TWI437985B - Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof - Google Patents

Description

Bicyclic substituted pyrazolone azo derivative, preparation method thereof and application thereof in medicine

The present invention relates to a novel bicyclic-substituted pyrazolone azo derivative of the formula (I), a process for the preparation thereof, and a pharmaceutical composition containing the same, and a therapeutic agent thereof, particularly thrombopoietin (TPO) And their use as thrombopoietin receptor agonists.

Thrombopoietin (TPO), also known as megakaryocyte growth and development factor (MGDF), thrombocytopoiesis stimulating factor (TSF), c-myeloproliferative feukemia ligand (c-myeloproliferative feukemia ligand, c-Mpl), mpl ligand, megapoietin is a glycoprotein associated with platelet production (Wendling, F., et. al., Biotherapy 10(4): 269-77 (1998); Kuter D. l. et al , The Oncologist; 1: 98-106 (1996); Metcalf, Nature 369: 519-520 (1994)).

In some cases, the activity of TPO is derived from the binding of TPO to the TPO receptor (also known as MPL). The TPO receptor has been successfully cloned and the amino acid sequence has also been sequenced (Vigon et al., Proc. Nat. Acad. Sci., 89: 5640-5644 (1992)).

TPO is a 332-amino acid glycosylation polypeptide that plays a key role in regulating megakaryocyte production and platelet production by bone marrow megakaryocytes (Kuter et al., Proc. Nat. Acad. Sci. USA 91:11104- 11108 (1994); Barley et al., Cell 77: 1117-1124 (1994); Kaushansky et al., Nature 369: 568-571 (1994); Wendling et al., Nature 369: 571-574 (1994); And Sauvage et al., Nature 369: 533-538 (1994)). TPO is produced in the liver but mainly acts on the bone marrow, stimulating the differentiation of stem cells into megakaryocytes and proliferation of megakaryocytes, polyploidization, and most importantly, into the platelet body cycle. TPO is a major regulator of thrombocytopenia and a large number of studies on increasing the number and size of platelets and increasing the isotope of experimental animals into platelets (Metcalf Nature 369:519-520 (1994)). TPO is thought to affect megakaryocyte production mainly through several pathways: (1) causing an increase in the size and number of megakaryocytes; (2) increasing DNA inclusions, polyploid forms, megakaryocytes; (3) increasing megakaryocytes Mitochondrial mitosis; (4) increase of mature megakaryocytes; (5) increase the percentage of precursor cells, small acetylcholinease-positive forms of cells, bone marrow cells.

Platelets are essential for blood clotting, and when it is very low, the patient is at risk of bleeding. Therefore, TPO has been used to diagnose and treat a variety of blood diseases, such as those caused primarily by platelet defects. At the same time, TPO can be used to treat thrombocytopenia, especially chemotherapy, radiation and bone marrow transplants for the treatment of cancer and lymphoma.

Patients with thrombocytopenia due to thrombocytopenia are a serious problem, so it is hoped that an active TPO analog for thrombocytopenia can be found. A few years ago, the development of peptide TPO analogs was reported. (WO 96/40750, WO 98/25965) These polypeptides bind to and activate the TPO receptor, but do not possess the sequence homology of native TPO. In recent years, some small molecule active TPO analogs have been reported. Including 1,4-benzodiazepine-2-ones (JP11001477), metal complexes obtained from Schiff base ligands (WO 99/11262), cyclic polyamine derivatives (WO 00/28987), thiazole -2-yl-benzoguanamines (WO 01/07423, WO 01/53267), azo-aryl derivatives (WO 00/35446, WO 1/17349), 2-aryl-naphthazoles (WO 01/39773, WO 01) /53267) and a semicarbazone derivative (WO 01/34585). Within a cell-based system, all of these molecules activate the signal transduction pathway of the TPO receptor on the cell membrane, and some types act directly on the TPO receptor itself. According to reports, the replacement of thiourea is actually a very effective TPO receptor agonist. Some of the most preferential compounds in this series have been found to stimulate the proliferation and differentiation of TPO in TPO-responsive human cell lines and human bone marrow broth below 100 nM.

The thrombopoietin analog eltrombopag is reported by the GSK company in the patent (WO-00189457/WO-01089457/WO-2006064957) and exhibits considerable activity.

The present invention discloses a series of compounds and is more effective as a TPO receptor agonist and is a potent TPO analog.

In order to overcome the deficiencies of the prior art, the object of the present invention is to provide a bicyclic substituted pyrazolone azo derivative represented by the general formula (I), and their tautomers, enantiomers and diastereoisomers. Body, racemate and pharmaceutically acceptable salts, hydrates or solvates, as well as metabolites and metabolic precursors or prodrugs.

among them:

A is selected from a carbon atom or an oxygen atom;

R is selected from a hydrogen atom or an alkyl group;

R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, an aryl group or a heteroaryl group, wherein the aryl group or the heteroaryl group may be further selected by one or more Substituted from a substituent of an alkyl group, a halogen, a hydroxyl group, a tetrazolyl group, an imidazole, a dihydroimidazole, a carboxylic acid or a carboxylic acid ester;

R ₅ , R ₆ and R ₇ are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxylic acid or a carboxylic acid ester;

R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently selected from a hydrogen atom or an alkyl group;

n is 0, 1 or 2.

In a preferred embodiment of the invention,

A is selected from a carbon atom or an oxygen atom;

R is selected from a hydrogen atom or an alkyl group;

R _{1 is} selected from aryl or heteroaryl, wherein the aryl or heteroaryl group may be further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, tetrazolyl, imidazole, dihydroimidazole, carboxylic acid or carboxylic acid ester. Substituted by a substituent; R ₂ , R ₃ and R ₄ are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group or a halogen;

R ₅ , R ₆ and R ₇ are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxylic acid or a carboxylic acid ester;

R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently selected from a hydrogen atom or an alkyl group;

n is 0, 1 or 2.

