica sinensis head aqueous extract, dehydrated furazan compounds thereof, derivatives, preparation and application of hydroxime compounds and dehydrated furazan compounds in angelica sinensis head aqueous extract

Abstract

The invention belongs to the technical field of medicines, and discloses a hydroxime compound derived from an aqueous extract of heads of angelica sinensis, a dehydrated furazan compound of the hydroxime compound, and preparation and application of the hydroxime compound and the dehydrated furazan compound. In particular discloses a hydroxime compound, a dehydrated furazan compound thereof, pharmaceutically acceptable salts of the dehydrated furazan compound and a pharmaceutical composition of the dehydrated furazan compound. The invention also discloses application of the compound in preparation of medicines for treating arthritis, asthma, chronic obstructive pneumonia, pneumonia, cystic fibrosis, diabetes, obesity, hypercholesterolemia, contact dermatitis, psoriasis, atopic dermatitis, stasis dermatitis, seborrheic dermatitis, neurodermatitis and the like, inflammatory enteritis, multiple sclerosis, Parkinson's disease, cardiovascular disease, autoimmune disease, gout and the like. The invention also relates to applications in medicines or health-care products for treating hyperuricemia and cancers. Activity evaluation of a cell model for starting reporter gene expression by using an NF-kappa B reaction element proves that the compound can significantly inhibit NF-kappa B induced transcriptional regulation and is expected to become a therapeutic drug for treating the various diseases.

Description

Hydroxyoxime compounds and their dehydrated furazolidone derivatives in the first aqueous extract of Angelica sinensis, preparation and uses. Technical Field

[0001] This invention relates to a class of hydroxyoxime compounds and their dehydrated furazolidone compounds derived from Angelica sinensis heads, their pharmaceutically acceptable salts, methods for their preparation, pharmaceutical compositions containing these compounds, and the application of these compounds in the treatment of various diseases such as arthritis, asthma, chronic obstructive pulmonary disease, pneumonia, cystic fibrosis, diabetes, obesity, hypercholesterolemia, contact dermatitis, psoriasis, atopic dermatitis, stasis dermatitis, seborrheic dermatitis, neurodermatitis, inflammatory bowel disease, multiple sclerosis, Parkinson's syndrome, cardiovascular diseases, autoimmune diseases, gout, hyperuricemia, and cancer, belonging to the field of pharmaceutical technology. Background Technology

[0002] Angelica sinensis (Oliv.) Diels (Umbelliferae family) is the original plant of the commonly used traditional Chinese medicine Angelica sinensis. Its entire root is called "whole root," the head is called "root head," the main root is called "root body," and the lateral roots and root tips are called "root tail." Different parts have different traditional medicinal properties and commercial value. 1 Angelica sinensis also has a long history of use in Western countries. 2 Previous studies have shown that Angelica sinensis extract and its chemical components possess a variety of pharmacological activities, including anti-inflammatory, antispasmodic, antioxidant, anti-fibrotic, and neuroprotective effects. 1-3 Approximately 180 chemical components of various structural types, including phthalides, phenylpropanoids, lignans, coumarins, flavonoids, polyenes, terpenes, steroids, alkaloids, and polysaccharides, have been isolated, identified, or detected. However, the pharmacodynamic components corresponding to clinical efficacy are not yet fully identified. 2-10 In particular, previous studies on Angelica sinensis mainly focused on ethanol or methanol extracts. 5-10 This differs from the classic method of medication, which primarily involves decoction; furthermore, it was found that the content of some components is significantly affected by the extraction method. 11,12 Furthermore, although the market price of "Angelica sinensis root" is much higher than that of other medicinal parts of Angelica sinensis, there are very few research reports on "Angelica sinensis root". Therefore, we conducted a study on the chemical composition of the water extract of "Angelica sinensis root", focusing on the systematic isolation and identification of chemical components, especially trace components, in order to obtain compounds with different structures. This will lay the foundation for further revealing the chemical components and pharmacological activities of "Angelica sinensis root" and the development of new drugs based on related active ingredients.

[0003] NF-κB is a nuclear factor named for its binding to the enhancer element of the immunoglobulin kappa light chain in activated cells. NF-κB is an important transcription factor that regulates the expression of various genes involved in immune responses, inflammatory responses, and cell survival. 13 NF-κB is a heterodimer composed of RelA(p65) and p50, where RelA(p65) is the active subunit with a Rel homology domain at its amino terminus and a transactivation domain at its carboxyl terminus. In the resting state, NF-κB binds to its repressive subunit IκB and exists in the cytoplasm in an inactive form. When the cell is stimulated, IκB is phosphorylated by IκB kinase (IKK) and rapidly ubiquitinated and degraded by the 26S proteasome complex. This exposes the NF-κB nuclear localization signal, allowing NF-κB to enter the nucleus and bind to the κB site of target genes, activating the transcription of those genes. 13,14 .

[0004] NF-κB is a key nuclear factor in the body's response to various stimuli and changes. Studies have shown that a variety of stimuli can activate NF-κB, such as bacteria, fungi, viruses, parasites, environmental factors, physiological conditions, oxidative stress, cytokines, modified proteins, endoplasmic reticulum overload, ligands, apoptosis mediators, mitogens, growth factors, and chemical substances (https: / / www.bu.edu / nf-kb / physiological-mediators / inducers / ). When a stimulus occurs, it activates various receptors on the cell surface, such as pattern recognition receptors, the tumor necrosis factor receptor superfamily, T cell receptors, and B cell receptors. Activation of these receptors can rapidly activate NF-κB and allow it to enter the nucleus, regulating the transcription of target genes. 14,15 .

[0005] NF-κB is a key factor in the response of immune and inflammatory cells to external stimuli and changes in intrinsic stress. These cells include macrophages, dendritic cells, neutrophils, T cells, and B cells. NF-κB affects processes such as immunity, inflammation, development, cell growth, and apoptosis by regulating the expression of various genes. 14More than 300 target genes of NF-κB are known (https: / / www.bu.edu / nf-kb / physiological-mediators / inducers / ), including cytokine and chemokine genes (such as BAFF, CCL5, CCL-17, CCL-22, IFN-γ, IL-1a, IL-1b, IL-2, IL-6, IL-8, IL-13, IL-17, bata-interferon, CXCL6, MIP-1a,b, MIP2, TNFalpha, and TNFbeta), immune receptor genes (such as CD80, BRL-1, CCR5, CCR7, CXCR, CD137, CD40, CD154, CD48, CD83, CD86, CD134, Nod2, TLR2, and TLR9), and genes involved in antigen presentation (such as Complement B, Peptide Transporter). TAP1 and Tapasin, etc.), cell adhesion molecules (such as CD44, DC-SIGN, ELAM, ICAM-1, NCAM, P-selectin and VCAM-1, etc.), stress response genes (such as COX-2, HSP90-alpha, Phospholipase A2, SEPS1 and iNOS, etc.), cell surface receptor genes (such as ABCA1, A2A, Lox-1 and P-gp, etc.), and apoptosis-related protein genes (such as Bax, Bcl-2, Caspase-11 and CD44). 95, etc.), growth factor and ligand genes (such as BCAP, G-CSF, GM-CSF and VEGF-C, etc.), transcription factors and their regulatory protein genes (such as A20, Bcl-3, c-myc, Gata-3, IRF-1, IRF-2, IRF-4, IRF-7, p53 and Stat5a, etc.) and various enzymes (https: / / www.bu.edu / nf-kb / gene-resources / target-genes / ).

[0006] NF-κB regulates the expression of numerous genes involved in processes such as immunity, inflammation, development, cell growth, and apoptosis, and is therefore closely related to the occurrence and development of various diseases, such as arthritis. 13 Asthma and chronic obstructive pneumonia 16 ,pneumonia 17 Cystic fibrosis 18 ,diabetes 19 ,obesity 20 Hypercholesterolemia 21 Contact dermatitis 22 ,psoriasis 23 Atopic dermatitis 24 Stasis dermatitis25 Seborrheic dermatitis 26 Inflammatory bowel disease 27 Multiple sclerosis 28 Parkinson's syndrome 29 Cardiovascular diseases 30 Autoimmune diseases 31 gout and hyperuricemia 32 ,cancer 33 wait.

[0007] NF-κB plays a crucial role in the development and progression of various diseases, and its inhibitors are used to treat immune disorders, inflammation, metabolic diseases, and cancer. Currently, over 800 NF-κB inhibitors are known (https: / / www.bu.edu / nf-kb / physiological-mediators / inhibitors / ), such as CHS-828 for treating solid tumors. 34 IMD-1041 for the treatment of COPD 35 SAR-113945 for the treatment of osteoarthritis 36 JKB-122 for the treatment of non-alcoholic fatty liver disease 35 Tripterygium wilfordii for the treatment of diabetes 37 Disulfiram for the treatment of glioblastoma 35 The search for novel NF-κB inhibitors is considered an important avenue for the development of new drugs to treat a variety of diseases.

[0008] The pGL4.32 plasmid contains a plasmid that initiates luciferase expression using five NF-κB reaction elements (NF-κB-RE). Cell models constructed using the pGL4.32 plasmid are widely used for screening NF-κB inhibitors. 38-40 Baicalein, a flavonoid natural product with antioxidant and anti-inflammatory effects. 41 Using the methods described above, it was discovered that its various biological activities are achieved by inhibiting the NF-κB pathway. In vitro screening results showed that baicalin, at a final concentration of 50 μM, had significant inhibitory activity against the TNF-α-activated NF-κB pathway, with an inhibition rate of approximately 27%. 42 Subsequent studies also confirmed that baicalin, at a final concentration of 133 μM, can significantly inhibit LPS-activated NF-κB in mouse macrophages, with an inhibition rate of approximately 35%. 43 .

[0009] This invention utilizes a cell model that initiates reporter gene expression using NF-κB response elements for activity evaluation. It was found that compounds 1–63 can significantly inhibit NF-κB-induced transcriptional regulation, and thus have potential applications in treating various diseases including arthritis, asthma, chronic obstructive pulmonary disease, pneumonia, cystic fibrosis, diabetes, obesity, hypercholesterolemia, contact dermatitis, psoriasis, atopic dermatitis, stasis dermatitis, seborrheic dermatitis, neurodermatitis, inflammatory bowel disease, multiple sclerosis, Parkinson's syndrome, cardiovascular diseases, autoimmune diseases, gout, hyperuricemia, and cancer. These findings indicate a broad range of potential applications.

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[0054] The technical problem solved by this invention is to provide hydroxyoxime compounds derived from the head aqueous extract of Angelica sinensis and their dehydrated furazolidone compounds and pharmaceutically acceptable salts thereof, as well as their preparation methods, pharmaceutical compositions, and the use of such pharmaceutical compositions in the preparation of drugs or health products for the prevention and / or treatment of arthritis, asthma and chronic obstructive pulmonary disease, pneumonia, cystic fibrosis, diabetes, obesity, hypercholesterolemia, contact dermatitis, psoriasis, atopic dermatitis, stasis dermatitis, seborrheic dermatitis, neurodermatitis, inflammatory bowel disease, multiple sclerosis, Parkinson's syndrome, cardiovascular diseases, autoimmune diseases, gout, hyperuricemia, and cancer.

[0055] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0056] The first aspect of the present invention provides a class of α-arylhydroxyoximes as shown in general formula (I) and α-arylfurazan compounds as shown in general formula (II), and pharmaceutically acceptable salts thereof, characterized in that the compounds are as shown in general formulas (I) and (II):

[0057]

[0058] in,

[0059] In equation (I), n is selected from integers 1 and 2;

[0060] In formula (I) R 1 It consists of 1 to 2 substituents located at any position on the benzo[a] ring, wherein the substituents on the benzo[a] ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 cycloalkyl; R in formula (I) 2 It consists of 1 to 2 substituents located at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morpholinic, piperidine, piperazine, pyridine, furan, thiophene;

[0061] In formula (I), W is selected from O and NOH;

[0062] In formula (I), X is selected from gem-dimethyl, methylene, and O;

[0063] In formula (I), Y is selected from gem-dimethyl, methylene, and O;

[0064] In formula (I), Z is selected from hydrogen and C. 1-6 Alkyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclic aryl; wherein the substituent is optionally substituted by the following groups: hydrogen, halogen, OH, C 1-6 Alkoxy, C 1-6 Alkyl, NH2, NO2, C 1-6 Substituted or unsubstituted secondary amino groups, C 3-7 Cyclic amino, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6Cycloalkyl, secondary amino, tertiary amino, morpholinic, piperidine, piperazine, pyridine, furan, thiophene;

[0065] In equation (II), n is selected from integers 1 and 2;

[0066] In formula (II) R 1 It consists of 1 to 2 substituents located at any position on the benzo[a] ring, wherein the substituents on the benzo[a] ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 cycloalkyl; R in formula (II) 2 It consists of 1 to 2 substituents located at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morpholinic, piperidine, piperazine, pyridine, furan, thiophene;

[0067] In formula (II), X is selected from gem-dimethyl, methylene, and O;

[0068] In formula (II), Y is selected from gem-dimethyl, methylene, and O;

[0069] In formula (II), Z is selected from hydrogen and C. 1-6 Alkyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclic aryl; wherein the substituent is optionally substituted by the following groups: hydrogen, halogen, OH, C 1-6 Alkoxy, C 1-6 Alkyl, NH2, NO2, C 1-6 Substituted or unsubstituted secondary amino groups, C 3-7 Cyclic amino, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

[0070] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IA) and their pharmaceutically acceptable salts.

[0071]

[0072] in,

[0073] n is an integer selected from 1 and 2;

[0074] X is selected from gem-dimethyl, methylene, and O;

[0075] Y is selected from gem-dimethyl, methylene, and O;

[0076] R 1 It consists of 1 to 2 substituents located at any position on the benzo[a] ring, wherein the substituents on the benzo[a] ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 cycloalkyl; R in formula (I) 2 It consists of 1 to 2 substituents located at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

[0077] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IA1) and their pharmaceutically acceptable salts.

[0078]

[0079] in,

[0080] R 1 R 2 It consists of 1 to 2 substituents located at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, pyridine substituents, furan substituents, thiophene substituents.

[0081] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IA2) and their pharmaceutically acceptable salts.

[0082]

[0083] in,

[0084] R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

[0085] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IA3) and their pharmaceutically acceptable salts.

[0086]

[0087] in,

[0088] R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

[0089] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IA4) and their pharmaceutically acceptable salts.

[0090]

[0091] in,

[0092] R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

[0093] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IA5) and their pharmaceutically acceptable salts.

[0094]

[0095] in,

[0096] R 1 For hydrogen, halogen, C 1-6 Alkyl, C 1-3 Alkoxy, C 1-6 Unsaturated alkyl groups;

[0097] R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

[0098] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IA6) and their pharmaceutically acceptable salts.

[0099]

[0100] in,

[0101] R 1 For hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, benzyl, substituted or unsubstituted heteroaryl, wherein the substituents on the benzene ring and heteroaryl ring are optionally substituted with the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkyl, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl;

[0102] R 2 For hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, benzyl, substituted or unsubstituted heteroaryl, wherein the substituents on the benzene ring and heteroaryl ring are optionally substituted with the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl; or R 1 +R2 Selected from morphine substituents, piperidine substituents, and piperazine substituents.

[0103] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IB) and their pharmaceutically acceptable salts.

[0104]

[0105] in,

[0106] R 1 R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

[0107] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IC) and their pharmaceutically acceptable salts.

