Alpha, beta unsaturated ketone substituted chromone derivative and medicinal application thereof

Abstract

The invention discloses an alpha, beta unsaturated ketone substituted chromone derivative of which the structure is shown as a formula I or pharmaceutically acceptable salt and isomer I thereof. The compound can realize efficient selective inhibition on a BLT1 receptor through a specific molecular action mechanism, shows nanomole-level BLT1 inhibition activity and excellent selectivity, and meanwhile, shows a remarkable treatment effect in acute lung injury, chronic obstructive pulmonary disease and sepsis models. The invention discloses an application of the alpha, beta unsaturated ketone substituted chromone derivative or the pharmaceutically acceptable salt and isomer thereof in preparation of a BLT1 inhibitor, and also discloses an application of the alpha, beta unsaturated ketone substituted chromone derivative or the pharmaceutically acceptable salt and isomer thereof in preparation of the BLT1 inhibitor. The invention discloses an application of the alpha, beta unsaturated ketone substituted chromone derivative or the pharmaceutically acceptable salt and isomer thereof in preparation of medicines for treating acute lung injury, chronic obstructive pulmonary disease and sepsis, and also discloses an application of the alpha, beta unsaturated ketone substituted chromone derivative or the pharmaceutically acceptable salt and isomer thereof in preparation of medicines for treating acute lung injury, chronic obstructive pulmonary disease and sepsis.

Description

Technical Field

[0001] This invention relates to an α,β-unsaturated ketone-substituted chromogen derivative and its pharmaceutical uses. Background Technology

[0002] Macrophages are core effector cells of the innate immune system, playing a decisive role in the pathological process of inflammatory diseases. Macrophages are integrated into a key inflammatory positive feedback regulatory pathway through the high-affinity receptor BLT1, which specifically overexpresses leukotriene B4 (LTB4). Once activated by its ligand, the BLT1 receptor not only mediates the directed chemotaxis and recruitment of macrophages to sites of inflammation, but more importantly, it drives them towards classical activation (M1 type) polarization. This process leads to a significant upregulation of the transcription and secretion of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6, and synergistically enhances the production of reactive oxygen species (ROS) and nitric oxide (NO), thereby creating a self-amplifying "cytokine storm."

[0003] The macrophage-BLT1 signaling axis constitutes a core pathogenic link in the development of various acute and chronic inflammatory diseases. In acute lung injury (ALI), BLT1-mediated macrophage overactivation sustainably damages the tight junctions between alveolar epithelium and pulmonary vascular endothelium, as well as the integrity of the basement membrane, disrupting the alveolar-capillary barrier function. This is a crucial cytopathological basis for protein-rich pulmonary edema and refractory hypoxemia. In the context of sepsis and sepsis-related organ failure, this signaling pathway drives uncontrolled macrophage activation, triggering a systemic cytokine storm and directly attacking the microvascular system of distal organs such as hepatic sinusoids and peritubular capillaries of the kidneys, exacerbating endothelial leakage, microthrombus formation, and impaired tissue perfusion. During acute exacerbations of chronic obstructive pulmonary disease (COPD), BLT1 signaling can work in conjunction with other inflammatory mediators to promote the transformation of alveolar macrophages into a phenotype that highly secretes pro-inflammatory factors and matrix metalloproteinases (MMPs), thereby exacerbating airway mucus hypersecretion, smooth muscle hyperplasia, extracellular matrix degradation in lung tissue, and emphysema-like lesions.

[0004] The macrophage-BLT1 signaling pathway plays an upstream regulatory role in the inflammatory cascade, and its overactivation is a key factor driving the pathophysiological processes of various critical diseases. Therefore, developing highly selective BLT1 receptor antagonists to precisely intervene in abnormal macrophage activation and inflammatory phenotypes is crucial. Selective BLT1 receptor antagonists hold promise for intervening in the early stages of the inflammatory response, blocking or mitigating subsequent tissue damage and organ dysfunction. Clinically, they are applicable to the treatment of inflammatory diseases such as acute lung injury, chronic obstructive pulmonary disease, and sepsis, representing significant drug discovery potential.

[0005] BLT1 is a key protein regulating acute inflammatory responses; selectively blocking its signaling can effectively inhibit excessive inflammatory responses and reduce tissue damage. Over the past few decades, several selective BLT1 inhibitors (such as etalocib, amelubant, and moxilubant maleate) have been developed and entered clinical trials for treatments of asthma, chronic obstructive pulmonary disease, and inflammatory bowel disease. However, these candidates have all been discontinued in clinical trials due to insufficient efficacy, lack of selectivity, or adverse reactions. To date, no highly selective BLT1 inhibitor has been successfully marketed for clinical treatment.

[0006] Recent discoveries about the molecular mechanisms of BLT1 inhibitors have provided important insights for designing highly selective inhibitors. Therefore, developing next-generation BLT1 inhibitors with novel structures, high activity, high selectivity, and good safety profiles holds significant promise for meeting the clinical needs of major inflammatory diseases such as acute lung injury, chronic obstructive pulmonary disease, and sepsis, and has significant clinical translational and pharmaceutical value. Summary of the Invention

[0007] The purpose of this invention is to provide a chromogen, an α,β-unsaturated ketone-substituted chromogen derivative with highly efficient and selective BLT1 inhibitory activity. This invention also provides a method for preparing the α,β-unsaturated ketone-substituted chromogen derivative and its application in the preparation of BLT1 inhibitors and in the treatment of acute lung injury, chronic obstructive pulmonary disease and sepsis.

[0008] The objective of this invention is achieved through the following technical solution:

[0009] α,β-unsaturated ketone-substituted chromogen derivatives or their pharmaceutically acceptable salts or isomers as shown in Formula I:

[0010]

[0011] I;

[0012] Where: R 1 R 2 R3 Independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C6 allyl, C2-C6 ynyl, C1-C3 haloalkyl, C3-C8 heterocycloalkyl, C6-C 10 Aryl, C3-C 10 Heteroaryl or C3-C8 heterocyclic aryl;

[0013] The C6-C mentioned 10 Aryl, C3-C 10 The hydrogen atoms of the heteroaryl or C3-C8 heterocyclic aryl group are independently and optionally replaced by one or more groups selected from halogen, hydroxyl, amino, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylsulfonic acid, C3-C6 cycloalkyl, C3-C6 cycloalkyl ester, C6-C 10 Substituted with aryl, C3-C6 cycloalkyloxy or C4-C8 heterocyclic groups;

[0014] R 4 Selected from H, OH, and C1-C6 alkoxy groups;

[0015] R 5 Selected from H, C1-C6 alkyl, C1-C6 haloalkyl or X is OC(O) (i.e. ) or O(CH2) n (Right now ); n is an integer from 1 to 8.

[0016] Preferred, R 1 The phenyl group is selected from methyl, cyclopropyl, substituted or unsubstituted phenyl, 2-thienyl, 5-benzofuranyl, 4-pyridyl, and the phenyl group is methyl, methoxy, fluorine, chlorine, bromine, cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, phenyl, ethylsulfonic acid, cyclohexylcarboxylate, and the number of phenyl substituents is 1 to 3.

[0017] R 2 It is selected from H, methyl, substituted or unsubstituted phenyl, 2-furanyl, wherein the phenyl substituent is methyl, methoxy, or chlorine, and the number of phenyl substituents is 1 to 3;

[0018] R 3 Selected from H, methyl, or 4-methoxyphenyl;

[0019] R 4 Selected from H or OH;

[0020] R 5 Selected from H or X is selected from O(CH2). n n is an integer from 2 to 6;

[0021] But excluding: R 1 Selected from phenyl, R 2 Selected from phenyl, R 3 Selected from H, R 4 Selected from H, R 5 Selected from OH;R 1 Selected from 4-methoxyphenyl, R 2 Selected from 3-methylphenyl, R 3 Selected from H, R 4 Selected from H, R 5 Selected from OH;R 1 Selected from phenyl, 4-methoxyphenyl, 4-chlorophenyl, R 2 Selected from methyl, R 3 Selected from methyl, R 4 Selected from H, R 5 Selected from OH.

[0022] Further preferred, R 1 Selected from methyl, cyclopropyl, phenyl, 4-methylphenyl, 4-methoxyphenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-cyanophenyl, 4-nitrophenyl, 4-hydroxyphenyl, 2-thienyl, 4-trifluoromethylphenyl, 3,4-dimethoxyphenyl, 4-tert-butylphenyl, 3,4,5-trimethoxyphenyl, 4-phenylphenyl, 4-ethylsulfonic acid phenyl, 4-cyclohexylcarboxylate phenyl, 5-benzofuranyl, 4-pyridyl or 3-trifluoromethoxyphenyl;

[0023] R 2 Selected from H, methyl, phenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, 2-furanyl, 3,4-dimethoxyphenyl, 4-chlorophenyl, 3-methoxy-4-methylphenyl or 3,4,5-trimethoxyphenyl;

[0024] R 3 Selected from H, methyl, or 4-methoxyphenyl;

[0025] R 4 Selected from H or OH;

[0026] R 5 Selected from H or X is selected from O(CH2). n n is 2, 4, or 6;

[0027] But excluding: R 1 Selected from phenyl, R 2 Selected from phenyl, R 3 Selected from H, R 4 Selected from H, R 5 Selected from OH;R 1 Selected from 4-methoxyphenyl, R 2Selected from 3-methylphenyl, R 3 Selected from H, R 4 Selected from H, R 5 Selected from OH;R 1 Selected from phenyl, 4-methoxyphenyl, 4-chlorophenyl, R 2 Selected from methyl, R 3 Selected from methyl, R 4 Selected from H, R 5 Selected from OH.

[0028] Further optimized, R 1 Selected from phenyl, 4-bromophenyl, 4-cyanophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 4-tert-butylphenyl, 4-phenylphenyl, 4-ethylsulfonic acid phenyl; R 2 Selected from phenyl, 4-methoxyphenyl, 4-methylphenyl, 2-furanyl, and 3,4-dimethoxyphenyl;

[0029] R 3 Selected from H;

[0030] R 4 Selected from OH;

[0031] R 5 Selected from H or X is selected from O(CH2). n n is 2, 4, or 6.

[0032] The following are α,β-unsaturated ketone-substituted chromogen derivatives or their pharmaceutically acceptable salts or isomers:

[0033]

[0034]

[0035]

[0036] As a preferred embodiment of the present invention, α,β-unsaturated ketone-substituted chromogen derivatives or their pharmaceutically acceptable salts or isomers, as shown in Formula I, are used.

[0037]

[0038] I;

[0039] Where: R 1 Selected from 4-trifluoromethylphenyl; R 2 Selected from phenyl; R 3 Selected from H;R 4 Selected from OH;R 5 Selected from X is selected from O(CH2). nn is an integer from 2 to 6.

[0040] Preferably, n is 2, 4 or 6.

[0041] The pharmaceutically acceptable salt of the α,β-unsaturated ketone-substituted chromogen derivative is a salt formed by the α,β-unsaturated ketone-substituted chromogen derivative with an acid, a metal ion, or a pharmaceutically acceptable amine, ammonium ion, or choline.

[0042] The acids mentioned include, but are not limited to: methanesulfonic acid, neopentanoic acid, terephthalic acid, thiocyanate, cholic acid, n-dodecyl sulfuric acid, benzenesulfonic acid, citric acid, D-glucose, glycolic acid, lactic acid, malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulfuric acid, tartaric acid, succinic acid, formic acid, hydroiodic acid, hydrobromic acid, methanesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharinic acid, salicylic acid, gentian acid, p-toluenesulfonic acid, valeric acid, palmitic acid, sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid, carbonic acid, 4-benzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid, fumaric acid, 3-hydroxynaphthalene-2-carboxylic acid, 1-hydroxynaphthalene-2-carboxylic acid, oleic acid, undecenoic acid, ascorbic acid, camphoric acid, camphorsulfonic acid, dichloroacetic acid, and ethanesulfonic acid.

[0043] The metal ions mentioned include, but are not limited to, sodium, potassium, calcium, and magnesium.

[0044] The pharmaceutically acceptable amines include, but are not limited to, triethylamine, ethylenediamine, and tromethamine.

[0045] A method for preparing α,β-unsaturated ketone-substituted chromogen derivatives, wherein the chromogen synthesis routes include route 1, route 2, route 3, and route 4.

[0046] The synthesis route for Route 1 is as follows:

[0047] ;

[0048] Among them, R 1 R 2 R 4 As mentioned above, preferably, R 4 Selected from H, OH, and C1-C6 alkoxy groups;

[0049] Route 1 includes the following steps:

[0050] Step (1): The ethyl ketone derivative shown in Formula II reacts with a brominating reagent to generate intermediate III;

[0051] Step (2): Intermediate III reacts with triphenylphosphine and generates phosphine ylide as shown in Formula IV under alkaline conditions;

[0052] Step (3): Under alkaline conditions, 2,4-dihydroxyacetophenone of formula V reacts with methoxymethyl bromide (MOMBr) to generate intermediate VI;

[0053] Step (4): Under alkaline conditions, intermediate VI and formula The aromatic aldehyde shown underwent an Adol condensation reaction to give compound VII;

[0054] Step (5): Using I2 as a catalyst, catalyze compound VII to generate the chromone derivative shown in formula VIII;

[0055] Step (6): Under acidic conditions, the chromogen derivative reacts with hexamethylenetetramine (HXMT) in a Duff reaction to generate an aldehyde-substituted chromogen as shown in Formula IX;

[0056] Step (7): The aldehyde-substituted chromone reacts with the phosphine ylide shown in Formula IV to obtain the target compound shown in Formula I;

[0057] In step (1), the molar ratio of the ethyl ketone derivative to the brominated reagent is 1:1 to 1:1.5, preferably 1:1.2.

[0058] The brominating reagent is selected from N-bromosuccinimide, copper bromide, and liquid bromine, preferably copper bromide; the reaction solvent is selected from chloroform, ethyl acetate, dichloromethane, petroleum ether, and chloroform / ethyl acetate (v / v = 1:1), preferably chloroform / ethyl acetate (v / v = 1:1).

[0059] The reaction temperature is 40-100℃, preferably 70-80℃.

[0060] In step (2), the molar ratio of intermediate III to triphenylphosphine is 1:1 to 1:1.5, preferably 1:1.

[0061] The reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, chloroform, ethyl acetate, dichloromethane, petroleum ether, and methanol, with dichloromethane being preferred.

[0062] The alkaline conditions are provided by an alkali; the alkali is selected from potassium phosphate, potassium carbonate, sodium carbonate, cesium carbonate, potassium fluoride, potassium acetate, sodium acetate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, or sodium tert-butoxide, preferably sodium hydroxide.

[0063] The reaction temperature is 25-100℃, preferably 25-40℃.

[0064] In step (3), the molar ratio of 2,4-dihydroxyacetophenone or 2,4,6-trihydroxyacetophenone to MOMBr is 1:1 to 1:1.5, preferably 1:1.2.

[0065] The reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, chloroform, ethyl acetate, dichloromethane, petroleum ether, and methanol, with dichloromethane being preferred.

[0066] The alkaline conditions are provided by an alkali; the alkali is selected from potassium phosphate, N,N-diisopropylethylamine, triethylamine, potassium carbonate, sodium carbonate, cesium carbonate, potassium fluoride, potassium acetate, sodium acetate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, or sodium tert-butoxide, preferably N,N-diisopropylethylamine.

[0067] The reaction temperature is 25-100℃, preferably 25-40℃.

[0068] In step (4), the molar ratio of intermediate VI to aromatic aldehyde is 1:1 to 1:1.5, preferably 1:1.2.

[0069] The aromatic aldehyde is selected from benzaldehyde, 3-methylbenzaldehyde, 4-methylbenzaldehyde, furfural, 3,4-dimethoxybenzaldehyde, 3,4,5-trimethoxybenzaldehyde, 4-chlorobenzaldehyde, 3-methoxy-4-methylbenzaldehyde, or 4-fluorobenzaldehyde.

[0070] The reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, perfluoroisopropanol, n-butanol or tert-butanol, with ethanol being preferred.

[0071] The alkaline conditions are provided by an alkali; the alkali is selected from potassium phosphate, potassium carbonate, sodium carbonate, cesium carbonate, potassium fluoride, potassium acetate, sodium acetate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, or sodium tert-butoxide, preferably potassium hydroxide; the reaction temperature is 25-100℃, preferably 25-40℃.

[0072] In step (5), the amount of iodine used is the catalytic amount. Generally, the molar ratio of iodine to compound VII is 0.02:1.

[0073] The reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, perfluoroisopropanol, n-butanol or tert-butanol methanol, preferably dimethyl sulfoxide.

[0074] The reaction temperature is 100-200℃, preferably 150-180℃.

[0075] In step (6), the molar ratio of intermediate VIII to hexamethylenetetramine is 1:1 to 1:5, preferably 1:3.