Preferred compounds of the compound of the formula (I) of the present invention include, but are not limited to, the following:

Or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Further, the present invention includes a compound represented by the formula (IA) which is an intermediate for the synthesis of the compound of the formula (I):

among them:

A is selected from a carbon atom or an oxygen atom;

R ₅ , R ₆ and R ₇ are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxylic acid or a carboxylic acid ester;

R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently selected from a hydrogen atom or an alkyl group;

n is 0, 1 or 2.

Preferred compounds of the compound of the formula (IA) of the present invention include, but are not limited to, the following:

Another aspect of the invention is a process for the preparation of a compound of the intermediate (IA) comprising the steps of:

The amino-substituted benzopolycyclic ring is diazotized with sodium nitrite in an acidic solution, and then reduced by stannous chloride to obtain hydrazine, hydrazine and an electrophilic carbonyl compound such as ethyl acetate, in a suitable solvent. Condensation under heating (e.g., acetic acid, ethanol, etc.) gives the compound of the formula (IA).

Further, another aspect of the present invention provides a process for the preparation of a compound of the formula (I), which comprises:

The substituted aniline compound is diazotized with sodium nitrite in a suitable acidic solution (such as nitric acid, sulfuric acid, hydrochloric acid), and then mixed with a compound of the formula (IA) in an alkaline solution (such as sodium hydrogencarbonate or hydrogencarbonate). A coupling reaction occurs in potassium) to give a compound of the formula (I).

The present invention relates to the use of the compounds of the formulae (I) and (IA) for the preparation of TPO receptor agonists,

The present invention relates to the use of the compounds of the general formulae (I) and (IA) for the preparation of a medicament for the treatment of thrombocytopenia. This includes combining a therapeutically effective amount of a drug selected from the group consisting of colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor agonist or antagonist, soluble receptor, receptor agonist or antagonist An antibody or a peptide or small molecule that functions in the same mechanism as one or more of the drugs.

The present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the formula (I) and (IA), and a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable salt thereof. The composition may further comprise a therapeutically effective amount of a drug selected from the group consisting of a colony stimulating factor, a cytokine, a chemokine, an interleukin or a cytokine receptor agonist, and the pharmaceutical composition for preparing a therapeutic platelet The use of a reduction medication.

The combined use includes the simultaneous or sequential use of the compounds described herein.

The present invention relates to a process for the preparation of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of formula (I) and (IA), and a pharmaceutically acceptable salt, hydrate or solvate thereof, comprising The compounds of formula (I) and (IA) are combined with a pharmaceutically acceptable carrier and diluent.

Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

"Alkyl" means a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms is preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl or pentyl groups and the like. More preferred are lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, aryl. Base, heteroaryl, carboxylic acid or carboxylic acid ester.

"Aryl" means a group having at least one aromatic ring structure, that is, an aromatic ring having a conjugated π-electron system, including a carbocyclic aryl group, a heteroaryl group, and a biaryl group. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, aryl. Base, heteroaryl, carboxylic acid or carboxylic acid ester.

"Heteroaryl" refers to an aryl group having from 1 to 4 heteroatoms as ring atoms, the remaining ring atoms being carbon, and heteroatoms including oxygen, sulfur and nitrogen. The ring can be a 5 or 6 member ring. Examples of heteroaryl groups include furyl, thienyl, pyridyl, pyrrole, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, Aryl, heteroaryl, carboxylic acid or carboxylic acid ester.

"Hydroxy" refers to an -OH group.

"Alkoxy" means -O-(alkyl) and -O-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, Aryl, heteroaryl, carboxylic acid or carboxylic acid ester.

"Halogen" means fluoro, chloro, bromo or iodo.

"Amino" means -NH ₂ .

"Cyano" means -CN.

"Nitro" means -NO ₂ .

"Alkoxy" means -O-(alkyl).

"Carboxylic acid" means (alkyl)C(=O)OH.

"Carboxylic acid ester" means (alkyl)C(=O)O(alkyl).

"Pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable Carrier and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

Method for synthesizing the compound of the present invention

In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:

Flowchart I

The amino-substituted benzopolycyclic ring is diazotized with sodium nitrite in an acidic solution, and then reduced by stannous chloride to obtain hydrazine, hydrazine and an electrophilic carbonyl compound such as ethyl acetate, in a suitable solvent. Condensation under heating (e.g., acetic acid, ethanol, etc.) affords the compound of formula (IA).

Flowchart II

Substituted o-bromophenol is nitrated to obtain nitrophenol, and nitrophenol is alkylated with a haloalkyl group such as methyl iodide at a suitable temperature to obtain a hydroxy-protected nitrophenol; a hydroxy-protected nitrophenol Suzuki coupling with a substituted aryl boronic acid under the catalysis of tetrakis(triphenylphosphine)palladium or a reaction with a boric acid compound, the resulting aryl boronic acid compound is Suzuki coupled with the halogenated compound R ₁ X to obtain R _{A 1-} substituted aryl compound; an R ₁ -substituted aryl compound is reduced by palladium on carbon under hydrogen atmosphere to give an aryl aniline, and the aryl aniline is removed from the alkyl bromide to give a deprotected aniline. Alternatively, the substituted aryl compound is deprotected from the alkyl group in hydrogen bromide to give the deprotected nitro compound. The nitro compound is reduced under palladium on carbon under hydrogen to give the deprotected aryl aniline.

Diluting the substituted aniline compound with sodium nitrite in a suitable acidic solution (such as nitric acid, sulfuric acid, hydrochloric acid), and then reacting the compound of the formula (IA) with an alkaline solution (such as sodium hydrogencarbonate or potassium hydrogencarbonate) The coupling reaction takes place to give a compound of the formula (I).

