Physiological function and homeostasis modulating compounds and uses thereof

Abstract

Disclosed is a compound of formula (I), a hydrate form, an anhydrous form or a salt form thereof, wherein M, X and n are as disclosed herein. The compounds may be used to modulate the activity of the aromatic hydrocarbon receptor (AhR) and to treat diseases associated with modulation of AhR activity. Also disclosed are pharmaceutical compositions containing the compounds of Formula (I), hydrate forms, anhydrous forms or salt forms thereof. (I)

Description

Cross-references to related applications

[0001] This application claims the benefit and priority of both U.S. Provisional Patent Applications No. 63 / 546372 and No. 63 / 546365, both filed on October 30, 2023. The contents of the aforementioned patent applications are hereby expressly incorporated herein by reference in the detailed description thereof. Technical Field

[0002] This specification relates to compounds that can be used to regulate cellular physiological functions and homeostasis, as well as methods of their use. Background Technology

[0003] Regulation of physiological functions and cellular homeostasis is essential for the normal development and activity of many human cell lines.

[0004] The role of the aryl hydrocarbon receptor (AhR) in mediating the detoxification of xenobiotic compounds was initially investigated, and the AhR is now known to play an important role in normal cell development and homeostasis. Regulation of the AhR is central to major signal transduction systems and transcriptional programs, and is essential for a variety of physiological functions (Kou Z, Dai W. Aryl hydrocarbon receptor: Its roles in physiology. Biochemical pharmacology. 2021 Mar 1; 185:114428; incorporated herein by reference).

[0005] It is known that the activation of the aryl hydrocarbon receptor (AhR) and its downstream signal transduction occur through both classical and non-classical pathways in the presence of various exogenous and endogenous ligands (Kou Z, Dai W. Aromatic hydrocarbon receptor: its role in physiology. Biochemical Pharmacology. 1 Mar 2021; 185:114428; Denison MS, Nagy SR. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annual review of pharmacology and toxicology. 1 April 2003; 43(1):309-34; incorporated herein by reference).

[0006] The retention of inactive AhR complexes with molecular chaperones such as heat shock protein 90 (Hsp90) in the cytoplasm is typical of the classical pathway. Upon activation, AhR undergoes a conformational change, releasing the receptor from the chaperone protein and subsequently translating into the nucleus. In the nucleus, AhR heterodimerizes with aryl receptor nuclear transporters (ARNTs) and then binds to xenobiotic response elements (XREs) of target genes, including cytochrome P450 superfamily enzymes Cyp1a1, Cyp1a3, and Cyp1b1, thereby regulating their expression. Thus, CYP1A1 induction has been used as a model system to define the mechanism by which AhR regulates gene expression (Denison MS, Nagy SR. Activation of aryl receptors by structurally different exogenous and endogenous chemicals. Annual Review of Pharmacology and Toxicology. 1 April 2003;43(1):309-34; incorporated herein by reference). AhR's binding to various nuclear transcription factors may lead to non-classical signaling pathways through the binding of non-XRE deoxyribonucleic acid (DNA) elements.

[0007] Activation of the AhR pathway is known to occur through a variety of synthetic ligands in nature as well as naturally occurring ligands. Most compounds that activate AhR include planar hydrophobic halogenated aromatic hydrocarbons (HAHs) and polycyclic aromatic hydrocarbons (PAHs) or their related compounds (Denison MS, Nagy SR. Activation of aromatic receptors by structurally different exogenous and endogenous chemicals. Annual Review of Pharmacology and Toxicology. April 1, 2003; 43(1):309-34; incorporated herein by reference). Known exogenous ligands include theaflavins (epigallocatechin gallate), bacterial metabolic byproducts (including indigo), and high molecular weight aromatic hydrocarbons from coal tar (Palermo CM, Westlake CA, Gasiewicz TA. Epigallocatechin gallate inhibits aryl hydrocarbon receptor gene transcription through an indirect mechanism involving binding to a 90 kDa heat shock protein. Biochemistry. April 5, 2005; 44(13): 5041-52; Adachi J, Mori Y, Matsui S, Takigami H, Fujino J, Kitagawa H, Miller CA, Kato T, Saeki K, Matsuda T. Indigo and indigo are potent aryl hydrocarbon receptor ligands present in human urine. Receptor ligands present in humanurine. Journal of Biological Chemistry. August 24, 2001; 276(34):31475-8; Furue M, Tsuji G, Mitoma C, Nakahara T, Chiba T, Morino-Koga S, Uchi H. Gene regulation of offilaggrin and other skin barrier proteins via aryl hydrocarbon receptor.Journal of Dermatological Science. November 1, 2015; 80(2):83-8; Hahn ME. The aryl hydrocarbon receptor: a comparative perspective. Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology and Endocrinology. November 1, 1998; 121(1-3):23-53; all cited in this article). Known endogenous ligands include kynurenine, photopigment, lipoxygen A4, bilirubin, kynurenic acid, and 6-formylindolo[3,2-b]carbazole (FICZ) (Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. The Journal of Immunology. Sep 15, 2010; 185(6):3190-8; Kou Z, Dai W. Aromatic hydrocarbon receptor: its role in physiology. Biochemical Pharmacology. Mar 1, 2021; 185:114428; Sinal CJ, Bend JR. Bilirubin in mouse hepatocellular carcinoma ... Aryl hydrocarbon receptor-dependent induction of cyp1a1 bybilirubin in mouse hepatoma hepa 1c1c7 cells. Molecular Pharmacology. October 1, 1997; 52(4):590-9; DiNatale BC, Murray IA, Schroeder JC, Flaveny CA, Lahoti TS, Laurenzana EM, Omiecinski CJ, Perdew GH.Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling. *Toxicological Sciences*, May 1, 2010; 115(1):89-97; Rannug A, Rannug U. The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation. *Critical Reviews in Toxicology*. August 9, 2018; 48(7):555-74; all cited and incorporated herein by reference.

[0008] As a heterogeneous receptor, various ligand populations can activate the AhR pathway. The aforementioned AhR ligands are known to initiate downstream pathways of differentiation by activating AhR. This variable activation, along with co-activation of other AhR-independent pathways, can lead to detrimental effects seen in ligands such as 2,3,7,8-tetrachlorodibenzo-dioxin (TCDD) or beneficial effects found in naturally occurring and drug-derived ligands (Larigot L, Juricek L, Dairou J, Coumoul X. AhR signaling pathways and regulatory functions. Biochimie Open. Dec 1, 2018; 7:1-9, incorporated herein by reference). The inherent role of AhR as a regulator of physiological function and homeostasis is influenced by a variety of ligands that generate complex systems in pathway interactors, with downstream effects depending on ligand structure (Rothhammer V, Quintana FJ. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nature Reviews Immunology. March 2019; 19(3):184-97, incorporated herein by reference).

[0009] Despite the great potential of AhR pathway regulation in many therapeutic applications, the exploration of novel AhR-activating compounds has historically been limited. This is partly due to the observation that many exogenous ligands are known to induce harmful or undesirable effects through the unintended production of reactive oxygen species (Harmon AC, Hebert VY, Cormier SA, Subramanian B, Reed JR, Backes WL, Dugas TR. Particulate matter containing environmentally persistent free radicals induces AhR-dependent cytokine and reactive oxygen species production in human bronchial epithelial cells. PLOS ONE. 2018 Oct 11;13(10):e0205412, incorporated herein by reference). In these cases, AhR ligands activate the CYP1A1 pathway but not the nuclear factor erythrocyte-associated factor 2 (NRF2) pathway, subsequently upregulating downstream heme oxygenase 1 (HMOX-1), glutamate-cysteine ​​ligase modifying subunit (GCLM), and NAD(P)H dehydrogenase [quinone]1 (NQO1) to attenuate ROS production. Constructive therapeutic pathways that evoke AhR are also known to upregulate FLG and LOR via the OVOL-1 pathway.

[0010] There is a need in the art for one or more compounds that activate AhR. Additionally, there is a need in the art for one or more compounds that activate AhR, wherein AhR discretely regulates pathways that elicit favorable therapeutic outcomes. Furthermore, there is a need in the art for a method of preparing one or more compounds that activate AhR. Moreover, there is a need in the art for compositions containing one or more compounds that activate AhR.

[0011] The background information included herein is for illustrative purposes only. It does not imply an admission that any material mentioned as of the priority date has been published, is known to the public, or is part of common sense. Summary of the Invention

[0012] In one aspect, this specification relates to a compound of formula (I): (I) It exists in hydrated form, anhydrous form, or salt form; Where M is Ag, and n is 1, 2, or 3; X is a bidentate ligand, and each X independently is: (i)

[0013] in A 1 and A 2 Each can be CH, N, or SH independently; Each R 1 R 2 or R 3 Independently -H, optionally having one or more heteroatoms C 1-9 Substituents, -OR 4 -SR 4 -N(R) 4 )2、-C(=O)NR 4 -NC(=O)R 4 -C(=O)R 4 -C(=O)OR 4 Or halogen, or R 1 and R 2 Together they form a C5 or C6 membered ring having one or more heteroatoms, said C5 or C6 membered ring being optionally divided by C 1-3 Alkyl, C 1-3 Alkoxy, phenyl, -N(R) 4 )2、-C(O)R 4 -COOR 4 Or halogen mono- or di-substituted; and wherein when A 1 and A 2 When neither is CH, R 3 It does not exist; Each R 4 It is independently -H or optionally has one or more heteroatoms. 1-3 Substituents; D 1 and D 2 Each is independently -H, -OH, -N(R) 5 )2、-SH、-CO2R 6 or -C(=O)R 7 If D 1 Or D 2 If one of them is -H, then the other is D. 1 Or D 2 Not -H, Each R 5 Independently -H, C 1-3 alkyl, or Or two Rs 5 Together , R 6 yes (-) (Non-existent and negatively charged), -H or C 1-3 alkyl; R 7 It is a -H, -C1-C5 substituent or aryl group, wherein the -C1-C5 substituent or aryl group optionally has one or more heteroatoms; R 8 It is a C with -H, -OH, or optionally one or more heteroatoms. 1-3 Alkyl substituents, optionally having one or more heteroatoms -OC 1-3 Alkyl substituents or halogens; and R 9 It is -H or optionally has one or more heteroatoms. 1-3 Alkyl substituents; (ii)

[0014] in A 11 and A 12 Each can be either -CH or N independently; R 11 and R 12 Each is independently a -H, optionally having one or more heteroatoms. 1-3 Substituents, -OC 1-3 Substituents or halogens; ------ Is it a single bond or a double bond, and ------ A 14 and ------ R 14 In ------ Only one of them is a double bond; When A 13 With R 13 Between ------ When it is a single bond, A 13 It is CH or N, and R 13 It is -H, When A 13 With R 13 Between ------ When it is a double bond, A 13 It is C, and R 13 It is CH y , where y is 1 or 2; and when y is 1, CH is coupled with substituted or unsubstituted aryl or heteroaryl groups; when ------ A 14 of ------When it is a single bond, A 14 It is NH or CH2. when ------ A 14 of ------ When it is a double bond, A 14 Is it N or CR? 15 , where R 15 It is -C(=O)- coupled with substituted or unsubstituted heteroaryl groups; when ------ R 14 of ------ When it is a single bond, R 14 It is -H, -COO (-) or -S(=O)R 16 , where R 16 CH is optionally coupled with substituted or unsubstituted aryl or heteroaryl groups. z , where z is 1, 2 or 3; when ------ R 14 of ------ When it is a double bond, R 14 Is it O or S? (iii)