[0076] The reaction solvent is selected from formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid or hydrofluoric acid, preferably acetic acid; the reaction temperature is 100-200℃, preferably 90-120℃.

[0077] In step (7), the molar ratio of the aldehyde-substituted chromone to the phosphine ylide is 1:1 to 1:1.5, preferably 1:1.2.

[0078] The reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, chloroform, ethyl acetate, dichloromethane, petroleum ether, and methanol, with dichloromethane being preferred.

[0079] The reaction temperature is 25-100℃, preferably 25-40℃.

[0080] Route 2 is R 2 Selected from methyl, R 3 Selected from methyl, R 5 The synthetic route for the target compound selected from H is as follows:

[0081] ;

[0082] Among them, R 1 R 4 As mentioned above;

[0083] Route 2 includes the following steps:

[0084] Step (1): In the presence of acetic anhydride and sodium acetate, 2,4-dihydroxyphenylacetones with different substitutions shown in Formula X react with chromone derivatives shown in Formula XI under reflux conditions. In this process, 2,4-dihydroxyphenylacetones with different substitutions shown in Formula X first generate acetylated chromone intermediates, and then deacetylate them under alkaline conditions to generate chromone derivatives shown in Formula XI.

[0085] Step (2): Using organic acid as the reaction solvent, under acidic conditions, the chromogen derivative reacts with hexamethylenetetramine in a Duff reaction to generate an aldehyde-substituted chromogen as shown in formula XII.

[0086] Step (3): The aldehyde-substituted chromone reacts with the phosphine ylide shown in Formula IV to obtain the target compound shown in Formula I.

[0087] In step (1), the molar ratio of the different substituted 2,4-dihydroxyphenylacetone to sodium acetate is 1:1-1:8, preferably 1:5; the molar ratio of the different substituted 2,4-dihydroxyphenylacetone to acetic anhydride is 1:20-1:100, preferably 1:44.

[0088] The alkaline conditions are provided by an alkali; the alkali is selected from potassium phosphate, potassium carbonate, sodium carbonate, cesium carbonate, potassium fluoride, potassium acetate, sodium acetate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, or sodium tert-butoxide, preferably sodium hydroxide.

[0089] The reaction temperature is 100-200℃, preferably 90-120℃.

[0090] In step (2), the molar ratio of intermediate XI to hexamethylenetetramine is 1:1 to 1:5, preferably 1:3.

[0091] The reaction solvent is selected from formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid or hydrofluoric acid, preferably acetic acid.

[0092] The temperature for the Duff reaction is 100-200℃, preferably 90-120℃.

[0093] In step (3), the molar ratio of the aldehyde-substituted chromone to the phosphine ylide is 1:1 to 1:1.5, preferably 1:1.2.

[0094] The reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, chloroform, ethyl acetate, dichloromethane, petroleum ether, and methanol, with dichloromethane being preferred.

[0095] The reaction temperature is 25-100℃, preferably 25-40℃.

[0096] Route 3 is R 2 Selected from methyl, R 3 Selected from 4-methoxyphenyl, R 4 Selected from H, R 5 The synthetic route for the target compound selected from H, route 3, is as follows:

[0097] ;

[0098] Among them, R 1 As mentioned above;

[0099] Route 3 includes the following steps:

[0100] Step (1): Under nitrogen protection, in the presence of boron trifluoride ether and Vilsmeier reagent, the m-diphenol of formula XIII reacts with 4-methoxyphenylpropionic acid of formula XIV to generate the isoflavone derivative shown in XV.

[0101] Step (2): Using organic acid as the reaction solvent, under acidic conditions, the isoflavone derivative reacts with hexamethylenetetramine in a Duff reaction to generate an aldehyde-substituted chromone as shown in formula XVI.

[0102] Step (3): The aldehyde-substituted isoflavone reacts with the phosphine ylide shown in Formula IV to obtain the target compound shown in Formula I.

[0103] In step (1), the molar ratio of m-diphenol to 4-methoxyphenylpropionic acid is 1:1; the molar ratio of m-diphenol to boron trifluoride ether is 1:1-1:5, preferably 1:5; and the molar ratio of m-diphenol to Wilsmer reagent is 1:1-1:2, preferably 1:1.5.

[0104] The reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, chloroform, ethyl acetate, dichloromethane, petroleum ether, and methanol, with N,N-dimethylformamide being preferred.

[0105] The reaction temperature is 25-100℃, preferably 50-60℃.

[0106] In step (2), the molar ratio of the isoflavone derivative to hexamethylenetetramine is 1:1 to 1:5, preferably 1:3.

[0107] The reaction solvent is selected from formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid or hydrofluoric acid, with acetic acid being preferred; the reaction temperature of Duff is 100-200℃, preferably 90-120℃.

[0108] In step (3), the molar ratio of the aldehyde-substituted chromone to the phosphine ylide is selected from 1:1 to 1:1.5, preferably 1:1.5.

[0109] The reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, chloroform, ethyl acetate, dichloromethane, petroleum ether, and methanol, with dichloromethane being preferred.

[0110] The reaction temperature is 25-100℃, preferably 25-40℃.

[0111] The synthesis route for route 4 is as follows:

[0112] ;

[0113] Among them, R 1 R 2 R 3 R 4 As mentioned earlier, R 5 Selected from X and n are as described above;

[0114] Preferred, R 1 Selected from 4-trifluoromethylphenyl, 4-cyanophenyl, R 2 Selected from methyl, R 3 Selected from methyl, R 4 Selected from H, or R 1 Selected from 4-trifluoromethylphenyl, R 2 Selected from phenyl, R 3 Selected from H, R4 Selected from OH.

[0115] Route 4 includes reacting the compound shown in Formula VXI with the compound shown in Formula XVII under alkaline conditions to obtain the target compound shown in Formula I.

[0116] The molar ratio of the compound represented by formula VXI to the compound represented by formula XVII is 1:1 to 1:1.5, preferably 1:1.

[0117] The reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, chloroform, ethyl acetate, dichloromethane, petroleum ether, and methanol, with N,N-dimethylformamide being preferred.

[0118] The reaction temperature is 25-100℃, preferably 55-70℃.

[0119] Invention Principle: Currently, no highly selective BLT1 inhibitors have been successfully applied clinically to treat acute lung injury, chronic obstructive pulmonary disease (COPD), and sepsis. The key to this invention lies in the discovery of a novel class of compounds based on α,β-unsaturated ketone-substituted chromone structures. These compounds achieve highly efficient and selective inhibition of the BLT1 receptor through a specific molecular mechanism of action. The resulting α,β-unsaturated ketone-substituted chromone derivatives exhibit nanomolar-level BLT1 inhibitory activity and excellent selectivity, while also demonstrating significant therapeutic effects in acute lung injury, COPD, and sepsis models, providing a novel structural type for the development of novel anti-inflammatory drugs.

[0120] The use of the α,β-unsaturated ketone-substituted chromone derivatives or their pharmaceutically acceptable salts or isomers in the preparation of BLT1 inhibitors according to the present invention.

[0121] The use of the α,β-unsaturated ketone-substituted chromone derivatives or their pharmaceutically acceptable salts or isomers described in this invention in the preparation of medicaments for treating acute lung injury, chronic obstructive pulmonary disease, and sepsis.

[0122] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of an α,β-unsaturated ketone-substituted chromone derivative or a pharmaceutically acceptable salt thereof or an isomer thereof, and a pharmaceutically acceptable carrier.

[0123] Therapeutic effective amount can be an amount that, to some extent, alleviates one or more symptoms of a disease or condition in the subject, partially or completely restores one or more physiological or biochemical parameters related to or caused by the disease or condition to normal, and / or reduces the likelihood of the onset of the disease or condition; pharmaceutically acceptable carrier refers to an excipient or diluent that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the compound given.

[0124] The pharmaceutically acceptable excipients are selected from one or more of fillers, disintegrants, binders, and lubricants. This includes, but is not limited to, any and all solvents, dispersion media, coatings, absorption delay agents, etc., such media and agents are used for the application of pharmaceutically active substances in the art.

[0125] Compared with the prior art, the present invention has the following significant advantages:

[0126] (1) The α,β-unsaturated ketone-substituted chromone derivatives provided by the present invention have efficient and selective BLT1 inhibitory activity, and show significant anti-inflammatory effects in acute lung injury and sepsis models. They can effectively improve lung tissue pathological damage, reduce inflammatory factor levels, and improve animal survival rate. They also have excellent oral bioavailability and good drug safety.

[0127] (2) The synthetic route of the compound described in this invention is simple, with few steps, mild reaction conditions, and easy post-processing. The key intermediates and raw materials are readily available, making it suitable for large-scale preparation and possessing good industrialization prospects. Attached Figure Description

[0128] Figure 1 This is a schematic diagram showing the in vivo efficacy of compound 59 in an acute lung injury model; where A represents the animal administration period, B represents the dry / wet weight ratio of mouse lung tissue, and C represents the detection results of lung tissue pathology and RAGE expression.

[0129] Figure 2 This is a schematic diagram showing the in vivo efficacy of compound 59 in a septic lung injury model; where A represents the animal administration time period, B represents the survival curve of mice after 36 hours, C represents the dry / wet weight ratio of mouse lung tissue, D represents the expression level of TNF-α in lung tissue, E represents the expression level of IL-1β in lung tissue, E represents the expression level of IL-6 in lung tissue, G represents the pathological examination results of lung tissue, and H represents the detection results of re-RAGE expression in lung tissue.

[0130] Figure 3Figure 1 shows the in vivo efficacy results of compound 59 in a chronic obstructive pulmonary disease model; where A to C represent the expression levels of IL-6, TNF-α, and IL-1β in lung tissue, respectively; and D to I represent the minute ventilation, expiratory time, peak expiratory flow rate, airway stenosis index, peak expiratory time ratio, and peak inspiratory flow rate of mice, respectively.

[0131] Figure 4 This is a schematic diagram of the safety evaluation of compound 59; where A is the organ coefficient diagram of female mice after administration of compound 59, and B is the organ coefficient diagram of male mice after administration of compound 59.

[0132] Figure 5 This is a schematic diagram of HE staining results; where A is the HE staining image of various tissues in female mice, and B is the HE staining image of various tissues in male mice. Detailed Implementation

[0133] The technical solution of the present invention will be specifically described below through embodiments.

[0134] Example 1

[0135] Acetophenone (1.20 g, 0.01 mol) and copper(II) bromide (4.47 g, 0.02 mol) were dissolved in a mixed solvent of chloroform and ethyl acetate (chloroform to ethyl acetate volume ratio = 1:1, 30 mL). The mixture was heated under reflux for 6 hours, and the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the reaction system was cooled to room temperature, and excess copper(II) bromide was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by normal-phase silica gel column chromatography (elution with petroleum ether / ethyl acetate volume ratio of 3:1 to 1:3) to give α-bromoacetophenone in 68% yield.

[0136] α-Bromoacetophenone (1.99 g, 10 mmol) was dissolved in dichloromethane (20 mL), and triphenylphosphine (2.62 g, 10 mmol) was added. The mixture was stirred at room temperature for 24 hours, and the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether to obtain a crude phosphonium salt, which was used directly in the next reaction without purification. This phosphonium salt was dissolved in dichloromethane (20 mL), and 2 M sodium hydroxide aqueous solution (30 mL) was added. The mixture was stirred at room temperature, and the reaction progress was monitored by TLC. After 3 hours, ethyl acetate (40 mL) was added, and the organic layer was separated. The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. The residue was suspended in methanol (10 mL) by sonication, and the solid product was obtained by vacuum filtration and then dried under reduced pressure to obtain 1-phenyl-2-(triphenyl-λ) 5 (-phosphine subunit) ethyl-1-one, yield 92%.

[0137] N,N-diisopropylethylamine (DIEPA, 35 mL, 200 mmol) was added to a suspension of 1-(2,4-dihydroxyphenyl)ethyl-1-one (15.2 g, 100 mmol) in dichloromethane (100 mL), and the mixture was stirred at room temperature for 0.5 h. Methoxymethyl bromide (MOMBr, 15 g, 120 mmol) was slowly added dropwise to the mixture under ice bath cooling. After the addition was complete, the mixture was heated to room temperature and stirred for another 4 h. TLC monitoring showed that the reaction was complete at this point. The reaction mixture was poured into ice water (150 mL), and the organic layer was separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by normal-phase silica gel column chromatography (elution with petroleum ether / ethyl acetate at a volume ratio of 10:1 to 8:1) to obtain 1-(2-hydroxy-4-(methoxymethoxy)phenyl)ethyl-1-one, in 87% yield.

[0138] To a suspension of 1-(2-hydroxy-4-(methoxymethoxy)phenyl)ethyl-1-one (1.96 g, 10 mmol) and benzaldehyde (1.27 g, 12 mmol) in anhydrous ethanol (20 mL), 10 mL of 6 N potassium hydroxide solution was added. The mixture was stirred at room temperature for 24 hours. TLC monitoring showed that the reaction was complete at this point. The reaction mixture was poured into water (50 mL), and the pH was adjusted to neutral with 2 N hydrochloric acid solution. The mixture was then extracted with dichloromethane (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by normal-phase silica gel column chromatography (elution with a petroleum ether / ethyl acetate gradient of 10:1 to 1:1, v / v) to give (E)-1-[2-hydroxy-4-(methoxymethoxy)phenyl]-3-phenylprop-2-en-1-one, yield 84%.

[0139] A catalytic amount (5 mg, 0.02 mmol) of iodine was added to a DMSO (10 mL) solution of (E)-1-[2-hydroxy-4-(methoxymethoxy)phenyl]-3-phenylprop-2-en-1-one (0.28 g, 1 mmol), and the mixture was heated to 160°C and maintained for 8 hours. After TLC monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature, and then added dropwise to a 1 N sodium thiosulfate aqueous solution (50 mL). The precipitated solid was collected by vacuum filtration, dried under reduced pressure, and purified by normal-phase silica gel column chromatography (elution with petroleum ether / ethyl acetate at a volume ratio of 3:1 to 1:1) to give 7-hydroxy-2-phenyl-4H-chromogen-4-one in 82% yield.

[0140] 7-Hydroxy-2-phenyl-4H-chromogen-4-one (0.24 g, 1 mmol) was mixed with hexamethylenetetramine (HMTA, 421 mg, 3 mmol) and acetic acid (4 mL) and heated under reflux for 2 hours. Then, 1 M hydrochloric acid (2 mL) was added, and the mixture was stirred at 60 °C for 1 hour. TLC monitoring showed that the reaction was complete at this point. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by normal-phase silica gel column chromatography (elution with a petroleum ether / ethyl acetate gradient of 3:1 to 1:1 v / v) to give 7-hydroxy-4-oxo-2-phenyl-4H-chromogen-8-carboxaldehyde in 64% yield.

[0141] 1-Phenyl-2-(triphenyl-λ) 5 A solution of (-phosphine-1-yl)-ethyl-1-one (456 mg, 1.2 mmol) and 7-hydroxy-4-oxo-2-phenyl-4H-chromogen-8-carboxaldehyde (0.27 g, 1.0 mmol) in anhydrous dichloromethane (20 mL) was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by normal-phase silica gel column chromatography (petroleum ether / dichloromethane volume ratio 5:1) to give target compound 1 ((E)-7-hydroxy-8-(3-oxo-3-phenylprop-1-en-1-yl)-2-phenyl-4H-chromogen-4-one) in 84% yield. 1 H NMR (300 MHz, DMSO-d6) δ 8.30 (d, J= 3.1 Hz, 2H), 8.00 (d, J = 7.5 Hz, 4H), 7.91 (dd, J = 8.9, 2.3 Hz, 1H), 7.69(d, J = 7.5 Hz, 1H), 7.57 (q, J = 8.1 Hz, 5H), 7.06 – 6.98 (m, 1H), 6.93 (d,J = 2.4 Hz, 1H); 13 C NMR (151 MHz, DMSO-d6) δ 191.1, 176.5, 166.1, 162.5,156.9, 138.7, 134.9, 133.2, 132.2, 131.9, 129.6, 129.3, 128.6, 128.1, 126.7,124.9, 116.6, 115.5, 110.1, 107.8; ESI-HRMS (m / z): [M + H] + calcd for C 24 H17 O4:369.1127, found 369.1118. HPLC, t R = 5.13 min, purity 98.74%.

[0142] Example 2

[0143] Following the method of Compound 1, acetophenone in step (1) was replaced with an equal amount of 4-methoxyacetophenone to prepare (E)-7-hydroxy-8-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)-2-phenyl-4H-chromogen-4-one (Compound 2), which was a white solid with a yield of 76%. 1 H NMR (300 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.27 (s, 2H), 8.04 (t, J = 7.4 Hz, 4H), 7.96 (d, J = 8.8 Hz, 1H), 7.60 (dt, J= 14.4, 6.9 Hz, 3H), 7.10 (d, J = 8.8 Hz, 3H), 6.97 (s, 1H), 3.88 (s, 3H); 13 CNMR (151 MHz, DMSO-d6) δ 188.8, 176.7, 164.0, 163.6, 162.8, 156.5, 133.2,132.1, 131.2, 131.0, 129.7, 128.0, 126.8, 125.7, 116.5, 115.8, 114.6, 110.5,107.8, 56.1; ESI-HRMS (m / z): [M + H] + calcd for C 25 H 19 O5: 399.1232, found399.1228. HPLC, t R = 8.41 min, purity 99.55%.