The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

Example

The structure of the compound is determined by nuclear magnetic resonance ( ¹ H NMR) or mass spectrometry (MS). ^{The 1} H NMR shift (δ) is in parts per million (ppm). ^{The 1} H NMR measurement was performed on a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ), and the hexa-deuterated dimethyl hydrazine (DMSO-d6) was internally labeled as four. Methyl decane (TMS), chemical shift in units of 10 ^-6 (ppm);

The measurement of MS was performed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX;

The IC ₅₀ value was determined using a NovoStar plate reader (BMG, Germany);

Thin layer of silicone rubber using Yantai Yellow Sea HSGF254 or Qingdao GF254 silicone sheet;

Tannin tube chromatography is generally carried out using Yantai Huanghai Silicone 200 to 300 mesh silicone as a carrier;

The HPLC test was performed using an Agilent 1200 DAD high pressure liquid chromatography (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatography (Gimini C18 150 x 4.6 mm column).

The pressurized hydrogenation reaction uses a Pau 3916EKX type hydrogenation apparatus and a clear blue QL type hydrogen generator; the microwave reaction uses a CEM Discover-S 908860 type microwave reactor;

Unless otherwise stated in the examples, the reactions were all carried out under a nitrogen atmosphere;

The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume;

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume;

Unless otherwise specified in the examples, the solution in the reaction means an aqueous solution;

TLC refers to thin layer chromatography.

Example 1 2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl ]-biphenyl-3-carboxylic acid

first step 2-bromo-6-nitrophenol

60 mL of concentrated sulfuric acid was diluted into 186 mL of water, and after cooling to room temperature, sodium nitrate (79.2 g, 0.932 mol) was added thereto, and the mixture was kept at 25 ° C or lower, and o-bromophenol 1a (60 mL, 0.516 mol) was added dropwise thereto, and the mixture was reacted at room temperature for 2 hours. The residue was removed by TLC, and the precipitated solid was dissolved by adding ethyl acetate (320 mL), and washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography. The title product 2-bromo-6-nitrophenol 1b (48.2 g, yellow solid) was obtained. Yield: 42.8%. MS m/z (ESI): 218 [M + 1] ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.88 - 7.02 (m, 1H), 7.89 - 7.91 (d, J = 8 Hz, 1H), 8.12 - 8.15 (m, 1H), 11.18 (s, 1H)

Second step 1-bromo-2-methoxy-3-nitrobenzene

2-Bromo-6-nitrophenol 1b (46.55 g, 0.214 mol) was dissolved in 500 mL of acetone, potassium carbonate (35.36 g, 0.256 mol) and methyl iodide (20.1 mL, 0.32 mol) were added, and heated at 70 ° C under reflux 40 hour. The residue was evaporated to dryness with EtOAc (EtOAc) (EtOAc) The residue was dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ . Yield: 90.0%. MS m/z (ESI): 234 [M+1]

third step 2'-Methoxy-3'-nitrobiphenyl-3-carboxylic acid

1-Bromo-2-methoxy-3-nitrobenzene 1c (23.25 g, 0.10 mol), 3-carboxyphenylboronic acid (19.5 g, 0.117 mol) and tetrakis(triphenylphosphine)palladium (8.86 g) 7.7 mol) was dissolved in a mixed solvent of 100 mL of 2N sodium carbonate solution and 500 mL of 1,4-dioxane, and heated under reflux at 105 ° C for 43 hours. The residue was evaporated to dryness eluting with EtOAc (EtOAc) (EtOAc) Concentration gave the title product 2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid 1d (53.93 g, pale yellow solid). MS m/z (ESI): 272 [M-1] ¹ H NMR (400 MHz, CDCl ₃ ): δ 3.44 - 3.46 (d, J = 8 Hz, 3H), 7.42 - 7.46 (m, 1H), 7.63 - 7.67 (m, 1H), 7.21-7.75 (m, 1H), 7.82-7.84 (m, 1H), 7.90-7.92 (m, 1H), 8.01-8.03 (d, J = 8 Hz, 1H), 8.11 (s, 1H)

the fourth step 2'-Methoxy-3'-aminobiphenyl-3-carboxylic acid

2'-Methoxy-3'-nitrobiphenyl-3-carboxylic acid 1d (0.48 g, 1.74 mmol) was dissolved in 60 mL of ethanol, and 0.5 g of palladium-carbon and ammonium formate (1.1 g, 17.4 mmol) were added. The mixture was heated to reflux at 80 ° C for 20 minutes. The residue was evaporated to dryness eluted with EtOAc (EtOAc) elute Yield: 93.3%. MS m/z (ESI): 242 [M-1]

the fifth step 3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide salt

2'-Methoxy-3'-aminobiphenyl-3-carboxylic acid 1e (2.5 g, 10.3 mmol) was dissolved in 100 mL of a hydrobromic acid solution (40%), and heated to reflux overnight at 120 °C. The residue was purified by TLC, and then evaporated to dryness. g, khaki solid), Yield: 88.8%. MS m/z (ESI): 230 [M + 1] [Note: Reference: WO0189457]

Step 6 5-肼基茚满

5-Aminoindan 1 g (3.59 g, 27.0 mmol) was dissolved in 20 mL of concentrated hydrochloric acid under ice-cooling and stirred for 10 min. 10 mL of sodium nitrite solution (1.86 g, 27.0 mmol) was added dropwise, and stirring was continued for 15 minutes in an ice bath.

Stannous chloride dihydrate (24.4 g, 108.0 mmol) was dissolved in 10 mL of concentrated hydrochloric acid under ice-salt bath, and the intermediate intermediate solution was added thereto, and the mixture was allowed to react at room temperature for 1.5 hours. The mixture was adjusted to pH 9 with a 40% EtOAc EtOAc. EtOAc (EtOAc) Yield: 51.3%. MS m/z (ESI): 149 [M+1]

Seventh step 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one

The 5-mercaptopurpur 1 h (2.05 g, 13.8 mmol) was dissolved in 50 mL of ethyl acetate. ethyl acetate ethyl acetate (1.76 mL, 13.8 mmol) The residue was purified by TLC, evaporated, evaporated, evaporated, evaporated, - Ketone 1i (1.84 g, yellow solid). Yield: 62.3%. MS m/z (ESI): 215 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.69 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8 Hz, lH), 3.44 (s, 2H), 2.90-2.97 (m, 4H), 3.21 (s, 3H), 2.07-2.14 (m, 2H).