[0108]

[0109] in,

[0110] R 1 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morpholinic, piperidine, piperazine, pyridine, furan, thiophene;

[0111] R 2 C 1-6 Alkyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclic aryl; wherein the substituent is optionally substituted by the following groups: hydrogen, halogen, OH, C 1-6 Alkoxy, C 1-6 Alkyl, NH2, NO2, C 1-6Substituted or unsubstituted secondary amino groups, C 3-7 Cyclic amino, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

[0112] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (ID) and their pharmaceutically acceptable salts.

[0113]

[0114] n is an integer selected from 1 and 2;

[0115] X is selected from gem-dimethyl, methylene, and O;

[0116] Y is selected from gem-dimethyl, methylene, and O;

[0117] R 1 It consists of 1 to 2 substituents located at any position on the benzo[a] ring, wherein the substituents on the benzo[a] ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 cycloalkyl; R in formula (I) 2 It consists of 1 to 2 substituents located at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

[0118] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (ID1) and their pharmaceutically acceptable salts.

[0119]

[0120] in,

[0121] R 1 R 2"A" can be a substituent at any position on the benzene ring, wherein the substituent on the benzene ring is optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, substituted amino, aromatic heterocyclic substituents; R 2 C 1-6 Alkyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, pyridine substituents, furan substituents, thiophene substituents.

[0122] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (ID2) and their pharmaceutically acceptable salts.

[0123]

[0124] in,

[0125] R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

[0126] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (ID3) and their pharmaceutically acceptable salts.

[0127]

[0128] in,

[0129] R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

[0130] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (ID4) and their pharmaceutically acceptable salts.

[0131]

[0132] in,

[0133] R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

[0134] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (ID5) and their pharmaceutically acceptable salts.

[0135]

[0136] in,

[0137] R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

[0138] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (ID6) and their pharmaceutically acceptable salts.

[0139]

[0140] in,

[0141] R 1 For hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, benzyl, substituted or unsubstituted heteroaryl, wherein the substituents on the benzene ring and heteroaryl ring are optionally substituted with the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkyl, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl;

[0142] R 2 For hydrogen, C1-6 Alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, benzyl, substituted or unsubstituted heteroaryl, wherein the substituents on the benzene ring and heteroaryl ring are optionally substituted with the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl; or R 1 +R 2 Selected from morphine substituents, piperidine substituents, and piperazine substituents.

[0143] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IE) and their pharmaceutically acceptable salts.

[0144]

[0145] in,

[0146] R 1 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morpholinic, piperidine, piperazine, pyridine, furan, thiophene;

[0147] R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

[0148] Preferred compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IF) and their pharmaceutically acceptable salts.

[0149]

[0150] in,

[0151] R 1Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morpholinic, piperidine, piperazine, pyridine, furan, thiophene;

[0152] R 2 C 1-6 Alkyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclic aryl; wherein the substituent is optionally substituted by the following groups: hydrogen, halogen, OH, C 1-6 Alkoxy, C 1-6 Alkyl, NH2, NO2, C 1-6 Substituted or unsubstituted secondary amino groups, C 3-7 Cyclic amino, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

[0153] Preferred compounds of formula (II) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IIA) and their pharmaceutically acceptable salts.

[0154]

[0155] in,

[0156] n is an integer selected from 1 and 2;

[0157] X is selected from gem-dimethyl, methylene, and O;

[0158] Y is selected from gem-dimethyl, methylene, and O;

[0159] R 1 It consists of 1 to 2 substituents located at any position on the benzo[a] ring, wherein the substituents on the benzo[a] ring are optionally replaced by the following groups: hydrogen, halogen, C. 1-6 Alkyl, C 1-3 Alkoxy, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 cycloalkyl; R 2It consists of 1 to 2 substituents located at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkoxy, C 1-6 Alkyl, NH2, NO2, C 1-6 Substituted or unsubstituted secondary amino groups, C 3-7 Cyclic amino, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

[0160] Preferred compounds of formula (II) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IIA1) and their pharmaceutically acceptable salts.

[0161]

[0162] in,

[0163] R 1 R 2 It consists of 1 to 2 substituents located at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, pyridine substituents, furan substituents, thiophene substituents.

[0164] Preferred compounds of formula (II) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IIA2) and their pharmaceutically acceptable salts.

[0165]

[0166] in,

[0167] R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, C 1-6 Alkyl, C 1-3 Alkyl group, halogen, NH2, NO2, cyano group, carboxyl group, phenyl group, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

[0168] Preferred compounds of formula (II) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IIA3) and their pharmaceutically acceptable salts.

[0169]

[0170] in,

[0171] R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, C 1-6 Alkyl, C 1-3 Alkoxy, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

[0172] Preferred compounds of formula (II) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IIA4) and their pharmaceutically acceptable salts.

[0173]

[0174] in,

[0175] R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, C 1-6 Alkyl, C 1-3 Alkoxy, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

[0176] Preferred compounds of formula (II) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IIA5) and their pharmaceutically acceptable salts.

[0177]

[0178] in,

[0179] R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, C 1-6 Alkyl, C 1-3 Alkoxy, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

[0180] Preferred compounds of formula (II) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IIA6) and their pharmaceutically acceptable salts.

[0181]

[0182] in,

[0183] R 1 For hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, benzyl, substituted or unsubstituted heteroaryl, wherein the substituents on the benzene ring and heteroaryl ring are optionally substituted with the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkyl, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl;

[0184] R 2 For hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, benzyl, substituted or unsubstituted heteroaryl, wherein the substituents on the benzene ring and heteroaryl ring are optionally substituted with the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl; or R 1 +R 2 Selected from morphine substituents, piperidine substituents, and piperazine substituents.

[0185] Preferred compounds of formula (II) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IIB) and their pharmaceutically acceptable salts.

[0186]

[0187] in,

[0188] R 1 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morpholinic, piperidine, piperazine, pyridine, furan, thiophene;

[0189] R 2Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

[0190] Preferred compounds of formula (II) and their pharmaceutically acceptable salts include, but are not limited to, compounds of formula (IIIC) and their pharmaceutically acceptable salts.

[0191]

[0192] in,

[0193] R 1 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morpholinic, piperidine, piperazine, pyridine, furan, thiophene;

[0194] R 2 C 1-6 Alkyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclic aryl; wherein the substituent is optionally substituted by the following groups: hydrogen, halogen, OH, C 1-6 Alkoxy, C 1-6 Alkyl, NH2, NO2, C 1-6 Substituted or unsubstituted secondary amino groups, C 3-7 Cyclic amino, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

[0195] The second aspect of the present invention is to provide a method for preparing the compound described in the first aspect, which can be synthesized through the following two steps and methods:

[0196] The first type:

[0197]

[0198] Where R 1 R 2 The definitions of , n, X, Y, and Z are the same as those in any one of claims 1-22.

[0199] The substituted aryl ethyl ketone derivative S1 reacts with tert-butyl nitrite S2 under sodium hydride as a base to give α-carbonyl monohydroxyoxime compounds IA-IC; the monohydroxyoxime compounds IA-IC react with hydroxylamine hydrochloride S3 under reflux under sodium acetate as a base and ethanol as a solvent to give dihydroxyoxime compounds ID-IF; the dihydroxyoxime compounds ID-IF undergo intramolecular dehydration under acid anhydride as a dehydrating agent and toluene as a solvent to give the corresponding substituted furazan compound II.

[0200] The second type:

[0201] After drying and pulverizing Angelica sinensis root, distilled water was used as the solvent. The mixture was boiled and heated for 30 minutes, and extracted three times. The filtrates were combined, and the solvent was recovered under reduced pressure to obtain an extract. The extract was separated by macroporous resin column chromatography, eluting sequentially with a water:ethanol gradient of 1:0 to 0:1, monitored by TLC or HPLC. The solvent was recovered under reduced pressure to obtain the corresponding eluent fractions. The 50% ethanol fraction was separated using MCI resin, eluting sequentially with a water:ethanol gradient of 1:0 to 0:1, monitored by TLC or HPLC, and the same fractions were combined. The 50% ethanol eluent fraction from the MCI column chromatography was further separated by Toyopearl HW-40C gel column chromatography with ethanol-water as the mobile phase to obtain subfractions. Subfraction B2 was separated by Sephadex LH-20 gel column chromatography with a methanol-water system as the mobile phase. The separated components were further separated by silica gel column chromatography, Sephadex LH-20 gel column chromatography, and semi-preparative HPLC to obtain compound 33. Subfraction B3 was further separated by Toyopearl HW-40C gel column chromatography with ethanol-water as the mobile phase, and then separated by reversed-phase semi-preparative HPLC to obtain 63.

[0202] A third aspect of the present invention is to provide a pharmaceutical composition comprising the compound described in the first aspect and its pharmaceutically acceptable salt, wherein the pharmaceutical composition contains a therapeutically effective amount of the hydroxyoxime compound and its dehydrated furazolidone compound of the present invention and its pharmaceutically acceptable salt, and optionally contains a pharmaceutical carrier. The pharmaceutical carrier refers to a pharmaceutical carrier commonly used in the pharmaceutical field; the pharmaceutical composition can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be formulated by combining the compound of the present invention and its pharmaceutically acceptable salt with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants.

[0203] The compounds of the present invention and their pharmaceutically acceptable salts are typically present in pharmaceutical compositions at a concentration of 0.1-95% by weight.

[0204] The compounds of this invention or pharmaceutical compositions containing them can be administered in unit dose form via enteral or non-enteric routes, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum, or rectum.

[0205] The compounds of this invention or pharmaceutical compositions containing them can be administered by injection. Injection includes intravenous injection, intramuscular injection, subcutaneous injection, and intradermal injection.

[0206] Dosage forms can be liquid or solid. Liquid dosage forms include true solutions, colloids, microparticles, emulsions, and suspensions. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, and lyophilized powder injections.

[0207] The dosage of the compounds and pharmaceutical compositions of this invention depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality, and individual response of the patient or animal, the route of administration, frequency of administration, and therapeutic purpose. Therefore, the therapeutic dosage of this invention can vary widely. Generally speaking, the dosage of the pharmaceutical components used in this invention is well known to those skilled in the art. The actual amount of drug contained in the final formulation of the compound composition according to this invention can be appropriately adjusted to achieve the required therapeutic dose and fulfill the preventive or therapeutic purpose of this invention. The appropriate daily dosage range for the compounds of this invention is 0.001-150 mg / kg body weight, preferably 0.01-100 mg / kg body weight, more preferably 0.01-60 mg / kg body weight, and most preferably 0.1-10 mg / kg body weight. The above dosages can be administered in a single dose or divided into several doses, such as two, three, or four doses. This is limited by the clinical experience of the dispensing physician and the administration regimen, including the use of other treatment methods.

[0208] The total dose required for each treatment can be divided into multiple administrations or administered as a single dose. The compounds or pharmaceutical compositions of the present invention can be taken alone or in combination with other therapeutic or symptomatic medications. When the compounds of the present invention exhibit synergistic effects with other therapeutic agents, their dosage should be adjusted according to the specific circumstances.

[0209] The fourth aspect of the present invention is to provide the use of the compound described in the first aspect and its pharmaceutically acceptable salt, and the pharmaceutical composition described in the third aspect, in the preparation of drugs or health products for the prevention and / or treatment of arthritis, asthma and chronic obstructive pulmonary disease, pneumonia, cystic fibrosis, diabetes, obesity, hypercholesterolemia, contact dermatitis, psoriasis, atopic dermatitis, stasis dermatitis, seborrheic dermatitis, neurodermatitis, inflammatory bowel disease, multiple sclerosis, Parkinson's syndrome, cardiovascular diseases, autoimmune diseases, gout, hyperuricemia, and cancer.

[0210] When using the hydroxyoxime compounds and their dehydrated furazans, or pharmaceutically acceptable salts, or the compositions of the present invention to treat the above-mentioned diseases, the dosage may refer to the dosage used when treating with hydroxyoxime compounds and their dehydrated furazans; when using the hydroxyoxime compounds and their dehydrated furazans, or the compositions of the present invention, as health products, or adding them to health products, the dosage should be less than the usual therapeutic dosage.

[0211] Detailed description of the invention:

[0212] The various aspects and features of the present invention will be further described below.

[0213] All references cited in this invention are incorporated herein by reference in their entirety, and in the event of any inconsistency between the meanings expressed in these references and those expressed herein, the meanings expressed herein shall prevail. Furthermore, the various terms and phrases used in this invention have their general meanings known to those skilled in the art; however, this invention still intends to provide a more detailed explanation and interpretation of these terms and phrases. In the event of any inconsistency between the mentioned terms and their known meanings and those expressed herein, the meanings expressed herein shall prevail. The following are definitions of various terms used in this invention, and these definitions apply to all terms used throughout this specification, unless otherwise specified in the specific context.

[0214] As mentioned in this invention, the terms "halogen", "halogen", "halogen atom", "halogenated", etc., refer to fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.

[0215] The following provides definitions of various groups in the compounds of this invention, which, unless otherwise defined, are used consistently in the specification and claims.

[0216] As mentioned in this invention, the term "alkyl" refers to an alkyl group having a specified number of carbon atoms, which can be a straight-chain or branched alkyl group, such as the "C" mentioned above. 1-6 When "alkyl" is used, it refers to alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, and may include C4+ alkyl groups. 1-5 Alkyl, C 1-4 Alkyl, C 2-5 Alkyl, C 2-4Alkyl, C 2-3 Alkyl, C 3-5 Groups in the subrange represented by alkyl, etc., and preferred specific groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl;

[0217] As mentioned in this invention, the term "C" 3-6 "Cycloalkyl" refers to cycloalkyl groups with 3, 4, 5, or 6 carbon atoms, and may include C64 groups. 3-5 cycloalkyl, C 3-4 cycloalkyl, C 4-6 cycloalkyl, C 4-5 cycloalkyl, C 5-6 Cycloalkyl, etc., and preferred specific groups such as cyclopropane, cyclopentane, and cyclohexane.

[0218] As mentioned in this invention, the term "C" 1-6 "Alkoxy group" refers to alkoxy groups with 1, 2, 3, 4, 5, or 6 carbon atoms, and can include C46 atoms. 1-5 Alkoxy, C 1-3 Alkoxy, C 2-5 Alkoxy, C 2-3 Alkoxy, C 3-4 Groups in the subrange represented by alkoxy, etc., and preferred specific groups such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, tert-butyloxy;

[0219] As mentioned in this invention, the term "C" 1-6 "Unsaturated alkyl group" refers to an unsaturated alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, and may include C14 and C24. 1-5 unsaturated alkyl groups, C 1-4 unsaturated alkyl groups, C 2-5 unsaturated alkyl groups, C 2-4 The subrange of groups represented by unsaturated alkyl groups, and preferred specific groups such as vinyl, ethynyl, isopropenyl, isopropynyl, isobutylenyl, isopentenyl, 1,4-dibutenyl.

[0220] Beneficial technical effects:

[0221] In their research on the active components of the traditional Chinese medicine Angelica sinensis root, the inventors of this invention isolated compounds with special structures, namely 2-(4-hydroxy-3-methoxyphenyl)-2-(hydroxyimino)acetaldehyde oxime and 4-(1,2,5-oxadiazol-3-yl)phenyl-1,2-diol. Based on this, they chemically synthesized and derivatized 2-(4-hydroxy-3-methoxyphenyl)-2-(hydroxyimino)acetaldehyde oxime and 4-(1,2,5-oxadiazol-3-yl)phenyl-1,2-diol. The activity of these compounds was evaluated using a cell model initiating reporter gene expression with an NF-κB reaction element, revealing that these compounds significantly inhibit NF-κB-induced transcriptional regulation. Because NF-κB regulation is closely related to the occurrence and development of various diseases such as arthritis, asthma and chronic obstructive pulmonary disease (COPD), pneumonia, cystic fibrosis, diabetes, obesity, hypercholesterolemia, contact dermatitis, psoriasis, atopic dermatitis, stasis dermatitis, seborrheic dermatitis, neurodermatitis, inflammatory bowel disease, multiple sclerosis, Parkinson's disease, cardiovascular disease, autoimmune diseases, gout, hyperuricemia, and cancer, these compounds have the potential to prevent and / or treat these diseases. Attached Figure Description

[0222] Figure 1. The NF-κB signaling pathway plays an important role in immune and inflammatory responses.