[0015] in A 21 It is N, and A 22 To A 27 Each of them is independently -CH or N; R 21 Yes - OR 24 or -SR 25 , where R 24 or R 25 It does not exist, is -H, -C1-C3 alkyl or aryl, and R 22 and R 23 Each is independently a -H, optionally having one or more heteroatoms. 1-3 Substituents, halogens, or R 22 and R 23 Together they form a C5 or C6 aromatic ring, wherein the C5 or C6 aromatic ring is optionally surrounded by a C1-C3 alkyl group, a C1-C3 alkoxy group, or a -NR group. 26 2. -C(O)R 27 -COOR 28 -CHO or halogen mono- or di-substituted; Where R 26 To R 28 Each of them is independently -H, -C1-C3 alkyl, or aryl; or (iv)

[0016] in A 31 It consists of elements from groups 16 to 17; and Each R 31 It does not exist independently; it is -H, -CO2H, or -CO2. - -OC(=O)-C 1-6 Alkyl group, -C(=O)NH2, -CO(CH2) 1-6 CHNH2CO2 - -CO(CH2) 1-6 CHNH2CO2H、-CONH2(CH2) 1-6 CH3、-CONH2(CH2) 1-6 CH3, =O, -O - OH, -C 3-6 Alkyl ketones, -C 3-6 Alkoxy, NO3 - NO3H, NO2 - NO2H, NH2, -NH(CH2) 1-6 CH3、-N((CH2) 1-6 CH3)2, SH, S-alkyl, -C5-C 10 Substituents or aryl groups, wherein the -C5-C 10 The substituent or aryl group may optionally have one or more heteroatoms; SO2 alkyl, SO3H, SO3 having 3-6 carbon atoms and optionally one or more oxygen or nitrogen atoms. - Halogens, CN; and p is 1 to 4; and in This indicates the coordination bond between the ligand and Ag.

[0017] In a second aspect, this specification relates to a pharmaceutical composition comprising a compound of formula (I) disclosed herein, in its hydrated form, anhydrous form, solvated form, or a salt thereof, and a pharmaceutically acceptable excipient.

[0018] In a third aspect, this specification relates to the use of a compound of formula (I) as disclosed herein, in its hydrated form, anhydrous form, solvated form or salt thereof, for the treatment of diseases associated with activation of the aryl hydrocarbon receptor (AhR).

[0019] In the fourth aspect, this specification relates to the use of a compound of formula (I) disclosed herein, in its hydrated form, anhydrous form, solvated form or salt thereof, for the regulation of aromatic hydrocarbon acceptor (AhR) activity.

[0020] In a fifth aspect, this specification relates to a pharmacological treatment method for a disease associated with activation of aryl hydrocarbon receptor (AhR) activity, the method comprising administering to a subject a pharmaceutically effective amount of a compound of formula (I) disclosed herein, in its hydrated form, anhydrous form, solvated form or a salt thereof.

[0021] In a sixth aspect, this specification relates to a method for regulating the activity of an aromatic hydrocarbon acceptor (AhR), the method comprising providing a compound of formula (I) as disclosed herein, in its hydrated form, anhydrous form, solvated form or a salt thereof.

[0022] In a seventh aspect, this specification relates to a method for preparing a compound of formula (I), its hydrated form, anhydrous form, solvated form, or a salt thereof, said method comprising: The silver salt or silver compound having chelated ligands is reacted with one or more ligands in a solvent. Attached Figure Description

[0023] Reference will now be made to the accompanying drawings, which illustrate exemplary embodiments of the present application, and the present application can be further understood from the drawings and the following description. The present application includes the accompanying drawings, in which: Figure 1 This is a bar graph showing the gene expression of CYP1A1 in HaCaT human keratinocytes after 6 hours of exposure to C5 (10 uM) relative to (untreated) cells adhered to a medium with 30-50% confluence (calculated fold change relative to time zero).

[0024] Figure 2 This is a bar graph showing the gene expression of CYP1B1 in HaCaT human keratinocytes after 6 hours of exposure to C5 (10 uM) relative to (untreated) cells adhered to a medium with 30-50% confluence (calculated fold change relative to time zero).

[0025] Figure 3 This is a bar graph showing the gene expression of KRT16, HMOX-1, and GCLM in HaCaT human keratinocytes after 6 hours of exposure to C5 (10 uM) relative to adherent medium control (untreated) cells.

[0026] Figure 4This is a bar graph showing a significant reduction in thymic stromal lymphopoietin (TSLP) gene expression induced by compound 4 in an inflammation-dominated model of atopic dermatitis in mice (calculated fold change relative to the untreated MC903+ mediator control). TSLP is negatively regulated by AhR activation. The black dashed line represents the uninduced, untreated sham-operated control.

[0027] Figure 5 This is a bar graph showing a significant reduction in ear thickness and swelling achieved by compound 4 in a mouse model of atopic dermatitis dominated by barrier dysfunction, compared to the untreated MC903+ mediator control.

[0028] Figure 6 This is a bar graph showing a significant increase in filaggrin gene expression induced by compound 4 in a mouse model of atopic dermatitis dominated by barrier dysfunction (calculated fold change relative to untreated MC903+ mediator control). The black dashed line represents the uninduced, untreated sham-operated control.

[0029] Figure 7 The percentage change in body weight in mice in a barrier dysfunction-dominated model indicates that mice tolerate compound 4 treatment well with little effect on body weight. Detailed Implementation

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. While methods and materials similar to or equivalent to any of the methods and materials described herein may be used in practice to test the invention, typical materials and methods are described herein. Common terms commonly used in describing and claiming the invention are described below. It should also be understood that the terminology used herein is for descriptive purposes only and is not intended to be limiting.

[0031] This article cites numerous patent applications, patents, and publications to aid in understanding the aspects described. Each of these references is incorporated herein by way of citation in its entirety.

[0032] When describing the elements disclosed herein, the articles “a / an,” “the,” and “said” are intended to mean that one or more of the said elements may exist.

[0033] As used herein, the term "comprising" and its derivatives are intended as open-ended terms that specify the presence of stated features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers, and / or steps. The foregoing also applies to words with similar meanings, such as the terms "comprising," "having," and their derivatives. It will be understood that any embodiment described as "comprising" certain components may also be "consisting of these components" or "generally composed of these components," where "consisting of" has a closed or limiting meaning, and "generally composed of" means including the specified components but excluding components other than materials present as impurities, unavoidable materials present as a result of the process used to provide said components, and components added for purposes other than achieving the technical effects described herein. For example, a composition defined using the phrase "generally composed of" encompasses any known acceptable additives, excipients, diluents, carriers, etc., suitable for the compositions described herein. Typically, a composition consisting of a group of components will contain less than 5% by weight, typically less than 3% by weight, and more typically less than 1% by weight of unspecified components.

[0034] It will be understood that any component included herein as defined may be expressly excluded from the claimed invention by conditional or negative limitation (such as any specific compound or method step, whether implied or expressly defined herein).

[0035] In addition, all ranges given in this article include the endpoints of the ranges as well as any intermediate points, whether or not explicitly stated.

[0036] Finally, as used herein, degree terms such as “basically,” “about,” and “approximately” mean a reasonable amount of deviation from the modified term that does not significantly alter the final result. These degree terms should be interpreted to include at least ±5% of the deviation from the modified term if this deviation does not negate the meaning of the word it modifies.

[0037] The abbreviation "e.g." originates from Latin. exempli gratia The abbreviation “eg” is used herein to indicate non-limiting instances. Therefore, the abbreviation “e.g.” is synonymous with the term “for example.” Unless the context clearly indicates otherwise, the word “or” is intended to include “and.”

[0038] The phrase “at least one of…” is understood to mean one or more. If not explicitly listed, the phrase “at least one of… and…” is understood to mean at least one of the listed elements or a combination thereof. For example, “at least one of A, B and C” is understood to mean A alone, or B alone, or C alone, or a combination of A and B, or a combination of A and C, or a combination of B and C, or a combination of A, B and C.

[0039] This specification relates to a compound, in its salt, hydrate, or anhydrous form, that induces activation of the AhR pathway, the activation of which can be used to treat diseases that may benefit from regulation of the AhR pathway.

[0040] This specification includes subheadings to aid the reader's understanding. The disclosure under each subheading is not exclusive, nor is it limited to that subheading, but should be taken into account when considering and understanding the entire disclosure of this specification.

[0041] compound In one aspect, this specification relates to compounds of formula (I): (I) It exists in hydrated form, anhydrous form, or salt form; Where M is Ag, and n is 1, 2, or 3; X is a bidentate ligand, and each X independently is: (i)

[0042] in A 1 and A 2 Each can be CH, N, or SH independently; Each R 1 R 2 or R 3 Independently -H, optionally having one or more heteroatoms C 1-9 Substituents, -OR 4 -SR 4 -N(R) 4 )2、-C(=O)NR 4 -NC(=O)R 4 -C(=O)R 4 -C(=O)OR 4 Or halogen, or R 1 and R 2 Together they form a C5 or C6 membered ring having one or more heteroatoms, said C5 or C6 membered ring being optionally divided by C 1-3 Alkyl, C 1-3Alkoxy, phenyl, -N(R) 4 )2、-C(O)R 4 -COOR 4 Or halogen mono- or di-substituted; and wherein when A 1 and A 2 When neither is CH, R 3 It does not exist; Each R 4 It is independently -H or optionally has one or more heteroatoms. 1-3 Substituents; D 1 and D 2 Each is independently -H, -OH, -N(R) 5 )2、-SH、-CO2R 6 or -C(=O)R 7 If D 1 Or D 2 If one of them is -H, then the other is D. 1 Or D 2 Not -H, Each R 5 Independently -H, C 1-3 alkyl, or Or two Rs 5 Together , R 6 yes (-) (Non-existent and negatively charged), -H or C 1-3 alkyl; R 7 It is a -H, -C1-C5 substituent or aryl group, wherein the -C1-C5 substituent or aryl group optionally has one or more heteroatoms; R 8 It is a C with -H, -OH, or optionally one or more heteroatoms. 1-3 Alkyl substituents, optionally having one or more heteroatoms -OC 1-3 Alkyl substituents or halogens; and R 9 It is -H or optionally has one or more heteroatoms. 1-3 Alkyl substituents; (ii)