Eighth step 2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl ]-biphenyl-3-carboxylic acid

3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 1f (267 mg, 1.16 mmol) was dissolved in 10 mL of hydrochloric acid (1 N) under ice bath, and 10 mL of sodium nitrite solution (88 mg) was added dropwise. , 1.28 mmol), followed by 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (249 mg, 1.16 mmol), using a saturated sodium hydrogen carbonate solution The pH was adjusted to 8, and 10 mL of ethanol was added and allowed to warm to room temperature overnight. The residue was traced by TLC, filtered, dried and recrystallized from methanol to give the title product 2'-hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-carbonyl- 1,5-Dihydropyrazole-4-ylidene)-indenyl]-biphenyl-3-carboxylic acid 1 (60 mg, yellow solid). Yield: 11.4%. MS m/z (ESI): 453 [M-1] ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 2.03-2.10 (m, 2H), 2.34 (s, 3H), 2.86-2.93 (m, 4H) ), 7.13-7.17 (m, 2H), 7.28-7.30 (d, J = 8.1 Hz, 1H), 7.60-7.82 (m, 5H), 7.96-7.98 (d, J = 8.1 Hz, 1H), 8.13 ( s, 1H), 9.66 (s, 1H), 13.03 (s, 1H), 13.76 (s, 1H).

Example 2 5'-Fluoro-2'-hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-oxy-1,5-dihydropyrazole-4-arylene Base)-fluorenyl]-biphenyl-3-carboxylic acid

first step 2-bromo-4-fluoro-6-nitrophenol

2-Bromo-4-fluoro-phenol 2a (8.0 g, 41.9 mmol) was dissolved in 10 mL of sulfuric acid solution (50%) under ice salt bath, and sodium nitrate (7.1 g, 83.5 mmol) in 24 mL of sulfuric acid solution (25) was added dropwise. %), reacted at room temperature for 1.5 hours. The residue was evaporated to dryness with EtOAc (EtOAc) (EtOAc (EtOAc) Concentration by pressure gave the title product 2-bromo-4-fluoro-6-nitrophenol 2b (8.0 g, red solid).

Second step 1-bromo-5-fluoro-2-methoxy-3-nitrobenzene

2-Bromo-4-fluoro-6-nitrophenol 2b (24.7 g, 104.7 mmol) and potassium carbonate (17.34 g, 125.6 mmol) were dissolved in 300 mL of acetone, and methyl iodide (9.8 mL, 157.1 mmol) was quickly added. The mixture was heated to reflux at 80 ° C for 22 hours. The residue was evaporated to dryness with EtOAc (EtOAc) (EtOAc) (EtOAc) Drying over anhydrous magnesium sulfate, EtOAc (EtOAc m. , white solid). Yield: 61.8%. MS m/z (ESI): 252 [M+1] ¹ H NMR (CDC1 ₃ ): δ 3.99 (s, 3H), 7.81 (d, J = 8.0 Hz, 1H), 7.28 (q, J = 8.0) Hz, 4.0 Hz, 1H), 7.89 (q, J = 8.0 Hz, 4.0 Hz, 1H).

third step 5'-Fluoro-2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid

1-Bromo-5-fluoro-2-methoxy-3-nitrobenzene 2c (16.18 g, 64.7 mmol), 3-carboxyphenylboronic acid (13.88 g, 77.7 mmol) and tetrakis(triphenylphosphine) Palladium (3.73 g, 3.2 mmol) was dissolved in a mixed solvent of 65 mL of sodium carbonate solution (2N) and 300 mL of 1,4-dioxane, and heated under reflux at 120 ° C for 24 hours. The residue was evaporated to dryness eluted with EtOAc (EtOAc) (EtOAc) (EtOAc) Concentration under reduced pressure gave the title product 5'-fluoro-2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid 2d (7.86 g, yellow solid). Yield: 41.7%. MS m/z (ESI): 290 [M-1]

the fourth step 3'-Nitro-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid

2'-Fluoro-2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid 2d (2.91 g, 10.0 mmol) was dissolved in 10 mL of hydrobromic acid solution (40%), heated at 120 ° C Reflux overnight. The residue was purified by TLC, and the residue was evaporated to purified crystals. (2.38 g, yellow solid) was used directly in the next step. Yield: 85.7%. MS m/z (ESI): 277 [M-1]

the fifth step 3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid

3'-Nitro-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 2e (417 mg, 1.5 mmol) was dissolved in 60 mL of ethanol, and 0.5 g of palladium-carbon and ammonium formate were added. (0.95 g, 1.5 mmol), heated to reflux at 80 ° C for 20 min. The residue was purified by TLC, filtered, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Yield: 91.5%. MS m/z (ESI): 246 [M-1]

Step 6 5'-Fluoro-2'-hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-oxy-1,5-dihydropyrazole-4-arylene Base)-fluorenyl]-biphenyl-3-carboxylic acid

3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid 2f (296 mg, 1.20 mmol) was dissolved in 10 mL of hydrochloric acid (1 N) under ice-cooling, and 10 mL of sodium nitrite solution was added dropwise ( 91 mg, 1.32 mmol), followed by 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (257 mg, 1.20 mmol). The pH of the solution was adjusted to 8, and 10 mL of ethanol was added and allowed to warm to room temperature overnight. The material disappeared by TLC, filtered, dried and recrystallized from methanol to give the title product 5'-fluoro-2'-hydroxy-3'-[N'-(1-indane-5-yl 1-3-A 5-O-oxy-1,5-dihydropyrazole-4-ylidene)-indenyl]-biphenyl-3-carboxylic acid 2 (87 mg, red solid). Yield: 14.1%. MS m / z (ESI): 471 [M-1] l HNMR (400MHz, DMSO-d6): δ 2.02 (m, 2H), 2.34 (s, 3H), 2.87 (m, 4H), 7.03 (dd, J1=9.2 Hz, J2=2.8 Hz, lH), 7.28 (d, J=8.0 Hz, 1H), 7.48 (m, 1H), 7.61 (m, 2H), 7.76 (s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 8.17 (s, 1H), 9.59 (s, lH), 13.03 (s, 1H), 13.62 (s, 1H)

Example 3 2'-Hydroxy-3'-{N'-"3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro Pyrazole-4-ylidene-indenyl}-biphenyl-3-carboxylic acid

first step 2-mercapto-5,6,7,8-tetrahydronaphthalene

2-Amino-5,6,7,8-tetrahydronaphthalene 3 g (3.68 g, 25.0 mmol) was dissolved in 20 mL of concentrated hydrochloric acid and stirred for 10 min. 10 mL of sodium nitrite solution (1.72 g, 25.0 mmol) was added dropwise, and stirring was continued for 15 minutes under ice bath.