[0144] Example 3

[0145] Following the method of Compound 1, acetophenone in step (1) was replaced with an equal amount of 4-bromoacetophenone to prepare (E)-7-hydroxy-8-(3-(4-bromophenyl)-3-oxoprop-1-en-1-yl)-2-phenyl-4H-chromogen-4-one (Compound 3), which was a white solid with a yield of 88%. 1H NMR (300 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.26 (d, J =16.0 Hz, 1H), 8.11 (d, J = 16.0 Hz, 1H), 8.04 – 7.86 (m, 5H), 7.79 (d, J =8.5 Hz, 2H), 7.68 – 7.50 (m, 3H), 7.12 (d, J = 8.8 Hz, 1H), 6.96 (s, 1H); 13 CNMR (151 MHz, DMSO-d6) δ 190.2, 176.6, 163.4, 162.8, 156.4, 137.3, 134.5,132.4, 132.2, 132.1, 130.7, 129.6, 128.5, 127.4, 126.8, 125.9, 116.9, 115.3,110.24, 107.8; ESI-HRMS (m / z): [M + H] + calcd for C 24 H 16 O4Br: 447.0232, found447.0234. HPLC, t R = 4.87 min, purity 98.04%.

[0146] Example 4

[0147] Following the method of Compound 1, benzaldehyde in step (4) was replaced with an equal amount of 3-methylbenzaldehyde to prepare (E)-7-hydroxy-8-(3-oxo-3-phenylprop-1-en-1-yl)-2-(m-tolyl)-4H-chromogen-4-one (Compound 4), which was a white solid with a yield of 68%. 1 H NMR (300 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.24 (d, J= 10.9 Hz, 2H), 8.01 (d, J = 7.8 Hz, 3H), 7.83 (s, 2H), 7.72 – 7.67 (m, 1H),7.56 (d, J = 6.8 Hz, 2H), 7.41 (d, J = 3.5 Hz, 2H), 7.13 (d, J = 9.0 Hz, 1H), 6.96 (s, 1H), 2.27 (s, 3H); 13C NMR (151 MHz, DMSO-d6) δ 190.7, 176.6, 163.2,163.0, 156.3, 139.1, 138.4, 134.0, 133.4, 132.7, 132.0, 129.5, 129.3, 128.7,128.3, 127.3, 126.2, 123.9, 116.9, 115.2, 110.5, 107.6, 21.3; ESI-HRMS (m / z):[M + H] + calcd for C 25 H 19 O4: 383.1283, found 383.1283. HPLC, t R = 4.95 min, purity 97.39%.

[0148] Example 5

[0149] Following the method of Compound 1, acetophenone in step (1) was replaced with an equal amount of 4-methoxyacetophenone, and benzaldehyde in step (4) was replaced with an equal amount of 3-methylbenzaldehyde to prepare (E)-7-hydroxy-8-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)-2-(m-tolyl)-4H-chromogen-4-one (Compound 5), which was a white solid with a yield of 70%. 1 H NMR (300 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.23 ​​(d, J = 2.6 Hz, 2H), 8.04 – 7.96 (m, 3H), 7.85 (s, 2H), 7.44 (d, J = 5.4 Hz, 2H), 7.15 – 7.07 (m,3H), 6.96 (s, 1H), 3.87 (s, 3H), 2.28 (s, 3H); 13 C NMR (151 MHz, DMSO-d6) δ188.6, 176.7, 163.6, 163.1, 162.9, 156.2, 139.1, 133.0, 132.7, 132.0, 131.1,131.0, 129.5, 128.0, 127.3, 126.1, 123.9, 116.9, 115.2, 114.6, 110.62, 107.6,56.0, 21.3; ESI-HRMS (m / z): [M + H] + calcd for C 26H 21 O5: 413.1389, found413.1382. HPLC, t R = 7.04 min, purity 98.52%.

[0150] Example 6

[0151] Following the method of Compound 1, in step (1) acetophenone was replaced with an equal amount of 4-chloroacetophenone, and in step (4) benzaldehyde was replaced with an equal amount of 3-methylbenzaldehyde to prepare (E)-8-(3-(4-chlorophenyl)-3-oxoprop-1-en-1-yl)-7-hydroxy-2-(m-tolyl)-4H-chromogen-4-one (Compound 6), which was a white solid with a yield of 59%. 1 H NMR (300 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.27 (d, J = 16.2 Hz, 1H), 8.14 (d,J = 15.9 Hz, 1H), 7.99 (dd, J = 12.9, 8.3 Hz, 3H), 7.79 (d, J = 7.6 Hz, 2H), 7.63 (d, J = 7.8 Hz, 2H), 7.42 (t, J = 3.0 Hz, 2H), 7.11 (d, J = 9.3 Hz, 1H), 6.94 (d, J = 2.6 Hz, 1H), 2.27 (s, 3H); 13 C NMR (151 MHz, DMSO-d6) δ 189.6,176.6, 163.3, 162.8, 156.2, 139.0, 138.3, 136.9, 134.4, 132.7, 131.9, 130.5,129.4, 128.4, 127.2, 125.7, 123.8, 116.8, 115.2, 110.3, 107.5, 21.3; ESI-HRMS(m / z): [M + H] + calcd for C 25 H 18 O4Cl: 417.0894, found 417.0894. HPLC, t R = 7.14 min, purity 99.71%.

[0152] Example 7

[0153] Following the method of Compound 1, acetophenone in step (1) was replaced with an equal amount of 4-trifluoromethylacetophenone, and benzaldehyde in step (4) was replaced with an equal amount of furfural to prepare (E)-2-(furan-2-yl)-7-hydroxy-8-(3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-4H-chromogen-4-one (Compound 7), which was a white solid with a yield of 76%. 1 H NMR (300 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.23 ​​(d, J = 11.8 Hz, 4H), 8.07 – 7.95 (m, 4H), 7.28 (d, J = 3.1 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 6.82(s, 1H), 6.73 (d, J = 2.6 Hz, 1H); 13 C NMR (151 MHz, DMSO-d6) δ 190.2, 175.8,163.4, 156.0, 154.4, 147.4, 145.8, 141.7, 134.8, 132.6 (J C-F = 31.5 Hz),129.3, 128.7, 126.3 (J C-F = 3.0 Hz), 125.4, 117.0, 115.2, 114.1, 113.5, 109.9,105.3; 19 F NMR (282 MHz, DMSO-d6) δ -61.40; ESI-HRMS (m / z): [M + H] + calcd forC 23 H 14 O5F3: 427.0793, found 427.0795. HPLC, t R = 5.57 min, purity 98.42%.

[0154] Example 8

[0155] Following the method of Compound 1, acetophenone in step (1) was replaced with an equal amount of 4-trifluoromethylacetophenone, and benzaldehyde in step (4) was replaced with an equal amount of 3,4-dimethoxybenzaldehyde. (E)-2-(3,4-dimethoxyphenyl)-7-hydroxy-8-(3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-4H-chromogen-4-one (Compound 8) was prepared as a white solid with a yield of 55%. 1H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.31 (d, J = 15.9 Hz, 1H), 8.14 (d, J = 9.9 Hz, 3H), 7.93 (dt, J = 8.3, 3.5 Hz,3H), 7.54 (d, J = 8.7 Hz, 2H), 7.11 – 7.03 (m, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 2.7 Hz, 1H), 3.84 (dd, J = 7.7, 2.6 Hz, 6H); 13 C NMR (151 MHz, DMSO-d6) δ 190.1, 176.5, 163.2, 162.4, 156.1, 152.1, 149.5, 141.6, 134.8,132.5 (J C-F = 33.0 Hz), 129.4, 128.5, 126.3 (J C-F = 4.5 Hz), 125.5, 124.0,119.8, 116.7, 115.1, 112.0, 110.0, 109.5, 106.2, 56.0; 19 F NMR (282 MHz, DMSO-d6) δ -61.49; ESI-HRMS (m / z): [M + H] + calcd for C 27 H 20 O6F3: 497.1212, found497.1212. HPLC, t R = 7.38 min, purity 99.87%.

[0156] Example 9

[0157] Following the method of Compound 1, acetophenone in step (1) was replaced with an equal amount of 4-trifluoromethylacetophenone, and benzaldehyde in step (4) was replaced with an equal amount of 3,4,5-trimethoxybenzaldehyde. (E)-7-hydroxy-8-(3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-2-(3,4,5-trimethoxyphenyl)-4H-chromogen-4-one (Compound 9) was prepared as a white solid with a yield of 76%. 1H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 1H),8.40 – 8.29 (m, 1H), 8.20 – 8.07 (m, 3H), 7.89 (dd, J = 8.7, 3.9 Hz, 3H),7.27 (d, J = 2.8 Hz, 2H), 7.05 (q, J = 3.7 Hz, 2H), 3.84 (s, 6H), 3.74 (d, J= 2.9 Hz, 3H); 13 C NMR (151 MHz, DMSO-d6) δ 188.8, 175.7, 162.3, 161.1, 155.2,152.6, 140.5, 139.7, 133.5, 131.8, 128.4, 127.5, 126.0, 125.3, 124.3, 124.1,122.3, 115.6, 114.2, 109.0, 106.1, 103.0, 59.5, 55.4; 19 F NMR (282 MHz, DMSO-d6) δ -61.57; ESI-HRMS (m / z): [M + H] + calcd for C 28 H 22 O7F3: 527.1318, found527.1323. HPLC, t R = 5.88 min, purity 97.38%.

[0158] Example 10

[0159] Following the method of Compound 1, acetophenone in step (1) was replaced with an equal amount of 4-trifluoromethylacetophenone to prepare (E)-7-hydroxy-8-(3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-2-phenyl-4H-chromogen-4-one (Compound 10), which was a white solid with a yield of 82%. 1 H NMR (300 MHz, DMSO-d6) δ 12.03 (s,1H), 8.28 (d, J = 15.9 Hz, 1H), 8.14 (dd, J = 11.2, 7.8 Hz, 3H), 7.97 (d, J =8.7 Hz, 5H), 7.65 – 7.45 (m, 3H), 7.11 (d, J = 8.9 Hz, 1H), 6.95 (s, 1H); 13CNMR (151 MHz, DMSO-d6) δ 190.4, 176.5, 163.4, 162.7, 156.3, 141.7, 135.0,132.5 (J C-F = 31.5 Hz), 132.0, 132.0, 129.5, 129.4, 128.6, 126.7, 126.2 (J C-F =4.5 Hz), 125.8, 116.8, 115.3, 110.0, 107.8; 19 F NMR (282 MHz, DMSO-d6) δ -61.45; ESI-HRMS (m / z): [M + H] + calcd for C 25 H 16 O4F3: 437.1001, found 437.1003.HPLC, t R = 5.70 min, purity 99.89%.

[0160] Example 11

[0161] Following the method of Compound 1, acetophenone in step (1) was replaced with an equal amount of 4-trifluoromethylacetophenone, and benzaldehyde in step (4) was replaced with an equal amount of 4-chlorobenzaldehyde. (E)-2-(4-chlorophenyl)-7-hydroxy-8-(3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-4H-chromogen-4-one (Compound 11) was prepared as a white solid with a yield of 79%. 1 H NMR (300 MHz, DMSO-d6) δ 12.17 – 11.83 (m, 1H), 8.26 – 8.02(m, 4H), 7.93 (d, J = 7.9 Hz, 5H), 7.53 (d, J = 7.4 Hz, 2H), 7.08 (d, J = 8.7Hz, 1H), 6.94 (s, 1H); 13 C NMR (151 MHz, DMSO-d6) δ 190.7, 176.5, 163.5,161.6, 156.2, 141.7, 136.9, 135.0, 132.5, 132.0, 130.9, 129.6, 129.5, 129.2,128.6, 128.5, 126.3, 116.7, 115.4, 110.0, 108.1; 19F NMR (282 MHz, DMSO-d6) -61.50; HRMS (m / z): [M + H] + calcd for C 25 H 15 O4F3Cl: 471.0611, found 471.0614.HPLC, t R = 9.40 min, purity 97.17%.

[0162] Example 12

[0163] Following the method of Compound 1, acetophenone in step (1) was replaced with an equal amount of 4-trifluoromethylacetophenone, and benzaldehyde in step (4) was replaced with an equal amount of 3-methoxy-4-methylbenzaldehyde. (E)-7-hydroxy-2-(3-methoxy-4-methylphenyl)-8-(3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-4H-chromogen-4-one (Compound 12) was prepared as a white solid with a yield of 59%. 1 H NMR (300 MHz, DMSO-d6) δ 8.38 – 8.13 (m,3H), 8.07 – 7.74 (m, 5H), 7.61 (d, J = 12.6 Hz, 1H), 7.20 – 6.96 (m, 2H), 6.88 (s, 1H), 3.87 (s, 3H), 2.08 (s, 3H); 13 C NMR (151 MHz, DMSO-d6) δ 190.1,176.5, 163.2, 162.4, 156.1, 152.1, 149.5, 141.6, 134.8, 132.5, 129.4, 128.5,126.3, 125.5, 124.0, 119.8, 116.7, 115.1, 112.0, 110.0, 109.5, 106.2, 56.0; 19 F NMR (282 MHz, DMSO-d6) δ -61.47; HRMS (m / z): [M + H] + calcd for C 27 H 20 O5F3:481.1259, found 481.1263. HPLC, t R = 5.27 min, purity 95.23%.

[0164] Example 13

[0165] Following the method of Compound 1, acetophenone in step (1) was replaced with an equal amount of 4-trifluoromethylacetophenone, and benzaldehyde in step (4) was replaced with an equal amount of 3-methylbenzaldehyde to prepare (E)-7-hydroxy-8-(3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-2-(m-tolyl)-4H-chromogen-4-one (Compound 13), which was a white solid with a yield of 51%. 1 H NMR (300 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.31 (d, J = 16.0Hz, 1H), 8.22 – 8.11 (m, 3H), 7.97 (dd, J = 14.4, 8.5 Hz, 3H), 7.80 (d, J =4.5 Hz, 2H), 7.41 (d, J = 4.9 Hz, 2H), 7.13 (d, J = 8.9 Hz, 1H), 6.96 (s,1H), 2.25 (s, 3H); 13 C NMR (151 MHz, DMSO-d6) δ 190.3, 176.6, 163.4, 162.9,156.3, 141.7, 139.1, 135.0, 132.8, 131.9, 129.5, 129.5, 128.7, 127.2, 126.4(J C-F = 3.0 Hz), 126.1, 123.9, 116.9, 115.3, 110.2, 107.7, 21.3; 19 F NMR (282MHz, DMSO-d6) δ -61.52; HRMS (m / z): [M + H] + calcd for C 26 H 18 O4F3: 451.1161, found 451.1157. HPLC, t R = 7.36 min, purity 99.39%.

[0166] Example 14

[0167] Anhydrous sodium acetate (2.47 g, 30.1 mmol) was added to a solution of 2,4-dihydroxyphenylacetone (1.0 g, 6.0 mmol) in acetic anhydride (25 mL, 265 mmol), and the mixture was heated under reflux for 18 hours. The reaction mixture was then poured into ice water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A 2 N sodium hydroxide aqueous solution was added to an anhydrous ethanol (50 mL) suspension of the residue, and the mixture was heated at 60 °C for 2 hours. TLC monitoring showed that the reaction was complete at this point. The pH was adjusted to neutral with concentrated hydrochloric acid, and the precipitated solid was filtered under vacuum. The filter cake was collected, dried, and purified by normal-phase silica gel column chromatography (elution with a petroleum ether / ethyl acetate gradient of 3:1 to 2:1) to obtain 7-hydroxy-2,3-dimethyl-4H-chromogen-4-one.

[0168] 7-Hydroxy-2,3-dimethyl-4H-chromogen-4-one (0.19 g, 1 mmol), hexamethylenetetramine (HMTA, 421 mg, 3 mmol), and acetic acid (4 mL) were mixed and refluxed for 2 hours. Then, 1 M hydrochloric acid (2 mL) was added, and the mixture was stirred at 60 °C for 1 hour. Once TLC monitoring showed the reaction was complete, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by normal-phase silica gel column chromatography (elution with a petroleum ether / ethyl acetate gradient of 3:1 to 1:1 v / v) to give 7-hydroxy-2,3-dimethyl-4-oxo-4H-chromogen-8-carboxaldehyde in 70% yield.