[0043] in A 11 and A 12 Each can be either -CH or N independently; R 11 and R 12Each is independently a -H, optionally having one or more heteroatoms. 1-3 Substituents, -OC 1-3 Substituents or halogens; ------ Is it a single bond or a double bond, and ------ A 14 and ------ R 14 In ------ Only one of them is a double bond; When A 13 With R 13 Between ------ When it is a single bond, A 13 It is CH or N, and R 13 It is -H, When A 13 With R 13 Between ------ When it is a double bond, A 13 It is C, and R 13 It is CH y , where y is 1 or 2; and when y is 1, CH is coupled with substituted or unsubstituted aryl or heteroaryl groups; when ------ A 14 of ------ When it is a single bond, A 14 It is NH or CH2. when ------ A 14 of ------ When it is a double bond, A 14 Is it N or CR? 15 , where R 15 It is -C(=O)- coupled with substituted or unsubstituted heteroaryl groups; when ------ R 14 of ------ When it is a single bond, R 14 It is -H, -COO (-) or -S(=O)R 16 , where R 16 CH is optionally coupled with substituted or unsubstituted aryl or heteroaryl groups. z , where z is 1, 2 or 3; when ------ R 14 of ------ When it is a double bond, R 14 Is it O or S? (iii)

[0044] in A 21It is N, and A 22 To A 27 Each of them is independently -CH or N; R 21 Yes - OR 24 or -SR 25 , where R 24 or R 25 It does not exist, is -H, -C1-C3 alkyl or aryl, and R 22 and R 23 Each is independently a -H, optionally having one or more heteroatoms. 1-3 Substituents, halogens, or R 22 and R 23 Together they form a C5 or C6 aromatic ring, wherein the C5 or C6 aromatic ring is optionally surrounded by a C1-C3 alkyl group, a C1-C3 alkoxy group, or a -NR group. 26 2. -C(O)R 27 -COOR 28 -CHO or halogen mono- or di-substituted; Where R 26 To R 28 Each of them is independently -H, -C1-C3 alkyl, or aryl; (iv)

[0045] in A 31 It consists of elements from groups 16 to 17; and Each R 31 It does not exist independently; it is -H, -CO2H, or -CO2. - -OC(=O)-C 1-6 Alkyl group, -C(=O)NH2, -CO(CH2) 1-6 CHNH2CO2 - -CO(CH2) 1-6 CHNH2CO2H、-CONH2(CH2) 1-6 CH3、-CONH2(CH2) 1-6 CH3, =O, -O - OH, -C 3-6 Alkyl ketones, -C 3-6 Alkoxy, NO3 - NO3H, NO2 - NO2H, NH2, -NH(CH2) 1-6 CH3、-N((CH2) 1-6 CH3)2, SH, S-alkyl, -C5-C 10 Substituents or aryl groups, wherein the -C5-C10 The substituent or aryl group may optionally have one or more heteroatoms; SO2 alkyl, SO3H, SO3 having 3-6 carbon atoms and optionally one or more oxygen or nitrogen atoms. - Halogens, CN; and p is 1 to 4; and in This indicates the coordination bond between the ligand and Ag.

[0046] As used herein, the term 'hydrate' is not particularly limited and should be known or understood by those skilled in the art. A hydrate is a substance containing water or one of its constituent elements. A hydrate can be considered an inorganic salt containing water molecules that are combined in precise proportions to form an integral part of a crystal bonded to a metal center or crystallized together with a metal complex. Such hydrates are also said to contain water of crystallization or water of hydration.

[0047] As disclosed herein, the term 'anhydrous' is not particularly limited in form and should be known or understood by those skilled in the art. An anhydrous form of a substance refers to a compound that contains no water or is substantially free of water. In practice, achieving complete drying is very difficult because anhydrous compounds gradually absorb water from the atmosphere, requiring careful storage. In one embodiment, an anhydrous compound refers to a compound in which water is generally absent from the crystal lattice.

[0048] As disclosed herein, the term 'salt' is not particularly limited and should be known or understood by those skilled in the art. The term includes acid addition salts or base addition salts, in which case an acid or base is present or added to the compound to form its acid addition salt or base addition salt. In one embodiment, for example, but not limited thereto, the compound of formula (I) forms a pharmaceutically acceptable salt.

[0049] The pharmaceutically acceptable salt form of the compound of formula (I) may initially endow the active ingredient, which is not present in the non-salt form, with the desired pharmacokinetic properties and may even positively influence the pharmacodynamics of the active ingredient in vivo in terms of its therapeutic activity.

[0050] A pharmaceutically acceptable salt of a compound of formula (I) is a salt that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Non-limiting examples of such salts may include, but are not limited to, acid addition salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or from organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, dodecyl sulfate, gluconic acid, glutamic acid, salicylic acid, mucoacin, etc.; or base addition salts formed from the conjugate base of any of the inorganic acids listed above, wherein the conjugate base comprises a cationic component selected from: Na + K + Mg +2 Ca +2 And quaternary ammonium. In one embodiment, for example but not limited to, when the compound of formula (I) has a positive charge, the counterion can be, for example but not limited to, HCO3-. - BF4 - CO3 2- NO3 - ClO4 - SO4 2- F - ,Br - C3H3O 2 -, NH3, MnO4 - NO2 - BrO3 - IO3 - Cr2O7 2- OH - ,ClO 3- HCO 2- wait.

[0051] The metal (M) present in the compound of formula (I) is silver (Ag). The electronic configuration of silver is [Kr]4d. 10 5s 1 Silver is a member of Group 11 in the periodic table. In the context of this specification, in the compound of formula (I), the oxidation state of silver is +2 or +3, and it is expressed as Ag. +2 or Ag +3 It exists in the form of Ag. +2 or Ag +3 The electronic configurations are [Kr]4d 9 Or [Kr]4d 8In the context of this specification, the geometry of the complex may be in the form of a square plane, a deformed square plane, an octahedron, or a deformed octahedron.

[0052] As used herein, the term "ligand" is not particularly limited and should be known or understood by those skilled in the art. In coordination chemistry, a ligand is an ion or molecule (with a functional group) that binds to a central metal atom to form a coordination complex. This is typically achieved by the ligand donating an electron pair (forming a coordinate bond) to the electronegative central element M. In other words, binding to a metal usually involves the formal donation of one or more ligand electron pairs, typically via a Lewis base. The nature of metal-ligand bonding can range from covalent to ionic. Furthermore, the bond order of metal-ligand bonding can typically range from one to three, with higher bond orders known to exist. Ligands are considered Lewis bases, although some cases involving Lewis acidic "ligands" are known.

[0053] The ligands disclosed herein chelate with silver to form silver complexes. The silver complexes may have one, two, or three ligands bound to silver. Furthermore, when two or three ligands are bound to silver, the ligands may be the same or different. The formed silver complexes may exist in the form of salts. Moreover, the silver complexes may be in anhydrous or hydrated form. Furthermore, when the silver complexes exist in anhydrous or hydrated form, they may also exist as hydrated or anhydrous salts. In the hydrated form of the silver complex, water may bind with the silver metal during complex formation.

[0054] In the presence of one or more ligands in the compound of formula (I), each of the one or more ligands is a bidentate ligand. The term bidentate ligand is not particularly limited and should be known or understood by those skilled in the art. A bidentate ligand is a Lewis base that can donate two electron pairs (“doubles”) to a metal atom. A bidentate ligand generally refers to a chelating ligand (“chelate” originates from the Greek word meaning “claw”) because it can “grab” a metal atom in two places. It should be noted that the ligands disclosed herein can bind to silver from more than two sites. For example, the ligand can bind from three (tridentate) or four (tetradentate) sites. In the context of this specification, the ligands disclosed herein are at least bidentate ligands. Therefore, the ligands contemplated herein can also be tridentate or tetradentate, and thus have three or four atoms bonded to silver.

[0055] There are no particular restrictions on the position of the atom that donates the lone pair of electrons to bond with silver. As disclosed herein, bonding can be achieved by donating the electron pair from an atom present on or coupled to an aromatic ring of the ligand. The bidentate ligands disclosed herein can have the following nuclear structures: (i) (ii) (iii) (iv) .

[0056] In one embodiment, for example but not limited to, one or more ligands present in the compound of formula (1) are ligands (i) (or ligand type (i)), as follows: (i) in A 1 and A 2 Each can be CH, N, or SH independently; Each R 1 R 2 or R 3 Independently -H, optionally having one or more heteroatoms C 1-9 Substituents, -OR 4 -SR 4 -N(R) 4 )2、-C(=O)NR 4 -NC(=O)R 4 -C(=O)R 4 -C(=O)OR 4 Or halogen, or R 1 and R 2 Together they form a C5 or C6 membered ring having one or more heteroatoms, said C5 or C6 membered ring being optionally divided by C 1-3 Alkyl, C 1-3 Alkoxy, phenyl, -N(R) 4 )2、-C(O)R 4 -COOR 4 Or halogen mono- or di-substituted; and wherein when A 1 and A 2 When neither is CH, R 3 It does not exist; Each R 4 It is independently -H or optionally has one or more heteroatoms. 1-3 Substituents; D 1 and D 2 Each is independently -H, -OH, -N(R) 5 )2、-SH、-CO2R 6 or -C(=O)R 7 If D 1 Or D 2 If one of them is -H, then the other is D.1 Or D 2 Not -H, Each R 5 Independently -H, C 1-3 alkyl, or Or two Rs 5 Together , R 6 yes (-) (Non-existent and negatively charged), -H or C 1-3 alkyl; R 7 It is a -H, -C1-C5 substituent or aryl group, wherein the -C1-C5 substituent or aryl group optionally has one or more heteroatoms; R 8 It is a C with -H, -OH, or optionally one or more heteroatoms. 1-3 Alkyl substituents, optionally having one or more heteroatoms -OC 1-3 Alkyl substituents or halogens; and R 9 It is -H or optionally has one or more heteroatoms. 1-3 Alkyl substituents.

[0057] The binding of bidentate ligands to silver can occur through multiple different atoms on the ligand. For example, when ligand (i) is present in the silver complex, the lone pair of electrons from the ligand can be generated by A... 1 A 2 D 1 D 2 R 1 R 2 or R 3 Or by A 1 A 2 D 1 D 2 R 1 R 2 or R 3 The structure represented is supplied. Since the ligand is a bidentate ligand, the two electron pairs that donate silver can come from A. 1 A 2 D 1 D 2 R 1 R 2 or R 3 Either or a combination of both. Alternatively, the two electron pairs can be formed by a single functional group, such as -COO. (-) The supply, the functional group can represent A 1 A 2 D1 D 2 R 1 R 2 or R 3 Either of the atoms in the formula (I) can be used. The position of the atoms in the ligand that donate the lone pair is not particularly restricted, as long as the ligand can chelate with silver. Similarly, when ligand (ii) is present in the silver complex of formula (I), the two lone pairs from the bidentate ligand can be donated by either one or both A atoms. 11 A 12 A 13 A 14 R 11 R 12 R 13 or R 14 Supply. Similarly, when ligand (iii) is present in the silver complex of formula (I), the two lone pairs of electrons from the bidentate ligand can be supplied by either one or both A 21 A 22 A 23 A 24 A 25 A 26 A 27 R 21 R 22 or R 23 supply.

[0058] The bidentate ligand present in the silver complex of formula (I) can be any one or a combination of ligands (i), (ii), or (iii). Therefore, the silver complex of formula (I) can have only one type of ligand, such as ligands (i), (ii), or (iii). Alternatively, the silver complex of formula (I) can have any two types of bidentate ligands, such as ligands (i) and (ii), ligands (i) and (iii), or ligands (ii) and (iii). Furthermore, the silver complex of formula (I) can have all types of ligands (i), (ii), and (iii), depending on the compound of formula (I) formed.