Stannous chloride dihydrate (22.6 g, 100 mmol) was dissolved in 10 mL of concentrated hydrochloric acid under ice salt bath, and the intermediate intermediate solution was added thereto, and the mixture was allowed to react at room temperature for 1.5 hours. The pH was adjusted to 9 with 40% sodium hydroxide solution under ice-cooling, extracted with ethyl acetate (400 mL), and concentrated under reduced pressure and dried to give the title product 2-meryl-5,6,7,8-tetrahydronaphthalene 3h (2.19) g, yellow oily liquid). Yield: 53.7%. MSm/z (ESI): 163 [M+1]

Second step 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazol-3-one

2-Mercapto-5,6,7,8-tetrahydronaphthalene 3h (2.0g, 12.3mmol) was dissolved in 50mL of acetic acid, then ethyl acetate ethyl acetate (1.57mL, 12.3mmol) was added and heated to 100 ° C overnight. The residue was purified by TLC, and the residue was evaporated to dryness. -2,4-Dihydropyrazol-3-one 3i (1.58 g, colorless oily liquid). Yield: 56.2%. MS m/z (ESI): 495 [2M +1] ¹ H NMR (CDCl ₃ ): δ 7.54 - 7.58 (m, 2H), 7.08-7.10 (d, J = 8 Hz, 1H), 3.43 (s, 2H), δ 2.77-2.81 (m, 4H), 2.21 (s, 3H), 1.80-1.83 (m, 4H).

third step 2'-Hydroxy-3'-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro Pyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid

3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 1f (250 mg, 1.09 mmol) was dissolved in 10 mL of hydrochloric acid (1 N) under ice bath, and 10 mL of sodium nitrite solution (82 mg) was added dropwise. , 1.2 mmol), further adding 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazol-3-one 3i (249 mg, 1.09 mmol The pH of the reaction mixture was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and 10 mL of ethanol was added, and the mixture was allowed to warm to room temperature overnight. It was traced by TLC until the material disappeared, filtered, dried and recrystallized from methanol to give the title product 2'-hydroxy-3'-{N'-[3-methyl-5-sideoxy-1-(5,6, 7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid 3 (59 mg, yellow solid). Yield: 11.6%. MS m/z (ESI): 467 [M-1] ¹ H NMR (400 MHz, DMSO-d6): δ 1.75 (m, 4H), 2.33 (s, 3H), 2.70 (m, 4H), 7.13 (m, 3H), 7.36 (m, 1H), 7.60 (m, 2H), 7.71 (m, 1H), 7.75 (m, 1H), 7.97 (d, J = 7.6 Hz, 1H), 8.14 (s, 1H), 9.66(s,1H), 13.03(br,1H),13.76(s,1H)

Example 4 5'-Fluoro-2'-hydroxy-3'-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1 ,5-dihydropyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid

3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid 2f (250 mg, 1.01 mmol) was dissolved in 10 mL of hydrochloric acid (1 N) under ice-cooling, and 10 mL of sodium nitrite solution was added dropwise. 77 mg, 1.12 mmol), then 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazol-3-one 4i (230 mg, 1.01) (mmol), the pH of the reaction mixture was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and then 10 mL of ethanol was added and the mixture was allowed to warm to room temperature overnight. The residue was traced by TLC, filtered, dried, and then recrystallized from methanol to give the title product 5'-fluoro- 2'-hydroxy-3'-{N'-[3-methyl-5-sideoxy-1- (5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4-ylidene]-indenyl}-biphenyl-4-carboxylic acid 4 (64 mg, red solid). Yield: 13.1%. MS m/z (ESI): 495 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.74 (m, 4H), 2.33 (s, 1H), 2.73 (m, 4H), 7.02 (dd , J1=9.2Hz, J2=2.0Hz, 1H), 7.11(d,d=8.0Hz,1H), 7.47(m,1H), 7.63(m,3H),7.82(d,J=7.6Hz,1H ), 7.98 (d, J = 7.6 Hz, 1H), 8.18 (s, 1H), 9.58 (s, 1H), 13.05 (s, 1H), 13.62 (s, 1H)

Example 5 3'-"N'-(1-bicyclo"4.2.0]octane-1(6),2,4-trien-3-yl-3-methyl-5-sideoxy-1,5- Dihydropyrazol-4-ylidene)-indenyl]-2'-hydroxybiphenyl-3-carboxylic acid

first step 3-bromo-bicyclo[4.2.0]octane-1(6), 2,4-triene

Bicyclo[4.2.0]octane-1(6), 2,4-triene 5a (7.9 g, 76 mmol) was dissolved in 80 mL of water at room temperature, and 3.9 mL of bromine was slowly added dropwise after cooling in an ice bath. The ice bath was removed and the reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was monitored by TLC until the starting material was completely reacted and the reaction was stopped. 50 mL of n-hexane and Na ₂ SO ₃ (3 g, 23.8 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was separated, the organic layer was dried (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Alkene 5b (13.53 g, colorless oily liquid) was directly introduced into the next step. MS m/z (ESI): 181.8 [M-1]

Second step (N-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-N'-t-butoxycarbonyl-indenyl)-tert-butyl carbonate