[0223] Figure 2. NF-κB target genes are involved in immune and inflammatory processes.

[0224] Figure 3. The compound can significantly inhibit NF-κB.

[0225] Figure 4. The compound can significantly inhibit NF-κB.

[0226] Figure 5. The compound can significantly inhibit NF-κB.

[0227] Figure 6. The compound can significantly inhibit NF-κB.

[0228] Figure 7. The compound can significantly inhibit NF-κB.

[0229] Figure 8. The compound can significantly inhibit NF-κB.

[0230] Figure 9. The compound can significantly inhibit NF-κB. Detailed Implementation

[0231] The following examples further illustrate the invention, but do not limit the invention in any way.

[0232] Example 1: Preparation of 2-(4-ethylphenyl)-2-oxoacetaldehyde oxime

[0233]

[0234] 48 mg of NaH was dissolved in 3.0 mL of DMF solvent. The mixture was stirred at 0 °C for 5 minutes, and 148 mg of p-ethyl acetophenone was added. The reaction was continued at 0 °C for 45 minutes. Then, 113 mg of tert-butyl nitrite was added at 0 °C and the reaction was continued for 5 minutes. Finally, the temperature was raised to room temperature and the reaction was carried out for 3 hours. The reaction was quenched with saturated ammonium chloride, and the reaction solution was extracted with ethyl acetate. The organic layers were combined, dried, and the organic solvent was removed under reduced pressure. Column chromatography yielded an orange-red solid, 2-(4-ethylphenyl)-2-oxoacetaldehyde oxime (80 mg, 45%). MP: 68-69 °C; IR (neat): 3177, 2958, 1629, 1605, 1464, 1315, 1284, 1014 cm⁻¹ -1 ; 1 H NMR (CDCl3, 500MHz): δ H 14.77(s,0.3H),8.64(s,1H),8.25(s,0.3H),8.06(s,1H),7.98(d,J=8.0Hz,2H),7.95(d,J=8.0Hz, 0.6H),7.37(d,J=8.0Hz,0.6H),7.30(d,J=8.0Hz,2H),2.77-2.69(m,2.6H),1.30-1.25(m,4H)ppm; 13 C NMR (CDCl3, 125MHz): δ C 188.2,151.0,148.5,133.6,130.3,128.2,29.2,15.2ppm; HRMS m / z calcd for C 10 H 12 O2N[M+H] + :178.0863; found:178.0861.

[0235] Example 2: Preparation of 2-oxo-2-(4-propylphenyl)acetaldehyde oxime

[0236]

[0237] 48 mg of NaH was dissolved in 3.0 mL of DMF solvent. The mixture was stirred at 0 °C for 5 minutes, and 162 mg of p-propyl acetophenone was added. The reaction was continued at 0 °C for 45 minutes. Then, 113 mg of tert-butyl nitrite was added at 0 °C and the reaction was continued for 5 minutes. Finally, the temperature was raised to room temperature and the reaction was carried out for 3 hours. The reaction was quenched with saturated ammonium chloride, and the reaction solution was extracted with ethyl acetate. The organic layers were combined, dried, and the organic solvent was removed under reduced pressure. Column chromatography yielded an orange-red solid, 2-oxo-2-(4-propylphenyl)acetaldehyde oxime (86 mg, 45%). MP: 92-94 °C; IR (neat): ν = 3177, 2960, 1626, 1597, 1375, 1316, 1003 cm⁻¹ -1 ; 1 H NMR (CD3OD, 500MHz): δ8.00 (s, 1H), 7.98 (d, J = 8.5Hz, 2H), 7.28 (d, J = 8.5Hz, 2H), 2.64 (t, J = 7.5Hz, 2H), 1.66 (m, 2H), 0.94 (t, J = 7.5Hz, 3H) ppm; 13 C NMR (CD3OD, 125MHz): δ190.3,150.2,148.8,135.2,131.2,129.5,39.0,25.3,14.0ppm; HRMS m / z calcd for C 11 H 14 O2N[M+H] + :192.1019; found:192.1023.

[0238] Example 3: Preparation of 2-(4-Butylphenyl)-2-oxoacetaldehyde oxime

[0239]

[0240] 48 mg of NaH was dissolved in 3.0 mL of DMF solvent. The mixture was stirred at 0 °C for 5 minutes, and 176 mg of p-butylacetophenone was added. The reaction was carried out at 0 °C for 45 minutes. Then, 113 mg of tert-butyl nitrite was added at 0 °C and the reaction was continued for 5 minutes. Finally, the temperature was raised to room temperature and the reaction was carried out for 3 hours. The reaction was quenched with saturated ammonium chloride, and the reaction solution was extracted with ethyl acetate. The organic layers were combined, dried, and the organic solvent was removed under reduced pressure. Column chromatography yielded an orange-red solid, 2-(4-butylphenyl)-2-oxoacetaldehyde oxime (103 mg, 50%). MP: 81-83 °C; IR (neat): ν = 3303, 2954, 1675, 1608, 1465, 1237, 1055 cm⁻¹ -1 ; 1 H NMR (CD3OD, 500MHz): δ H8.00(s,1H),7.99(d,J=8.5Hz,2H),7.29(d,J=8.5Hz,2H),2.68(t,J=7.5Hz,2H),1.62(m,2H),1.36(m,2H)0.94(t,J=7.5Hz,3H)ppm; 13 C NMR (CD3OD, 100MHz): δ C 190.3,150.5,148.8,135.1,131.2,129.5,36.6,34.5,23.4,14.2ppm; HRMS m / z calcd forC 12 H 16 O2N[M+H] + :206.1176; found:206.1179.

[0241] Example 4: Preparation of 2-(4-ethoxyphenyl)-2-oxoacetaldehyde oxime

[0242]

[0243] 48 mg of NaH was dissolved in 3.0 mL of DMF solvent. The mixture was stirred at 0 °C for 5 minutes, and 164 mg of p-ethoxyacetophenone was added. The reaction was carried out at 0 °C for 45 minutes. Then, 113 mg of tert-butyl nitrite was added at 0 °C and the reaction was continued for 5 minutes. Finally, the temperature was raised to room temperature and the reaction was carried out for 3 hours. The reaction was quenched with saturated ammonium chloride, and the reaction solution was extracted with ethyl acetate. The organic layers were combined, dried, and the organic solvent was removed under reduced pressure. Column chromatography yielded an orange-red solid, 2-(4-ethoxyphenyl)-2-oxoacetaldehyde oxime (100 mg, 52%). MP: 100-105 °C; IR (neat): ν = 3164, 2981, 1596, 1567, 1317, 1265, 1193, 1044 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 15.09(s,0.3H),8.24(s,0.3H),8.12(s,1H),8.08(d,J=8.8Hz,2H),8.12(s,1H),8.01(d,J=8.8Hz, 0.6H),6.99(d,J=8.8Hz,0.6H),6.94(d,J=8.8Hz,2H),4.17-4.09(m,2.6H),1.48-1.43(m,4H)ppm; 13 C NMR (CDCl3, 100MHz): δ C186.7,163.7,148.7,132.5,128.6,114.4,64.0,14.8ppm; HRMS m / z calcd for C 10 H 12 O3N[M+H] + :194.0812; found:194.0810.

[0244] Example 5: Preparation of 2-oxo-2-(4-(trifluoromethyl)phenyl)acetaldehyde oxime

[0245]

[0246] 48 mg of NaH was dissolved in 3.0 mL of DMF solvent and stirred at 0 °C for 5 minutes. 188 mg of p-trifluoromethylacetophenone was added and the reaction was continued at 0 °C for 45 minutes. Then, 113 mg of tert-butyl nitrite was added at 0 °C and the reaction was continued for 5 minutes. Finally, the temperature was raised to room temperature and the reaction was carried out for 3 hours. The reaction was quenched with saturated ammonium chloride, and the reaction mixture was extracted with ethyl acetate. The organic layers were combined, dried, and the organic solvent was removed under reduced pressure. Column chromatography yielded an orange-red solid, 2-oxo-2-(4-(trifluoromethyl)phenyl)acetaldehyde oxime (109 mg, 50%). MP: 110-112 °C; IR (neat): ν = 3269, 1673, 1644, 1567, 1463, 1260, 1040 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 8.30(s,1H),8.16(m,2H),7.99(s,1H),7.73(m,2H)ppm; 13 C NMR (acetone-d6, 125MHz): δ C 188.3,148.4,139.5,133.3(q,J=32.1Hz),130.5,125.1(q,J=3.5Hz),123.9(q,J=269.6Hz)ppm; HRMS m / z calcd for C9H6F3O2N[MH] - :216.0278; found:216.0275.

[0247] Example 6: Preparation of 2-(3-bromophenyl)-2-oxoacetaldehyde oxime

[0248]

[0249] 48 mg of NaH was dissolved in 3.0 mL of DMF solvent. The mixture was stirred at 0 °C for 5 minutes, and 198 mg of 3-bromoacetophenone was added. The reaction was continued at 0 °C for 45 minutes. Then, 113 mg of tert-butyl nitrite was added at 0 °C and the reaction was continued for 5 minutes. Finally, the temperature was raised to room temperature and the reaction was carried out for 3 hours. The reaction was quenched with saturated ammonium chloride, and the reaction solution was extracted with ethyl acetate. The organic layers were combined, dried, and the organic solvent was removed under reduced pressure. Column chromatography yielded an orange-red solid, 2-(3-bromophenyl)-2-oxoacetaldehyde oxime (114 mg, 51%). MP: 112-113 °C; IR (neat): ν = 3269, 1673, 1644, 1567, 1463, 1260, 1040 m -1 ; 1 H NMR (CDCl3, 400MHz): δ H 8.26(s,1H),8.21(m,1H),7.99(d,J=9.4Hz,1H),7.96(s,1H),7.72(d,J=10.0Hz,1H),7.35(t,J=10.0Hz,1H)ppm; 13 C NMR (CDCl3, 100MHz): δ C 187.4,149.1,137.5,136.5,133.2,130.1,128.7,122.7ppm; HRMS m / z calcd for C8H5O2BrN[MH] - :225.9509; found:225.9509.

[0250] Example 7: Preparation of 2-oxo-2-(4-(piperidin-1-yl)phenyl)acetaldehyde oxime

[0251]

[0252] 48 mg of NaH was dissolved in 3.0 mL of DMF solvent. The mixture was stirred at 0 °C for 5 minutes, and 203 mg of 4-piperidine acetophenone was added. The reaction was carried out at 0 °C for 30 minutes. Then, 116 mg of tert-butyl nitrite was added at 0 °C and the reaction was continued for 5 minutes. Finally, the temperature was raised to room temperature and the reaction was carried out for 3 hours. The reaction was quenched with saturated ammonium chloride, and the reaction solution was extracted with ethyl acetate. The organic layers were combined, dried, and the organic solvent was removed under reduced pressure. Column chromatography yielded a pale yellow solid, 2-oxo-2-(4-(piperidinephenyl)acetaldehyde oxime) (116 mg, 50%). MP: 173-175 °C; IR (neat): ν = 2936, 2850, 1586, 1527, 1397, 1239, 1195, 1126 cm⁻¹ -1 ; 1H NMR (acetone-d6, 400MHz): δ H 12.85(s,0.3H),11.25(s,1H),8.04-7.99(m,2H),7.90(s,1H),7.90-7.85(m,0.6H),7.81(s,1H) ,7.02-6.97(m,0.6H),6.97-6.92(m,2H),3.50(m,1H),3.45-3.43(m,4H),1.69-1.63(m,8H)ppm; 13 C NMR (CD3OD, 100MHz): δ C 188.0,186.2,156.0,155.5,149.4,144.3,132.9,132.5,125.7,124.3,113.8,113.7,48.9,48.7,26.1,25.1ppm; HRMS m / z calcd for C 13 H 17 O2N2[M+H] + :233.1285; found:233.1288.

[0253] Example 8: Preparation of 2-(4-morpholinophenyl)-2-oxoacetaldehyde oxime

[0254]

[0255] 48 mg of NaH was dissolved in 3.0 mL of DMF solvent. The mixture was stirred at 0 °C for 5 minutes, and 205 mg of 4-morpholinoacetophenone was added. The reaction was continued at 0 °C for 30 minutes. Then, 116 mg of tert-butyl nitrite was added at 0 °C and the reaction was continued for 5 minutes. Finally, the temperature was raised to room temperature and the reaction was carried out for 3 hours. The reaction was quenched with saturated ammonium chloride, and the reaction solution was extracted with ethyl acetate. The organic layers were combined, dried, and the organic solvent was removed under reduced pressure. Column chromatography yielded a pale yellow solid, 2-(4-morpholinophenyl)-2-oxoacetaldehyde oxime (117 mg, 50%). MP: 145-147 °C; IR (neat): ν = 2966, 1593, 1392, 1317, 1242, 1200, 1116 cm⁻¹ -1 ; 1 H NMR (acetone-d6, 400MHz): δ H 12.33(s,1H),7.92-7.87(m,2H),7.74(s,1H),7.07-7.02(m,2H),3.81-3.77(m,4H),3.44-3.38(m,4H)ppm; 13C NMR (acetone-d6, 100MHz): δ C 188.9,156.2,145.0,132.2,125.8,114.0,67.0,47.8; HRMS m / z calcd for C 12 H 15 O3N2[M+H] + :235.1077; found:235.1074.

[0256] Example 9: Preparation of 2-(4-nitrophenyl)-2-oxoacetaldehyde oxime

[0257]

[0258] 48 mg of NaH was dissolved in 3.0 mL of DMF solvent. The mixture was stirred at 0 °C for 5 minutes, and 165 mg of 4-nitroacetophenone was added. The reaction was continued at 0 °C for 30 minutes. Then, 116 mg of tert-butyl nitrite was added at 0 °C and the reaction was continued for 5 minutes. Finally, the temperature was raised to room temperature and the reaction was carried out for 3 hours. The reaction was quenched with saturated ammonium chloride, and the reaction solution was extracted with ethyl acetate. The organic layers were combined, dried, and the organic solvent was removed under reduced pressure. Column chromatography yielded a pale yellow solid, 2-(4-nitrophenyl)-2-oxoacetaldehyde oxime (98 mg, 51%). MP: 135-137 °C; IR (neat): ν = 3188, 3054, 1639, 1596, 1523, 1457, 1344, 1286, 1008 cm⁻¹ -1 ; 1 H NMR (CDCl3, 500MHz): δ H 8.31(d,J=8.5Hz,2H),8.28(s,1H),8.21(d,J=8.5Hz,2H),7.98(s,1H)ppm; 13 C NMR (CDCl3, 125MHz): δ C 188.5,150.1,146.3,140.8,130.8,124.4ppm; HRMS m / z calcd for C8H5O4N2[MH] - :193.0255; found:193.0253.