[0169] 1-Phenyl-2-(triphenyl-λ) 5 (-phosphine-1-yl)-1-one (456 mg, 1.2 mmol), 7-hydroxy-2,3-dimethyl-4-oxo-4H-chromogen-8-carboxaldehyde (0.26 g, 1.0 mmol), and anhydrous dichloromethane (20 mL) were mixed and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by normal-phase silica gel column chromatography (petroleum ether / dichloromethane volume ratio 5:1) to give the target compound 14 ((E)-7-hydroxy-2,3-dimethyl-8-(3-oxo-3-phenylprop-1-en-1-yl)-4H-chromogen-4-one) in 82% yield. 1H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.17 (d, J = 1.5 Hz, 2H), 8.07 – 7.99 (m, 2H), 7.93 (d, J = 8.8 Hz, 1H), 7.74– 7.54 (m, 3H), 7.06 (d, J = 8.9 Hz, 1H), 2.48 (s, 3H), 1.94 (s, 3H); 13 C NMR(151 MHz, DMSO-d6) δ 190.4, 176.1, 162.7, 161.7, 156.0, 138.4, 133.5, 133.4,129.4, 128.6, 125.1, 116.2, 115.5, 114.7, 109.4, 18.5, 10.0; ESI-HRMS (m / z):[M + H] + calcd for C 20 H 17 O4: 321.1127, found 321.1130. HPLC, t R = 5.56 min, purity 98.70%.

[0170] Example 15

[0171] Referring to the method of compound 14, the 1-phenyl-2-(triphenyl-λ) in step (3) 5 -phosphine) ethyl-1-one is replaced with an equal amount of 1-(4-methoxyphenyl)-2-(triphenyl-λ) 5 (-phosphine-1-yl) ethyl-1-one was prepared to give (E)-7-hydroxy-8-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)-2,3-dimethyl-4H-chromogen-4-one (compound 15), which was a white solid with a yield of 85%. 1 H NMR (300 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.22 – 8.11 (m,2H), 8.05 – 8.01 (m, 2H), 7.90 (d, J = 8.8 Hz, 1H), 7.14 – 7.09 (m, 2H), 7.04(d, J = 8.8 Hz, 1H), 3.87 (s, 3H), 2.49 – 2.46 (m, 3H), 1.95 – 1.92 (m, 3H); 13C NMR (151 MHz, DMSO-d6) δ 188.4, 176.2, 163.6, 162.5, 161.6, 156.0, 132.6,131.2, 130.9, 128.4, 125.0, 116.2, 115.5, 114.6, 109.5, 56.0, 18.5, 10.0;ESI-HRMS (m / z): [M + H] + calcd for C 21 H 19 O5: 351.1232, found 351.1232. HPLC, t R = 6.78 min, purity 98.60%.

[0172] Example 16

[0173] Referring to the method of compound 14, the 1-phenyl-2-(triphenyl-λ) in step (3) 5 -phosphine) ethyl-1-one is replaced with an equal amount of 1-(4-chlorophenyl)-2-(triphenyl-λ) 5 (-phosphine) ethyl-1-one was prepared to give (E)-8-(3-(4-chlorophenyl)-3-oxoprop-1-en-1-yl)-7-hydroxy-2,3-dimethyl-4H-chromogen-4-one (compound 16), which was a white solid with a yield of 77%. 1 H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.11 (d, J = 1.6 Hz,2H), 8.04 – 7.97 (m, 2H), 7.90 (d, J = 8.8 Hz, 1H), 7.69 – 7.61 (m, 2H), 7.02(d, J = 8.9 Hz, 1H), 2.47 – 2.39 (m, 3H), 1.97 – 1.86 (m, 3H); 13 C NMR (151MHz, DMSO-d6) δ 189.2, 176.1, 162.7, 161.7, 156.1, 138.4, 137.0, 134.0,130.4, 129.5, 128.8, 124.7, 116.3, 115.5, 114.7, 109.3, 18.5, 10.0; ESI-HRMS(m / z): [M + H] + calcd for C 20 H 16O4Cl: 355.0737, found 355.0733. HPLC, t R = 3.60 min, purity 97.01%.

[0174] Example 17

[0175] Referring to the method of compound 14, the 1-phenyl-2-(triphenyl-λ) in step (3) 5 -phosphine group) ethyl-1-one is replaced with 1-(4-trifluoromethylphenyl)-2-(triphenyl-λ) 5 (-phosphine-1-yl) ethyl-1-one was prepared to give (E)-7-hydroxy-2,3-dimethyl-8-(3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-4H-chromogen-4-one (compound 17), which was a white solid with a yield of 89%. 1 H NMR (300 MHz, DMSO-d6) δ 11.83 (d, J = 3.9 Hz, 1H), 8.27 –8.09 (m, 4H), 8.00 – 7.88 (m, 3H), 7.05 (dd, J = 9.0, 3.0 Hz, 1H), 2.47 (d, J= 3.1 Hz, 3H), 1.94 (d, J = 2.2 Hz, 3H); 13 C NMR (151 MHz, DMSO-d6) δ 189.7,176.1, 162.9, 161.7, 156.1, 141.6, 134.6, 132.6 (J C-F = 31.5 Hz), 129.3,129.1, 126.3 (J C-F = 4.5 Hz), 124.6, 116.3, 115.4, 114.7, 109.2, 18.5, 10.0;ESI-HRMS (m / z): [M + H] + calcd for C 21 H 16 O4F3: 389.1001, found 389.1006. HPLC,t R = 6.92 min, purity 98.23%.

[0176] Example 18

[0177] Referring to the method of compound 14, the 1-phenyl-2-(triphenyl-λ) in step (3) 5-phosphine) ethyl-1-one is replaced with an equal amount of 1-(4-cyanophenyl)-2-(triphenyl-λ) 5 (-phosphine-1-yl)ethyl-1-one was used to prepare (E)-4-(3-(7-hydroxy-2,3-dimethyl-4-oxo-4H-chromogen-8-yl)acryloyl)benzonitrile (compound 18), which was a white solid with a yield of 88%. 1 H NMR (300 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.25 – 8.03 (m, 6H), 7.94 (d, J = 9.4 Hz, 1H), 7.05 (d, J = 9.8 Hz, 1H), 2.47 (s, 3H), 1.94 (s, 3H); 13 CNMR (151 MHz, DMSO-d6) δ 188.1, 175.1, 163.5, 159.9, 157.5, 153.7, 149.4,135.6, 131.0, 127.8, 123.6, 123.5, 118.8, 116.7, 116.2, 111.4, 111.0, 103.0,56.3, 56.0; ESI-HRMS (m / z): [M + H] + calcd for C 21 H 16 NO4: 346.1077, found346.1079. HPLC, t R = 5.23 min, purity 96.51%.

[0178] Example 19

[0179] Referring to the method of compound 14, in step (1), 2,4-dihydroxyphenylacetone is replaced with an equal amount of 2,4,6-trihydroxyphenylacetone, and in step (3), 1-phenyl-2-(triphenyl-λ) 5 -phosphine) ethyl-1-one is replaced with an equal amount of 1-(4-trifluoromethylphenyl)-2-(triphenyl-λ) 5 (-phosphine-1-yl) ethyl-1-one was prepared to give (E)-5,7-dihydroxy-2,3-dimethyl-8-(3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-4H-chromogen-4-one (compound 19), which was a white solid with a yield of 78%. 1H NMR (300 MHz, DMSO-d6) δ 14.75 (s, 1H), 11.86 (s, 1H), 8.15(d, J = 8.1 Hz, 2H), 8.09 (d, J = 2.6 Hz, 2H), 7.94 (d, J = 8.2 Hz, 2H), 6.44(s, 1H), 2.40 (s, 3H), 1.93 (s, 3H); 13 C NMR (151 MHz, DMSO-d6) δ 189.8,181.7, 164.1, 163.3, 158.1, 141.9, 135.7, 132.6 (J C-F = 27.0 Hz), 129.2, 126.2 (J) C-F = 4.5 Hz), 122.4, 114.8, 106.3, 102.9, 93.5, 18.6, 9.2; 19 F NMR (282 MHz, DMSO-d6) δ -61.47; ESI-HRMS (m / z): [M + H] + calcd for C 21 H 16 O5F3: 405.0950, found 405.0953. HPLC, t R = 7.58 min, purity 99.02%.

[0180] Example 20

[0181] Under nitrogen protection, a boron trifluoride diethyl ether complex (BF3·Et2O, 100 mL, 150 mmol) was added to a mixture of resorcinol (3.3 g, 30 mmol) and 4-methoxyphenylacetic acid (5.0 g, 30 mmol), and the mixture was refluxed at 90 °C for 1.5 h. The reaction mixture was cooled to 10 °C, and DMF (46 mL) was slowly added dropwise to Vilsmeier reagent (5.7 g, 45 mmol) at room temperature. The mixture was irradiated under microwave conditions (100 W) for 0.5 h. TLC monitoring showed that the reaction was complete at this point. The reaction mixture was poured into 1 M hydrochloric acid and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by normal-phase silica gel column chromatography (elution with petroleum ether / ethyl acetate at a volume ratio of 1:1 to 2:1) to give 7-hydroxy-3-(4-methoxyphenyl)-4H-chromogen-4-one as a white solid with a yield of 77%.

[0182] A solution of 7-hydroxy-3-(4-methoxyphenyl)-4H-chromogen-4-one (0.27 g, 1 mmol) and hexamethylenetetramine (HMTA, 421 mg, 3 mmol) in acetic acid (4 mL) was heated under reflux for 2 hours. Then, 1 M hydrochloric acid (2 mL) was added, and the mixture was stirred at 60 °C for 1 hour. TLC monitoring showed that the reaction was complete at this point. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by normal-phase silica gel column chromatography (elution with a petroleum ether / ethyl acetate gradient of 3:1 to 1:1 v / v) to give 7-hydroxy-3-(4-methoxyphenyl)-4-oxo-4H-chromogen-8-carboxaldehyde in 70% yield.

[0183] 1-Phenyl-2-(triphenyl-λ) 5 A solution of 7-hydroxy-3-(4-methoxyphenyl)-8-(3-oxo-3-phenylprop-1-en-1-yl)-4H-chromogen-4-one (0.30 g, 1.0 mmol) in anhydrous dichloromethane (20 mL) was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by normal-phase silica gel column chromatography (petroleum ether / dichloromethane volume ratio 5:1) to give compound 20 ((E)-7-hydroxy-3-(4-methoxyphenyl)-8-(3-oxo-3-phenylprop-1-en-1-yl)-4H-chromogen-4-one) in 69% yield. 1 H NMR (300 MHz, DMSO-d6) δ8.61 (s, 1H), 8.27 – 8.20 (m, 2H), 8.07 (dd, J = 8.0, 2.5 Hz, 3H), 7.70 (t, J= 7.3 Hz, 1H), 7.65 – 7.47 (m, 5H), 7.14 (d, J = 8.9 Hz, 1H), 7.02 (d, J =8.8 Hz, 2H), 3.80 (s, 3H); 13C NMR (151 MHz, DMSO-d6) δ 190.5, 175.0, 163.4,159.9, 159.6, 156.6, 153.7, 151.6, 138.3, 133.4, 131.9, 130.5, 129.4, 129.1,128.8, 125.5, 124.4, 123.7, 117.2, 115.5, 114.1, 114.1, 109.9, 55.6; ESI-HRMS(m / z): [M + H] + calcd for C 25 H 19 O5: 399.1232, found 399.1236. HPLC, t R = 5.63min, purity 95.13%.

[0184] Example 21

[0185] Referring to the method of compound 20, the 1-phenyl-2-(triphenyl-λ) in step (3) 5 -phosphine) ethyl-1-one is replaced with an equal amount of 1-(4-methoxyphenyl)-2-(triphenyl-λ) 5 (-phosphine-1-yl) ethyl-1-one was prepared to yield (E)-7-hydroxy-3-(4-methoxyphenyl)-8-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)-4H-chromogen-4-one (compound 21), which was a white solid with a yield of 75%. 1 H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.60 (d,J = 1.5 Hz, 1H), 8.30 – 8.12 (m, 2H), 8.07 (t, J = 7.9 Hz, 3H), 7.57 (d, J =8.7 Hz, 2H), 7.12 (t, J = 8.4 Hz, 3H), 7.02 (d, J = 8.6 Hz, 2H), 3.88 (s,3H), 3.80 (s, 3H); 13C NMR (151 MHz, DMSO-d6) δ 189.5, 174.9, 163.2, 159.6,156.5, 153.7, 137.3, 133.8, 132.4, 130.8, 130.5, 129.2, 127.6, 125.1, 124.4,123.8, 117.3, 115.4, 114.1, 109.8, 55.6; ESI-HRMS (m / z): [M + H] + calcd forC 26 H 21 O6: 429.1338, found 429.1338. HPLC, t R = 6.01 min, purity 99.95%.

[0186] Example 22

[0187] Referring to the method of compound 20, the 1-phenyl-2-(triphenyl-λ) in step (3) 5 -phosphine) ethyl-1-one is replaced with an equal amount of 1-(4-bromophenyl)-2-(triphenyl-λ) 5 (-phosphine) ethyl-1-one was prepared to give (E)-8-(3-(4-bromophenyl)-3-oxoprop-1-en-1-yl)-7-hydroxy-3-(4-methoxyphenyl)-4H-chromogen-4-one (compound 22), which was a white solid with a yield of 78%. 1 H NMR (300 MHz, DMSO-d6) δ 11.96 (s, 1H), 8.58 (s, 1H), 8.19(s, 2H), 8.10 – 7.94 (m, 3H), 7.79 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.7 Hz,2H), 7.13 (d, J = 8.9 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H); 13 C NMR(151 MHz, DMSO-d6) δ 188.6, 175.0, 163.7, 162.9, 159.6, 156.5, 153.7, 132.4,131.1, 130.5, 128.8, 125.6, 124.4, 123.7, 117.4, 115.4, 114.6, 114.1, 110.1,56.0, 55.6. ESI-HRMS (m / z): [M + H]+ calcd for C 25 H 18 O5Br: 477.0338, found477.0334. HPLC, t R = 8.27 min, purity 99.83%.

[0188] Example 23

[0189] Referring to the method of compound 20, the 1-phenyl-2-(triphenyl-λ) in step (3) 5 -phosphine) ethyl-1-one is replaced with an equal amount of 1-(4-trifluoromethylphenyl)-2-(triphenyl-λ) 5 (-phosphine-1-yl) ethyl-1-one was prepared to yield (E)-7-hydroxy-3-(4-methoxyphenyl)-8-(3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-4H-chromogen-4-one (compound 23), which was a white solid with a yield of 69%. 1 H NMR (300 MHz, CDCl3) δ8.59 (s, 1H), 8.24 (d,J = 6.6 Hz, 4H), 8.08 (d, J = 8.9 Hz, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.59 –7.52 (m, 2H), 7.13 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H); 13 C NMR(151 MHz, DMSO-d6) δ 189.8, 174.9, 163.3, 159.6, 156.5, 153.6, 141.6, 134.4,132.9, 130.5, 129.5, 126.3 (J C-F = 31.5 Hz), 125.1, 124.3, 123.8, 117.3,115.4, 114.1, 109.7, 55.6; 19 F NMR (282 MHz, DMSO-d6) δ -61.52; ESI-HRMS (m / z): [M + H] + calcd for C 26 H 18 O5F3: 467.1106, found 467.1105. HPLC, t R = 5.26min, purity 98.89%.

[0190] Example 24

[0191] Following the method of Compound 1, in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone to prepare (E)-5,7-dihydroxy-8-(3-oxo-3-phenylprop-1-en-1-yl)-2-phenyl-4H-chromogen-4-one (Compound 24), which was a yellow solid with a yield of 71%. 1 H NMR (300 MHz, DMSO- d6 ) δ 14.50 (s,1H), 12.01 (s, 1H), 8.10 (dd, J = 6.2, 3.0 Hz, 4H), 8.02 – 7.94 (m, 2H), 7.61(dddd, J = 17.8, 8.7, 5.3, 2.3 Hz, 7H), 7.08 (s, 1H), 6.68 (s, 1H); 13 C NMR(126 MHz, DMSO-d6) δ 190.6, 182.7, 164.6, 163.9, 163.0, 158.2, 138.7, 134.3,133.2, 132.7, 130.9, 129.6, 129.3, 128.5, 127.0, 123.4, 107.0, 105.8, 104.2,94.4; ESI-HRMS (m / z): [M + H] + calcd for C 24 H 17 O5: 385.1076, found 385.1071.HPLC, t R = 5.42 min, purity 99.57%.