3-Bromo-bicyclo[4.2.0]octane-1(6), 2,4-triene 5b (13.5 g, 73.8 mmol) was dissolved in 100 mL of tetrahydrofuran (dry) and cooled with dry ice-ethanol bath - After 78 ° C, n-butyllithium (66 mL, 165 mmol) was added, and the mixture was stirred at low temperature. Ditributyl azodicarboxylate (20.1 g, 87.4 mmol) was dissolved in 80 mL of tetrahydrofuran (dry), slowly added to the above reaction solution, and the dry ice-ethanol bath was removed, and the temperature of the reaction system was slowly raised to room temperature. Stir overnight. The TLC monitors the reaction of the starting material and stops the reaction. The reaction mixture was quenched by adding 100 mL of water, and the reaction mixture was separated. The aqueous phase was extracted with ethyl acetate (100 mL×2), and the organic phase was combined, and the organic phase was washed with saturated sodium chloride solution (150 mL×1), anhydrous sulfuric acid The sodium was dried, filtered to remove the desiccant, and the filtrate was subjected to column chromatography to give the title product (N-bicyclo[4.2.0]octane-1(6), 2,4-trien-3-yl-N'-tributyl Oxycarbonyl-indenyl)-tert-butyl carbonate 5c (4.07 g, yellow oily liquid), yield: 16.5%.

third step 2-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-5-methyl-2,4-dihydropyrazol-3-one

(N-Bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-N'-t-butoxycarbonyl-fluorenyl)-tert-butyl carbonate 5c (4.0 g, 12 mmol) was dissolved in 30 mL of acetic acid, 30 mL of trifluoroacetic acid was added, and stirred at room temperature for 30 minutes. To the reaction system was added 3-oxo-butyric acid methyl ester (1.6 mL, 15 mmol) and stirred in a 100 ° C oil bath. After 1.5 hours, TLC indicated that the starting material was completely reacted and the reaction was stopped. The reaction solution was evaporated under reduced pressure. EtOAc (EtOAc) (EtOAc,EtOAc. The organic phase was washed with a saturated sodium chloride solution (100 mL×1), dried over anhydrous sodium sulfate, and then filtered and evaporated. 6) 2,4-Trien-3-yl-5-methyl-2,4-dihydropyrazol-3-one 5d (910 mg, yellow solid), yield: 37.9%. MS m/z (ESI): 201.2 [M+1]

the fourth step 3'-[N'-(1-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-3-methyl-5-oxo-1,5- Dihydropyrazol-4-ylidene)-indenyl]-2'-hydroxybiphenyl-3-carboxylic acid

3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid 1f (258 mg, 0.83 mmol) was dissolved in 10 mL of hydrochloric acid (1 N), and 10 mL of sodium nitrite solution (63 mg, 0.92 mmol) was added dropwise. , then add 2-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-5-methyl-2,4-dihydropyrazol-3-one 5d (150mg , 0.75 mmol), the pH of the reaction mixture was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and 10 mL of ethanol was added thereto, and the mixture was stirred at room temperature overnight. Followed by TLC until the starting material disappeared and filtered. The obtained solid was dissolved in 30 mL of water, and the pH was adjusted to about 3-4 with concentrated hydrochloric acid, followed by filtration, and the obtained solid was washed with methylene chloride (8mL), and dried to give the title product 3'-[N'-(1-bicyclo[ 4.2.0] Octane-1(6),2,4-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-oxime Base]-2'-hydroxybiphenyl-3-carboxylic acid 5 (198 mg, red solid), yield: 60%. MS m/z (ESI): 439.5 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 2.33 (s, 3H), 3.16 (m, 4H), 7.14 (m, 3H), 7.64 (m, 2H), 7.79 (m, 2H), 7.80 (m, 1H), 7.98 (m, 1H), 8.18 (s, 1H), 9.61 (s, 1H), 12.93 (br, 1H), 13.75 (br, 1H) )

Example 6 5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1, Ethyl 5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate

first step 2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate

1-Bromo-2-methoxy-3-nitrobenzene 1c (67 g, 0.289 mol), 4,4,4',4',5,5,5',5'-octamethyl-2, Ethyl 2'-linked-1,3,2-borate (110 g, 0.433 mol), tetrakis(triphenylphosphine)palladium (11.80 g, 14.44 mmol) and potassium acetate (71 g, 0.724 mol) were dissolved in 600 mL The mixture was heated under reflux for 17 hours in dimethyl oxalate. The residue was traced by TLC to dryness, concentrated under reduced pressure and purified by silica gel column chromatography to give the title product 2-(2-methoxy-3-nitrophenyl)-4,4,5,5-tetra. Base-[1,3,2]ethylene glycol borate 6a (50.5 g, yellow crystals). Yield: 61.9%.

Second step 4,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid 4-ethyl ester

3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-t-butyl ester 4-ethyl ester 6b (5.34 g, 20 mmol) was dissolved in trifluoroacetic acid (7.4 mL). , 100 mmol), stirred for 2 hours, the reaction was monitored by TLC until the starting material was completely reacted, 40 mL of water was added to the reaction mixture, and the filtrate was washed with dichloromethane and dried to give the title product 3,5-dimethyl-1H-pyrrole. 4-Ethyl 4-ethyldicarboxylate 6c (3.65 g, pink solid), yield: 86.5%. MS m/z (ESI): 209.8 [M-1]

third step Ethyl 5-iodo-2,4-dimethyl-1H-pyrrole-3-carboxylate

Add 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid 4-ethyl ester 6c (3.65 g, 17.3 mmol) to a mixed solvent of 100 mL of dichloromethane and 10 mL of water, and then add potassium iodide ( 11.5g, 69.2mmol) and iodine (4.39g, 17.3mmol), after heating and refluxing for 2 hours, the reaction was monitored by TLC until the reaction of the starting material was complete, the reaction solution was cooled to room temperature, and 20 mL of water and 10 mL of sodium thiosulfate solution were added. 2M), extracted with methylene chloride (30 mL × 3), EtOAcjjjjjjjjjjjj Ethyl dimethyl-1H-pyrrole-3-carboxylate 6d (4.1 g, orange solid), yield: 80.8%.