[0059] As used in this article, the term C 1-9 Substituents, etc., are not particularly limited and should be known or understood by those skilled in the art. The term refers to organic substituents having one to nine carbon atoms. The number of carbon atoms present in the substituent is indicated by the subscript C (representing carbon atom). Therefore, C... 1-3 Substituents refer to organic substituents having one to three carbon atoms, or C... 1-5 A substituent is an organic substituent having one to five carbon atoms. As used herein, an organic substituent is any chemical moiety containing carbon. Therefore, C 1-9Substituents can be, for example, but not limited to, alkyl, alkenyl, alkynyl, cyclic structures, for example, but not limited to, carbocyclic moieties, aromatic moieties, polycyclic moieties, or combinations thereof. 1-9 Non-limiting examples of substituents may include methyl, ethyl, vinyl, ethynyl, propyl, propenyl, propynyl, isopropyl, butyl, butenyl, butynyl, phenyl, benzyl, cyclohexyl, ethyl-cyclohexyl, coumarin moiety, etc.

[0060] As disclosed in this article, C 1-9 The substituents may be optionally substituted, having one or more heteroatoms, -OR 4 -SR 4 -N(R) 4 )2 or halogen. The presence of non-carbon atoms changes the class of an organic compound, but is considered to be included in this specification as long as the total number of carbon atoms is in the range of one to nine. Therefore, other organic classes, such as alcohols and ethers (in the form of -OR), are contemplated. 4 (represented by -SR) thiols or thioethers 4 (represented by -NR) amines 4 (represented by -C(=O)NR) amide (in the form of -C(=O)NR) 4 and -NC(=O)R 4 ), aldehydes and ketones (represented by -C(=O)R 4 (represented by), carboxylic acids (or their anionic forms), and esters (represented by -C(=O)OR) 4 (This indicates that) within the scope of this specification, any substituent having a total of one to nine carbon atoms and not preventing the binding of the ligand to silver is acceptable. The C atoms optionally having one or more heteroatoms are contemplated in this specification. 1-9 Non-limiting examples of substituents include trifluoromethyl (-CF3), ethoxy (-OCH2CH3), propanol (-CH2CH2OH), propanethiol (HSCH2CH2-), methylene ethyl sulfide (CH3CH2SCH2-), pyridine, aniline, acetic acid moiety (-CH2C(=O)OH), or bromine, to name just a few.

[0061] As used herein, the term heteroatom is not particularly limited and should be known or understood by those skilled in the art. A heteroatom refers to any atom other than carbon and hydrogen. In one embodiment, for example, but not limited to, a heteroatom is one or more of nitrogen, oxygen, sulfur, or halogen.

[0062] As used herein, the term halogen is not particularly limited and should be known or understood by one of skill in the art. Halogens are elements that form Group 17 of the periodic table. Halogens include fluorine, chlorine, bromine, or iodine.

[0063] In the type (i) ligands disclosed in this specification, R 1 and R2 Together, they can form optionally substituted C5 or C6 membered rings as disclosed herein. The C5 or C6 membered ring bonds to the aromatic core structure of ligand (i) to form a polycyclic structure. Furthermore, the C5 or C6 membered ring can be an aromatic ring, a saturated ring, or an unsaturated ring. Therefore, it is envisioned that... , , , All such structures are within the scope of this specification. Furthermore, the C5 or C6 ring is optionally replaced by C... 1-3 Alkyl, C 1-3 Alkoxy, phenyl, -N(R) 4 )2、-C(O)R 4 -COOR 4 It may be a halogen mono- or di-substituted substance.

[0064] In ligand (i), when A 1 and A 2 When neither is CH, R 3 It does not exist. Therefore, R 1 R 2 and R 3 Only one or two A's are allowed. 1 and A 2 It exists when it is CH. When A 1 and A 2 When both are, for example, N and / or SH, then R is not present in ligand (i). 3 .

[0065] In ligand (i), when D 1 Or D 2 When one of them is -H, the other is D. 1 Or D 2 Not -H. Therefore, in ligand (i), D 1 and D 2 Neither can be -H. If D 1 If one of them is -H, then the other is D. 2 It is a substituent other than -H. Furthermore, in the ligand (i) disclosed herein, D... 1 and D 2 Neither of them can be -H.

[0066] As used herein, the term alkyl is not particularly limited and should be known or understood by those skilled in the art. In organic chemistry, an alkyl group is an alkane lacking one hydrogen atom. The term alkyl is intentionally left unspecified to include many possible substitutions. The general formula for acyclic alkyl groups is -C n H 2n+1 Cycloalkyl groups are obtained from cycloalkanes by removing hydrogen atoms from the ring, and have the general formula -C n H2n 1. Typically, alkyl groups are part of larger molecules. The smallest alkyl group is the methyl group, with the chemical formula -CH3. As used herein, the term C... 1-3 Alkyl groups are alkyl groups having one to three carbon atoms. C 1-3 Examples of alkyl groups include methyl, ethyl, propyl, or isopropyl.

[0067] As used herein, the term alkoxy is not particularly limited and should be known or understood by those skilled in the art. Description C 1-3 Alkoxy An alkoxy group is an alkyl group that is single-bonded to oxygen and can be represented by the structure RO, where R is an organic substituent. C 1-3 Alkoxy groups are alkoxy groups having one to three carbon atoms. C 1-3 Examples of alkoxy groups include methoxy (CH3O-), ethoxy (CH3CH2O-), propoxy (CH3CH2CH2O-), or isopropoxy ((CH3)2CHO-).

[0068] As used herein, the term aryl is not particularly limited and should be known or understood by those skilled in the art. An aryl group is any compound, functional group, or substituent derived from an aromatic ring, typically an aromatic hydrocarbon. An example of an aryl group is a compound having the structure... phenyl (C6H5-), in which This indicates the bonding sites between the phenyl group and the remaining chemical structures.

[0069] As used herein, the term heteroaryl is not particularly limited and should be known or understood by those skilled in the art. A heteroaryl is an aryl group having one or more heteroatoms.

[0070] In the ligands disclosed herein, when a carboxylic acid or phenolic group is present on the ligand, the carboxylic acid or phenolic group may be in a protonated form (-COOH or -OH), or it may be in a deprotonated form (-COO). (-) or -O (-) When referring to the terms carboxylic acid or phenolic structures, both protonated and deprotonated forms are contemplated within the context of this specification. Furthermore, when referring to the protonated form of a carboxylic acid or phenolic group, the deprotonated form is also considered to be included. As those skilled in the art will recognize, the presence of the carboxylic acid or phenolic group in the stated form depends on the pH of the solution, and the protonated form can convert to the deprotonated form at lower pH and vice versa. Additionally, depending on the conditions used, the amine group present on the chelate can be in a protonated form (-N). (+)(H) or deprotonated form (-N:). Similar to the carboxylic acid and phenolic groups mentioned herein, in the context of this specification, when the form of an amine (primary, secondary, or tertiary amine) is disclosed, both protonated and deprotonated forms are contemplated and considered within the scope of this specification.

[0071] Non-limiting examples of ligand (i) include , , , , , , , , , , , , , , , or .

[0072] And among them (Arrows) indicate potential chelation sites for the bidentate ligand Ag. Those skilled in the art will recognize that, as mentioned herein, multiple chelation sites exist between ligands and metals. The specific complex formed may depend on the reaction conditions. The specific chelation site between the ligand and silver may also be influenced by kinetics, thermodynamics, and steric hindrance factors. Therefore, it is more likely that the ligand will bind to silver and form a five- or six-membered ring without adjacent large or sterically hindered portions, rather than when the chelating atoms are more widely separated in the ligand or adjacent to a large or sterically hindered structure.

[0073] In some cases, as mentioned in this article, specific ligands can chelate with silver from more than two sites. For example, and without limitation, ligands... Chelation with silver can begin from two different positions, as shown below, where chelation starting from the N and O atoms of the carboxylic acid moiety is more likely. Another possible chelation of the ligand occurs when it begins from the two oxygen atoms of the carboxylic acid group, but this is less likely to happen. Complexes formed by various types of chelation are envisioned and considered, and are covered in this specification.

[0074] (In contrast, chelation via N and O is more likely to occur.) (Chelination via the two oxygen atoms of a carboxylic acid is possible, however unlikely to occur.)

[0075] As mentioned herein, ligand chelation can also begin from more than two atoms, thus becoming, for example, but not limited to, tridentate or tetradentate ligands. In one embodiment, for example, but not limited to, the ligand is a tetradentate ligand, wherein the binding of the ligand begins from four different atoms in the ligand, as shown below, wherein (Arrow) indicates the chelation point between the ligand and the metal.

[0076] . In one embodiment, for example but not limited thereto, one or more ligands present in the compound of formula (1) are ligands (ii) (or ligand type (ii)), as follows: (ii) in A 11 and A 12 Each can be either -CH or N independently; R 11 and R 12 Each is independently a -H, optionally having one or more heteroatoms. 1-3 Substituents, -OC 1-3 Substituents or halogens; ------ Is it a single bond or a double bond, and ------ A 14 and ------ R 14 In ------ Only one of them is a double bond; When A 13 With R 13 Between ------ When it is a single bond, A 13 It is CH or N, and R 13 It is -H, When A 13 With R 13 Between ------ When it is a double bond, A 13 It is C, and R 13 It is CH y , where y is 1 or 2; and when y is 1, CH is coupled with substituted or unsubstituted aryl or heteroaryl groups; when ------ A 14 of ------ When it is a single bond, A 14 It is NH or CH2. when ------ A 14 of ------ When it is a double bond, A 14 Is it N or CR? 15 , where R15 It is -C(=O)- coupled with substituted or unsubstituted heteroaryl groups; when ------ R 14 of ------ When it is a single bond, R 14 It is -H, -COO (-) or -S(=O)R 16 , where R 16 CH is optionally coupled with substituted or unsubstituted aryl or heteroaryl groups. z , where z is 1, 2 or 3; when ------ R 14 of ------ When it is a double bond, R 14 Is it O or S? As disclosed herein, the structural features of ligand (ii) are characterized by " ------ "It can be a single bond or a double bond. There are three distinct positions in ligand (ii), in the characteristic..." ------ "If it exists, a location is located at A." 13 With R 13 Between (represented as A) 13 ------ R 13 The second scenario may occur when the ligand (ii) has structural features A. 14 ------- In the case of C (where C is the carbon of the five-membered ring of ligand (ii)), and in the case of the third possibility where ligand (iii) has the structural feature C ------ R 14 In the case of (where C is the carbon of the five-membered ring of ligand (ii)). Those skilled in the art will recognize that, with A 13 A 14 and R 14 The bonded C can only be in A 14 With R 14 A double bond is formed between one of the ligands, rather than between both, because this would produce a carbon atom with five bonds. Therefore, in ligand (ii), the ligand (ii)... ------ A 14 and ------ R 14 "in ------ In ligand (ii), only one of them is a double bond, and the other must be a single bond. Therefore, in ligand (ii), when ------ A 14 Between ------ When it is a double bond, ------ R 14 "in ------ "It is a single bond. Therefore, in ligand (ii), when------ R 14 Between ------ When it is a double bond, ------ A 14 "in ------ "It is a single key."