[0192] Example 25

[0193] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-methoxyacetophenone, and in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, to prepare (E)-5,7-dihydroxy-8-(3-(4-methoxyphenyl)-3-oxopropyl-1-en-1-yl)-2-phenyl-4H-chromogen-4-one (Compound 25), which was a yellow solid with a yield of 67%. 1H NMR (300 MHz, DMSO-d6) δ 14.47 (d, J = 2.2 Hz, 1H), 11.97 (s, 1H), 8.20 – 8.04 (m, 4H), 8.00 (dt, J = 8.9, 2.0 Hz, 2H), 7.60 (dtd, J = 8.7, 6.3, 2.9 Hz, 3H), 7.13 – 7.04 (m, 3H), 6.68 (d, J = 3.0 Hz,1H), 3.87 (s, 3H); 13 C NMR (151 MHz, DMSO-d6) δ 188.7, 182.7, 164.5, 163.9,163.4, 162.8, 158.0, 133.4, 132.7, 131.4, 130.8, 129.6, 127.0, 123.4, 114.6,107.1, 105.7, 104.2, 94.4, 56.0; ESI-HRMS (m / z): [M + H] + calcd for C 25 H 19 O6:415.1182, found 415.1187. HPLC, t R = 9.39 min, purity 99.38%.

[0194] Example 26

[0195] Following the method of Compound 1, in step (1) acetophenone was replaced with an equal amount of 4-bromoacetophenone, and in step (3) 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, to prepare (E)-8-(3-(4-bromophenyl)-3-oxopropyl-1-en-1-yl)-5,7-dihydroxy-2-phenyl-4H-chromogen-4-one (Compound 26), which was a yellow solid with a yield of 65%. 1 H NMR (300 MHz, DMSO-d6) δ 14.52 (s, 1H), 12.01 (s, 1H), 8.12– 8.02 (m, 4H), 7.90 (dq, J = 8.6, 2.0 Hz, 2H), 7.80 – 7.74 (m, 2H), 7.66 –7.52 (m, 3H), 7.06 (s, 1H), 6.65 (s, 1H); 13C NMR (126 MHz, DMSO-d6) δ 189.5,182.7, 164.6, 163.9, 163.1, 158.3, 137.6, 134.8, 132.7, 132.4, 130.9, 130.5,129.6, 127.3, 127.0, 122.8, 107.0, 105.8, 104.2, 94.4; ESI-HRMS (m / z): [M +H] + calcd for C 24 H 16 O5Br: 463.0181, found 463.0172. HPLC, t R = 6.21 min, purity 97.75%.

[0196] Example 27

[0197] Following the method of Compound 1, in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, and in step (4), benzaldehyde was replaced with an equal amount of 4-methoxybenzaldehyde. This yielded (E)-5,7-dihydroxy-2-(4-methoxyphenyl)-8-(3-oxo-3-phenylprop-1-en-1-yl)-4H-chromogen-4-one (Compound 27), which was a yellow solid with a yield of 56%. 1 H NMR (300 MHz, DMSO-d6) δ 14.61 (s, 1H), 8.09 (d, J =4.3 Hz, 2H), 8.06 – 8.01 (m, 2H), 8.00 – 7.94 (m, 2H), 7.69 – 7.62 (m, 1H), 7.58 (dd, J = 8.1, 6.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.95 (s, 1H), 6.63(s, 1H), 3.85 (s, 3H); 13 C NMR (151 MHz, DMSO-d6) δ 190.6, 182.5, 164.4,164.1, 163.0, 158.1, 138.7, 134.4, 133.2, 129.3, 128.9, 128.5, 123.3, 123.0,115.1, 106.9, 104.1, 94.3, 56.0; ESI-HRMS (m / z): [M + H] + calcd for C 25 H19 O6:415.1182, found 415.1184. HPLC, t R = 4.56 min, purity 96.89%.

[0198] Example 28

[0199] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-methoxyacetophenone, in step (3) 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, and in step (4) benzaldehyde was replaced with an equal amount of 4-methoxybenzaldehyde. This yielded (E)-5,7-dihydroxy-2-(4-methoxyphenyl)-8-(3-(4-methoxyphenyl)-3-oxopropyl-1-en-1-yl)-4H-chromogen-4-one (Compound 28), which was a yellow solid with a yield of 71%. 1 H NMR (300 MHz, DMSO-d6) δ 14.58 (d, J = 2.5 Hz, 1H), 11.88 (s, 1H), 8.18– 8.09 (m, 1H), 8.08 – 7.93 (m, 5H), 7.15 – 7.04 (m, 4H), 6.95 (d, J = 2.6Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 3.85 (d, J = 3.0 Hz, 6H); 13 C NMR (151 MHz, DMSO-d6) δ 188.7, 182.5, 164.3, 164.0, 162.9, 162.8, 157.9, 133.5, 131.4, 130.8, 128.9, 123.2, 123.0, 115.1, 114.6, 107.0, 104.0, 94.3, 56.0; ESI-HRMS(m / z): [M + H] + calcd for C 26 H 21 O7: 445.1287, found 445.1292. HPLC, t R = 5.74min, purity 96.18%.

[0200] Example 29

[0201] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-bromoacetophenone, in step (3) 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, and in step (4) benzaldehyde was replaced with an equal amount of 4-methoxybenzaldehyde. This yielded (E)-8-(3-(4-bromophenyl)-3-oxopropyl-1-en-1-yl)-5,7-dihydroxy-2-(4-methoxyphenyl)-4H-chromogen-4-one (Compound 29), which was a yellow solid with a yield of 62%. 1 HNMR (300 MHz, DMSO-d6) δ 14.65 (d, J = 2.4 Hz, 1H), 11.94 (s, 1H), 8.12 –7.98 (m, 4H), 7.94 – 7.85 (m, 2H), 7.77 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 8.4Hz, 2H), 6.95 (d, J = 2.4 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 3.85 (d, J = 2.5Hz, 3H); 13 C NMR (151 MHz, DMSO-d6) δ 189.6, 182.6, 164.5, 163.2, 163.0,158.3, 137.6, 134.9, 132.4, 130.6, 129.0, 127.3, 123.0, 122.8, 115.1, 106.8,104.1, 94.4, 56.1; ESI-HRMS (m / z): [M + H] + calcd for C 25 H 18 O6Br: 493.0287, found 493.0288. HPLC, t R = 11.48 min, purity 96.87%.

[0202] Example 30

[0203] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-methylacetophenone, and in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone. (E)-5,7-dihydroxy-8-(3-oxo-3-(p-tolyl)prop-1-en-1-yl)-2-phenyl-4H-chromogen-4-one (Compound 30) was prepared as a yellow solid with a yield of 58%. 1H NMR (300 MHz, DMSO-d6) δ 14.48 (s, 1H), 11.97 (s, 1H), 8.13 – 8.00 (m, 4H), 7.93 – 7.86 (m, 2H), 7.67 – 7.54 (m, 3H), 7.37 (d, J =7.9 Hz, 2H), 7.07 (s, 1H), 6.66 (s, 1H), 2.40 (s, 3H); 13 C NMR (126 MHz, DMSO-d6) δ 189.9, 182.6, 164.5, 163.8, 162.9, 158.1, 143.5, 136.1, 133.9, 132.6,130.9, 129.8, 129.6, 128.7, 126.9, 123.3, 107.1, 105.7, 104.2, 94.4, 21.7;ESI-HRMS (m / z): [M + H] + calcd for C 25 H 19 O5: 399.1232, found 399.1226. HPLC, t R = 8.59 min, purity 95.21%.

[0204] Example 31

[0205] Following the method of Compound 1, acetophenone in step (1) was replaced with an equal amount of 3,4-dimethoxyacetophenone, and 2,4-dihydroxyacetophenone in step (3) was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, to prepare (E)-8-(3-(3,4-dimethoxyphenyl)-3-oxopropyl-1-en-1-yl)-5,7-dihydroxy-2-phenyl-4H-chromogen-4-one (Compound 31), which was a yellow solid with a yield of 79%. 1 H NMR (300 MHz, DMSO-d6) δ 14.45 (s, 1H),11.97 (s, 1H), 8.17 – 8.00 (m, 4H), 7.72 – 7.59 (m, 4H), 7.52 (d, J = 2.0 Hz,1H), 7.15 – 7.06 (m, 2H), 6.68 (s, 1H), 3.86 (d, J = 5.4 Hz, 6H); 13C NMR (151MHz, DMSO-d6) δ 188.7, 182.7, 164.5, 164.0, 162.8, 158.1, 153.4, 149.3,133.3, 132.7, 131.5, 130.9, 129.7, 127.0, 123.4, 123.1, 111.5, 111.0, 107.2,105.8, 104.3, 94.4, 56.2, 56.0; ESI-HRMS (m / z): [M + H] + calcd for C 26 H 21 O7:445.1287, found 445.1291. HPLC, t R = 5.21 min, purity 95.10%.

[0206] Example 32

[0207] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-tert-butylacetophenone, and in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, to prepare (E)-8-(3-(4-(tert-butyl)phenyl)-3-oxopropyl-1-en-1-yl)-5,7-dihydroxy-2-phenyl-4H-chromogen-4-one (Compound 32), which was a yellow solid with a yield of 66%. 1 H NMR (300 MHz, DMSO-d6) δ 14.49 (s, 1H), 12.01 (s,1H), 8.11 (d, J = 8.6 Hz, 4H), 7.94 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.5 Hz,5H), 7.10 (s, 1H), 6.69 (s, 1H), 1.33 (s, 9H); 13 C NMR (126 MHz, DMSO-d6) δ190.0, 182.6, 164.6, 163.9, 162.9, 158.1, 156.3, 136.1, 133.9, 132.7, 130.9,129.6, 128.5, 127.1, 127.0, 126.1, 123.5, 107.1, 105.8, 104.2, 94.4, 35.3,31.4; ESI-HRMS (m / z): [M + H] + calcd for C 28 H25 O5: 441.1702, found 441.1702.HPLC, t R = 4.72 min, purity 95.74%.

[0208] Example 33

[0209] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 3,4,5-trimethoxyacetophenone, and in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, to prepare (E)-5,7-dihydroxy-8-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)-2-phenyl-4H-chromogen-4-one (Compound 33), which was a yellow solid with a yield of 68%. 1 H NMR (300 MHz, DMSO-d6) δ 14.42 (s, 1H), 12.04 (s, 1H), 8.13 – 8.06 (m, 4H), 7.66 – 7.58 (m, 3H), 7.27 (s, 2H), 7.10 (s, 1H), 6.68 (s, 1H), 3.89 (s, 6H), 3.77 (s, 3H); 13 C NMR (151 MHz, DMSO-d6)δ 189.5, 182.7, 164.6, 164.0, 162.9, 158.2, 153.4, 134.1, 132.7, 130.9,129.7, 127.0, 123.6, 107.1, 106.2, 105.8, 104.3, 94.5, 60.7, 56.5; ESI-HRMS(m / z): [M + H] + calcd for C 27 H 23 O8: 475.1393, found 475.1397. HPLC, t R = 5.23min, purity 96.34%.

[0210] Example 34

[0211] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-phenylacetophenone, and in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone. This yielded (E)-8-(3-([1,1'-biphenyl]-4-yl)-3-oxopropyl-1-en-1-yl)-5,7-dihydroxy-2-phenyl-4H-chromogen-4-one (Compound 34), which was a yellow solid with a yield of 59%. 1 H NMR (300 MHz, DMSO-d6) δ 14.53 (s, 1H), 8.21 –8.03 (m, 6H), 7.91 – 7.85 (m, 2H), 7.81 – 7.73 (m, 4H), 7.65 – 7.58 (m, 3H),7.57 – 7.49 (m, 3H), 7.47 – 7.41 (m, 1H); 13 C NMR (126 MHz, DMSO-d6) δ 189.9,182.7, 164.7, 164.0, 163.0, 158.2, 144.7, 139.5, 137.4, 134.3, 132.7, 130.9,129.7, 129.6, 129.3, 128.8, 127.5, 127.5, 127.0, 123.3, 107.1, 105.8, 104.2,94.5; ESI-HRMS (m / z): [M + H] + calcd for C 30 H 21 O5: 461.1389, found 461.1380.HPLC, t R = 5.44 min, purity 95.45%.

[0212] Example 35

[0213] Following the method of Compound 1, acetophenone in step (1) was replaced with an equal amount of 4-fluoroacetophenone, and 2,4-dihydroxyacetophenone in step (3) was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, to prepare (E)-8-(3-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)-5,7-dihydroxy-2-phenyl-4H-chromogen-4-one (Compound 35), which was a yellow solid with a yield of 79%. 1H NMR (300 MHz, DMSO-d6) δ 14.53 (s, 1H), 12.03 (s, 1H), 8.13– 8.05 (m, 6H), 7.67 – 7.58 (m, 3H), 7.44 – 7.36 (m, 2H), 7.10 (s, 1H), 6.69(s, 1H); 13 C NMR (126 MHz, DMSO-d6) δ 188.9, 182.6, 164.6, 163.9, 163.0,158.2, 134.5, 132.6, 131.4, 131.4, 130.9, 129.6, 127.0, 122.9, 116.4, 116.2,107.0, 105.7, 104.2, 94.4; 19 F NMR (282 MHz, DMSO-d6) δ -106.55; ESI-HRMS (m / z): [M + H] + calcd for C 30 H 21 O5: 403.0982, found 403.0978. HPLC, t R = 4.19 min, purity 95.60%.

[0214] Example 36

[0215] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-nitroacetophenone, and in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone. (E)-5,7-dihydroxy-8-(3-(4-nitrophenyl)-3-oxoprop-1-en-1-yl)-2-phenyl-4H-chromogen-4-one (Compound 36) was prepared as a yellow solid with a yield of 88%. 1 H NMR (300 MHz, DMSO-d6) δ 14.60 (s, 1H), 12.10 (s, 1H), 8.44 – 8.32 (m, 2H), 8.22 – 8.15 (m, 2H), 8.14 – 8.03 (m, 4H), 7.70 – 7.49(m, 3H), 7.09 (s, 1H), 6.68 (s, 1H); 13C NMR (151 MHz, DMSO-d6) δ 182.7,174.4, 164.8, 164.1, 163.4, 158.5, 150.1, 143.5, 135.8, 132.7, 130.8, 129.9,129.7, 127.0, 124.5, 122.9, 106.8, 105.8, 104.2, 94.5; ESI-HRMS (m / z): [M +H] + calcd for C 24 H 16 NO7: 430.0927, found 430.0922. HPLC, t R = 12.39 min, purity 97.51%.

[0216] Example 37

[0217] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-ethylsulfonic acid acetophenone, and in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, to prepare (E)-4-(3-(5,7-dihydroxy-4-oxo-2-phenyl-4H-chromogen-8-yl)acryloyl)phenylethane sulfonate (Compound 37), which is a yellow solid with a yield of 51%. 1 H NMR (300 MHz, DMSO-d6) δ 14.53 (s, 1H), 12.04(s, 1H), 8.09 (d, J = 8.3 Hz, 6H), 7.73 – 7.41 (m, 5H), 7.08 (d, J = 1.5 Hz,1H), 6.67 (d, J = 3.2 Hz, 1H), 3.62 (q, J = 7.3 Hz, 2H), 1.41 (t, J = 7.3 Hz, 3H); 13 C NMR (151 MHz, DMSO-d6) δ 189.1, 182.6, 164.7, 163.9, 163.2, 158.3,149.1, 140.7, 135.3, 132.7, 131.6, 130.8, 129.6, 127.6, 127.0, 125.6, 122.7,120.4, 106.9, 105.7, 104.2, 94.4; ESI-HRMS (m / z): [M + H] + calcd for C 26 H21 O8S:493.0957, found 493.0956. HPLC, t R = 4.63 min, purity 97.85%.

[0218] Example 38

[0219] Following the method of Compound 1, acetophenone in step (1) was replaced with an equal amount of 3-fluoroacetophenone, and 2,4-dihydroxyacetophenone in step (3) was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, to prepare (E)-8-(3-(3-fluorophenyl)-3-oxoprop-1-en-1-yl)-5,7-dihydroxy-2-phenyl-4H-chromogen-4-one (Compound 38), which was a yellow solid with a yield of 65%. 1 H NMR (300 MHz, DMSO-d6) δ 14.69 – 14.26 (m, 1H), 12.04 (s,1H), 8.09 (q, J = 2.6 Hz, 5H), 7.93 – 7.37 (m, 6H), 7.11 (d, J = 16.5 Hz,1H), 6.67 (s, 1H); 13 C NMR (151 MHz, DMSO-d6) δ 189.4, 182.7, 164.7, 163.1,158.4, 140.9, 135.0, 132.7, 131.6, 130.9, 129.6, 127.0, 124.7, 123.0, 120.3,114.8, 105.8, 94.4; 19 F NMR (282 MHz, DMSO-d6) δ -112.05; ESI-HRMS (m / z): [M +H] + calcd for C 24 H 16 O5F: 403.0982, found 403.0983. HPLC, t R = 7.14 min, purity 95.37%.