the fourth step Ethyl 5-iodo-1,2,4-trimethyl-1H-pyrrole-3-carboxylate

6-Iodo-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6d (4.1 g, 13.99 mmol) was dissolved in 80 mL of tetrahydrofuran, and methyl 4-methylbenzenesulfonate (2.73 g) was added. , 14.69 mmol) and sodium butoxide sodium (2.02 g, 20.99 mmol), after stirring, the mixture was stirred at room temperature for 0.5 hr, and the reaction was monitored by TLC until the reaction mixture was completed, and the reaction mixture was filtered, and the filtrate was washed with THF. The title product 5-iodo-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6e (3.8 g, m.p.). MS m/z (ESI): 308.1 [M + 1] ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.287~4.340 (q, 2H), 3.561 (s, 3H), 2.618 (s, 3H), 2.888 ( s,3H), 1.369~1.405(t,3H)

the fifth step Ethyl 5-(3-nitro-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate

Ethyl 5-iodo-1,2,4-trimethyl-1H-pyrrole-3-carboxylate 6e (2.88 g, 9.38 mmol) was dissolved in 25 mL of 1,4-dioxane, and 2-(2) was added. -methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (3.6 g, 10.3 mmol), tetrakis (triphenyl) Palladium (270 mg, 0.234 mmol), sodium carbonate (1.99 g, 18.77 mmol) and 10 mL of water. After the addition, the mixture was heated to reflux for 3 hours. The reaction was monitored by TLC until the reaction mixture was completed. The extract was extracted with ethyl acetate (30 mL×3), and the organic layer was evaporated. Ethyl-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate 6f (1.25 g, yellow oily). Yield: 40.4%. MS m/z (ESI): 333.2 [M + 1] ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.8 s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s ), 4.322~4.375(q,2H), 3.521(s,3H), 3.316(s,3H),.2.625(s,3H), 2.177(s,3H),1.398~1.434(t,3H)

Step 6 Ethyl 5-(3-amino-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate

Ethyl 5-(3-nitro-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate 6f (300 mg, 0.9 mmol) was dissolved in 5 mL of acetic acid To the ethyl ester, toluidine (227 mg, 1.61 mmol) and 60 mg of palladium/carbon were added, and the mixture was heated to reflux for 1 hour. The reaction was monitored by TLC until the reaction mixture was completed. The reaction mixture was filtered, and the filtrate was washed with ethyl acetate. Product title: 5-(3-Amino-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6 g (234 mg, white solid) 86%. MS m/z (ESI): 303.4 [M + 1] ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.968~7.006 (m, 1H), 6.818~6.840 (m, 1H), 6.559~6.618 (m, 1H) ), 4.311~4.364(q,2H), 3.381(s,3H),3.315(s,3H),2.615(s,3H),2.181(s,3H),1.391~1.426(t,3H)

Seventh step 5-(3-Amino-2-hydroxyphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester hydrobromide

Ethyl 5-(3-amino-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate 6 g (210 mg, 0.69 mmol) was dissolved in 5 mL of dichloro To the methane, boron bromide (1.39 mL, 2.78 mmol) was added, and the mixture was reacted at room temperature for 0.5 hour. The reaction was monitored by TLC until the reaction mixture was completed. The reaction was quenched with methanol. The mixture was concentrated under reduced pressure. The sodium hydrogen hydride solution was stirred, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate Phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester hydrobromide 6h (165 mg, white solid), yield: 82.5%. MS m/z (ESI): 289.3 [M+1] ¹ H NMR (400 MHz, DMSO- d6 ): δ7.313~7.396 (m, 1H), 7.098~7.117 (m, 1H), 6.993~7.032 (m, 1H), 4.173~4.227(q,2H), 3.221(s,3H), 1.979(s,3H),1.242~1.295(t,3H)

Eighth step 5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1, Ethyl 5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate

Dissolve 5-(3-amino-2-hydroxyphenyl)-1,2,4-trimethyl-lH-pyrrole-3-carboxylic acid ethyl ester hydrobromide 6 h (140 mg, 0.51 mmol) in an ice bath 11.7 mL of sodium nitrite solution (39 mg, 0.56 mmol) was added dropwise to 1.76 mL of hydrochloric acid (1N), stirred for 20 minutes, and then 5-methyl-2-(5,6,7,8-tetrahydronaphthalene-2 was added. -yl)-2,4-dihydropyrazol-3-one 3i (105 mg, 0.46 mmol). The pH of the reaction mixture was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and 1 The title material was obtained as a title product 5-(2-hydroxy-3-{N). The residue was purified by chromatography. '-[3-Methyl-5-o-oxy-1-(5,6,7,8-tetrahydronaphthalenylene-2-yl)-1,5-dihydropyrazole-4-ylidene ]-Mercapto}-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6 (120 mg, red solid). Yield: 50.8%. MS m/z (ESI): 514.1 [M+1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.84 (m, 4H), 2.14 (s, 3H), 2.41 (s, 3H), 2. , 3H), 2.80 (m, 4H), 3.34 (s, 3H), 3.87 (s, 3H), 6.51 (m, 1H), 7.00 (d, J = 7, 6 Hz, 1H), 7.11 (m, 2H) ), 7.71 (m, 2H), 13.82 (br, 1H)

Example 7 3'-{N'-[1-(2,3-dihydrobenzofuran-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene ]-mercapto}-2'-hydroxybiphenyl-3-carboxylic acid

first step 1-(2,3-dihydrobenzofuranyl)indolyl-1,2-dicarboxylic acid bis(2,2,2-trichloroethyl ester)

2,3-Dihydrobenzofuran 7a (0.6 mL, 5.32 mmol), bis(2,2,2-trichloroethyl)azodicarbonate (1.96 g, 5.15 mmol) and zinc chloride (920 mg) , 6.76 mmol) was dissolved in 40 mL of dichloromethane and allowed to react at room temperature overnight. The material disappeared by TLC, and purified by silica gel column chromatography to give the title product 1-(2,3-dihydrobenzofuranyl)indolyl-1,2-dicarboxylic acid (2,2,2). - Trichloroethyl ester) 7b (2.5 g, white solid). Yield: 96.6%.