[0259] Example 10: Preparation of (E)-2-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphth-2-yl)-2-oxoacetaldehyde oxime

[0260]

[0261] NaH (48 mg) was dissolved in 3.0 mL of DMF solvent and stirred at 0 °C for 5 minutes. Then, 258 mg of tuna was added and the mixture was reacted at 0 °C for 30 minutes. Next, 116 mg of tert-butyl nitrite was added at 0 °C and the reaction continued for 5 minutes. Finally, the mixture was heated to room temperature and reacted for 3 hours. The reaction was quenched with saturated ammonium chloride, and the reaction solution was extracted with ethyl acetate. The organic layers were combined, dried, and the organic solvent was removed under reduced pressure. Column chromatography yielded a colorless solid (E)-2-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthyl-2-yl)-2-oxoacetaldehyde oxime (130 mg, 45%). MP: 132-134 °C; IR (neat): ν = 3322, 2965, 2929, 1656, 1607, 1542, 1455, 1364, 1243, cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 8.00(s,1H),7.56(s,1H),2.44(s,2H),1.96-1.85(m,1H),1.67(t,J=13.2Hz,1H),1.43(dd,J=1 3.2,2.8Hz,1H),1.37(s,3H),1.32(s,3H),1.28(s,3H),1.11(s,3H),1.03(d,J=6.9Hz,3H)ppm; 13 C NMR (CDCl3, 100MHz): δ C 192.2,150.6,149.7,142.1,135.2,133.6,130.3,129.0,43.5,38.1,34.5,34.2,32.5,32.0,28.4,24.8,20.5,16.9ppm; HRMS m / z calcd for C 18 H 26 O2N[M+H] + :288.1958; found:288.1962.

[0262] Example 11: Preparation of 2-(2,3-dihydrobenzofuran-5-yl)-2-oxoacetaldehyde oxime

[0263]

[0264] NaH (48 mg) was dissolved in 3.0 mL of DMF solvent and stirred at 0 °C for 5 minutes. 5-Acetyl-2,3-dihydrobenzo[b]furan (162 mg) was added and reacted at 0 °C for 30 minutes. Then, tert-butyl nitrite (116 mg) was added at 0 °C and the reaction continued for 5 minutes. Finally, the temperature was raised to room temperature and reacted for 3 hours. The reaction was quenched with saturated ammonium chloride, and the reaction mixture was extracted with ethyl acetate. The organic layers were combined, dried, and the organic solvent was removed under reduced pressure. Column chromatography yielded a pale yellow solid, 2-(2,3-dihydrobenzofuran-5-yl)-2-oxo (84 mg, 44%). MP: 93-96 °C; IR (neat): ν = 3290, 1656, 1603, 1491, 1442, 1286, 1245 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 8.17(s,0.15H),8.08(s,1H),7.96-7.93(m,2H),7.87-7.85(m,0.3H),6.88( d,J=8.0Hz,0.15H),6.82(d,J=8.0Hz,1H),4.68(m,2.3H),3.25(m,2.3H)ppm; 13 C NMR (CDCl3, 100MHz): δ C 181.4,160.1,143.2,127.3,123.9,122.8,122.1,104.1,67.3,23.8ppm; HRMS m / z ca cld for C 10 H 10 O3N[M+H] + :192.0655; found:192.0654.

[0265] Example 12: Preparation of (E)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxoacetaldehyde oxime

[0266]

[0267] NaH (48 mg) was dissolved in 3.0 mL of DMF solvent and stirred at 0 °C for 5 minutes. 6-Acetyl-1,4-benzodioxane (178 mg) was added and reacted at 0 °C for 30 minutes. Then, tert-butyl nitrite (116 mg) was added at 0 °C and the reaction continued for 5 minutes. Finally, the temperature was raised to room temperature and reacted for 3 hours. The reaction was quenched with saturated ammonium chloride, and the reaction mixture was extracted with ethyl acetate. The organic layers were combined, dried, and the organic solvent was removed under reduced pressure. Column chromatography yielded an orange-red solid (E)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxoacetaldehyde oxime (85 mg, 41%). MP: 193-196 °C; IR (neat): ν = 3221, 1580, 1515, 1457, 1315, 1287, 1069 cm⁻¹ -1 ; 1 H NMR (acetone-d6, 400MHz): δ H 10.90(s,1H),10.85(s,1H),8.59(s,1H),7.18-7.12(m,2H),6.80(d,J=8.4Hz,1H),4.29-4.23(m,4H)ppm; 13 C NMR (acetone-d6, 100MHz): δ C 151.5,145.5,143.9,142.2,128.1,122.6,118.4,117.3,65.3,65.1ppm; HRMS m / z calcd for C 10 H 10 O4N[M+H] + :208.0604; found:208.0603.

[0268] Example 13: Preparation of 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-2-oxoacetaldehyde oxime

[0269]

[0270] 48 mg of NaH was dissolved in 3.0 mL of DMF solvent and stirred at 0 °C for 5 minutes. 1-(benzo[d][1,3]dioxacyclopenten-5-yl)ethane-1-one (164 mg) was added and reacted at 0 °C for 30 minutes. Then, 116 mg of tert-butyl nitrite was added at 0 °C and the reaction continued for 5 minutes. Finally, the temperature was raised to room temperature and reacted for 3 hours. The reaction was quenched with saturated ammonium chloride, and the reaction mixture was extracted with ethyl acetate. The organic layers were combined, dried, and the organic solvent was removed under reduced pressure. Column chromatography yielded an orange-red solid, 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-2-oxoacetaldehyde oxime (97 mg, 51%). MP: 183-186 °C; IR (neat): ν = 3213, 1657, 1600, 1504, 1454, 1260, 1033 cm⁻¹ -1 ; 1 H NMR (CD3OD, 400MHz): δ H 7.99(s,1H),7.79(dd,J=8.3,1.7Hz,1H),7.57(dd,J=8.0,1.6Hz,0.6H),7.55(d,J=1.6Hz,1H),7.43(s,0.6 H),7.37(d,J=1.6Hz,0.6H),6.95(d,J=8.0Hz,0.6H),6.92(d,J=8.0Hz,1H),6.09(s,1.2H),6.07(s,2H)ppm; 13 C NMR (CD3OD, 100MHz): δ C 191.3,188.3,154.5,153.8,150.0,149.5,148.7,146.1,131.8,131.2,128.1,110.1,109.2,108.8,108.6,103.7,103.5ppm; HRMS m / z calcd for C9H8O4N[M+H] + :194.0448; found:194.0447.

[0271] Example 14: Preparation of 2-(3,4-dihydroxyphenyl)-2-oxoacetaldehyde oxime

[0272]

[0273] 48 mg of NaH was dissolved in 3.0 mL of DMF solvent and stirred at 0 °C for 5 minutes. 152 mg of 3,4-dihydroxyacetophenone was added and the reaction was continued at 0 °C for 30 minutes. Then, 116 mg of tert-butyl nitrite was added at 0 °C and the reaction was continued for 5 minutes. Finally, the temperature was raised to room temperature and the reaction was carried out for 3 hours. The reaction was quenched with saturated ammonium chloride, and the reaction solution was extracted with ethyl acetate. The organic layers were combined, dried, and the organic solvent was removed under reduced pressure. Column chromatography yielded an orange-red solid, 2-(3,4-dihydroxyphenyl)-2-oxoacetaldehyde oxime (95 mg, 51%). MP: 202-206 °C; IR (neat): ν = 3246, 1660, 1580, 1478, 1287, 1197 cm⁻¹ -1 ; 1 H NMR (acetone-d6, 500MHz): δ H 7.92(s,1H),7.65-7.61(m,2H),6.91(m,1H)ppm; 13 C NMR (acetone-d6, 125MHz): δ C 187.3,151.6,149.1,145.7,129.5,124.9,117.5,115.6ppm; HRMSm / z calcd for C8H8O4N[M+H] + :182.0448; found:182.0449.

[0274] Example 15: Preparation of 2-(4-hydroxy-3-methoxyphenyl)-2-oxoacetaldehyde oxime

[0275]

[0276] 48 mg of NaH was dissolved in 3.0 mL of DMF solvent and stirred at 0 °C for 5 minutes. 1-(3-hydroxy-4-methoxyphenyl)ethane-1-one (166 mg) was added and reacted at 0 °C for 30 minutes. Then, 116 mg of tert-butyl nitrite was added at 0 °C and the reaction continued for 5 minutes. Finally, the temperature was raised to room temperature and reacted for 3 hours. The reaction was quenched with saturated ammonium chloride, and the reaction mixture was extracted with ethyl acetate. The organic layers were combined, dried, and the organic solvent was removed under reduced pressure. Column chromatography yielded an orange-red solid, 2-(4-hydroxy-3-methoxyphenyl)-2-oxoacetaldehyde oxime (98 mg, 51%). MP: 172-173 °C; IR (neat): ν = 3267, 165, 1570, 1521, 1470, 1274, 1215 cm⁻¹ -1 ; 1 H NMR (acetone-d6, 400MHz): δ H11.42(s,1H),8.55(s,1H),7.97(s,1H),7.77(dd,J=8.4,2.0Hz,1H),7.67(d,J=2.0Hz,1H),6.92(d,J=8.4Hz,1H),3.90(s,3H)ppm; 13 C NMR (acetone-d6, 100MHz): δ C 187.0,152.8,149.1,148.2,129.2,126.3,115.3,113.1,56.2ppm; HRMS m / z calcd for C9H 10 O4N[M+H] + :196.0604; found:196.0604.

[0277] Example 16: Preparation of 2-(4-hydroxyphenyl)-2-oxoacetaldehyde oxime

[0278]

[0279] 48 mg of NaH was dissolved in 3.0 mL of DMF solvent. The mixture was stirred at 0 °C for 5 minutes, and 135 mg of 4-hydroxyacetophenone was added. The reaction was continued at 0 °C for 30 minutes. Then, 116 mg of tert-butyl nitrite was added at 0 °C and the reaction was continued for 5 minutes. Finally, the temperature was raised to room temperature and the reaction was carried out for 3 hours. The reaction was quenched with saturated ammonium chloride, and the reaction solution was extracted with ethyl acetate. The organic layers were combined, dried, and the organic solvent was removed under reduced pressure. Column chromatography yielded an orange-red solid, 2-(4-hydroxyphenyl)-2-oxoacetaldehyde oxime (88 mg, 52%). MP: 163-165 °C; IR (neat): ν = 3239, 1669, 1607, 1575, 1461, 1248, 1179, 1059 cm⁻¹ -1 ; 1 HNMR (acetone-d6, 500MHz): δ H 11.42(s,1H),9.25(s,1H),8.04(d,J=9.0Hz,2H),7.92(s,1H),6.93(d,J=9.0Hz,2H)ppm; 13 C NMR (aacetone-d6, 125MHz): δ C 187.4,163.1,149.3,133.4,129.0,115.9ppm; HRMS m / z calcd for C8H8O3N[M+H] + :166.0501; found:166.0499.

[0280] Example 17: Preparation of 2-(4-Butylphenyl)-2-(hydroxyimino)acetaldehyde oxime

[0281]

[0282] Weigh 206 mg of 2-(4-butylphenyl)-2-oxoacetaldehyde oxime, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and react under reflux for 4 h. Remove the organic solvent under reduced pressure and perform column chromatography to obtain a purple-red solid, 2-(4-butylphenyl)-2-(hydroxyimino)acetaldehyde oxime (210 mg, 95%). MP: 163-165℃; IR (neat): ν = 3266, 2957, 2930, 1615, 1516, 1424, 1457, 1270, 1001 cm⁻¹ -1 ; 1 H NMR (CD3OD, 500MHz): δ H 8.56(s,1H),7.87(s,0.5H),7.48(d,J=8.0Hz,2H),7.29(d,J=8.0Hz,1H),7.19(d,J=8.0Hz,1H),7. 16(d,J=8.0Hz,2H),2.64-2.60(m,3H),1.65-1.57(m,3H),1.41-1.32(m,3H),0.96-0.92(m,5H)ppm; 13 C NMR (CD3OD, 125MHz): δ C 155.0,153.1,149.8,145.0,144.6,142.5,132.7,130.4,129.8,129.0,128.9,128.6,36.5,36.4,34.8,23.4,23.3,14.3ppm; HRMS m / z calcdfor C 12 H 17 O2N2[M+H] + :221.1285; found:221.1289.

[0283] Example 18: Preparation of 2-(hydroxyimino)-2-(4-pentylphenyl)acetaldehyde oxime

[0284]

[0285] Weigh 220 mg of 2-oxo-2-(4-pentylphenyl)acetaldehyde oxime, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and react under reflux for 4 h. Remove the organic solvent under reduced pressure and perform column chromatography to obtain a colorless solid, 2-(hydroxyimino)-2-(4-pentylphenyl)acetaldehyde oxime (211 mg, 90%). MP: 106-108 °C; IR (neat): ν = 3288, 2956, 2927, 1615, 1517, 1424, 1456, 1270, 1005 cm⁻¹ -1 ; 1 H NMR (CD3OD, 500MHz): δ H 8.56(s,1H),7.87(s,0.5H),7.48(d,J=8.0Hz,2H),7.29(d,J=8.0Hz,1H),7.19(d,J=8.0Hz,1H),7.1 5(d,J=8.0Hz,2H),2.63-2.59(m,3H),1.66-1.59(m,,3H),1.40-1.29(m,6H),0.93-0.89(m,5H)ppm; 13 C NMR (CD3OD, 125MHz): δ C 155.0,153.1,149.7,145.0,144.7,142.5,132.7,130.4,129.8,128.9,128.9,128.6,36.8,36.6,32.6,32.5,32.3,23.6,14.4ppm; HRMS m / z calcdfor C 13 H 19 O2N2[M+H] + :235.1452; found:235.1441.

[0286] Example 19: Preparation of 2-(hydroxyimino)-2-(o-tolyl)acetaldehyde oxime

[0287]

[0288] Weigh 164 mg of 2-oxo-2-(2-methylphenyl)acetaldehyde oxime, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and reflux for 4 h. Remove the organic solvent under reduced pressure and perform column chromatography to obtain a yellow solid, 2-(hydroxyimino)-2-(2-methylphenyl)acetaldehyde oxime (151 mg, 85%). MP: 144-146 °C; IR (neat): ν = 3271, 2956, 1493, 1456, 1263, 1090 cm⁻¹ -1 ;1 H NMR (CD3OD, 500MHz): δ H 8.60(s,2H),7.91(s,1H),7.28-7.13(m,10H),7.00(d,J=6.0Hz,1H),2.22(s,5H),2.17(s,3H)ppm; 13 C NMR (CD3OD, 125MHz): δ C 156.4,154.6,149.4,142.3,138.3,137.0,135.3,133.0,131.0,130.9,130.5,129.7,129.4,129.3,126.3,126.1,20.1,19.8ppm; HRMS m / z calcd for C9H 11 O2N2[M+H] + :179.0815; found:179.0819.

[0289] Example 20: Preparation of 2-(hydroxyimino)-2-(4-isobutylphenyl)acetaldehyde oxime

[0290]

[0291] Weigh 206 mg of 2-oxo-2-(4-isobutylphenyl)acetaldehyde oxime, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and reflux for 4 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid 2-(hydroxyimino)-2-(4-isobutylphenyl)acetaldehyde oxime (205 mg, 93%). MP: 159-161℃; IR (neat): ν = 3287, 2956, 2923, 2868, 1466, 1264, 1008 cm⁻¹ -1 ; 1 H NMR (CD3OD, 500MHz): δ H 9.77(s,2H),9.03(s,1H),8.70(d,J=8.0Hz,4H),8.49(d,J=8.0Hz,2H),8.34(d,J=8.0Hz, 2H),8.31(d,J=8.0Hz,4H),3.65-3.63(m,7H),3.25-3.18(m,15H),3.06-3.03(m,4H)ppm; 13 C NMR (CD3OD, 125MHz): δ C154.3,152.1,149.3,143.3,142.9,142.0,132.6,130.1,129.3,129.3,128.9,45.8,45.6,30.9,22.6,22.6ppm; HRMS m / z calcd for C 12 H 17 O2N2[M+H] + :221.1285; found:221.1290.