[0220] Example 39

[0221] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-cyclohexyl acetophenone, and in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, to prepare (E)-4-(3-(5,7-dihydroxy-4-oxo-2-phenyl-4H-chromogen-8-yl)acryloyl)phenylcyclohexane carboxylate (Compound 39), which is a yellow solid with a yield of 74%. 1 H NMR (300 MHz, DMSO-d6) δ 14.51 (s, 1H),12.00 (s, 1H), 8.20 – 7.98 (m, 6H), 7.68 – 7.52 (m, 3H), 7.35 – 7.25 (m, 2H),7.07 (s, 1H), 6.66 (s, 1H), 2.65 (tt, J = 10.7, 3.7 Hz, 1H), 2.06 – 1.95 (m,2H), 1.81 – 1.69 (m, 2H), 1.69 – 1.20 (m, 6H); 13 C NMR (151 MHz, DMSO-d6) δ189.3, 182.6, 173.9, 164.6, 163.9, 163.0, 158.2, 154.4, 136.1, 134.4, 132.7,130.9, 130.2, 129.6, 127.0, 123.1, 122.7, 107.0, 105.7, 104.2, 94.4, 42.6,28.9, 25.7, 25.2; ESI-HRMS (m / z): [M + H] + calcd for C 31 H 27 O7: 511.1757, found511.1756. HPLC, t R = 6.76 min, purity 99.54%.

[0222] Example 40

[0223] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 2-thiophene acetophenone, and in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, to prepare (E)-5,7-dihydroxy-8-(3-oxo-3-(thiophen-2-yl)prop-1-en-1-yl)-2-phenyl-4H-chromogen-4-one (Compound 40), which was a yellow solid with a yield of 70%. 1H NMR (300 MHz, DMSO-d6) δ 14.49 (s, 1H), 12.03 (s, 1H),8.17 – 8.01 (m, 5H), 7.96 (dd, J = 3.8, 1.1 Hz, 1H), 7.69 – 7.53 (m, 3H),7.30 (dd, J = 4.9, 3.8 Hz, 1H), 7.09 (s, 1H), 6.68 (s, 1H); 13 C NMR (151 MHz, DMSO-d6) δ 182.7, 182.6, 164.6, 163.9, 163.0, 158.2, 146.0, 135.2, 133.5, 132.7, 132.6, 130.9, 129.6, 129.4, 127.0, 123.2, 106.8, 105.8, 104.2, 94.4;ESI-HRMS (m / z): [M + H] + calcd for C 22 H 15 O5S: 391.0640, found 391.0637. HPLC,t R = 5.01 min, purity 95.63%.

[0224] Example 41

[0225] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-chloroacetophenone, and in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, to prepare (E)-8-(3-(4-chlorophenyl)-3-oxoprop-1-en-1-yl)-5,7-dihydroxy-2-phenyl-4H-chromogen-4-one (Compound 41), which was a yellow solid with a yield of 49%. 1 H NMR (300 MHz, DMSO-d6) δ 14.54 (s, 1H), 12.03 (s, 1H), 8.10 (d, J = 4.1 Hz, 4H), 8.05 – 7.94 (m, 2H), 7.69 – 7.53 (m, 5H), 7.08 (s, 1H),6.67 (s, 1H); 13C NMR (151 MHz, DMSO-d6) δ 182.6, 164.6, 163.9, 163.1, 158.2,138.1, 137.2, 134.7, 132.7, 130.8, 130.4, 129.6, 129.4, 127.0, 122.8, 106.9,105.7, 104.2, 94.4; ESI-HRMS (m / z): [M + H] + calcd for C 24 H 16 O5Cl: 419.0686, found 419.0681. HPLC, t R = 4.81 min, purity 97.78%.

[0226] Example 42

[0227] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 5-benzofuran acetophenone, and in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone. (E)-8-(3-(benzofuran-5-yl)-3-oxoprop-1-en-1-yl)-5,7-dihydroxy-2-phenyl-4H-chromogen-4-one (Compound 42) was prepared as a yellow solid with a yield of 47%. 1 H NMR (300 MHz, DMSO-d6) δ 14.59 (s, 1H), 12.08 (s,1H), 8.16 – 8.07 (m, 4H), 7.92 (dd, J = 4.2, 0.9 Hz, 1H), 7.89 – 7.84 (m,1H), 7.81 – 7.72 (m, 1H), 7.63 – 7.52 (m, 4H), 7.45 – 7.33 (m, 1H), 7.12 (d,J = 13.2 Hz, 1H), 6.68 (d, J = 4.4 Hz, 1H); 13C NMR (151 MHz, DMSO-d6) δ191.4, 182.6, 180.0, 164.7, 164.0, 163.3, 158.4, 155.6, 154.1, 133.9, 129.6,127.0, 124.5, 124.1, 122.8, 113.9, 112.7, 107.1, 106.8, 105.8, 105.7, 104.2,95.1, 94.4; ESI-HRMS (m / z): [M + H] + calcd for C 26 H 17 O6: 425.1025, found425.1028. HPLC, t R = 5.94 min, purity 96.74%.

[0228] Example 43

[0229] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 3-trifluoromethoxyacetophenone, and in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone. (E)-5,7-dihydroxy-8-(3-oxo-3-(3-(trifluoromethoxy)phenyl)prop-1-en-1-yl)-2-phenyl-4H-chromogen-4-one (Compound 43) was prepared as a yellow solid with a yield of 68%. 1 H NMR (300 MHz, DMSO-d6) δ 14.53 (s, 1H), 12.05 (s, 1H), 8.10 – 7.99 (m, 5H), 7.76 – 7.55 (m, 6H), 7.07 (s, 1H), 6.66(s, 1H); 13 C NMR (151 MHz, DMSO-d6) δ 191.4, 189.3, 182.6, 164.6, 163.9,163.1, 158.2, 152.4, 137.3, 134.7, 130.8, 130.7, 129.6, 127.0, 127.0, 122.9,122.9, 106.9, 105.7, 104.2, 94.4, 45.5, 8.5; 19 F NMR (282 MHz, DMSO-d6) δ -56.79; ESI-HRMS (m / z): [M + H] + calcd for C 25H 16 O6F3: 469.0899, found 469.0899.HPLC, t R = 4.67 min, purity 99.98%.

[0230] Example 44

[0231] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-cyanoacetophenone, and in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, to prepare (E)-4-(3-(5,7-dihydroxy-4-oxo-2-phenyl-4H-chromogen-8-yl)acryloyl)benzonitrile (Compound 44), which is a yellow solid with a yield of 52%. 1 H NMR (300 MHz, DMSO-d6) δ 14.55 (d, J = 1.3 Hz, 1H), 12.04 (s,1H), 8.06 (t, J = 3.3 Hz, 5H), 7.59 (tt, J = 8.8, 4.9 Hz, 4H), 7.06 (d, J =1.7 Hz, 1H), 6.64 (d, J = 2.2 Hz, 1H), 1.40 (s, 1H), 0.99 – 0.77 (m, 1H); 13 CNMR (151 MHz, DMSO-d6) δ 191.4, 189.7, 182.8, 182.6, 135.6, 133.3, 133.0,129.6, 129.1, 127.1, 127.0, 122.7, 118.7, 115.1, 107.2, 105.9, 105.7, 104.2,95.1, 94.4, 26.8; ESI-HRMS (m / z): [M + H] + calcd for C 25 H 16 NO5: 410.1028, found410.1024. HPLC, t R = 8.80 min, purity 93.60%.

[0232] Example 45

[0233] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-trifluoromethylacetophenone, and in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone. This yielded (E)-5,7-dihydroxy-8-(3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-2-phenyl-4H-chromogen-4-one (Compound 45), which was a yellow solid with a yield of 79%. 1 H NMR (300 MHz, DMSO-d6) δ 14.57 (s, 1H), 12.07 (s, 1H), 8.19 – 8.03 (m, 6H), 7.94 (d, J = 8.2 Hz, 2H), 7.69 – 7.52 (m,3H), 7.09 (s, 1H), 6.67 (s, 1H); 13 C NMR (151 MHz, DMSO-d6) δ 189.8, 182.6,164.7, 163.9, 163.3, 158.4, 141.9, 135.4, 132.7, 130.8, 129.6, 129.3, 127.0,126.3, 126.2, 123.3, 122.8, 106.9, 105.7, 104.2, 94.4; 19 F NMR (282 MHz, DMSO-d6) δ -61.47; ESI-HRMS (m / z): [M + H] + calcd for C 25 H 16 O5F3: 453.0950, found453.0951. HPLC, t R = 6.66 min, purity 95.41%.

[0234] Example 46

[0235] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of acetone, and in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, to prepare (E)-5,7-dihydroxy-8-(3-oxobut-1-en-1-yl)-2-phenyl-4H-chromogen-4-one (Compound 46), which was a yellow solid with a yield of 62%. 1HNMR (300 MHz, DMSO-d6) δ 14.32 (d, J = 10.4 Hz, 1H), 11.91 (s, 1H), 8.06 (t,J = 7.8 Hz, 2H), 7.77 (dd, J = 16.8, 8.2 Hz, 1H), 7.58 (tq, J = 11.6, 4.3 Hz, 3H), 7.16 (dd, J = 16.1, 7.4 Hz, 1H), 7.01 (d, J = 10.3 Hz, 1H), 6.65 – 6.55(m, 1H), 2.26 (d, J = 5.2 Hz, 3H); 13 C NMR (151 MHz, DMSO-d6) δ 199.0, 182.6,164.7, 163.9, 162.6, 158.1, 132.8, 132.7, 130.9, 129.6, 128.9, 127.0, 106.5,105.7, 104.0, 94.5, 28.1; ESI-HRMS (m / z): [M + H] + calcd for C 19 H 15 O5:323.0919, found 323.0923. HPLC, t R = 3.91 min, purity 90.03%.

[0236] Example 47

[0237] Following the method of Compound 1, acetophenone in step (1) was replaced with an equal amount of cyclopropylacetophenone, and 2,4-dihydroxyacetophenone in step (3) was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, to prepare (E)-8-(3-cyclopropyl-3-oxopropyl-1-en-1-yl)-5,7-dihydroxy-2-phenyl-4H-chromogen-4-one (Compound 47), which was a yellow solid with a yield of 51%. 1H NMR (300 MHz, DMSO-d6) δ 14.31 (s, 1H), 11.84 (s, 1H), 8.10 –7.99 (m, 2H), 7.83 (d, J = 16.3 Hz, 1H), 7.57 (qd, J = 7.7, 3.7 Hz, 3H), 7.35(d, J = 16.3 Hz, 1H), 7.00 (s, 1H), 6.59 (s, 1H), 2.33 – 2.21 (m, 1H), 0.99 –0.88 (m, 4H); 13 C NMR (151 MHz, DMSO-d6) δ 200.2, 182.6, 164.4, 163.9, 162.6,158.0, 132.6, 131.6, 130.9, 129.6, 128.0, 127.0, 106.6, 105.7, 104.1, 94.3,19.9, 10.9; ESI-HRMS (m / z): [M + H] + calcd for C 21 H 17 O5: 349.1076, found349.1080. HPLC, t R = 4.21 min, purity 95.30%.

[0238] Example 48

[0239] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-pyridineacetophenone, and in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, to prepare (E)-5,7-dihydroxy-8-(3-oxo-3-(pyridin-4-yl)prop-1-en-1-yl)-2-phenyl-4H-chromogen-4-one (Compound 48), which was a yellow solid with a yield of 73%. 1H NMR (300 MHz, DMSO-d6) δ 14.50 (s, 1H), 9.10 (dt, J =2.8, 1.4 Hz, 1H), 8.81 (dd, J = 4.8, 1.6 Hz, 1H), 8.28 (ddt, J = 7.2, 5.2,1.9 Hz, 1H), 8.15 – 7.98 (m, 4H), 7.71 – 7.43 (m, 4H), 7.05 (s, 1H), 6.64 (s,1H), 1.18 (t, J = 7.1 Hz, 1H); 13 C NMR (151 MHz, DMSO-d6) δ 189.7, 182.6,164.7, 163.2, 158.3, 153.4, 153.3, 149.5, 149.5, 136.1, 135.1, 130.8, 129.6,129.6, 126.9, 124.4, 106.8, 105.7, 94.4; ESI-HRMS (m / z): [M + H] + calcd forC 23 H 16 NO5: 386.1028, found 386.1032. HPLC, t R = 7.42 min, purity 97.46%.

[0240] Example 49

[0241] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-hydroxyacetophenone, and in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone. This yielded (E)-5,7-dihydroxy-8-(3-(4-hydroxyphenyl)-3-oxopropyl-1-en-1-yl)-2-phenyl-4H-chromogen-4-one (Compound 49), which was a yellow solid with a yield of 59%. 1H NMR (300 MHz, DMSO-d6) δ 14.44 (s, 1H), 11.91 (s, 1H), 10.39 (s, 1H), 8.19 – 8.09 (m, 2H), 8.08 (d, J = 1.9 Hz, 1H), 8.02 (d, J =15.8 Hz, 1H), 7.96 – 7.85 (m, 2H), 7.59 (qd, J = 7.6, 3.7 Hz, 3H), 7.07 (s,1H), 7.04 – 6.86 (m, 2H), 6.67 (s, 1H); 13 C NMR (151 MHz, DMSO-d6) δ 188.5,182.6, 164.4, 163.9, 162.7, 162.3, 157.9, 133.0, 132.6, 131.1, 130.9, 130.1,129.6, 126.9, 123.5, 115.9, 107.2, 105.7, 104.2, 94.4; ESI-HRMS (m / z): [M +H] + calcd for C 24 H 17 O6: 401.1025, found 401.1024. HPLC, t R = 7.00 min, purity 96.52%.

[0242] Example 50

[0243] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-trifluoromethylacetophenone; in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone; and in step (4), benzaldehyde was replaced with an equal amount of 4-methoxybenzaldehyde. This yielded (E)-5,7-dihydroxy-2-(4-methoxyphenyl)-8-(3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-4H-chromogen-4-one (Compound 50), a yellow solid with a yield of 68%. 1H NMR (300 MHz, DMSO-d6) δ 14.72 (s, 1H), 12.03 (s, 1H), 8.16 (d, J = 8.1 Hz, 2H), 8.12 (s, 2H), 8.10 – 8.05 (m, 2H), 7.95 (d, J = 8.2 Hz,2H), 7.18 – 7.09 (m, 2H), 7.01 (s, 1H), 6.67 (s, 1H), 3.87 (s, 3H); 13 C NMR (151 MHz, DMSO-d6) δ 189.6, 182.4, 164.4, 163.9, 163.3, 162.9, 158.2, 141.8,135.5, 132. 4 (J C-F = 31.5 Hz), 129.2, 126.2 (J C-F = 4.5 Hz), 122.9, 122.5,115.0, 55.9; 19 F NMR (282 MHz, DMSO-d6) δ -61.49; ESI-HRMS (m / z): [M + H] + calcd for C 26 H 18 O6F3: 483.1055, found 483.1056. HPLC, t R = 5.67 min, purity 95.00%.

[0244] Example 51

[0245] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-trifluoromethylacetophenone; in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone; and in step (4), benzaldehyde was replaced with an equal amount of 4-fluorobenzaldehyde. This yielded (E)-2-(4-fluorophenyl)-5,7-dihydroxy-8-(3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-4H-chromogen-4-one (Compound 51), a yellow solid with a yield of 71%. 1H NMR (300 MHz, DMSO-d6) δ 14.54 (s, 1H), 12.07 (s, 1H), 8.21 – 8.06(m, 6H), 7.93 (d, J = 8.1 Hz, 2H), 7.42 (t, J = 8.8 Hz, 2H), 7.08 (s, 1H),6.66 (s, 1H); 13 C NMR (151 MHz, DMSO-d6) δ 189.6, 182.5, 165.6, 164.7, 164.0,163.2, 162.9, 158.2, 141.8, 135.3, 132.4 (J C-F = 33.0 Hz), 129.7 (J C-F = 12Hz), 129.2 (J C-F = 6.0 Hz), 127.3, 126.2 (J C-F = 3.0 Hz), 122.6, 116.6, 106.8,105.5, 104.0, 94.4; 19 F NMR (282 MHz, DMSO-d6) δ -61.47, -107.27; ESI-HRMS (m / z): [M + H] + calcd for C 25 H 15 O5F4: 471.0856, found 471.0858. HPLC, t R = 5.19 min, purity 98.71%.

[0246] Example 52

[0247] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-trifluoromethylacetophenone, in step (3) 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone, and in step (4) benzaldehyde was replaced with an equal amount of 3,4-dimethoxybenzaldehyde. (E)-2-(3,4-dimethoxyphenyl)-5,7-dihydroxy-8-(3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-4H-chromogen-4-one (Compound 52) was prepared as a yellow solid with a yield of 82%. 1H NMR (300 MHz, DMSO-d6) δ 14.71 (s, 1H), 12.00 (s,1H), 8.21 – 8.07 (m, 4H), 7.94 (d, J = 8.2 Hz, 2H), 7.71 (dd, J = 8.5, 2.2Hz, 1H), 7.58 (dd, J = 6.8, 2.2 Hz, 1H), 7.15 – 7.08 (m, 2H), 6.67 (s, 1H), 3.87 (d, J = 9.8 Hz, 6H); 13 C NMR (151 MHz, DMSO-d6) δ 189.9, 182.6, 164.5,164.2, 163.3, 158.4, 152.9, 149.5, 141.9, 135.5, 129.3, 126.3, 123.0, 122.8,120.8, 112.1, 110.0, 106.7, 104.4, 104.0, 94.4, 56.3, 56.2; 19 F NMR (282 MHz, DMSO-d6) δ -61.50; ESI-HRMS (m / z): [M + H] + calcd for C 27 H 20 O7F3: 513.1161, found 513.1160. HPLC, t R = 4.58 min, purity 98.31%.