[0077] In ligand (ii), as disclosed herein, when A 13 With R 13 Between ------ When it is a single bond, A 13 It is CH or N, and R 13 It is -H. Furthermore, in ligand (ii), when A... 13 With R 13 Between ------ When it is a double bond, A 13 It is C, and R 13 It is CH y , where y is 1 or 2. Therefore, CH y It can be -CH2 or -CH- bonded to a substituted or unsubstituted heteroaryl group. Therefore, when y is 1, CH is coupled to a substituted or unsubstituted aryl or heteroaryl group. In one embodiment, for example, but not limited to this, the heteroaryl group is not particularly limited and can have four to nine carbon atoms (i.e., C...). 4-9 (Heteroaryl). In another embodiment, for example, but not limited to, the heteroaryl group can be one or more C atoms having one or more heteroatoms. 1-3 Substituent substitution.

[0078] In one embodiment according to this specification, when ------ R 14 of ------ When it is a single bond, R 14 It is -H, -COO (-) or -S(=O)R 16 , where R 16 CH is optionally coupled with substituted or unsubstituted aryl or heteroaryl groups. z , where z is 1, 2, or 3. Therefore, CH z It can be -CH3, -CH2-, or -CH<, where CH2 is bonded to another moiety, and CH is bonded to two other chemical moieties. Therefore, when CH... z When it is CH2 or CH, it is coupled with a substituted or unsubstituted aryl or heteroaryl group. In one embodiment, for example, but not limited to this, the heteroaryl group is not particularly limited and can have four to nine carbon atoms (i.e., C46, ​​C56, C6 ... 4-9 (Heteroaryl). In another embodiment, for example, but not limited to, the heteroaryl group can be one or more C atoms having one or more heteroatoms. 1-3 Substituent substitution.

[0079] Furthermore, as disclosed herein, in one embodiment, for example but not limited thereto, in ligand (ii), when ------ R 14 of ------ When it is a double bond, R 14 It is O (oxygen) or S (sulfur).

[0080] Non-limiting examples of ligand (ii) include , , or .

[0081] And among them (Arrows) indicate potential chelation sites for the bidentate ligand Ag. Those skilled in the art will recognize that, as described herein with respect to ligand (i), there are multiple chelation sites between the ligand and the metal, and as disclosed herein, the description of ligand (i) also applies to ligand (ii).

[0082] In one embodiment, for example but not limited thereto, one or more ligands present in the compound of formula (1) are ligands (iii) (or ligand type (iii)), as follows: (iii) Where A 21 It is N, and A 22 To A 27 Each of them is independently -CH or N. Further, in ligand (iii), R... 21 Yes - OR 24 or -SR 25 , where R 24 or R 25 It does not exist; it is -H, -C1-C3 alkyl, or aryl. When R... 24 or R 25 When it is absent, O or S has a negative charge (the resulting anion) (represented as O). (-) or S (-) ).

[0083] In ligand (iii), R 22 and R 23 Each is independently a -H, optionally having one or more heteroatoms. 1-3 Substituents, halogens, or R 22 and R 23 Together they form a C5 or C6 aromatic ring, wherein the C5 or C6 aromatic ring is optionally surrounded by a C1-C3 alkyl group, a C1-C3 alkoxy group, or a -NR group. 26 2. -C(O)R27 -COOR 28 -CHO or halogen mono- or di-substituted; wherein R 26 To R 28 Each of them is independently -H, -C1-C3 alkyl or aryl.

[0084] Non-limiting examples of ligand (iii) include

[0085] And among them (Arrows) indicate potential chelation sites for the bidentate ligand Ag. Those skilled in the art will recognize that, as described herein with respect to ligands (i) and (ii), there are multiple chelation sites between the ligands and the metal, and as disclosed herein, the descriptions of ligands (i) and (ii) also apply to ligand (iii).

[0086] In one embodiment, for example but not limited thereto, one or more ligands present in the compound of formula (1) are ligands (iv) (or ligand types (iv)) as follows: (iv) in A 31 It consists of elements from groups 16 to 17; and Each R 31 R 31 Independently -H, -CO2H, -CO2 - -OC(=O)-C 1-6 -alkyl, -C(=O)NH2, -CO(CH2) 1- 6CHNH2CO2 - -CO(CH2) 1-6 CHNH2CO2H、-CONH2(CH2) 1-6 CH3、-CONH2(CH2) 1-6 CH3, =O, -O - OH, -C 3-6 -alkyl ketones, -C 3-6 -alkoxy group, NO3 - NO3H, NO2 - NO2H, NH2, -NH(CH2) 1-6 CH3、-N((CH2) 1-6 CH3)2, SH, S-alkyl, -C5-C 10 Substituents or aryl groups, wherein the -C5-C 10The substituent or aryl group may optionally have one or more heteroatoms; SO2 alkyl, SO3H, SO3 having 3-6 carbon atoms and optionally one or more oxygen or nitrogen atoms. - Halogens, CN; and p is 1 to 4; and in This indicates the coordination bond between the ligand and Ag.

[0087] As used herein, the phrase "group 16" or "group 17" is not particularly limited and should be known or understood by those skilled in the art. Group 16 elements are considered to be chalcogens or the oxygen family. In one embodiment, for example, but not limited to, in ligand (iv) with A 31 One or more Group 16 elements are oxygen (O) or sulfur (S). Group 17 elements are considered to be the halogen group. Halogens are a group of six elements in the periodic table: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), and dichroism (Ts). In one embodiment, for example, but not limited to, as disclosed above, A 31 It is sulfur, selenium, tellurium, polonium, or iodine. In another embodiment, for example, but not limited to, one or more group 17 elements, tellurium (Te) or iodine (I), present in the ligand.

[0088] Term C 1-12 Alkyl and C 1-12 Alkenes are not particularly limited and should be known or understood by those skilled in the art. The subscript following carbon (C) indicates the possible number of carbon atoms present in the chemical part. In C... 1-12 In this case, the chemical part may contain one to 12 carbon atoms. The terms alkyl and alkene are not particularly limited and should be known or understood by those skilled in the art. An alkyl group is an alkene lacking one hydrogen atom. The term alkyl is intentionally not specified to include many possible substitutions. The general formula for acyclic alkyl groups is -C n H 2n+1 The alkyl group is denoted by n, where n represents the number of carbon atoms. Non-limiting examples of alkyl groups include methyl (-CH3), ethyl (CH3-CH2-), propyl (CH3-(CH2)2-), or butyl (CH3-(CH2)3-). An olefinic group is a hydrocarbon containing a carbon-carbon double bond. An alkenyl group is a hydrocarbon group formed by removing a hydrogen atom from an olefinic group. Alkenyl compounds are named by replacing the -hydrocarbon in the name derived from the parent olefin with a -yl group. A non-limiting example of an alkenyl group is H2C=CH- (ethenyl, or commonly referred to as vinyl).

[0089] As used herein, the term alkyl ketone refers to the general formula: RC(=O)-, where R is an alkyl substituent. Alternatively, alkyl ketones can also have the general formula RC(=O)-R', where both R and R' are alkyl substituents. When an alkyl ketone has the formula RC(=O)-, A 31 Bonded to the carbon atom in RC(=O)-. When an alkyl ketone has the formula RC(=O)-R', A 31 Bonded to R or R'.

[0090] As disclosed herein, the terms 2-amino and 3-amino are not particularly limited and should be known or understood by those skilled in the art. 2-Amino refers to an amine having two organic substituents and having the formula RR'-NH, where R and R' are organic substituents. 3-Amino refers to an amine having three organic substituents and having the formula RR'R''-N, where R, R', and R'' are organic substituents.

[0091] An imine is a functional group or organic substituent containing a carbon-nitrogen double bond. The nitrogen atom can be bonded to hydrogen or an organic group. The carbon atom also has two additional single bonds. An imine-alkyl group has an alkyl group that is partially bonded to the imine.

[0092] Oximes are organic substituents belonging to the imine family, with the general formula RR'C=N. OH, where R is an organic side chain and R' can be hydrogen, thus forming an aldoxime, or it can be another organic group, thus forming a ketoxime. O-substituted oximes form a closely related family of compounds.

[0093] A non-limiting example of ligand (iv) is the periodate ion (IO4). (-) ) or positive periodate ion (IO6) (5-) ).

[0094] Regarding silver complexes in their hydrated, anhydrous, or salt forms, in a first embodiment, for example, but not limited to, the minimum solubility of the compound, its hydrated, anhydrous, or salt forms in an aqueous medium at neutral pH, 25°C, and 1 bar is 0.1 nM. In a second embodiment, the minimum solubility of the compound, its hydrated, anhydrous, or salt forms in an aqueous medium at 25°C is 0.1 μM.

[0095] Regarding silver complexes in their hydrated form, anhydrous form, or salts thereof, in a first embodiment, for example, but not limited to, the minimum solubility of the compound, its hydrated form, anhydrous form, or salts thereof in a non-aqueous medium, including DMSO, at neutral pH, 25°C, and 1 bar, is 0.1 μM. In a second embodiment, the minimum solubility of the compound, its hydrated form, anhydrous form, or salts thereof in a non-aqueous medium, including DMSO, at 25°C, is 1.0 μM.

[0096] Regarding silver complex compounds, their hydrated form, anhydrous form, or salts thereof, in the first embodiment, for example, but not limited to, the formation constant (Kf) or stability constant of compounds of Formula 1, their hydrated form, anhydrous form, or salts thereof, as determined by Kf = [MxLy] / [M]x[L]y at neutral pH, 25°C, and 1 bar, is defined as the range of Kf = 1.0 x 10⁻⁶. 5 To Kf = 1.0 x 10 35 In the second embodiment, for example but not limited to, the formation constant (Kf) of the compound, its hydrated form, anhydrous form, or its salt can be in the range of Kf = 1.0 x 10⁻⁶. 5 To Kf = 1.0 x 10 25 In the third embodiment, for example, but not limited to, the formation constant (Kf) of the compound, its hydrated form, its anhydrous form, or its salt can be in the range of Kf = 1.0 x 10⁻⁶. 10 To Kf = 1.0 x 10 25 .

[0097] The structures disclosed above allow for second-order interactions with solvent-derived atoms encountered by the compound, its hydrated form, anhydrous form, solvated form, or salts thereof during synthesis, separation, formulation, and / or therapeutic use. During synthesis, separation, formulation, and therapeutic use, these interactions can produce structures comprising derivative atoms and ligands encountered by the compound, its hydrated form, anhydrous form, solvated form, or salts thereof. Such second-order interactions may result in ligand translocation, thereby creating open or exchange states, where atoms and ligands encountered in the second-order interactions may imply their own entry into the compound, its hydrated form, anhydrous form, solvated form, or salts thereof. Such structures are explicitly contemplated in this specification.

[0098] Composition This specification also provides examples of the compounds disclosed herein, in their hydrated, anhydrous, solvated, or salt thereof, as pharmaceutical formulations.

[0099] Pharmaceutical formulations of the compounds described herein, in their hydrated, anhydrous, solvated, or salt forms, may be manufactured in known manners, including but not limited to dissolution, granulation, emulsification, mixing, encapsulation, lyophilization, or combinations thereof.