[0292] Example 21: Preparation of 2-(hydroxyimino)-2-(4-(trifluoromethyl)phenyl)acetaldehyde oxime

[0293]

[0294] Weigh 218 mg of 2-oxo-2-(4-trifluoromethylphenyl)acetaldehyde oxime, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and reflux for 4 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid 2-(hydroxyimino)-2-(4-trifluoromethylphenyl)acetaldehyde oxime (219 mg, 94%). MP: 161-163℃; IR (neat): ν = 3270, 1407, 1330, 1172, 1116, 1068 cm⁻¹ -1 ; 1 H NMR (CD3OD, 500MHz): δ H 8.59(s,1.5H),7.91(s,1H),7.80(d,J=8.0Hz,3H),7.68(d,J=8.0Hz,2H),7.64(d,J=8.0Hz,3H),7.52(d,J=8.0Hz,2H)ppm; 13 C NMR (CD3OD, 125MHz): δ C 154.1, 151.8, 149.1, 141.8, 139.4(q,J=1.3Hz), 136.1(q,J=1.3Hz), 131.6(q,J=31.3Hz), 131.4(q,J=31.3Hz) HRMS m / z calcd for C9H8O2N2F3[M+H] + :233.0532; found:233.0537.

[0295] Example 22: Preparation of 2-(3-fluorophenyl)-2-(hydroxyimino)acetaldehyde oxime

[0296]

[0297] Weigh 168 mg of 2-oxo-2-(3-fluorophenyl)acetaldehyde oxime, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and reflux for 4 h. Remove the organic solvent under reduced pressure and perform column chromatography to obtain a colorless solid, 151 mg (83%), of 2-(hydroxyimino)-2-(3-fluorophenyl)acetaldehyde oxime. MP: 139-141℃; IR (neat): ν = 3278, 2926, 1583, 1490, 1446, 1271, 1211, 1097 cm⁻¹ -1 ; 1 H NMR (acetone-d6, 500MHz): δ H 8.62(s,2H),7.90(s,1H),7.49(d,J=9.0Hz,2H),7.47-7.37(m,6H),7.22(d,J=9.0Hz,1H),7.19-7.11(m,4H)ppm; 13 C NMR (acetone-d6, 125MHz): δ C 163.0(d,J=243.2Hz),162.9(d,J=243.2Hz),153.3,151.0,148.7,141. 5,137.2(d,J=8.9Hz),133.7(d,J=8.9Hz),130.4(d,J=8.9Hz),130.2(d, HRMS m / z calcd for C9H8O2N2F3[M+H] + :183.0564; found:183.0568.

[0298] Example 23: Preparation of 2-(hydroxyimino)-2-(4-(piperidin-1-yl)phenyl)acetaldehyde oxime

[0299]

[0300] Weigh 233 mg of 2-oxo-2-(4-piperidinylphenyl)acetaldehyde oxime, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and reflux for 4 h. Remove the organic solvent under reduced pressure and perform column chromatography to obtain a yellow solid, 2-(hydroxyimino)-2-(4-piperidinylphenyl)acetaldehyde oxime (236 mg, 95%). MP: 139-141℃; IR (neat): ν = 2936, 1603, 1517, 1457, 1228, 1202, 1033 cm⁻¹ -1 ; 1 H NMR (acetone-d6, 500MHz): δ H 10.83(s,1H),10.65(s,1H),10.63(s,0.1H),10.39(s,0.1H),8.59(s,1H),7.84(s,0.1H),7.54-7.50(m,2H), 7.41-7.37(m,0.2H),6.93-6.87(m,2.2H),3.26-3.19(m,4.4H),1.70-1.62(m,4.4H),1.62-1.56(m,2.2H)ppm; 13 C NMR (acetone-d6, 125MHz): δ C 151.8,149.8,149.4,142.5,132.9,131.6,130.2,125.7,124.7,115.5,115.0,113.7,50.3,48.9,26.4,26.3,25.1,25.1ppm; HRMS m / zcalcd for C 13 H 18 O2N3[M+H] + :248.1394; found:248.1396.

[0301] Example 24: Preparation of 2-(hydroxyimino)-2-(4-morpholinophenyl)acetaldehyde oxime

[0302]

[0303] Weigh 234 mg of 2-(4-morpholinophenyl)-2-oxoacetaldehyde oxime, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and reflux for 4 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a yellow solid, 2-(hydroxyimino)-2-(4-morpholinophenyl)acetaldehyde oxime (242 mg, 97%). MP: 144-146℃; IR (neat): ν = 3269, 1605, 1520, 1450, 1236, 1265, 1114 cm⁻¹-1 ; 1 H NMR (acetone-d6, 500MHz): δ H 10.85(s,1H),10.71(s,1H),10.68(s,0.3H),10.42(s,0.3H),8.60(s,1H),7.85(s,0.3H),7.56(d,J=8.5Hz,2 H),7.40(d,J=8.5Hz,0.6H),6.94(d,J=8.5Hz,0.6H),6.92(d,J=8.5Hz,2H),3.78(m,5.2H),3.18(m,5.2H)ppm; 13 C NMR (acetone-d6, 125MHz): δ C 152.9,149.7,149.3,142.4,132.8,131.6,130.3,125.7,115.0,114.5,113.7,67.3,67.1,49.3,48.0ppm; HRMS m / z calcd forC 12 H 16 O3N3[M+H] + :250.1186; found:250.1183.

[0304] Example 25: Preparation of 2-(hydroxyimino)-2-(4-nitrophenyl)acetaldehyde oxime

[0305]

[0306] Weigh 194 mg of 2-(4-nitrophenyl)-2-oxoacetaldehyde oxime, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and reflux for 4 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a yellow solid, 2-(hydroxyimino)-2-(4-nitrophenyl)acetaldehyde oxime (205 mg, 98%). MP: 170-173℃; IR (neat): ν = 3265, 1601, 1519, 1403, 1348, 1271, 1033 cm⁻¹ -1 ; 1 H NMR (acetone-d6, 500MHz): δ H 8.28-8.22(m,2H),7.73-7.67(m,2H)ppm; 13 C NMR (acetone-d6, 125MHz): δ C153.5,151.2,149.3,149.1,148.8,141.9,141.6,138.8,131.8,130.9,123.8,123.7ppm; HRMS m / z calcd for C8H6O4N3[MH] - :208.0364; found:208.0362.

[0307] Example 26: Preparation of 1-phenylpropane-1,2-dione dioxime

[0308]

[0309] Weigh 163 mg of 2-(hydroxyimino)-1-phenylprop-1-one, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and react under reflux for 4 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a yellow solid, 1-phenylpropane-1,2-dione dioxime (175 mg, 98%). MP: 170-173℃; IR (neat): ν = 3258, 1496, 1445, 1424, 1370, 1200, 1018 cm⁻¹ -1 ; 1 H NMR (MeOD, 400MHz): δ H 7.66-7.60(m,2H),7.56-7.49(m,2H),7.52-7.45(m,1H)ppm; 13 C NMR (CD3OD, 125MHz): δ C 157.1,148.6,130.9,130.9,128.2,127.3,16.6ppm; HRMS m / z calcd for C9H 11 O2N2[M+H] + :179.0815; sound:179.0813.

[0310] Example 27: Preparation of (1E)-2-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthyl-2-yl)-2-(hydroxyimino)acetaldehyde oxime

[0311]

[0312] Weigh 288 mg of 2-oxo-2-(2,4,4,5,7,7-hexamethyltetrahydronaphthalene)acetaldehyde oxime, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and react under reflux for 4 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid (1E)-2-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene-2-yl)-2-(hydroxyimino)acetaldehyde oxime (273 mg, 90%). MP: 210-211 °C; IR (neat): ν = 3287, 2966, 2877, 1457, 1363, 1262, 1033, 1016 cm⁻¹ -1 ; 1 H NMR (acetone-d6, 500MHz): δ H 10.80(s,1H),10.71(s,1.4H),10.34(s,0.4H),8.65(s,1H),7.91(s,0.4H ),7.24(s,0.4H),7.21(s,1H),7.13(s,1H),6.99(s,0.4H),2.17(s,3H),2 .13(s,1.2H),1.93-1.84(m,1.4H),1.66-1.61(m,1.4H),1.40-1.37(m,1. 4H),1.33-1.31(m,4.2H),1.28-1.22(m,8.4H),1.08-1.07(m,4.2H),1.00 -0.99(m,4.2H)ppm; 13 C NMR (acetone-d6, 125MHz): δ C 155.2,153.1,148.5,145.9,145.6,141.3,141.3,133.7,132.6,131.8,129.4,128.2,128.0,127.7,126.3,43. 6,43.6,37.4,37.4,34.6,34.6,33.7,33.7,31.8,31.8,31.5,31.5,28.1,24.4,24.3,19.2,18.8,16.3ppm; HRMS m / z calcd forC 18 H 27 O2N2[M+H] + :303.2067; found:303.2063.

[0313] Example 28: Preparation of (1E)-2-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthyl-2-yl)-2-(hydroxyimino)acetaldehyde oxime

[0314]

[0315] Weigh 208 mg of 2-oxo-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetaldehyde oxime, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and reflux for 4 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid (1E)-2-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthyl-2-yl)-2-(hydroxyimino)acetaldehyde oxime (201 mg, 90%). MP: 194-196℃; IR (neat): ν = 3221, 1580, 1515, 1457, 1315, 1287, 1069 cm⁻¹ -1 ; 1 H NMR (acetone-d6, 400MHz): δ H 10.90(s,1H),10.85(s,1H),8.59(s,1H),7.18-7.12(m,2H),6.80(d,J=8.4Hz,1H),4.29-4.23(m,4H)ppm; 13 C NMR (acetone-d6, 100MHz): δ C 151.5,145.5,143.9,142.2,128.1,122.6,118.4,117.3,65.3,65.1ppm; HRMS m / zcalcd for C 10 H 11 O4N2[M+H] + :223.0713; found:223.0712.

[0316] Example 29: Preparation of 2-(2,3-dihydrobenzofuran-5-yl)-2-(hydroxyimino)acetaldehyde oxime

[0317]

[0318] Weigh 192 mg of 2-oxo-2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde oxime, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and react under reflux for 4 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a pale yellow solid, 2-(2,3-dihydrobenzofuran-5-yl)-2-(hydroxyimino)acetaldehyde oxime (188 mg, 91%). MP: 164-166℃; IR (neat): ν = 3287, 1611, 1495, 1440, 1272, 1236, 1075 cm⁻¹-1 ; 1 H NMR (acetone-d6, 400MHz): δ H 8.60(s,1H),7.86(s,0.35H),7.48(s,1H),7.40(d,J=7.3Hz,1H),7.31(s,0.5H),7.21(d,J=7.3 Hz, 0.35H), 6.73 (d, J = 8.4Hz, 0.35H), 6.69 (d, J = 8.4Hz, 1H), 4.56 (m, 2.7H), 3.20 (m, 2.7H) ppm; 13 C NMR (acetone-d6, 100MHz): δ C 172.4,161.9,161.3,152.0,149.6,142.3,130.6,129.7,127.9,127.3,126.3,123.3,109.0,108.8,72.2,72.0,20.7ppm; HRMS m / z calcd for C 10 H 11 O3N2[M+H] + :207.0764; found:207.0764.

[0319] Example 30: Preparation of 1,2-diphenylethane-1,2-diketone dioxime

[0320]

[0321] Weigh 225 mg of 2-(hydroxyimino)-1,2-diphenylethane-1-one, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and reflux for 4 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a pale yellow solid, 1,2-diphenylethane-1,2-dione dioxime (235 mg, 98%). MP: 213-215℃; 1 H NMR (MeOD, 400MHz): δ H 7.70-7.64(m,4H),7.56-7.49(m,4H),7.52-7.45(m,2H)ppm; 13 C NMR (CD3OD, 100MHz): δ C 150.0,130.4,129.5,127.2,125.6ppm; IR(neat):ν=3265,1496,1444,1240,1088cm -1 HRMSm / z calcd for C 14 H13 O2N2[M+H] + :241.0972; found:241.0970.

[0322] Example 31: Preparation of 1,2-bis(4-methoxyphenyl)ethane-1,2-dione dioxime

[0323]

[0324] Weigh 285 mg of 2-(hydroxyimino)-1,2-bis(4-methoxyphenyl)ethane-1-one, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and react under reflux for 4 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a pale yellow solid, 1,2-bis(4-methoxyphenyl)ethane-1,2-dione dioxime (295 mg, 98%). MP: 192-194 °C; IR (neat): ν = 3296, 1604, 1513, 1302, 1248, 1175, 1028 cm⁻¹ -1 ; 1 H NMR (DMSO-d6, 500MHz): δ H 11.42(2H,s),7.39(4H,d,J=9.0Hz), 6.94(4H,d,J=9.0Hz), 3.76(6H,s)ppm; 13 C NMR (CD3OD, 125MHz): δ C 159.0,154.0,130.7,124.8,113.1,55.1ppm; HRMS m / z calcdfor C 16 H 17 O4N2[M+H] + :301.1183; found:301.1178.

[0325] Example 32: Preparation of 1,2-bis(4-chlorophenyl)ethane-1,2-dione dioxime

[0326]

[0327] Weigh 293 mg of 1,2-bis(4-chlorophenyl)-2-(hydroxyimino)ethane-1-one, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and reflux for 4 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a pale yellow solid, 1,2-bis(4-chlorophenyl)ethane-1,2-dione dioxime (309 mg, 99%). MP: 189-191℃; IR (neat): ν = 3265, 1593, 1492, 1398, 1248, 1095, 1013 cm⁻¹ -1 ; 1 H NMR (DMSO-d6, 500MHz): δ H 11.70(2H,s),7.48(4H,d,J=8.5Hz),7.39(4H,d,J=8.5Hz)ppm; 13 C NMR (DMSO-d6, 125MHz): δ C 154.2,132.7,131.3,131.0,127.7ppm; HRMS m / z calcd for C 14 H 11 Cl2O2N2[M+H] + :309.0192; found:309.0189.

[0328] Example 33: Preparation of 2-(4-hydroxy-3-methoxyphenyl)-2-(hydroxyimino)acetaldehyde oxime

[0329]

[0330] Method 1: Weigh 196 mg of 2-oxo-2-(3-methoxy-4-hydroxyphenyl)acetaldehyde oxime, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and react under reflux for 4 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid 194 mg (92%) of 2-(4-hydroxy-3-methoxyphenyl)-2-(hydroxyimino)acetaldehyde oxime.