[0248] Example 53

[0249] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-trifluoromethylacetophenone; in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone; and in step (4), benzaldehyde was replaced with an equal amount of furfural. This yielded (E)-2-(furan-2-yl)-5,7-dihydroxy-8-(3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-4H-chromogen-4-one (Compound 53), a yellow solid with a yield of 48%. 1H NMR (300 MHz, DMSO-d6) δ 14.56 (s, 1H), 8.21 – 8.10 (m, 4H), 7.95 (d, J =8.2 Hz, 2H), 7.52 (d, J = 3.6 Hz, 1H), 6.83 (dt, J = 5.7, 2.8 Hz, 2H), 6.65(s, 1H), 6.53 (s, 1H); 13 C NMR (151 MHz, DMSO-d6) δ 189.9, 181.9, 165.0,163.3, 157.9, 155.7, 148.2, 145.3, 141.9, 135.5 (J C-F = 33.0 Hz), 132.7,129.3, 126.3, 122.9, 115.6, 113.7, 107.0, 104.1, 103.2, 94.4; 19 F NMR (282MHz, DMSO-d6) δ -61.50; ESI-HRMS (m / z): [M + H] + calcd for C 23 H 14 O6F3: 443.0742, found 443.0745. HPLC, t R = 5.74 min, purity 95.52%.

[0250] Example 54

[0251] Following the method of Compound 1, in step (1), acetophenone was replaced with an equal amount of 4-trifluoromethylacetophenone; in step (3), 2,4-dihydroxyacetophenone was replaced with an equal amount of 2,4,6-trihydroxyacetophenone; and in step (4), benzaldehyde was replaced with an equal amount of 4-methylbenzaldehyde. This yielded (E)-5,7-dihydroxy-8-(3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-2-(p-tolyl)-4H-chromogen-4-one (Compound 54), a yellow solid with a yield of 70%. 1H NMR (300 MHz, DMSO-d6) δ 14.61 (s, 1H), 12.03 (s, 1H), 8.16 – 8.06(m, 4H), 7.94 (dd, J = 10.1, 8.2 Hz, 4H), 7.37 (d, J = 8.1 Hz, 2H), 7.01 (s,1H), 6.63 (s, 1H), 2.38 (s, 3H); 13 C NMR (151 MHz, DMSO-d6) δ 190.0, 182.7,164.6, 164.2, 163.3, 158.4, 143.1, 141.9, 135.5, 132.5, 130.3, 129.3, 128.1,127.0, 126.3, 122.9, 106.8, 105.1, 104.2, 95.1, 94.4, 21.6; 19 F NMR (282 MHz, DMSO-d6) δ -61.48; ESI-HRMS (m / z): [M + H] + calcd for C 26 H 18 O5F3: 467.1106, found 467.1104. HPLC, t R = 4.17 min, purity 95.79%.

[0252] Example 55

[0253] A solution of compound 17 (388 mg, 1.0 mmol), 4-[(6-bromohexyl)oxy]-N'-hydroxybenzomidine (314 mg, 1.0 mmol), and potassium carbonate (276 mg, 2 mmol) in anhydrous DMF (10 mL) was stirred at 65 °C for 12 hours. After the reaction was complete, the mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by normal-phase silica gel column chromatography (dichloromethane / methanol volume ratio 20:1) to give compound 55((E)-4-((6-((2,3-dimethyl-4-oxo-8-((E)-3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-4H-chromogenen-7-yl)oxy)hexyl)oxy)-N'-hydroxybenzomididine), as a white solid, in 77% yield. 1H NMR (300 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.29 – 8.13 (m, 4H), 8.08 (d, J = 9.0 Hz, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.60 – 7.52 (m,2H), 7.29 (d, J = 9.1 Hz, 1H), 6.89 – 6.80 (m, 2H), 5.73 (s, 2H), 4.29 (t, J = 6.1 Hz, 2H), 3.93 (t, J = 6.3 Hz, 2H), 2.49 – 2.46 (m, 3H), 1.97 – 1.92 (m,3H), 1.89 (d, J = 8.3 Hz, 2H), 1.69 (t, J = 6.7 Hz, 2H), 1.52 (s, 4H); 13 C NMR(151 MHz, DMSO-d6) δ 191.3, 177.7, 164.0, 163.8, 161.3, 157.0, 152.8, 143.1,135.5, 134.3, 131.0, 130.9, 128.7, 127.9, 127.2, 117.9, 115.9, 112.4, 71.4,69.4, 30.5, 27.4, 27.2, 20.1, 11.5; 19 F NMR (282 MHz, DMSO-d6) δ -61.54; ESI-HRMS (m / z): [M + H] + calcd for C 34 H 34 N2O6F: 623.2369, found 623.2373. HPLC, t R =6.03 min, purity 99.61%.

[0254] Example 56

[0255] Following the method for compound 55, in step (1), compound 17 was replaced with an equal amount of compound 18 to prepare (E)-4-((6-((8-(((E)-3-(4-cyanophenyl)-3-oxoprop-1-en-1-yl)-2,3-dimethyl-4-oxo-4H-chromogenen-7-yl)oxy)hexyl)oxy)-N'-hydroxybenzamide (compound 56), which is a yellow solid with a yield of 75%. 1HNMR (300 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.17 – 8.05 (m, 7H), 7.60 – 7.53 (m,2H), 7.30 (d, J = 9.1 Hz, 1H), 6.91 – 6.83 (m, 2H), 5.77 (s, 2H), 4.29 (t, J= 6.1 Hz, 2H), 3.95 (t, J = 6.3 Hz, 2H), 2.49 – 2.46 (m, 3H), 1.97 – 1.94 (m,3H), 1.89 (s, 2H), 1.70 (t, J = 6.5 Hz, 2H), 1.52 (s, 4H); 13 C NMR (151 MHz, DMSO-d6) δ 189.6, 176.1, 162.5, 162.2, 159.7, 155.4, 151.1, 141.6, 134.1,133.4, 129.1, 127.1, 126.1, 125.4, 118.6, 116.4, 115.5, 114.4, 110.8, 110.7,69.9, 67.8, 29.1, 25.9, 25.7, 18.6, 10.0; ESI-HRMS (m / z): [M + H] + calcd forC 34 H 34 N3O6: 580.2448, found 580.2445. HPLC, t R = 8.83 min, purity 99.46%.

[0256] Example 57

[0257] Following the method for compound 55, in step (1), compound 17 was replaced with an equal amount of compound 45, and 4-[(6-bromohexyl)oxy]-N'-hydroxybenzamide was replaced with an equal amount of 4-[(2-bromoethyl)oxy]-N'-hydroxybenzamide to prepare (E)-N'-hydroxy-4-(2-((5-hydroxy-4-oxo-8-((E)-3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-2-phenyl-4H-chromogenen-7-yl)oxy)ethoxy)benzamide (compound 57), which was a yellow solid with a yield of 61%. 1H NMR (300 MHz, DMSO-d6) δ 14.20 (s, 1H), 9.52 (s, 1H), 8.05 (t,J = 3.6 Hz, 4H), 7.91 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.56 (q,J = 8.2 Hz, 3H), 7.39 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.8 Hz, 4H), 5.75 (s,2H), 4.59 (d, J = 18.0 Hz, 4H); 13 C NMR (151 MHz, DMSO-d6) δ 188.9, 182.6,164.1, 162.3, 159.3, 158.7, 150.7, 141.2, 134.1, 132.8, 132.4, 130.6, 129.5,128.9, 127.2, 126.9, 125.9, 122.6, 114.6, 107.3, 106.0, 105.2, 92.5, 68.6,66.5; 19 F NMR (282 MHz, DMSO-d6) δ -61.65; ESI-HRMS (m / z): [M + H] + calcd forC 34 H 26 N2O7F3: 631.1692, found 631.1696. HPLC, t R = 6.31 min, purity 99.99%.

[0258] Example 58

[0259] Following the method of compound 55, in step (1), compound 17 was replaced with an equal amount of compound 45, and 4-[(6-bromohexyl)oxy]-N'-hydroxybenzamide was replaced with an equal amount of 4-[(4-bromobutyl)oxy]-N'-hydroxybenzamide to prepare (E)-N'-hydroxy-4-(4-((5-hydroxy-4-oxo-8-((E)-3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-2-phenyl-4H-chromogenen-7-yl)oxy)butoxy)benzamide (compound 58), which was a yellow solid with a yield of 54%. 1H NMR (300 MHz, DMSO-d6) δ 14.34 (s, 1H), 9.49 (s, 1H), 8.05 (dt,J = 14.4, 5.9 Hz, 6H), 7.87 – 7.82 (m, 2H), 7.65 – 7.51 (m, 5H), 7.08 (s,1H), 6.98 – 6.89 (m, 3H), 5.78 (s, 2H), 4.29 (s, 2H), 4.09 (t, J = 5.9 Hz,2H), 2.08 – 1.94 (m, 4H); 13 C NMR (151 MHz, DMSO-d6) δ 189.4, 182.6, 164.2,164.0, 162.4, 159.7, 158.7, 151.2, 141.7, 134.6, 132.7, 130.5, 129.5, 129.1,127.2, 126.8, 126.1, 122.9, 114.4, 107.2, 105.8, 104.9, 92.2, 69.7, 67.6,40.5, 40.3, 40.2, 40.0, 39.9, 39.8, 39.6, 25.9, 25.7; 19 F NMR (282 MHz, DMSO-d6) δ -61.52; ESI-HRMS (m / z): [M + H] + calcd for C 36 H 30 N2O7F3: 659.2005, found659.2002. HPLC, t R = 7.58 min, purity 99.39%.

[0260] Example 59

[0261] Following the method for compound 55, in step (1), compound 17 was replaced with an equal amount of compound 45 to prepare (E)-N'-hydroxy-4-((6-((5-hydroxy-4-oxo-8-((E)-3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-2-phenyl-4H-chromogenen-7-yl)oxy)hexyl)oxy)benzamide (compound 59), which was a yellow solid with a yield of 70%. 1H NMR (300 MHz, DMSO-d6) δ 14.36 (s, 1H), 9.54 (s, 1H), 8.07 (dd, J =13.5, 7.9 Hz, 6H), 7.90 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.2 Hz, 5H), 7.11(s, 1H), 6.99 (s, 1H), 6.90 (d, J = 8.5 Hz, 2H), 5.89 (s, 2H), 4.24 (s, 2H), 3.97 (t, J = 6.4 Hz, 2H), 1.90 (s, 2H), 1.72 (s, 2H), 1.53 (s, 4H); 13 C NMR(151 MHz, DMSO-d6) δ 189.5, 182.6, 164.2, 164.0, 162.7, 162.4, 158.7, 141.7,134.7, 132.7, 130.6, 129.8, 129.5, 129.1, 128.9, 126.8, 126.1, 122.9, 115.1,107.1, 105.8, 104.9, 92.2, 70.0, 68.4, 40.5, 40.3, 40.2, 40.0, 39.9, 39.8,39.6, 28.9, 28.8, 25.9, 25.7; 19 F NMR (282 MHz, DMSO-d6) δ -61.49; ESI-HRMS(m / z): [M + H] + calcd for C 38 H 34 N2O7F3: 687.2318, found 687.2317. HPLC, t R =6.21 min, purity 99.87%.

[0262] Example 60

[0263] Inhibitory effect of compound on nitric oxide production in lipopolysaccharide (LPS)-stimulated RAW264 cells

[0264] Preparation method of drug-containing culture medium: Take out different concentrations of compounds (compound 1-compound 59) from DMSO stock solution and dilute them to the final concentration with DMEM complete medium to ensure that the final concentration of DMSO is 0.1% (v / v).

[0265] RAW264.7 cells were fed at a rate of 1×10⁻⁶. 5 Cells were seeded at a density of [number] cells / mL in 96-well plates and cultured for 24 hours in DMEM complete medium containing 10% fetal bovine serum (FBS). The old medium was discarded, and the blank control group was replaced with fresh complete medium. All other groups were stimulated with fresh complete medium containing lipopolysaccharide (LPS, final concentration 1 μg / mL) for 30 minutes. After stimulation, the medium was replaced with drug-containing medium and incubated for another 24 hours. The amount of NO generated in the medium was detected using a nitric oxide assay kit, and the absorbance was measured at 560 nm. IC50 was analyzed using GraphPad Prism 8.0 software (San Diego, USA, RRID: SCR_002798). 50 Values ​​and curve fitting.

[0266] Table 1. Inhibitory effect of the compounds of this invention on nitric oxide production in LPS-stimulated RAW264 cells.

[0267]

[0268] Note: a The positive control LTB-019 is a leukotriene B4 receptor 1 antagonist—moxiluban hydrochloride (CAS: 146957-32-6).

[0269] The experimental results are shown in Table 1, indicating that compounds 24, 26, 32, 34, 36, 37, 41, 44, 45, 50, 52-54, and 57-59 exhibited strong inhibitory activity against nitric oxide in lipopolysaccharide-stimulated RAW264 cells, with activity below 200 nM. Example 62

[0270] Treatment medium: The DMSO stock solution of the compound was diluted with the corresponding complete medium to obtain a treatment medium containing a series of compounds with a final DMSO concentration of 0.1% (v / v).

[0271] Selective inhibitory activity of active compounds against BLT1 and BLT2: The experiment used a recombinant HEK293 cell line (Sino Biological) stably expressing human BLT1 or BLT2 receptors and carrying NF-κB response elements from firefly luciferase reporter genes. The recombinant cell line was seeded into 96-well plates in DMEM complete medium containing 10% fetal bovine serum (FBS) and allowed to adhere overnight. It was then pre-incubated with treatment media containing different concentration gradients of the test compounds, followed by incubation with a fixed concentration (EC50). 80Cells were stimulated with the natural agonist leukotriene B4 (MedChemExpress) and incubated for 5 hours to allow receptor signaling, NF-κB activation, and luciferase expression to proceed. Then, luciferase detection reagent was added to lyse the cells and initiate the luminescence reaction. The luminescence signal was measured using a microplate reader (BMG CLARIOstar Plus, BMG GmbH, Germany). Finally, relative luciferase activity, dose-dependent inhibition rate, and IC50 were calculated and fitted. 50 The IC50 values ​​were used to derive the selectivity index of the compounds for inhibiting BLT2 and BLT1 activity. IC50 values ​​were analyzed using GraphPad Prism 8.0 software (San Diego, USA, RRID: SCR_002798). 50 Values ​​and curve fitting.

[0272] Table 2. Inhibitory effects of compounds on BLT1 / BLT2 receptors

[0273]

[0274] Note: b Selectivity index: refers to the half-maximal inhibitory concentration (IC50) of BLT2. 50 ) and the half-maximal inhibitory concentration (IC50) of BLT1 50 The ratio of ).

[0275] The experimental results are shown in Table 2, which shows that compounds 57-59 exhibit approximately 20-fold selectivity for BLT1.

[0276] Example 63

[0277] Treatment medium: prepared by diluting the DMSO stock solution of the compound with the corresponding complete medium, ensuring that the final concentration of DMSO is 0.1% (v / v).

[0278] Cytotoxicity evaluation of the compounds: NCM460 cells (normal human colonic epithelial cells) were cultured in RPMI-1640 complete medium containing 10% fetal bovine serum, HFL1 cells (human embryonic lung fibroblasts) were cultured in F12K complete medium containing 10% fetal bovine serum, and HaCaT cells (human immortalized keratinocytes) were cultured in DMEM complete medium containing 10% fetal bovine serum. All cells were routinely cultured in a 37°C, 5% CO2 incubator. HFL1, NCM460, and HaCaT cells were all cultured at a rate of 1×10⁻⁶ cells / mL. 5Cells were seeded at a density of 100 cells / mL in 96-well plates and cultured for 24 h. The culture medium was then discarded, and each group was replaced with a treatment medium containing different concentrations of the target compound. A blank control group was included (replaced with the corresponding fresh complete culture medium). Three replicates were performed. After another 48 h of incubation, 20 μL of MTT solution (5 mg / mL) was added to each well, and the cells were cultured for another 4 h. The supernatant was discarded, and 150 μL of DMSO was added to each well. The plates were shaken for 10 min, and the absorbance was measured at 490 nm. The half-maximal concentration (IC50) was calculated using GraphPad Prism 8.0 software (San Diego, USA, RRID: SCR_002798). 50 value).