[0100] This specification also provides examples of compounds, their hydrated forms, anhydrous forms, solvated forms, or salts thereof, that can be formulated into suitable aqueous solutions for subcutaneous or intravenous injection. Such compositions may include suitable solutions, including but not limited to physiologically compatible buffer solutions. These compositions may be formulated for delivery by bolus injection or continuous infusion and may include excipients known in the art for achieving suspension, stabilization, delivery, or dispersion.

[0101] This specification also provides examples of compounds, in their hydrated, anhydrous, solvated, or salt forms, which can be formulated with suitable penetrants known in the art to achieve transmural or transdermal application. Such formulations may include carriers and may also include suitable excipients known in the art for producing control over rheological and release properties, said carriers including, but not limited to, liquids, gels, hydrogels, solids, and slurries.

[0102] This specification also provides examples of compounds, their hydrated forms, anhydrous forms, solvated forms, or salts thereof, which can be formulated into atomized, sprayed, or atomized forms with or without suitable propellants known in the art. Such formulations can be prepared in solid, liquid, or gel forms by including suitable excipients known in the art. These formulations can be used to deliver the compounds described herein, their hydrated forms, anhydrous forms, solvated forms, or salts thereof, as well as the formulations thereof, to the skin, hair, mucous membranes, or for inhalation.

[0103] This specification also provides examples of compounds, their hydrated forms, anhydrous forms, solvated forms, or salts thereof, that can be formulated into reservoirs so that the release or delivery of the compounds, their hydrated forms, anhydrous forms, solvated forms, or salts thereof can be carried out for extended periods of time for long-acting formulations.

[0104] This specification also provides examples of compounds that can be formulated in combination with excipients or pharmaceutical compounds that can be delivered directly or targeted to discrete sites within a biological system, in their hydrated, anhydrous, solvated, or salt forms. These formulations may be used as liposomes, emulsions, self-assembled structures, polymer compounds, sustained-release materials, or combinations thereof.

[0105] This specification also provides examples of compounds that can be formulated in combination with non-aqueous formulations, in their hydrated, anhydrous, solvated, or salt forms. Such formulations may utilize silica, silicone, crosslinked silicone, and suitable excipients known in the art for enhancing rheological and delivery properties.

[0106] The compounds described herein may be in the form of pharmaceutically compatible counterions, such as salts of sodium, potassium, calcium, or ammonium, or other non-toxic, pharmaceutically acceptable salts or combinations thereof known to those skilled in the art.

[0107] Pharmaceutical compositions of the compounds described in this specification, their hydrated, anhydrous, solvated forms, or salts thereof, can be formulated and administered in a variety of ways. Such administration can include systemic, localized, or topical administration, including but not limited to oral, rectal, transmucosal, transdermal, enteral, parenteral, intramuscular, subcutaneous, intramedullary, intrathecal, intravenous, intracardiac, intraperitoneal, intranasal, and intraocular administration. The mode of administration can be customized according to the desired site and delivery protocol.

[0108] Pharmaceutical compositions of the compounds described in this specification, their hydrated, anhydrous, solvated, or salts thereof, may be suitable, wherein the active ingredient is contained and delivered in an effective amount to achieve the desired results and intended purpose. Such a therapeutically effective amount may include an amount of the compounds described in this specification, their hydrated, anhydrous, solvated, or salts thereof, that can treat, prevent, or improve a subject's disease or condition. As used herein, the terms "treatment," "prevention," and "improvement" refer to an intervention aimed at improving symptoms associated with a disease, condition, or symptom, preventing the development of said disease, condition, or symptom, or altering the pathology of said disease, condition, or symptom. Therefore, in various embodiments, the terms may include prevention, mitigation, relief, or cure of various stages of a disease, condition, or symptom. Therefore, in various embodiments, a subject requiring therapy / treatment may include a subject who already has a disease, condition, or symptom and / or a subject who is predisposed to or at risk of developing a disease, condition, or symptom and / or a subject who wants to prevent a disease, condition, or symptom.

[0109] Pharmaceutical compositions of the compounds described in this specification, in their hydrated, anhydrous, solvated, or salt forms thereof, are suitable for use in the medical, dental, pharmaceutical, cosmeceutical, personal care, veterinary, agricultural, materials engineering, and over-the-counter fields. Such compositions can be used for the treatment and / or therapy of subjects, including humans or other vertebrates, wherein the composition provides subjective relief of symptoms or objectively identifiable improvement noted by a clinician or other qualified observer.

[0110] The therapeutically effective dose of any compound described in this specification, its hydrated form, anhydrous form, solvated form, or salt thereof, can initially be estimated using the in vitro cell culture assays disclosed herein. However, those skilled in the art will understand that the specific dose required for higher organisms (including animals and humans) can be determined more accurately through in vivo studies, including the determination of the lethal dose (LD50). 50) concentration and effective dose concentration (ED) 50 And its effective ratio. Those skilled in the art should also understand that dosing regimens can be more accurate through dose discovery studies conducted in a clinical setting. It should also be understood that the specific dose for any particular patient may depend on a variety of factors, including but not limited to age, sex, weight, height, health, time of administration, route of administration, pharmacokinetics and pharmacodynamics, drug interactions, disease severity, and the advice and judgment of the prescribing physician.

[0111] In one embodiment, the compounds disclosed herein, in their hydrated, anhydrous, solvated, or salt forms, may possess certain pharmacological properties, including low toxicity, low carcinogenicity, desired in vitro and in vivo half-life, and reasonable efficacy.

[0112] Preparation process As disclosed herein, in a seventh aspect, this specification relates to a method for preparing a compound of formula (I), its hydrated form, anhydrous form, solvated form, or a salt thereof, said method comprising: The silver salt or silver compound having chelated ligands is reacted with one or more ligands in a solvent.

[0113] In one embodiment, for example but not limited to, the compound is prepared by: initially dissolving the central M metal in an aqueous medium, followed by the addition of a suitable oxidizing or reducing agent and an acid or base to influence the desired orbital geometry, followed by the addition of the desired chelate to form a compound of formula (I), its hydrated form, anhydrous form, solvated form or a salt thereof.

[0114] The conjugate acid and conjugate base or desired salt of a compound can be prepared by appropriately adjusting the pH of the complex or by performing ion exchange to obtain the desired salt.

[0115] In one embodiment, such as, but not limited to, according to this specification, the process involves reacting a salt or chelate form of a central metal with a second chelate or a mixed chelate system to form a desired chelate complex exhibiting a variety of physicochemical properties, particularly stability and yield, thereby making it suitable for industrial and commercial applications.

[0116] In another embodiment, such as, but not limited to, the process involves dissolving the central metal in a suitable solvent, pH, and temperature to support dissolution. The solvent may be selected from aqueous or organic media; including but not limited to water, methanol, ethanol, dimethylformamide, dimethyl sulfoxide, toluene, or hexane. The pH of the medium can be adjusted to pH 2 to 14 using a suitable strong or weak acid or strong or weak base. In a more preferred embodiment, the pH of the medium can be adjusted to pH 4 to 10 using a strong acid or strong base. In some embodiments, the dissolution of the metal is carried out at a temperature ranging from about 0°C to about 100°C over a period of about 0 minutes to about 90 minutes. In another embodiment, such as, but not limited to, the dissolution of the metal is carried out at a temperature ranging from about 20°C to about 50°C over a period of about 0 minutes to 10 minutes. In yet another embodiment, such as, but not limited to, the concentration of the metal ranges from about 0.01 mM to about 2.0 M.

[0117] In one embodiment, for example but not limited to, the process may involve dissolving one or more ligand chelates in a suitable solvent, pH, and temperature to support dissolution. The solvent may be selected from aqueous or organic media; including but not limited to water, methanol, ethanol, dimethylformamide, dimethyl sulfoxide, toluene, or hexane. The pH of the medium may be adjusted to pH 2 to 14 by using a suitable strong or weak acid or strong or weak base. In a more preferred embodiment, the pH of the medium may be adjusted to pH 4 to 10 by using a strong acid or strong base. In another embodiment, for example but not limited to, the dissolution of the metal is carried out at a temperature ranging from about 0°C to about 100°C for about 0 minutes to about 90 minutes. In yet another embodiment, for example but not limited to, the dissolution of the metal is carried out at a temperature ranging from about 20°C to about 50°C for about 0 minutes to about 10 minutes. In one embodiment, for example but not limited to, the concentration of one or more ligand chelates ranges from about 0.01 mM to about 4.0 M.

[0118] In one embodiment, such as, but not limited to, the ligand chelate solution is continuously added to the metal solution. In another embodiment, such as, but not limited to, the mixed ligand chelate solution is simultaneously added to the metal solution. In yet another embodiment, such as, but not limited to, the ligand chelate or ligand chelate system is added directly to the metal solution. In still another embodiment, such as, but not limited to, the metal is added directly to the ligand chelate solution or the mixed ligand chelate solution.

[0119] In one embodiment, for example but not limited to, the pH of the reaction solution for forming the metal chelate complex can be adjusted to pH 2 to 14 using a suitable strong or weak acid or strong or weak base. In another embodiment, for example but not limited to, the pH of the medium can be adjusted to pH 4 to 10 using a strong acid or strong base. In yet another embodiment, for example but not limited to, the formation of the metal chelate complex can be carried out at a temperature ranging from about 0°C to about 100°C for about 0 minutes to about 48 hours. In yet another embodiment, for example but not limited to, the formation of the metal chelate complex is carried out at a temperature ranging from about 20°C to about 90°C for about 0 minutes to 90 minutes.

[0120] In one embodiment of this specification, for example but not limited to, the metal chelate complex can be separated by filtration and optionally further purified. In another embodiment of this specification, for example but not limited to, the metal chelate complex can be separated from the reaction solution by forming a conjugate acid or conjugate base and then by filtration, and optionally further purified. In yet another embodiment of this specification, for example but not limited to, the metal chelate complex can be separated from the reaction solution by adding a pharmaceutically suitable counterion to form a desired salt complex, separated by filtration, and optionally further purified.

[0121] In another embodiment, such as, but not limited to, further purification may be performed by recrystallization, sublimation, extraction, adsorption chromatography, column chromatography, high-performance liquid chromatography, or other methods known in the art.

[0122] Bioassay The historical agonist of AhR has been quantified by the following: nuclear translocation of AhR followed by ligand binding, thereby inducing cytochrome P450 activity and cyp1a1 Gene expression; exclusively and definitively downstream of AhR. However, recent findings have identified low... cyp1a1 The expression inducer is therapeutically beneficial and is consistent with the non-canonical pathway regulated by AhR.

[0123] This invention describes the induction of human HT29 colon adenocarcinoma or AhR reporter cells. cyp1a1 Compounds expressing genes in human keratinocytes (HaCaT). As illustrated herein, the chelates described herein have exhibited significant induction... cyp1a1 This refers to the expression of genes that are exclusively located downstream of the AhR promoter region and transcribed upon AhR activation. In the in vitro HaCaT model, the chelates described in this paper exhibited induction of... hmox-1 and gclm and cyp1a1 and cyp1b1 ,like Figure 1-3 As shown, this is consistent with pathway induction or non-classical pathway induction with therapeutic benefits. These results were translated in in vivo models of inflammatory skin diseases induced by calcipotriol or MC903, in which treatment with the chelate compounds described in this paper demonstrated reduced ear swelling and TSLP signaling, while significantly increasing the gene expression of filaggrin, a barrier function protein regulated by AhR (Jeong H, Shin JY, Kim MJ, Na J, Ju BG. Activation of aryl hydrocarbon receptor negatively regulates thymic stromal lymphopoietin gene expression via protein kinase Cδ-p300-NF-κB pathway in keratinocytes under inflammatory conditions). Journal of Investigative Dermatology. May 1, 2019; 139(5):1098-109), consistently had no significant effect on weight, such as Figure 4-7 As shown.