[0331] The second method: 97 kg of dried Angelica sinensis root was pulverized and extracted with distilled water (300 L of water each time, boiled and heated for 30 min each time). The extraction was repeated three times. The filtrates were combined, and the solvent was recovered under reduced pressure to obtain an extract. The extract was separated by HP20 macroporous resin column chromatography, eluting sequentially with water (650 L), 50% ethanol (500 L), and 95% ethanol (250 L), recovering the solvent under reduced pressure to obtain the corresponding eluent fractions (A–C). Fraction B (1.6 kg) was suspended in water and treated with CHP 20 MCI resin, eluting sequentially with water, 30% ethanol, 50% ethanol, and 95% ethanol to obtain subfractions B1–B4. B2 (435.0 g) was separated by Sephadex LH-20 gel column chromatography, eluting sequentially with water and methanol as solvents to obtain B2-1-B2-17. B2-13 (1.46 g) was separated by silica gel column chromatography with gradient elution using dichloromethane and methanol to obtain B2-13-1 to B2-13-18. B2-13-4 (43.6 mg) was separated by Sephadex LH-20 gel column chromatography (dichloromethane-methanol 1:1) to obtain B2-13-4-1 to B2-13-4-4. B2-13-4-1 (34.9 mg) was further separated by Sephadex LH-20 gel column chromatography (dichloromethane-methanol 1:1) to obtain B2-13-4-1-1 to B2-13-4-1-3. B2-13-4-2 (3.8 mg) was separated by semi-preparative HPLC (MGⅡC18 column, 18% acetonitrile, 2 mL·min⁻¹) to obtain 33 (0.5 mg, t…). R =15.6min).

[0332] 2-(4-Hydroxy-3-methoxyphenyl)-2-(hydroxyimino)acetaldehyde oxime: MP: 181-183℃; IR (neat): ν = 3309, 2966, 1600, 1517, 1425, 1263, 1096, 1033 cm⁻¹ -1 ; 1 H NMR (acetone-d6, 400MHz): δ H 10.89(s,1H),10.76(s,1H),10.72(s,0.2H),10.46(s,0.2H),8.60(s, 1H),7.86(s,0.2H),7.78(s,1H),7.26(d,J=2.0Hz,1H),7.16(dd,J=8. 4,2.0Hz,1H),7.08(s,0.2H),6.96(dd,J=8.4,2.0Hz,0.2H),6.84(d,J=8.4Hz,0.2H),6.80(d,J=8.4Hz,1H),3.83(s,3H),3.82(s,0.6H)ppm;13 C NMR (acetone-d6, 100MHz): δ C 153.9,151.7,149.5,148.4,147.8,147.6,147.2,142.2,126.4,123.9,122.9,115.0,114.7,114.2,112.6,56.2,56.1ppm; HRMS m / zcalcd for C9H 11 O4N2[M+H] + :211.0713; found:211.0713.

[0333] Example 34: Preparation of 2-(hydroxyimino)-2-(4-hydroxyphenyl)acetaldehyde oxime

[0334]

[0335] Weigh 165 mg of 2-(4-hydroxyphenyl)-2-oxoacetaldehyde oxime, 90 mg of hydroxylamine hydrochloride, and 107 mg of sodium acetate. Add 4.0 mL of ethanol as solvent and react under reflux for 4 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid, 177 mg (98.3%), of 2-(hydroxyimino)-2-(4-hydroxyphenyl)acetaldehyde oxime. MP: 188-190℃; IR (neat): ν = 3242, 2963, 2917, 1610, 1518, 1262, 1099, 1034 cm⁻¹ -1 ; 1 H NMR (acetone-d6, 500MHz): δ H 10.86(s,1H),10.74(s,1H),10.69(s,0.5H),10.43(s,0.5H),8.61(s,1H),8.51(s,1.5H),7. 85(s,0.5H),7.53-7.49(m,2H),7.36-7.32(m,1H),6.86-6.83(m,1H),6.83-6.79(m,2H)ppm; 13 C NMR (acetone-d6, 125MHz): δ C 159.1,158.5,154.0,151.9,149.7,142.3,132.1,130.9,126.3,122.3,115.5,115.0ppm; HRMS m / z calcd for C8H9O3N2[M+H] + :181.0608; found:181.0609.

[0336] Example 35: Preparation of 3-phenyl-1,2,5-oxadiazole

[0337]

[0338] Weigh 164 mg of 2-(hydroxyimino)-2-phenylacetaldehyde oxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and perform column chromatography to obtain a colorless liquid 3-phenyl-1,2,5-oxadiazole (80 mg, 55%). MP: 188-190℃; IR (neat): ν = 1559, 1457, 1376, 1057, 1033 cm⁻¹ -1 ; 1 H NMR (CDCl3, 500MHz): δ H 8.56(s,1H),7.86(m,2H),7.55-7.49(m,3H)ppm; 13 CNMR (CDCl3, 125MHz): δ C 154.5,139.6,131.2,129.5,127.6,125.5ppm; HRMS m / z calcd forC8H5N2O[MH] - :145.0407; found:145.0408.

[0339] Example 36: Preparation of 3-(p-Tolyl)-1,2,5-Oxadiazole

[0340]

[0341] Weigh 178 mg of 2-(hydroxyimino)-2-(p-tolyl)acetaldehyde oxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid 3-(p-tolyl)-1,2,5-oxadiazole (75 mg, 47%). MP: 50-51℃; IR (neat): ν = 1622, 1517, 1420, 1372, 1062 cm⁻¹ -1 ; 1 H NMR (CDCl3, 500MHz): δ H 8.52(s,1H),7.74(d,J=8.5Hz,2H),7.32(d,J=8.5Hz,2H),2.43(s,3H)ppm; 13 C NMR (CDCl3, 125MHz): δC 154.5,141.6,139.6,130.2,127.4,122.6,21.6ppm; HRMS m / z calcd for C9H9N2O[M+H] + :161.0709; found:161.0710.

[0342] Example 37: Preparation of 3-(4-propylphenyl)-1,2,5-oxadiazole

[0343]

[0344] Weigh 207 mg of 2-(hydroxyimino)-2-(4-propylphenyl)acetaldehyde oxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a yellow liquid 3-(4-propylphenyl)-1,2,5-oxadiazole (104 mg, 55%). IR (neat): ν = 2963, 2933, 1615, 1517, 1424, 1262, 1059 cm⁻¹ -1 ; 1 H NMR (CDCl3, 500MHz): δ H 8.52(s,1H),7.76(d,J=8.5Hz,2H),7.32(d,J=8.5Hz,2H),2.65(t,J=7.5Hz,2H),1.68(m,2H),0.96(t,J=7.4Hz3H)ppm; 13 C NMR (CDCl3, 125MHz): δ C 154.5,146.4,139.6,129.6,127.5,122.9,38.0,24.4,13.9ppm; HRMS m / z calcd for C 11 H 13 N₂O[M+H] + :189.1022; found:189.1026

[0345] Example 38: Preparation of 3-(4-Butylphenyl)-1,2,5-oxadiazole

[0346]

[0347] Weigh 221 mg of 2-(hydroxyimino)-2-(4-butylphenyl)acetaldehyde oxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a yellow liquid 3-(4-butylphenyl)-1,2,5-oxadiazole (100 mg, 50%). IR (neat): ν = 2960, 2932, 1614, 1519, 1423, 1261, 1033 cm⁻¹ -1 ; 1 H NMR (CDCl3, 500MHz): δ H 8.52(s,1H),7.76(d,J=8.4Hz,2H),7.33(d,J=8.5Hz,2H),2.68(t,J=8.0Hz,2H),1.68-1.59(m,2H),1.42-1.33(m,2H),0.94(t,J=7.5Hz,3H)ppm; 13 C NMR (CDCl3, 125MHz): δ C 154.5,146.6,139.6,129.6,127.5,122.8,35.7,33.5,22.4,14.0ppm; HRMS m / z calcd for C 12 H 13 N2O[MH] - :201.1033; found:201.1032.

[0348] Example 39: Preparation of 3-(4-pentylphenyl)-1,2,5-oxadiazole

[0349]

[0350] Weigh 235 mg of 2-(hydroxyimino)-2-(4-pentylphenyl)acetaldehyde oxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a yellow liquid 3-(4-pentylphenyl)-1,2,5-oxadiazole (130 mg, 60%). IR (neat): ν = 2957, 2930, 2858, 1615, 1517, 1422, 1373 cm⁻¹ -1 ; 1 H NMR (CDCl3, 500MHz): δ H8.52(s,1H),7.76(d,J=8.0Hz,2H),7.33(d,J=8.0Hz,2H),2.67(t,J=8.0Hz,2H),1.69-1.61(m,2H),1.41-1.28(m,4H),0.90(t,J=7.5Hz,3H)ppm; 13 C NMR (CDCl3, 125MHz): δ C 154.5,146.6,139.6,129.6,127.5,122.8,36.0,31.5,31.0,22.5,14.1ppm; HRMS m / z calcd for C 13 H 17 N₂O[M+H] + :217.1335; found:217.1336.

[0351] Example 40: Preparation of 3-(4-chlorophenyl)-1,2,5-oxadiazole

[0352]

[0353] Weigh 198 mg of 2-(4-chlorophenyl)-2-(hydroxyimino)acetaldehyde oxime, add 8.0 mL of toluene solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a yellow solid 3-(4-chlorophenyl)-1,2,5-oxadiazole (90 mg, 50%). MP: 99-101℃; IR (neat): ν = 1605, 1496, 1292, 1262, 1092, 1067 cm⁻¹ -1 ; 1 H NMR (CDCl3, 500MHz): δ H 8.54(s,1H),7.80(d,J=8.5Hz,2H),7.51(d,J=8.5Hz,2H)ppm; 13 C NMR (CDCl3, 125MHz): δ C 153.7,139.4,137.5,129.9,128.8,124.0ppm; HRMS m / z calcd for C8H4ClN2O[MH] - :179.0018; found:179.0018.

[0354] Example 41: Preparation of 3-(4-chlorophenyl)-1,2,5-oxadiazole

[0355]

[0356] Weigh 182 mg of 2-(4-fluorophenyl)-2-(hydroxyimino)acetaldehyde oxime, add 8.0 mL of toluene solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a yellow solid 3-(4-chlorophenyl)-1,2,5-oxadiazole (80 mg, 50%). MP: 42-43℃; IR (neat): ν = 1604, 1514, 1306, 1283, 1240, 1161, 1065 cm⁻¹ -1 ; 1 H NMR (CDCl3, 500MHz): δ H 8.52(s,1H),7.89-7.82(m,2H),7.22(t,J=8.5Hz,2H)ppm; 13 C NMR (CDCl3, 125MHz): δ C 164.4(d,J=253.3Hz),153.7,139.5,129.6(d,J=8.8Hz),121.7,116.9(d,J=22.7Hz)ppm; HRMS m / z calcd forC8H6FN2O[M+H] + :165.0459; found:165.0460.

[0357] Example 42: Preparation of 3-(4-isopropylphenyl)-1,2,5-oxadiazole

[0358]

[0359] Weigh 207 mg of 2-(hydroxyimino)-2-(4-isopropylphenyl)acetaldehyde oxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a yellow liquid 3-(4-isopropylphenyl)-1,2,5-oxadiazole (98 mg, 52%). IR (neat): ν = 2964, 1615, 1517, 1424, 1373, 1055 cm⁻¹ -1 ; 1 H NMR (CDCl3, 500MHz): δ H 8.52(s,1H),7.78(d,J=8.5Hz,2H),7.38(d,J=8.5Hz,2H),2.98(t,J=7.0Hz,1H),1.29(d,J=7.0Hz,6H)ppm; 13CNMR (CDCl3, 125MHz): δ C 154.5,152.5,139.6,127.6,123.0,34.3,23.9ppm; HRMS m / z calcdfor C 11 H 13 N₂O[M+H] + :189.1022; found:189.1029.

[0360] Example 43: Preparation of 3-(4-cyclohexylphenyl)-1,2,5-oxadiazole

[0361]

[0362] Weigh 247 mg of 2-(hydroxyimino)-2-(4-cyclohexylphenyl)acetaldehyde oxime, add 8.0 mL of toluene, and then add 0.1 mL of acetic anhydride in three portions, one hour apart, and reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid 3-(4-cyclohexylphenyl)-1,2,5-oxadiazole (126 mg, 55%). MP: 65-67℃; IR (neat): ν = 2927, 2853, 1616, 1449, 1424, 1261 cm⁻¹ -1 ; 1 HN MR (CDCl3, 400MHz):δ H 8.52(s,1H),7.79-7.75(m,2H),7.38-7.34(m,2H),2.62-2.52(m,1H),1.95-1.833(m,4H),1.78(m,1H),1.51-1.35(m,4H),1.29(m,1H)ppm; 13 C NMR (CDCl3, 100MHz): δ C 154.5,151.7,139.6,128.0,127.6,123.0,44.7,34.3,26.9,26.2ppm; HRMS m / z calcd for C 14 H 17 N₂O[M+H] + :229.1335; found:229.1342.

[0363] Example 44: Preparation of 3-(2,5-dimethylphenyl)-1,2,5-oxadiazole

[0364]

[0365] Weigh 193 mg of 2-(hydroxyimino)-2-(2,5-dimethylphenyl)acetaldehyde oxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a yellow liquid 3-(2,5-dimethylphenyl)-1,2,5-oxadiazole (79 mg, 45%). IR (neat): ν = 2963, 1559, 1509, 1442, 1367, 1262, 1033 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 8.39(s,1H),7.30(s,1H),7.22-7.13(m,2H),2.40(s,3H),2.32(s,3H)ppm; 13 C NMR (CDCl3, 100MHz): δ C 154.6,141.4,136.2,134.4,131.6,131.4,130.1,124.6,20.9,20.8ppm; HRMS m / z calcd forC 10 H 11 N₂O[M+H] + :175.0866; found:175.0871.

[0366] Example 45: Preparation of 3-(o-tolyl)-1,2,5-oxadiazole

[0367]

[0368] Weigh 178 mg of 2-(hydroxyimino)-2-(o-tolyl)acetaldehyde oxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a yellow liquid 3-(o-tolyl)-1,2,5-oxadiazole (96 mg, 60%). IR (neat): ν = 2963, 1262, 1094, 1034 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 8.46(s,1H),7.54(m,1H),7.45-7.30(m,3H),2.52(s,3H)ppm; 13 C NMR (CD3OD, 125MHz): δ C154.5,141.4,137.6,131.7,130.7,129.5,126.5,124.9,21.4ppm; HRMS m / z calcd for C9H9N2O[M+H] + :161.0709; found:161.0710.

[0369] Example 46: Preparation of 3-(4-isobutylphenyl)-1,2,5-oxadiazole

[0370]

[0371] Weigh 221 mg of 2-(hydroxyimino)-2-(4-isobutylphenyl)acetaldehyde oxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a yellow liquid 3-(4-isobutylphenyl)-1,2,5-oxadiazole (112 mg, 55%). IR (neat): ν = 2957, 2869, 1615, 1557, 1516, 1466, 1423, 1372, 1055 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 8.53(s,1H),7.76(d,J=8.4Hz,2H),7.29(d,J=8.4Hz,2H),2.54(d,J=7.1Hz,2H),1.91(m,1H),0.93(d,J=6.7Hz,6H)ppm; 13 C NMR (CDCl3, 100MHz): δ C 154.5,145.4,139.6,130.2,127.3,122.9,45.4,30.3,22.4ppm; HRMS m / z calcd for C 12 H 15 ON2[M+H] + :203.1179; found:203.1184.

[0372] Example 47: Preparation of 3-(3-bromophenyl)-1,2,5-oxadiazole

[0373]

[0374] Weigh 242 mg of 2-(3-bromophenyl)-2-(hydroxyimino)acetaldehyde oxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a yellow liquid 3-(3-bromophenyl)-1,2,5-oxadiazole (112 mg, 50%). IR (neat): ν = 1583, 1556, 1405, 1372, 1357, 1082, 1059 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 8.55(s,1H),7.99(m,1H),7.77(m,1H),7.64(m,1H),7.39(t,J=8.0Hz,1H)ppm; 13 C NMR (CD3OD, 125MHz): δ C 153.4,139.5,134.2,131.0,130.5,127.4,126.1,123.5ppm; HRMS m / z calcd for C8H6BrN2O[M+H] + :224.9658; found:224.9656.