[0279] Table 3. Cytotoxic effects of the compounds on three types of normal human cell lines (NCM460, HaCaT, and HFL1)

[0280]

[0281] The experimental results are shown in Table 3, which shows that compounds 32, 52, 56, 57, and 58-59 exhibited the lowest cytotoxicity (CC50 > 100 μM).

[0282] Based on the above results regarding anti-inflammatory activity, selectivity, and cytotoxicity, compound 59 is preferred.

[0283] Example 64

[0284] All working solutions of Compound 59 were prepared using an aqueous solution containing 0.1% Tween 20.

[0285] Pharmacokinetic determination of compound 59: Ten SD rats were randomly divided into two groups (n=5 per group): an intravenous injection group and an oral administration group, which were administered compound 59 via tail vein injection (5 mg / kg) and gavage (20 mg / kg), respectively. Blood samples were collected from the retroorbital venous plexus at predetermined time points (0.05 h, 0.083 h, 0.167 h, 0.25 h, 0.5 h, 0.75 h, 1 h, 2 h, 4 h, 6 h, 9 h, 12 h, and 24 h), with 150 μL collected at each time point. The concentration of the compound in the plasma samples of SD rats was determined by LC-MS / MS, and pharmacokinetic parameters were calculated using WinNolin software.

[0286] Table 4. Pharmacokinetic characteristics of compound 59

[0287]

[0288] The experimental results are shown in Figure 4The results showed that the half-life of the intravenous injection group was 0.74 h, the mean residence time was 1.58 h, and the AUC was 733.60 h·ng / mL; the half-life of the oral administration group was 1.34 h, the Tmax was 2 h, the Cmax was 711.10 ng / mL, the AUC was 2504.40 h·ng / mL, and the oral bioavailability was 85.30%. This indicates that compound 59 has good drug-like properties.

[0289] Example 64: Pharmacodynamic study of compound 59

[0290] 1. LPS-induced acute lung injury model in mice and drug treatment

[0291] The working solutions of dexamethasone and compound 59 were both prepared using an aqueous solution containing 0.1% Tween 20.

[0292] Mice were randomly divided into six experimental groups: a blank control group, an ALI model group (5 mg / kg LPS, intratracheal infusion), an ALI + dexamethasone (Dex) group (2 mg / kg, gavage), and an ALI + compound 59 group (5, 10, and 20 mg / kg, gavage). The animal dosing time period is detailed below. Figure 1 Mice in the A group, dexamethasone group, and different concentrations of compound groups were pre-administered once daily for 7 consecutive days. The blank control group and ALI model group received an equal volume of 0.1% Tween 20. On day 8, mice were anesthetized with isoflurane. Except for the blank control group, all other groups were induced with acute lung injury by intratracheal infusion of LPS (5 mg / kg, dissolved in distilled water). An acute lung injury model was successfully established 6 hours after LPS treatment. Mice in the dexamethasone group and different concentrations of compound groups were administered the corresponding drugs by gavage, while mice in the blank control group and ALI model group were given an equal volume of solvent (an aqueous solution containing 0.1% Tween 20). 24 hours after administration, mice were sacrificed by carbon dioxide over-inhalation, lung tissue was collected, lung wet-to-dry weight ratio was measured, lung histopathology was observed using HE staining, and RAGE expression was examined using immunohistochemical analysis.

[0293] Experimental results are as follows Figure 1 This indicates that LPS stimulation leads to an increase in the wet-to-dry weight ratio of the lungs. Treatment with compound 59 alleviated the aforementioned lung injury, manifested as a decrease in the wet-to-dry weight ratio. Figure 1 Histopathological examination revealed that LPS-induced lung injury was characterized by interstitial thickening, alveolar collapse, and alveolar fusion. Immunohistochemical analysis showed that LPS exposure upregulated the protein level of RAGE (a pattern recognition receptor that amplifies NF-κB-driven inflammatory signaling). Figure 1 (C). Treatment with compound 59 alleviated these lung injuries, as evidenced by a decrease in lung injury scores.

[0294] 2. Mouse sepsis model and drug treatment

[0295] Mice were randomly divided into six experimental groups: a blank control group, an LPS model group (15 mg / kg LPS), an LPS + dexamethasone group (2 mg / kg, by gavage), and an LPS + compound 59 group (10 and 20 mg / kg, by gavage). The animal dosing schedule is detailed below. Figure 2 Mice in the A group, dexamethasone group, and different concentrations of compound groups were pre-administered once daily for 7 consecutive days. The blank control group and LPS model group were given an equal volume of 0.1% Tween 20. On day 8, mice in the LPS model group and each LPS+compound group were intraperitoneally injected with LPS (15 mg / kg, dissolved in distilled water) to induce and successfully establish a sepsis model. Mice in the blank control group were intraperitoneally injected with an equal volume of physiological saline. Survival rates of mice were continuously recorded over 36 hours. After 36 hours, blood was collected from mice, and mice were euthanized by carbon dioxide overdose. Lung tissue was collected, and the wet-to-dry weight ratio of the lungs and the protein levels of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in the lung tissue were detected. HE staining was used to observe lung tissue pathology, and immunohistochemical analysis was used to examine RAGE expression.

[0296] Experimental results are as follows Figure 2 The results showed that within 36 hours after modeling, the mortality rate of mice in the LPS group was 37.5%, indicating a low survival rate. However, treatment with compound 59 (20 mg / kg) significantly improved the survival rate of the mice. Figure 2 (B). Compared with the blank control group, LPS treatment increased the lung wet-to-dry weight ratio, while compound 59 pretreatment decreased this ratio (B). Figure 2 In addition, compound 59 significantly reduced the protein levels of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in lung tissue after LPS stimulation. Figure 2 (D, E, F). More importantly, H&E staining results showed that pretreatment with compound 59 alleviated LPS-induced pathological changes in lung tissue (D, E, F). Figure 2 Immunohistochemical staining further showed that compound 59 reduced the infiltration of immune cells (G); Figure 2 H).

[0297] 3. Mouse model of chronic obstructive pulmonary disease (COPD) and drug treatment

[0298] C57BL / 6J mice were randomly divided into six experimental groups: a normal control group, a COPD model group, a COPD + dexamethasone group (DEX, 0.2 mg / kg, inhalation), and a COPD + compound 59 group (0.5, 1, 2 mg / kg, dry powder inhalation). Except for the normal control group, the other groups were sensitized by intranasal instillation of lipopolysaccharide (LPS, 50 μL, 1 mg / mL solution) on days 1, 15, and 30. Starting from day 3, all model mice were nebulized with 1 mg / mL papain solution for 1 minute every other day to induce protease-driven emphysema-like changes and successfully establish a chronic obstructive pulmonary disease (COPD) model. The entire COPD model establishment period lasted 4 weeks. During the 4-week model establishment period, mice in the COPD+DEX group were treated with daily inhalation of a corresponding dose of DEX dry powder, while mice in the COPD+compound 59 group were treated with daily inhalation of a corresponding dose of compound 59 dry powder. The normal control group and the COPD model group were given an equal volume of physiological saline daily. On day 40, a series of lung function parameters (minute ventilation, expiratory time, peak expiratory flow, airway stenosis index, peak expiratory time ratio, and peak inspiratory flow) were measured by whole-body plethysmography, and blood was collected from mice. Mice were then sacrificed by carbon dioxide overdose, and lung tissue was collected to detect the expression levels of IL-6, TNF-α, and IL-1β in the lung tissue.

[0299] Experimental results are as follows Figure 3 This indicates that compound 59 significantly reduced the protein levels of pro-inflammatory cytokines IL-6, TNF-α, and IL-1β in lung tissue in a chronic obstructive pulmonary disease model. Figure 3 (A, B, C). Furthermore, it can effectively alleviate respiratory dysfunction caused by chronic obstructive pulmonary disease by enhancing airway conductivity, reducing bronchial resistance, and restoring overall ventilation function. Figure 3 (DI).

[0300] Example 65: Safety evaluation of compound 59

[0301] Acute toxicity test: Balb / c mice were randomly divided into four groups: a male control group (n=5), a male compound 59 treatment group (n=10), a female control group (n=5), and a female compound 59 treatment group (n=10). Mice in the treatment groups were given a single oral dose of compound 59 (500 mg / kg, prepared using an aqueous solution containing 0.1% Tween 20), and weighed every two days. After 14 days, the mice were euthanized using cervical dislocation, and the major organs (heart, liver, spleen, lungs, and kidneys) were removed and weighed. The experimental results are shown below. Figure 4 and Figure 5This indicates that there was no difference in the weight of major organs, including heart, liver, spleen, lungs, and kidneys, between the control group and the compound 59 treatment group. Figure 4 H&E staining showed ( Figure 5 No obvious lesions were observed in the major organs of the mice in the treatment group. This indicates that compound 59 has good drug safety.

[0302] In summary, the α,β-unsaturated ketone-substituted chromone derivatives of the present invention exhibit highly efficient and selective BLT1 inhibitory activity, and show great clinical application potential in alleviating and / or treating acute lung injury and sepsis.

Claims

1. Chromoketone derivatives with α,β-unsaturated ketone substitutions as shown in Formula I, or their pharmaceutically acceptable salts or isomers: I； in: R 1 R 2 R 3 Independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C6 allyl, C2-C6 ynyl, C1-C3 haloalkyl, C3-C8 heterocycloalkyl, C6-C 10 Aryl, C3-C 10 Heteroaryl or C3-C8 heterocyclic aryl; The C6-C mentioned 10 Aryl, C3-C 10 The hydrogen atoms of the heteroaryl or C3-C8 heterocyclic aryl group are independently and optionally replaced by one or more groups selected from halogen, hydroxyl, amino, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylsulfonic acid, C3-C6 cycloalkyl, C3-C6 cycloalkyl ester, C6-C 10 Substituted with aryl, C3-C6 cycloalkyloxy or C4-C8 heterocyclic groups; R 4 Selected from H, OH, and C1-C6 alkoxy groups; R 5 Selected from H, C1-C6 alkyl, C1-C6 haloalkyl or X represents OC(O) or O(CH2). n n is an integer from 1 to 8.

2. The α,β-unsaturated ketone-substituted chromogen derivative according to claim 1, characterized in that: R 1 Selected from methyl, cyclopropyl, substituted or unsubstituted phenyl, 2-thienyl, 5-benzofuranyl, 4-pyridyl, wherein the substituent of the phenyl group is methyl, methoxy, fluorine, chlorine, bromine, cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, phenyl, ethylsulfonic acid, cyclohexylcarboxylate, and the number of substituents of the phenyl group is 1 to 3; R 2 Selected from H, methyl, substituted or unsubstituted phenyl, 2-furanyl, wherein the phenyl substituent is methyl, methoxy, or chlorine, and the number of phenyl substituents is 1 to 3; R 3 Selected from H, methyl, or 4-methoxyphenyl; R 4 Selected from H or OH; R 5 Selected from H or (X is selected from OCH2) n n is an integer from 2 to 6; Preferred, R 1 Selected from methyl, cyclopropyl, phenyl, 4-methylphenyl, 4-methoxyphenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-cyanophenyl, 4-nitrophenyl, 4-hydroxyphenyl, 2-thienyl, 4-trifluoromethylphenyl, 3,4-dimethoxyphenyl, 4-tert-butylphenyl, 3,4,5-trimethoxyphenyl, 4-phenylphenyl, 4-ethylsulfonic acid, 4-cyclohexylcarboxylate phenyl, 5-benzofuranyl, 4-pyridyl or 3-trifluoromethoxyphenyl R 2 Selected from H, methyl, phenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, 2-furanyl, 3,4-dimethoxyphenyl, 4-chlorophenyl, 3-methoxy-4-methylphenyl, or 3,4,5-trimethoxyphenyl. R 3 Selected from H, methyl, or 4-methoxyphenyl; R 4 Selected from H or OH; R 5 Selected from H or (X is selected from OCH2) n n is 2, 4, or 6.

3. The α,β-unsaturated ketone-substituted chromogen derivative according to claim 2, characterized in that: R 1 Selected from phenyl, 4-bromophenyl, 4-cyanophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 4-tert-butylphenyl, 4-phenylphenyl, 4-ethylsulfonic acid phenyl; R 2 Selected from phenyl, 4-methoxyphenyl, 4-methylphenyl, 2-furanyl, and 3,4-dimethoxyphenyl; R 3 Selected from H; R 4 Selected from OH; R 5 Selected from H or (X is selected from OCH2) n n is 2, 4, or 6.

4. Chromoketone derivatives with α,β-unsaturated ketone substitutions as shown below, or pharmaceutically acceptable salts thereof: 。 5. Chromoketone derivatives substituted with α,β-unsaturated ketones as shown in Formula I, or pharmaceutically acceptable salts thereof: I； in: R 1 Selected from 4-trifluoromethylphenyl; R 2 Selected from phenyl; R 3 Selected from H;R 4 Selected from OH;R 5 Selected from (X is selected from OCH2) n n is an integer from 2 to 6.

6. A method for preparing the α,β-unsaturated ketone-substituted chromogen derivative of claim 1, characterized in that: Including Route 1, Route 2, Route 3, and Route 4; The synthesis route for Route 1 is as follows: ； Among them, R 1 R 2 R 4 As described in claim 1; The synthesis route for Route 2 is as follows: ； Among them, R 1 R 4 As described in claim 1; The synthesis route for Route 3 is as follows: ； Among them, R 1 As described in claim 1; The synthesis route for route 4 is as follows: ； Among them, R 1 R 2 R 3 R 4 As described in claim 1, R 5 Selected from X and n are as described in claim 1.

7. The method for preparing α,β-unsaturated ketone-substituted chromogen derivatives according to claim 6, characterized in that: Route 1 includes the following steps: Step (1): The ethyl ketone derivative shown in Formula II reacts with a brominating reagent to generate intermediate III; Step (2): Intermediate III reacts with triphenylphosphine and generates phosphine ylide as shown in Formula IV under alkaline conditions; Step (3): Under alkaline conditions, 2,4-dihydroxyacetophenone of formula V reacts with methoxymethyl bromide (MOMBr) to generate intermediate VI; Step (4): Under alkaline conditions, intermediate VI and formula The aromatic aldehyde shown underwent an Adol condensation reaction to give compound VII; Step (5): Using I2 as a catalyst, catalyze compound VII to generate the chromone derivative shown in formula VIII; Step (6): Under acidic conditions, the chromogen derivative reacts with hexamethylenetetramine (HXMT) in a Duff reaction to generate an aldehyde-substituted chromogen as shown in Formula IX; Step (7): The aldehyde-substituted chromone reacts with the phosphine ylide shown in Formula IV to obtain the target compound shown in Formula I; Route 2 includes the following steps: Step (1): In the presence of acetic anhydride and sodium acetate, 2,4-dihydroxyphenylacetones with different substitutions shown in Formula X react with chromone derivatives shown in Formula XI under reflux conditions. In this process, 2,4-dihydroxyphenylacetones with different substitutions shown in Formula X first generate acetylated chromone intermediates, and then deacetylate them under alkaline conditions to generate chromone derivatives shown in Formula XI. Step (2): Using organic acid as the reaction solvent, under acidic conditions, the chromogen derivative reacts with hexamethylenetetramine in a Duff reaction to generate an aldehyde-substituted chromogen as shown in formula XII. Step (3): The aldehyde-substituted chromone reacts with the phosphine ylide shown in Formula IV to obtain the target compound shown in Formula I; Route 3 includes the following steps: Step (1): Under nitrogen protection, in the presence of boron trifluoride ether and Vilsmeier reagent, the m-diphenol of formula XIII reacts with 4-methoxyphenylpropionic acid of formula XIV to generate the isoflavone derivative shown in XV. Step (2): Using organic acid as the reaction solvent, under acidic conditions, the isoflavone derivative reacts with hexamethylenetetramine in a Duff reaction to generate an aldehyde-substituted chromone as shown in formula XVI. Step (3): The aldehyde-substituted isoflavone reacts with the phosphine ylide shown in Formula IV to obtain the target compound shown in Formula I; Route 4 includes reacting the compound shown in Formula VXI with the compound shown in Formula XVII under alkaline conditions to obtain the target compound shown in Formula I.

8. The use of the α,β-unsaturated ketone-substituted chromone derivatives of any one of claims 1-5, or their pharmaceutically acceptable salts or isomers, in the preparation of BLT1 inhibitors.

9. The use of the α,β-unsaturated ketone-substituted chromone derivatives of any one of claims 1-5, or their pharmaceutically acceptable salts or isomers, in the preparation of medicaments for treating acute lung injury, chronic obstructive pulmonary disease, and sepsis.

10. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises a therapeutically effective amount of the α,β-unsaturated ketone-substituted chromone derivative of any one of claims 1-5, or a pharmaceutically acceptable salt thereof or an isomer thereof, and a pharmaceutically acceptable carrier.

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