[0124] Example The foregoing disclosure generally describes the invention. A more complete understanding can be obtained by referring to the following specific examples. These examples are described for illustrative purposes only and are not intended to limit the scope of the invention. It is contemplated that circumstances may indicate or present convenient variations in form and alternatives to equivalent forms. Without further description, it is believed that those skilled in the art will be able to make and utilize constructs of the invention and practice the claimed methods using the foregoing description and the following illustrative examples. Therefore, the following working examples specifically point to typical aspects of the invention and should not be construed as limiting the remainder of this disclosure in any way. Although specific terminology is used herein, it is intended in a descriptive sense and not for limiting purposes.

[0125] Example 1Dissolve AgNO3 (0.5 mmol, 1 ml Milli-Q water) at room temperature by stirring. Dissolve 2-aminophenol (1 mmol, 5 ml Milli-Q water) by adding KOH (0.33 mmol, 500 μl Milli-Q water) while stirring at heat (50-60°C). Dissolve 6-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole (1 mmol, 10 ml Milli-Q water) with KOH (1 mmol, 1.5 ml Milli-Q water). Dissolve potassium persulfate solution in milli-Q water at 50-60°C, and add 50 μl (0.017 mmol) to the above-stirred room-temperature AgNO3 solution. After 30 seconds, 10 ml of 6-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole was slowly added over a 2-minute period, resulting in a turbid brown solution. Immediately following a final addition of 6-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5 ml of 2-aminophenol was slowly added over a 1-minute period. The reaction mixture was stirred at room temperature for 10 minutes, resulting in a dark brown product. Compound 1 [Ag(2-aminophenol)(6-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole)] was separated by vacuum filtration and characterized. FTIR: 3384 cm⁻¹ -1 br, 2996 cm -1 sh, 1616 cm -1 s, 1565cm -1 s, 1468 cm -1 s, 1420 cm -1 s; UV-Vis: λ 最大 310 nm, 423 nm, 441 nm.

[0126] Example 2AgNO3 (1 mmol, 5 ml Milli-Q water) was dissolved in hexane with stirring at room temperature. 2-Aminophenol was dissolved in hexane with an excess of KOH (5 ml Milli-Q water), and after drying, a portion of the solid (2 mmol) 2-aminophenol was added to the stirred room-temperature AgNO3 solution, followed by the addition of another 5 ml Milli-Q water. After stirring for 5 minutes at room temperature, a dark brown precipitate formed. Compound 2 [Ag(2-aminophenol)2] was separated by vacuum filtration after 25 minutes without stirring at room temperature and characterized. FTIR: 3374 cm⁻¹ -1 s, 3302 cm -1 s, 1568 cm -1 s, 1510 cm -1 s, 1457 cm -1 s; UV-Vis: λ 最大 = 285 nm, 420 nm, 440 nm.

[0127] Example 3 AgNO3 (0.5 mmol, 2.5 ml Milli-Q water) was dissolved at room temperature. 2-Aminophenol was deprotonated in hexane with an excess of KOH (5 ml Milli-Q water), and after drying, a portion of the solid (1 mmol) 2-aminophenol was dissolved in 10 ml Milli-Q water. Isoquinoline-1-carboxylic acid was dissolved at room temperature and added to 10 ml of the previously described solution while stirring at room temperature, resulting in an amber-colored solution. AgNO3 (0.5 mmol, 2.5 ml Milli-Q water) was dissolved at room temperature by stirring and added to the reaction mixture containing isoquinoline-1-carboxylic acid and 2-aminophenol, resulting in a light brown turbid solution. After 10 minutes, the reaction solution was dark brown and neutralized within 15 minutes by adding a total of 1.6 mmol KOH (800 μL Milli-Q water) and 0.4 mmol HNO3 (200 μL Milli-Q water). Compound 3 [Ag(2-aminophenol)(isoquinoline-1-carboxylate)] was isolated by vacuum filtration; it was a dark brown product. FTIR: 3374 cm⁻¹ -1 s, 3302 cm -1 s, 3100 cm -1 m, 2750 cm -1 m, 1593cm -1 s, 1510 cm -1 s, 1458 cm-1 s; 1380 cm -1 m; UV-Vis: λ 最大 = 280 nm, 420 nm, 440 nm.

[0128] Example 4: An aqueous solution of KOH (0.13 M) and KIO4 (0.43 M) was prepared by adding 0.75 g KOH and 10.0 g KIO4 to 100 mL of reverse osmosis (RO) water heated to 85 °C and stirred at 400 rpm. Silver oxide (AgO) was added to this solution to achieve a final concentration of 0.40 M. The turbid, brownish-black solution was maintained at 85 °C with stirring for 3 hours, during which time the turbidity decreased and the red color increased. After heating for 3 hours, the solution was hot-filtered through a fine glass Frit filter. Upon cooling, anhydrous compound 4[Ag(periodate)2K3] orange-red crystals were separated and recrystallized from hot water. Characterized by UV-Vis: λ 最大 = 280 nm and 364 nm, ε = 1.56 x 10 4 cm -1 M -1 . XRD (°2Θ): 13.1, 13.8, 14.2, 16.4, 19.0, 21.1, 24.2, 25.3, 26.1, 26.3.

[0129] Example 5. AgNO3 (0.5 mmol, 1 ml MilliQ water) was dissolved by stirring at room temperature. 2-Aminophenol (1 mmol, 5 ml MilliQ water) was dissolved by adding KOH (0.33 mmol, 500 μL MilliQ water) at heat (50-60°C) and stirring. Kynuric acid (1 mmol, 10 ml Milli-Q water) was dissolved in KOH (0.5 mmol, 1 ml Milli-Q water). Potassium persulfate solution was dissolved in Milli-Q water at 50-60°C, and 50 μL (0.017 mmol) was added to the stirred AgNO3 solution at room temperature. After 30 seconds, 5 ml of 2-aminophenol was slowly added over 2 minutes, resulting in an immediate dark precipitate and a reddish-orange solution. Immediately following the final addition of 2-aminophenol, 10 ml of kynuric acid was slowly added over 1 minute, resulting in a cloudy brown solution. The reaction mixture was stirred at room temperature for 10 minutes, resulting in a dark brown product. Compound 5 [Ag(2-aminophenol)(kynuric acid)] was separated by vacuum filtration and recrystallized in hot water. FTIR: 3095 cm⁻¹-1 br, 1628 cm -1 m, 1585 cm -1 s, 1468 cm -1 m, 1357 cm -1 m;UV-Vis: λ 最大 = 348nm, 418nm, 440 nm.

[0130] Example 6 Luciferase assay Human HT29 colon adenocarcinoma-AhR reporter cells (HT29-Lucia™ AhR cells; InvivoGen; ht2l-ahr) were used to determine the EC50 of the described compounds. HT29-Lucia™ AhR cells were engineered to express the Lucia luciferase reporter gene, in which human Cyp1a1 gene transcription occurs upon AhR activation. Briefly, cells were expanded using DMEM supplemented with 5% heat-inactivated FBS, 1% penicillin-streptomycin, 2 mM L-glutamine, and 100 µg / mL Normocin. After two passages, the selective antibiotic Zeocin was added to the medium at 100 µg / mL to select stably transfected cells. Dose response and EC50 were evaluated by seeding 56,000 cells / well into 96-well plates in test medium containing only DMEM + 5% heat-inactivated FBS, 2 mM L-glutamine, and 1% penicillin-streptomycin. The compounds were solubilized in DMSO, with 1 μL added to each well to achieve a final DMSO concentration of 0.5%. Cells were incubated with the compounds at 37 °C and 5% CO2 for 24 h. After 24 h of incubation, 20 µL of cell supernatant was transferred to a 96-well white opaque plate. A working stock solution of QUANTI-Luc™ 4 reagent was prepared by adding 23.75 mL of sterile H2O to the concentrated stock solution. 45 µL of QUANTI-Luc™ 4 reagent was added to each well containing cell supernatant. The luminescence of each compound at 6.25 μM was immediately evaluated, and the reported fold change was determined when a significant difference in induction relative to baseline was observed.

[0131]

[0132]

[0133] Example 7 External efficacy Immortalized human keratinocytes (HaCaT) were used at a concentration of 6.5 x 10⁻⁶. 4 cells / cm 2The sample was inoculated into 2 ml of complete DMEM (10% FBS, 1% penicillin / streptomycin) and incubated at 37°C with 5% CO2 for 18–24 hours, followed by treatment. The sample was then treated in complete DMEM (10% FBS, 1% penicillin / streptomycin) with the 10 µM compound prepared in Example 4 described herein, the DMEM being prepared by diluting a 10 mM stock solution 1000-fold in water. Sonication was used to aid dispersion and dissolution. The treated plate was then incubated at 37°C with 5% CO2 for 6 hours.

[0134] After 6 hours, gene analysis was performed by aspirating the culture medium and adding 400 μL of TRIzol. TRIzol and the remaining cells were homogenized using a 1000 μL pipette tip and incubated at room temperature for 15 minutes. After incubation, 80 μL of chloroform was added to each sample, followed by a 2–3 minute incubation and centrifugation at 12,000 xg for 15 minutes at 4°C. The clear aqueous layer was removed, and the sample was precipitated with isopropanol at room temperature for 10 minutes at 4°C, followed by centrifugation at 12,000 xg for 10 minutes at 4°C. The samples were washed twice with 70% ethanol and centrifuged at 7,500 xg for 5 minutes at 4°C. The RNA was air-dried for 15 minutes instead of being solubilized in H2O. The RNA samples were converted to cDNA using the GB-Script™ III First Strand cDNA Synthesis Kit (+ gDNA Cleanser) (catalog number R312-01). For the GB-Amp™ Sybr Green qPCR Mixture (catalog number P2092), use 5 ng / reaction cDNA template and 1 uM primers: cyp1b1 (forward: 5'-GCCACTATCACTGACA TCTTCGG-3', reverse: 5'-CACGACCTGATCCAATTCTGCC-3'), cyp1a1 (forward: 5'-GATTGAGCACTGTCAGGAGAAGC-3', reverse: 5'-ATGAGGCTCCAGGAGATAGCAG-3'), krt16 (forward: 5'-CTACCT GAGGAAGAACCACGAG-3', reverse: 5'-CTCGTACTGGTCACGCA The genes involved include TCTCA-3', homx-1 (forward: 5'-CCAGGCAGAGAATGCTGAGTTC-3', reverse: 5'-AAGACTGGGCTCTCCTTGTTGC-3'), gclm (forward: 5'-TCTTGCCTCCTGCTGTGTGATG-3', reverse: 5'-TTGGAAACTTGCTTCAGAAAGCAG-3'), and the housekeeping gene gapdh (forward: 5'-GTCTCCTCTGACTTCAACAGCG-3', reverse: 5'-ACCACCCTGTTGCCTGTAGCCAA-3'). Temperature profiles were performed at 95°C for 2 minutes, 95°C for 15 seconds, and 60°C for 1 minute, for 40 cycles. Results are shown in... Figure 1-3 middle.