[0375] Example 48: Preparation of 3-(2-chlorophenyl)-1,2,5-oxadiazole

[0376]

[0377] Weigh 198 mg of 2-(2-chlorophenyl)-2-(hydroxyimino)acetaldehyde oxime, add 8.0 mL of toluene, and then add 0.1 mL of acetic anhydride in three portions, one hour apart, refluxing for 3 hours. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a yellow solid 3-(2-chlorophenyl)-1,2,5-oxadiazole (112 mg, 62%). MP: 65-66℃; IR (neat): ν = 1608, 1480, 1439, 1377, 1262, 1058 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 8.77(s,1H),7.83(dd,J=7.6,2.0Hz,1H),7.55(dd,J=8.0,1.6Hz,1H),7.47(td,J=7.6,2.0Hz,1H),7.42(td,J=8.0,1.6Hz,1H)ppm; 13 C NMR (CD3OD, 125MHz): δ C152.8,141.6,133.0,132.1,131.6,130.8,127.7,124.8ppm; HRMS m / z calcd for C8H6ClN2O[M+H] + :181.0163; found:181.0167.

[0378] Example 49: Preparation of 3-(3-chlorophenyl)-1,2,5-oxadiazole

[0379]

[0380] Weigh 198 mg of 2-(3-chlorophenyl)-2-(hydroxyimino)acetaldehyde oxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, and reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a yellow liquid 3-(3-chlorophenyl)-1,2,5-oxadiazole (110 mg, 61%). IR (neat): ν = 1583, 1556, 1405, 1372, 1357, 1082, 1032 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 8.55(s,1H),7.86(t,J=2.0Hz,1H),7.74(dt,J=7.2,1.6Hz,1H),7.53-7.45(m,2H)ppm; 13 C NMR (CDCl3, 100MHz): δ C 153.6,139.5,135.7,131.3,130.9,127.7,127.2,125.7ppm; HRMS m / z calcd for C8H4ON2Cl[MH] - :179.0018; found:179.0019.

[0381] Example 50: Preparation of 3-(3-fluorophenyl)-1,2,5-oxadiazole

[0382]

[0383] Weigh 182 mg of 2-(3-fluorophenyl)-2-(hydroxyimino)acetaldehyde oxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a yellow liquid 3-(3-fluorophenyl)-1,2,5-oxadiazole (88 mg, 55%). IR (neat): ν = 1596, 1499, 1466, 1380, 1261, 1090, 1032 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 8.55(s,1H),7.63(m,1H),7.58(m,1H),7.51(m,1H),7.22(m,1H)ppm; 13 C NMR (CDCl3, 100MHz): δ C HRMS m / z calcd for C8H4ON2F[MH] - :163.0313; found:163.0315.

[0384] Example 51: Preparation of 3-(3,4-dimethoxyphenyl)-1,2,5-oxadiazole

[0385]

[0386] Weigh 225 mg of 2-(hydroxyimino)-2-(3,4-dimethoxyphenyl)acetaldehyde oxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid 3-(3,4-dimethoxyphenyl)-1,2,5-oxadiazole (99 mg, 48%). MP: 142-143 °C; IR (neat): ν = 2964, 2917, 1597, 1517, 1471, 1261, 1171 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H8.50(s,1H),7.43(s,1H),7.33(dd,J=8.0,2.0Hz,1H),6.96(dd,J=8.0,2.0Hz 1H),3.96(s,3H),3.94(s,3H)ppm; 13 C NMR (CDCl3, 100MHz): δ C 154.3,151.6,149.9,139.5,120.7,118.1,111.4,110.1,56.2,56.2ppm; HRMS m / z calcd for C 10 H 11 O3N2[M+H] + :207.0764; found:207.0769.

[0387] Example 52: Preparation of 3-(4-(piperidin-1-yl)phenyl)-1,2,5-oxadiazole

[0388]

[0389] Weigh 248 mg of 2-(hydroxyimino)-2-(4-piperidinylphenyl)acetaldehyde oxime, add 8.0 mL of toluene, and then add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a yellow solid 3-(4-piperidinylphenyl)-1,2,5-oxadiazole (138 mg, 60%). MP: 106-108℃; IR (neat): ν = 2959, 2940, 2836, 1610, 1519, 1442, 1360, 1252, 1129 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 8.45(s,1H),7.73 -7.68(m,2H),7.00 -6.95(m,2H),3.34-3.28(m,4H),1.75-1.67(m,4H),1.67-1.59(m,2H)ppm; 13 C NMR (CDCl3, 100MHz): δ C 154.4,153.5,139.4,128.6,115.5,114.4,49.3,25.6,24.4ppm; HRMS m / z calcd for C 13 H 16 ON3[M+H] + :230.1288; found:230.1292.

[0390] Example 53: Preparation of 4-(4-(1,2,5-oxadiazol-3-yl)phenyl)morpholine

[0391]

[0392] Weigh 249 mg of 2-(hydroxyimino)-2-(4-morpholinylphenyl)acetaldehyde oxime, add 8.0 mL of toluene, and then add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a pale yellow solid 3-(4-morpholinylphenyl)-1,2,5-oxadiazole (134 mg, 58%). MP: 148-150℃; IR (neat): ν = 2966, 2919, 1608, 1525, 1264, 1115, 1252, 1053, 1033 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 8.47(s,1H),7.77 -7.72(m,2H),7.01-6.95(m,2H),3.90-3.83(m,4H),3.30-3.23(m,4H)ppm; 13 C NMR (CDCl3, 100MHz): δ C 154.2,153.1,139.4,128.7,115.9,115.2,66.8,48.2ppm; HRMS m / z calcd for C 12 H 14 O2N3[M+H] + :232.1081; found:232.1083.

[0393] Example 54: Preparation of 3-(4-nitrophenyl)-1,2,5-oxadiazole

[0394]

[0395] Weigh 208 mg of 2-(hydroxyimino)-2-(4-nitrophenyl)acetaldehyde oxime, add 8.0 mL of toluene, and then add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid 3-(4-nitrophenyl)-1,2,5-oxadiazole (76 mg, 40%). MP: 141-143 °C; IR (neat): ν = 2962, 1608, 1516, 1341, 1262, 1079, 1039 cm⁻¹ -1 ; 1H NMR (CDCl3, 400MHz): δ H 8.66(s,1H),8.40(d,J=8.8Hz,2H),8.07(d,J=8.8Hz,2H)ppm; 13 C NMR (CDCl3, 100MHz): δ C 153.0,149.4,139.5,131.5,128.6,124.8ppm; HRMS m / z calcd for C8H4O3N3[MH] - :190.0258; found:190.0262.

[0396] Example 55: Preparation of 4-(4-(1,2,5-oxadiazol-3-yl)phenyl)morpholine

[0397]

[0398] Weigh 303 mg of 2-(hydroxyimino)-2-(2,4,4,5,7,7-hexamethyltetrahydronaphthalene)acetaldehyde oxime, add 8.0 mL of toluene solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid 3-(2,4,4,5,7,7-hexamethyltetrahydronaphthalene)-1,2,5-oxadiazole (123 mg, 43%). MP: 148-150℃; IR (neat): ν = 2965, 2931, 1503, 1457, 1364, 1020 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 8.43(s,1H),7.46(s,1H),7.32(s,1H),2.46(s,3H),1.90(ddq,J=13.6,6.8,2.8Hz,1H),1.66(t,J=13.6Hz,1H ),1.41(dd,J=13.6,2.8Hz,1H),1.36(s,3H),1.33(s,3H),1.28(s,3H),1.10(s,3H),1.01(d,J=6.8Hz,3H)ppm; 13 C NMR (CDCl3, 100MHz): δ C154.6,149.1,143.4,141.4,134.2,130.3,127.9,122.3,43.6,38.0,34.6,34.2,32.6,32.1,28.6,25.0,21.1,16.9ppm; HRMS m / z calcd for C 18 H 25 ON2[M+H] + :285.1961; found:285.1960.

[0399] Example 56: Preparation of 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,2,5-oxadiazole

[0400]

[0401] Weigh 223 mg of 2-(hydroxyimino)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetaldehyde oxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,2,5-oxadiazole (94 mg, 46%). MP: 128-130℃; IR (neat): ν = 1590, 1509, 1459, 1428, 1280, 1249, 1061 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 8.45(s,1H),7.37(d,J=2.0Hz,1H),7.32(dd,J=8.4,2.0Hz,1H),6.98(d,J=8.4Hz,1H),4.31(m,4H)ppm; 13 C NMR (CDCl3, 100MHz): δ C 154.1,146.2,144.3,139.5,120.9,118.6,118.4,116.6,64.7,64.4ppm; HRMS m / z calcd forC 10 H9O3N2[M+H] + :205.0608; found:205.0608.

[0402] Example 57: Preparation of 3-(2,3-dihydrobenzofuran-5-yl)-1,2,5-oxadiazole

[0403]

[0404] Weigh 207 mg of 2-(hydroxyimino)-2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde oxime, add 8.0 mL of toluene solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid 3-(2,3-dihydrobenzofuran-5-yl)-1,2,5-oxadiazole (95 mg, 50%). MP: 128-130℃; IR (neat): ν = 1615, 1570, 1503, 1411, 1387, 1251, 1003 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 8.46(s,1H),7.72(m,1H),7.59-7.56(m,1H),6.88(d,J=8.4Hz,1H),4.66(t,J=8.8Hz,2H),3.28(t,J=8.8Hz,2H)ppm; 13 C NMR (CDCl3, 100MHz): δ C 162.7,154.4,139.5,128.9,128.1,124.4,117.7,110.2,72.0,29.4ppm; HRMS m / z calcd for C 10 H9O2N2[M+H] + :189.0659; found:189.0659.

[0405] Example 58: Preparation of 3,4-bis(4-fluorophenyl)-1,2,5-oxadiazole

[0406]

[0407] Weigh 277 mg of 1,2-bis(4-fluorophenyl)glyoxime, add 8.0 mL of toluene, and then add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid 3,4-bis(4-fluorophenyl)-1,2,5-oxadiazole (142 mg, 52%). MP: 98-99℃; IR (neat): ν = 1607, 1500, 1455, 1228, 1163, 1099 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ C7.56-7.49(m,4H),7.18-7.11(m,4H)ppm; 13 C NMR (CDCl3, 100MHz): δ C 164.2(d,J=315.0Hz),152.3,131.1(d,J=10.1Hz),121.9(d,J=3.8Hz),116.5(d,J=27.7Hz)ppm; HRMS m / z calcd for C 14 H9ON2F2[M+H] + :259.0678; found:259.0678.

[0408] Example 59: Preparation of 3,4-diphenyl-1,2,5-oxadiazole

[0409]

[0410] Weigh 240 mg of 1,2-diphenylethane-1,2-dione dioxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid 3,4-diphenyl-1,2,5-oxadiazole (110 mg, 50%). MP: 90-91℃; IR (neat): ν = 1445, 1370, 1262, 1099, 1074, 1036 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 7.57-7.51(m,4H),7.51-7.47(m,2H),7.47-7.40(m,4H)ppm; 3 C NMR (CDCl3, 100MHz): δ C 153.2,130.6,129.1,129.0,126.0ppm; HRMS m / z calcd for C 14 H 11 ON2[M+H] + :223.0866; found:223.0866.

[0411] Example 60: Preparation of 3,4-bis(4-methoxyphenyl)-1,2,5-oxadiazole

[0412]

[0413] Weigh 300 mg of 1,2-bis(4-methoxyphenyl)ethane-1,2-dione dioxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid 3,4-bis(4-methoxyphenyl)-1,2,5-oxadiazole (140 mg, 50%). MP: 121-122℃; IR (neat): ν = 2967, 2919, 1612, 1508, 1445, 1257, 1101, 1026 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 7.48(d,J=8.8Hz,4H), 6.95(d,J=8.8Hz,4H), 3.86(s,6H)ppm; 13 C NMR (CDCl3, 100MHz): δ C 161.3,152.8,130.4,118.2,114.5,55.5ppm; HRMS m / z calcd for C 16 H 15 O3N2[M+H] + :283.1077; found:283.1073.

[0414] Example 61: Preparation of 3,4-bis(4-chlorophenyl)-1,2,5-oxadiazole

[0415]

[0416] Weigh 308 mg of 1,2-bis(4-chlorophenyl)ethane-1,2-dione dioxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid 3,4-bis(4-chlorophenyl)-1,2,5-oxadiazole (145 mg, 50%). MP: 139-140℃; IR (neat): ν = 1604, 1489, 1450, 1263, 1091, 1037 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 7.47(d,J=8.8Hz,4H),7.44(d,J=8.8Hz,4H)ppm; 13 C NMR (CDCl3, 100MHz): δ C152.3,137.2,130.3,129.6,124.1ppm; HRMS m / z calcd for C 14 H9ON2Cl2[M+H] + :291.0086; found:291.0083.

[0417] Example 62: Preparation of 4,4'-(1,2,5-oxadiazole-3,4-diyl)diphenol

[0418]

[0419] Weigh 273 mg of 1,2-bis(4-hydroxyphenyl)glyoxime, add 8.0 mL of toluene as solvent, and add 0.1 mL of acetic anhydride in three portions, one hour apart, reacting under reflux for 3 hours. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid, 4,4'-(1,2,5-oxadiazol-3,4-diyl)diphenol (115 mg, 45%). MP: 199-200℃; IR (neat): ν = 3346, 1613, 1508, 1447, 1267, 1237, 1174, 1107 cm⁻¹ -1 ; 1 H NMR (CDCl3, 400MHz): δ H 7.34(d,J=8.8Hz,4H), 6.84(d,J=8.8Hz,4H)ppm; 13 C NMR (CD3OD, 125MHz): δ C 160.8,154.3,131.4,118.0,116.8ppm; HRMS m / z calcd for C 14 H 11 O3N2[M+H] + :255.0764; found:255.0763.

[0420] Example 63: Preparation of 4-(1,2,5-oxadiazol-3-yl)phenyl-1,2-diol

[0421]

[0422] Weigh 273 mg of 1,2-bis(4-hydroxyphenyl)glyoxime, add 8.0 mL of toluene, and then add 0.1 mL of acetic anhydride in three portions, one hour apart, and react under reflux for 3 h. Remove the organic solvent under reduced pressure and separate by column chromatography to obtain a colorless solid 3,4-bis(4-hydroxyphenyl)-1,2,5-oxadiazole (115 mg, 45%).

[0423] The second method: 97 kg of dried Angelica sinensis root was pulverized and extracted with distilled water (300 L of water each time, boiled and heated for 30 min each time). The extraction was repeated three times. The filtrates were combined, and the solvent was recovered under reduced pressure to obtain an extract. The extract was separated by HP20 macroporous resin column chromatography, eluting sequentially with water (650 L), 50% ethanol (500 L), and 95% ethanol (250 L), recovering the solvent under reduced pressure to obtain the corresponding eluent fractions (A–C). Fraction B (1.6 kg) was suspended in water and treated with CHP 20 MCI resin, eluting sequentially with water, 30% ethanol, 50% ethanol, and 95% ethanol to obtain subfractions B1–B4. B3 (224.0 g) was separated by Toyopearl HW-40C gel column chromatography, eluting isocratically with 50% ethanol to obtain B3-1–B3-13. B3-12 (1.7 g) was separated by Sephadex LH-20 gel column chromatography, eluting with dichloromethane-methanol (1:1) to obtain B3-12-1 to B3-12-6; among which, B3-12-6 (112.3 mg) was separated by Toyopearl HW-40C gel column chromatography, eluting with dichloromethane-methanol (1:1) to obtain B3-12-6-1 to B3-12-6-4; among which, B3-12-6-3 (36.5 mg) was separated by reversed-phase semi-preparative HPLC (XSelect CSH C18 column, 38% methanol, 3.0 ml·min-1) to obtain 63 (t) R =22.4 min, 3.4 mg).