[0135] Example 8 Internal effects Atopic dermatitis-like state was induced in the ears of female C57BL / 6 mice by topical application of MC903 (calcipotriol). In the inflammation-dominant model, MC903 (1 nmol in 100% ethanol) was applied topically daily for 7 days, starting on day 0. Compound 4 was applied topically daily in DMSO three hours after MC903 administration. Body weight was measured daily before administration. On day 7, animals were sacrificed and ear tissue was collected. Half of the tissue was incubated overnight at -20°C in RNAlater for the detection of TSLP and β-actin by quantitative real-time PCR (qPCR).

[0136] In a model dominated by barrier dysfunction, starting on day 0, MC903 (in 100% ethanol) was topically applied to the ears of female C57BL / 6 mice at a concentration of 2 nmol for 5 consecutive days. After 5 days of induction, the MC903 application was switched to a maintenance dose of 1 nmol every other day, while compound 4 was topically applied daily 3 hours after MC903 application. Ear thickness and body weight were measured daily before administration. On day 12, mice were sacrificed and ear tissue was collected. Half of the tissue was incubated overnight at -20°C in RNAlater for quantitative real-time PCR (qPCR) detection of filaggrin (FLG) and GAPDH.

[0137] Compound 4 demonstrated the effect of inhibiting TSLP gene expression in the ear in an inflammation-dominated model. Figure 4 Compound 4 showed results in reducing ear thickness and increasing filaggrin gene expression in a barrier dysfunction model. Figure 5 and 6 middle.

[0138] The results showed that compound 4 significantly reduced ear swelling and TSLP signaling, while significantly increasing gene expression of filaggrin, a barrier protein regulated by AhR, without significantly affecting body weight. Figure 7 ).

[0139] All publications, patents and patent applications cited above are incorporated herein by reference in their entirety, to the same extent that each individual publication, patent or patent application is specifically and individually indicated as incorporated herein by reference in its entirety.

[0140] Although preferred embodiments of the invention have been described in detail herein, those skilled in the art will understand that modifications may be made thereto without departing from the spirit of the invention or the scope of the appended claims.

Claims

1. A compound of formula (I): （I） It exists in hydrated form, anhydrous form, or salt form; Where M is Ag, and n is 1, 2, or 3; X is a bidentate ligand, and each X independently is: （i） in A 1 and A 2 Each can be CH, N, or SH independently; Each R 1 R 2 or R 3 Independently -H, optionally having one or more heteroatoms C 1-9 Substituents, -OR 4 -SR 4 -N(R) 4 )2、-C(=O)NR 4 -NC(=O)R 4 -C(=O)R 4 -C(=O)OR 4 Or halogen, or R 1 and R 2 Together they form a C5 or C6 membered ring having one or more heteroatoms, said C5 or C6 membered ring being optionally divided by C 1-3 Alkyl, C 1-3 Alkoxy, phenyl, -N(R) 4 )2、-C(O)R 4 -COOR 4 Or halogen mono- or di-substituted; and wherein when A 1 and A 2 When neither is CH, R 3 It does not exist; Each R 4 It is independently -H or optionally has one or more heteroatoms. 1-3 Substituents; D 1 and D 2 Each is independently -H, -OH, -N(R) 5 )2、-SH、-CO2R 6 or -C(=O)R 7 If D 1 Or D 2 If one of them is -H, then the other is D. 1 Or D 2 Not -H, Each R 5 Independently -H, C 1-3 alkyl, or Or two Rs 5 Together , R 6 yes (-) (Non-existent and negatively charged), -H or C 1-3 alkyl; R 7 It is a -H, -C1-C5 substituent or aryl group, wherein the -C1-C5 substituent or aryl group optionally has one or more heteroatoms; R 8 It is a C with -H, -OH, or optionally one or more heteroatoms. 1-3 Alkyl substituents, optionally having one or more heteroatoms -OC 1-3 Alkyl substituents or halogens; and R 9 It is -H or optionally has one or more heteroatoms. 1-3 Alkyl substituents; (ii) in A 11 and A 12 Each can be either -CH or N independently; R 11 and R 12 Each is independently a -H, optionally having one or more heteroatoms. 1-3 Substituents, -OC 1-3 Substituents or halogens; ------ Is it a single bond or a double bond, and ------ A 14 and ------ R 14 In ------ Only one of them is a double bond; When A 13 With R 13 Between ------ When it is a single bond, A 13 It is CH or N, and R 13 It is -H, When A 13 With R 13 Between ------ When it is a double bond, A 13 It is C, and R 13 It is CH y , where y is 1 or 2; and when y is 1, CH is coupled with substituted or unsubstituted aryl or heteroaryl groups; when ------ A 14 of ------ When it is a single bond, A 14 It is NH or CH2. when ------ A 14 of ------ When it is a double bond, A 14 Is it N or CR? 15 , where R 15 It is -C(=O)- coupled with substituted or unsubstituted heteroaryl groups; when ------ R 14 of ------ When it is a single bond, R 14 It is -H, -COO (-) or -S(=O)R 16 , where R 16 CH is optionally coupled with substituted or unsubstituted aryl or heteroaryl groups. z , where z is 1, 2 or 3; when ------ R 14 of ------ When it is a double bond, R 14 Is it O or S? (iii) in A 21 It is N, and A 22 To A 27 Each of them is independently -CH or N; R 21 Yes - OR 24 or -SR 25 , where R 24 or R 25 It does not exist, is -H, -C1-C3 alkyl or aryl, and R 22 and R 23 Each is independently a -H, optionally having one or more heteroatoms. 1-3 Substituents, halogens, or R 22 and R 23 Together they form a C5 or C6 aromatic ring, wherein the C5 or C6 aromatic ring is optionally surrounded by a C1-C3 alkyl group, a C1-C3 alkoxy group, or a -NR group. 26 2. -C(O)R 27 -COOR 28 -CHO or halogen mono- or di-substituted; Where R 26 To R 28 Each of them is independently -H, -C1-C3 alkyl, or aryl; or (iv) in A 31 It consists of elements from groups 16 to 17; and Each R 31 Independently, they are -H, -CO2H, and -CO2. - -OC(=O)-C 1-6 Alkyl group, -C(=O)NH2, -CO(CH2) 1-6 CHNH2CO2 - -CO(CH2) 1-6 CHNH2CO2H、-CONH2(CH2) 1-6 CH3、-CONH2(CH2) 1-6 CH3, =O, -O - OH, -C 3-6 Alkyl ketones, -C 3-6 Alkoxy, NO3 - NO3H, NO2 - NO2H, NH2, -NH(CH2) 1-6 CH3、-N((CH2) 1-6 CH3)2, SH, S-alkyl, -C5-C 10 Substituents or aryl groups, wherein the -C5-C 10 The substituent or aryl group may optionally have one or more heteroatoms; SO2 alkyl, SO3H, SO3 having 3-6 carbon atoms and optionally one or more oxygen or nitrogen atoms. - Halogens, CN; and p is 1 to 4; and in This indicates the coordination bond between the ligand and Ag.

2. The compound according to claim 1, in its hydrated form, anhydrous form, or salt form, wherein at least one X is: , , , , , , , , , , , , , , , or , in This indicates the potential chelation point between the bidentate ligand and Ag.

3. The compound according to claim 1 or 2, in its hydrated form, anhydrous form, or salt form, wherein at least one X is: , , or , in This indicates the potential chelation point between the bidentate ligand and Ag.

4. The compound according to any one of claims 1 to 3, in its hydrated, anhydrous, or salt form, wherein at least one X is: ， in This indicates the potential chelation point between the bidentate ligand and Ag.

5. The compound according to any one of claims 1 to 4, in its hydrated, anhydrous, or salt form, wherein the compound of formula (I) is: , , , , , , , , , , , , , , , , , , , , , , or (No water).

6. The compound of formula (I) according to any one of claims 1 to 5, its hydrated form, anhydrous form or salt thereof, has a minimum solubility of 0.1 nM in an aqueous medium at neutral pH, 25°C and 1 bar.

7. The compound of formula (I) according to any one of claims 1 to 5, its hydrated form, anhydrous form or salt thereof, has a minimum solubility of 0.1 µM in an aqueous medium at 25°C.

8. The compound of formula (I) according to any one of claims 1 to 5, its hydrated form, anhydrous form or salt thereof, has a minimum solubility of 0.1 µM in a non-aqueous medium at neutral pH, 25°C and 1 bar.

9. The compound of formula (I) according to any one of claims 1 to 5, its hydrated form, anhydrous form or salt thereof, has a minimum solubility of 1.0 μM in a non-aqueous medium at 25°C.

10. The compound of formula (I) according to claim 8 or 9, its hydrated form, anhydrous form or salt thereof, wherein the non-aqueous medium is dimethyl sulfoxide (DMSO).

11. The formation constant of the compound of formula (I) according to any one of claims 1 to 10, its hydrated form, anhydrous form or salt thereof, determined at neutral pH, 25°C and 1 bar. K f The range is 1.0 x 10 5 Up to 1.0 x 10 35 .

12. The formation constant of the compound of formula (I) according to any one of claims 1 to 10, its hydrated form, anhydrous form or salt thereof, determined at neutral pH, 25°C and 1 bar. K f The range is 1.0 x 10 5 Up to 1.0 x 10 25 .

13. The formation constant of the compound of formula (I) according to any one of claims 1 to 10, its hydrated form, anhydrous form or salt thereof, determined at neutral pH, 25°C and 1 bar. K f The range is 1.0 x 10 10 Up to 1.0 x 10 25 .

14. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 13, in its hydrated form, anhydrous form, solvated form or a salt thereof, and a pharmaceutically acceptable excipient.

15. Use of a compound of formula (I) according to any one of claims 1 to 13, in its hydrated form, anhydrous form, solvated form or a salt thereof, for the treatment of diseases associated with activation of the aryl hydrocarbon receptor (AhR).

16. Use of a compound of formula (I) according to any one of claims 1 to 13, in its hydrated form, anhydrous form, solvated form or a salt thereof, for modulating the activity of an aromatic hydrocarbon acceptor (AhR).

17. A pharmacological treatment for a disease associated with activation of aryl hydrocarbon receptor (AhR) activity, the method comprising administering to a subject thereto a pharmaceutically effective amount of a compound of formula (I) according to any one of claims 1 to 13, in its hydrated form, anhydrous form, solvated form, or a salt thereof.

18. A method for regulating the activity of an aromatic hydrocarbon acceptor (AhR), the method comprising providing a compound of formula (I) according to any one of claims 1 to 13, in its hydrated form, anhydrous form, solvated form, or a salt thereof.

19. A method for preparing a compound of formula (I), its hydrated form, anhydrous form, solvated form, or a salt thereof, said method comprising: The silver salt or silver compound having chelated ligands is reacted with one or more ligands in a solvent.

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