[0424] 3,4-Di(4-hydroxyphenyl)-1,2,5-oxadiazole: MP: 134-135℃; IR (neat): ν = 3304, 1612, 1531, 1458, 1263, 1192, 1077 cm⁻¹ -1 ; 1 H NMR (acetone-d6, 500MHz): δ H 9.05(s,1H),8.59(s,1H),8.38(s,1H),7.48(d,J=2.0Hz,1H),7.37(dd,J=8.0,2.0Hz,1H),6.99(d,J=8.0Hz,1H)ppm; 13 C NMR (acetone-d6, 125MHz): δ C 155.5,148.9,146.8,141.1,120.9,118.1,116.8,115.1ppm; HRMS m / z calcd for C8H5O3N2[MH] - :177.0306; found:177.0307.

[0425] Example 64. Principle of Cell Viability Detection Model

[0426] Adenosine triphosphate (ATP) is an important indicator of living cell metabolism; the number of living cells can be detected by quantifying ATP. This model uses... The luminescent cell viability assay kit (Promega) measures ATP in cell lysates in culture plates to quantify cell viability and thus evaluate the effects of compounds on cell viability.

[0427] Example 65. Experimental methods and results for detecting the effect of compounds on cell viability

[0428] HEK293T cells were seeded at a density of 8,000–40,000 cells / well in 96-well plates, with 100 μL of cell culture medium per well. The cells were incubated at 37°C and 5% CO2 for 24 hours. The following day, different concentrations of the test compound were added to the cells, with an equal volume of DMSO (0.1% v / v) as a solvent control. Cells were cultured for another 4–48 hours, and then 100 μL of CellTiter-Glo reagent was added to each well. The cells were shaken to mix for 2 minutes and incubated at room temperature for 10 minutes. The relative fluorescence intensity was then measured. 32 Cell viability was calculated in wells containing the test compound, with the relative fluorescence intensity of the DMSO solvent wells set at 100%.

[0429] Cell viability % = fluorescence intensity 受试化合物组 / fluorescence intensity 溶剂对照组 ×100%.

[0430] When cell viability was >90%, the test compound was considered to have no effect on HEK293T cell viability at that concentration, indicating that the compound has good safety at the treatment concentration. Cell viability data for the test compounds are shown in Table 1.

[0431] Table 1. Effects of 63 compounds on HEK293T cell viability

[0432]

[0433] Example 66. Principle of using a somatic cell model of NF-κB response element-driven luciferase reporter gene expression for screening NF-κB inhibitors.

[0434] This model utilizes the pGL4.32[luc2P / NF-κB-RE / Hygro] plasmid (Promega, Cat#.E849A), which contains five NF-κB reactive elements (GGGAA / CTTTCC) and the human codon-optimized luciferase reporter gene luc2P driven by these NF-κB reactive elements. Transfection of cells with the pGL4.32[luc2P / NF-κB-RE / Hygro plasmid, followed by TNF-α stimulation to activate NF-κB, results in free NF-κB binding to the “GGGAA / CTTTCC” sequence and initiating luciferase gene transcription. Incubating the test compound with cells and detecting the luciferase activity of the cells incubated with the test compound, compared with the solvent group, can be used to screen NF-κB inhibitors (Promega website, https: / / www.promega.com.cn / resources / protocols / product-information-sheets / a / pgl432-vector-protocol / ).

[0435] Example 67. Experimental methods and results for screening NF-κB inhibitors.

[0436] HEK293T cells were prepared at a ratio of 2 × 10⁶ cells per dish. 6 One cell was seeded into a 100 mm cell culture dish. After culturing for 24 hours, [the cells were then] used... HEK293T cells were transfected with 0.1 μg–10 μg of pGL4.32 [luc2P / NF-κB-RE / Hygro] plasmid using transfection reagent (Polyplus). Cells were digested 2–12 hours after transfection, and the cells were divided into 3 × 10⁻⁶ cells per well. 4 ~5×10 4 Cells were seeded into 48-well plates. 0.5–6 hours after seeding, the compound (final concentration 10 μM–100 μM) was added, using baicalein as a control. An equal volume of DMSO was added to the solvent control group. Each group had three replicates. After drug treatment for 2–12 hours, TNF-α (1.25 ng / mL–20 ng / mL) was added for another 2–12 hours. The supernatant was discarded from each well, and 100 μL of cell lysis buffer was added. The cells were lysed on a horizontal shaker at 4°C for 15 minutes. After equilibration to room temperature, 2–20 μL of the lysate was added to a 1.5 mL EP tube containing 30 μL of firefly luciferase substrate (luciferase assay kit, Promega). The mixture was vortexed and the relative luciferase activity (RLUs) was measured using an FB12 single-tube chemiluminescence analyzer. The relative luciferase activity of the test compound was compared with that of the solvent control group (RLUs). 受试化合物 / R LUs 溶剂对照组The data were analyzed using software, and compounds with significant inhibitory activity against NF-κB were obtained using baicalein as a positive control. The inhibitory activity of the compounds against NF-κB is shown in Figures 3-9.

Claims

1. A class of α-arylhydroxyoximes as shown in general formula (I) and α-arylfurazan compounds as shown in general formula (II), and pharmaceutically acceptable salts thereof, characterized in that, The compounds are shown as those of general formula (I) or (II): In equation (I), n is selected from integers 1 and 2; in equation (I), R 1 It consists of 1 to 2 substituents located at any position on the benzo[a] ring, wherein the substituents on the benzo[a] ring are optionally replaced by the following groups: hydrogen, OH, C. 1-6 Alkyl, C 1-3 Alkyl group, halogen, NH2, NO2, cyano group, carboxyl group, phenyl group, C 1-6 Unsaturated alkyl, C 3-6 cycloalkyl; R in formula (I) 2 It consists of 1 to 2 substituents located at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morpholinic, piperidine, piperazine, pyridine, furan, thiophene; in formula (I), W is selected from O, NOH; in formula (I), X is selected from gem-dimethyl, methylene, O; in formula (I), Y is selected from gem-dimethyl, methylene, O; in formula (I), Z is selected from hydrogen, C 1-6 Alkyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclic aryl; wherein the substituent is optionally substituted by the following groups: hydrogen, halogen, OH, C 1-6 Alkoxy, C 1-6 Alkyl, NH2, NO2, C 1-6 Substituted or unsubstituted secondary amino groups, C 3-7 Cyclic amino, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morpholinic, piperidine, piperazine, pyridine, furan, thiophene; in formula (II), n is selected from integers 1 and 2; in formula (II), R 1 It consists of 1 to 2 substituents located at any position on the benzo[a] ring, wherein the substituents on the benzo[a] ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkyl group, halogen, NH2, NO2, cyano group, carboxyl group, phenyl group, C 1-6 Unsaturated alkyl, C 3-6 cycloalkyl; R in formula (II) 2 It consists of 1 to 2 substituents located at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morpholinic, piperidine, piperazine, pyridine, furan, thiophene; in formula (II), X is selected from gem-dimethyl, methylene, O; in formula (II), Y is selected from gem-dimethyl, methylene, O; in formula (II), Z is selected from hydrogen, C 1-6 Alkyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclic aryl; wherein the substituent is optionally substituted by the following groups: hydrogen, halogen, OH, C 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

2. The compound according to claim 1 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IA): Where n is an integer selected from 1 or 2; X is selected from gem-dimethyl, methylene, or O; Y is selected from gem-dimethyl, methylene, or O; R 1 It consists of 1 to 2 substituents located at any position on the benzo[a] ring, wherein the substituents on the benzo[a] ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 cycloalkyl; R in formula (I) 2 It consists of 1 to 2 substituents located at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

3. The compound according to claim 2 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IA1): Among them, R 1 ， R 2 It consists of 1 to 2 substituents located at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, pyridine substituents, furan substituents, thiophene substituents.

4. The compound according to claim 2 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IA2): Among them, R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

5. The compound according to claim 2 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IA3): Among them, R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

6. The compound according to claim 2 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IA4): Among them, R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

7. The compound according to claim 2 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IA5): Among them, R 1 For hydrogen, halogen, C 1-6 Alkyl, C 1-3 Alkoxy, C 1-6 Unsaturated alkyl group; R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

8. The compound according to claim 1 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IA6): Among them, R 1 For hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, benzyl, substituted or unsubstituted heteroaryl, wherein the substituents on the benzene ring and heteroaryl ring are optionally substituted with the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl; R 2 For hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, benzyl, substituted or unsubstituted heteroaryl, wherein the substituents on the benzene ring and heteroaryl ring are optionally substituted with the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl; or R 1 +R 2 Selected from morphine substituents, piperidine substituents, and piperazine substituents.

9. The compound according to claim 1 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IB): Among them, R 1 R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

10. The compound according to claim 1 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IC): Among them, R 1 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morpholinic, piperidine, piperazine, pyridine, furan, thiophene; R 2 C 1-6 Alkyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclic aryl; wherein the substituent is optionally substituted by the following groups: hydrogen, halogen, OH, C 1-6 Alkoxy, C 1-6 Alkyl, NH2, NO2, C 1-6 Substituted or unsubstituted secondary amino groups, C 3-7 Cyclic amino, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

11. The compound according to claim 1 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (ID): n is an integer selected from 1 or 2; X is selected from gem-dimethyl, methylene, or O; Y is selected from gem-dimethyl, methylene, or O; R 1 It consists of 1 to 2 substituents located at any position on the benzo[a] ring, wherein the substituents on the benzo[a] ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 cycloalkyl; R in formula (I) 2 It consists of 1 to 2 substituents located at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

12. The compound of claim 10 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (ID1): Among them, R 1 ， R 2 "A" can be a substituent at any position on the benzene ring, wherein the substituent on the benzene ring is optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, pyridine substituents, furan substituents, thiophene substituents.

13. The compound of claim 10 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (ID2): Among them, R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

14. The compound of claim 10 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (ID3): Among them, R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

15. The compound of claim 10 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (ID4): Among them, R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

16. The compound of claim 10 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (ID5): Among them, R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

17. The compound of claim 10 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (ID6): Among them, R 1 For hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, benzyl, substituted or unsubstituted heteroaryl, wherein the substituents on the benzene ring and heteroaryl ring are optionally substituted with the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl; R 2 For hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, benzyl, substituted or unsubstituted heteroaryl, wherein the substituents on the benzene ring and heteroaryl ring are optionally substituted with the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl; or R 1 +R 2 Selected from morphine substituents, piperidine substituents, and piperazine substituents.

18. The compound of claim 10 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IE): Among them, R 1 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morpholinic, piperidine, piperazine, pyridine, furan, thiophene; R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

19. The compound of claim 10 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IF): Among them, R 1 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morpholinic, piperidine, piperazine, pyridine, furan, thiophene; R 2 C 1-6 Alkyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclic aryl; wherein the substituent is optionally substituted by the following groups: hydrogen, halogen, OH, C 1-6 Alkoxy, C 1-6 Alkyl, NH2, NO2, C 1-6 Substituted or unsubstituted secondary amino groups, C 3-7 Cyclic amino, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

20. The compound according to claim 1 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IIA): Where n is an integer selected from 1 or 2; X is selected from gem-dimethyl, methylene, or O; Y is selected from gem-dimethyl, methylene, or O; R 1 It consists of 1 to 2 substituents located at any position on the benzo[a] ring, wherein the substituents on the benzo[a] ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 cycloalkyl; R 2 It consists of 1 to 2 substituents located at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

21. The compound of claim 20 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IIA1): Among them, R 1 ， R 2 It consists of 1 to 2 substituents located at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, pyridine substituents, furan substituents, thiophene substituents.

22. The compound of claim 20 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IIA2): Among them, R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

23. The compound of claim 20 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IIA3): Among them, R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

24. The compound of claim 20 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IIA4): Among them, R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

25. The compound of claim 20 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IIA5): Among them, R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amine, tertiary amine.

26. The compound of claim 20 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IIA6): Among them, R 1 For hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, benzyl, substituted or unsubstituted heteroaryl, wherein the substituents on the benzene ring and heteroaryl ring are optionally substituted with the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl; R 2 For hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, benzyl, substituted or unsubstituted heteroaryl, wherein the substituents on the benzene ring and heteroaryl ring are optionally substituted with the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl; or R 1 +R 2 Selected from morphine substituents, piperidine substituents, and piperazine substituents.

27. The compound according to claim 1 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IIB): Among them, R 1 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morpholinic, piperidine, piperazine, pyridine, furan, thiophene; R 2 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

28. The compound according to claim 1 and its pharmaceutically acceptable salt, characterized in that, The compound is shown in formula (IIC): Among them, R 1 Substituents at any position on the benzene ring, wherein the substituents on the benzene ring are optionally replaced by the following groups: hydrogen, halogen, OH, C. 1-6 Alkyl, C 1-3 Alkoxy, trifluoromethyl, NH2, NO2, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morpholinic, piperidine, piperazine, pyridine, furan, thiophene; R 2 C 1-6 Alkyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclic aryl; wherein the substituent is optionally substituted by the following groups: hydrogen, halogen, OH, C 1-6 Alkoxy, C 1-6 Alkyl, NH2, NO2, C 1-6 Substituted or unsubstituted secondary amino groups, C 3-7 Cyclic amino, cyano, carboxyl, phenyl, C 1-6 Unsaturated alkyl, C 3-6 Cycloalkyl, secondary amino, tertiary amino, morphine substituent, piperidine substituent, piperazine substituent, pyridine substituent, furan substituent, thiophene substituent.

29. The compound according to claim 1 and its pharmaceutically acceptable salt, characterized in that, The compounds are selected from the following group:

30. A method for preparing the compound and its pharmaceutically acceptable salt according to any one of claims 1-29, characterized in that, The preparation method of the compound is as follows: Where R 1 R 2 The definitions of n, X, Y, and Z are the same as any one of claims 1-22; the substituted aryl ethyl ketone derivative S1 reacts with tert-butyl nitrite S2 under alkaline conditions to give monohydroxyoxime compounds IA-IC, compounds IA-IC react with hydroxylamine hydrochloride S3 to give dihydroxyoxime compounds ID-IF, and compounds ID-IF undergo intramolecular dehydration under the action of acid anhydrides to give the corresponding aryl furazan compound II.

31. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the compound of any one of claims 1-29, its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient.

32. The use of the compound of any one of claims 1-29, its pharmaceutically acceptable salt, and the pharmaceutical composition of claim 31 in the preparation of an NF-κB inhibitor.

33. The use of the compounds of any one of claims 1-29 and their pharmaceutically acceptable salts, and the pharmaceutical compositions of claim 31, in the preparation of drugs or health products for the prevention and / or treatment of arthritis, asthma and chronic obstructive pulmonary disease, pneumonia, cystic fibrosis, diabetes, obesity, hypercholesterolemia, contact dermatitis, psoriasis, atopic dermatitis, stasis dermatitis, seborrheic dermatitis, neurodermatitis, inflammatory bowel disease, multiple sclerosis, Parkinson's syndrome, cardiovascular diseases, autoimmune diseases, gout, hyperuricemia, and cancer.

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