Second step 2-(2,3-dihydrobenzofuran-5-yl)-5-methyl-2,4-dihydropyrazol-3-one

Dissolving 1-(2,3-dihydrobenzofuranyl)indolyl-1,2-dicarboxylic acid bis(2,2,2-trichloroethyl ester) 7b (2.9 g, 5.8 mmol) in 50 mL of ethanol In a mixed solvent of 5 mL of methanol, zinc powder (10.8 g, 166 mmol) and ammonium acetate solution (15 mL, 1 mol/L) were further added to react at room temperature for 1 hour, and ethyl acetate (0.75 mL, 5.9 mmol) was added dropwise. Heat to reflux for 2 hours. The residue was evaporated to dryness by TLC, and the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the title product 2-(2,3-dihydrobenzofuran-5-yl. 5-methyl-2,4-dihydropyrazol-3-one 7c (706 mg, yellow solid). Yield: 56.5%. MS m/z (ESI): 217 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.63 (s, 1H), 7.51 (d, J = 1.2 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 4.57 (t, J = 8.8 Hz, 2H), 3.39 (s, 2H), 3.22 (t, J = 8.4 Hz, 2H), 2.16 (s, 3H).

third step 3'-{N'-[1-(2,3-dihydrobenzofuran-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene ]-mercapto}-2'-hydroxybiphenyl-3-carboxylic acid

3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 1f (155 mg, 0.5 mmol) was dissolved in 1.7 mL of hydrochloric acid (1 N) under ice bath, and 0.6 mL of sodium nitrite solution was added dropwise. (36 mg, 0.53 mmol), stirred for 10 minutes, then added 2-(2,3-dihydrobenzofuran-5-yl)-5-methyl-2,4-dihydropyrazol-3-one 7c ( 97 mg, 0.45 mmol) was added portionwise with saturated sodium bicarbonate solution (630 mg, 7.5 mmol). The product disappeared by TLC, the pH was adjusted to <5 with concentrated hydrochloric acid, filtered and dried to give the title product 3'-{N'-[1-(2,3-dihydrobenzofuran-5-yl)-3 Methyl-5-o-oxy-1,5-dihydropyrazole-4-ylidene]-indenyl}-2'-hydroxybiphenyl-3-carboxylic acid 7 (131 mg, brown solid). Yield: 63.9%. MS m/z (ESI): 455 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 2.33 (s, 3H), 3.24 (t, J = 8.4 Hz, 2H), 4.56 (t, J) = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 1H), 7.16 (m, 2H), 7.61 (m, 2H), 7.72 (m, 2H), 7.80 (d, J = 8.0 Hz, 1H) ), 7.96 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 9.64 (s, 1H), 13.01 (s, 1H), 13.75 (s, 1H)

Example 8 2-(3,3-Dimethylindan-5-yl)-4-{"2-hydroxy-3'-(1H-tetrazol-5-yl)-biphenyl-3-yl]-indole -5--5-methyl-2,4-dihydropyrazol-3-one

first step

5-(3-bromo-phenyl)-1H-tetrazole

3-Bromo-benzonitrile 8a (18.2 g, 0.1 mol) and ammonium chloride (5.9 g, 0.11 mol) were dissolved in 80 mL of N,N'-dimethylformamide under argon atmosphere, followed by azide Sodium (7.16 g, 0.11 mol) was heated to 100 ° C overnight. After cooling to 60 ° C, N,N'-dimethylformamide was concentrated under reduced pressure, and 100 mL of water and 4 mL of concentrated hydrochloric acid were added and stirred for 1 hour, filtered and dried to give the title product 5-(3-bromo-phenyl) -1H-tetrazole 8b (23 g, white solid).

Second step

5-(2'-methoxy-biphenyl-3-yl)-1H-tetrazole

5-(3-Bromo-phenyl)-1H-tetrazole 8b (20 g, 89 mmol) and o-methoxyphenylboronic acid (14.2 g, 93.3 mmol) were dissolved in 530 mL of 1,4-dioxane under argon. Tetrakis(triphenylphosphine)palladium (1.84 g) and sodium carbonate (18.9 g, 178 mmol) were added and heated to reflux overnight. The residue was traced by TLC, and 1,4-dioxane was removed under reduced pressure. Hydrochloric acid (200 mL, 6 mol/L) was added, and the mixture was cooled for 2 hours. The aqueous layer was discarded and the residue was dissolved in ethyl acetate (500 mL). The residue was washed with EtOAc (EtOAc m. -1H-tetrazole 8c (15 g, pale yellow solid). Yield: 68.2%.

third step

3'-(1H-tetrazol-5-yl)-biphenyl-2-ol

5-(2'-Methoxy-biphenyl-3-yl)-1H-tetrazole 8c (15.5 g, 61.5 mol) was dissolved in 195 mL of acetic acid under argon atmosphere, and 195 mL of hydrobromic acid was added and heated to reflux. hour. The residue was evaporated to dryness eluted with EtOAc (EtOAc) eluted eluted eluted eluted eluted eluted eluted Product 3'-(1H-tetrazol-5-yl)-biphenyl-2-ol 8d (12 g, white solid). Yield: 82.8%.

the fourth step

3-nitro-3'-(1H-tetrazol-5-yl)-biphenyl-2-ol

3'-(1H-tetrazol-5-yl)-biphenyl-2-ol 8d (3.5g, 14.7mmol) was dissolved in 145mL of ethanol under argon atmosphere, and fuming nitric acid (0.565mL) was added dropwise at 35 °C. , 13.2 mmol), react at room temperature for 1 hour, add 150 mL of water, stand overnight, filter, solid wash with 100 mL of water, dissolve in 500 mL of ethyl acetate and 250 mL of water, extract, and wash the organic phase with saturated sodium chloride solution, anhydrous Drying over MgSO4, EtOAc (EtOAc) Yield: 27.0%. MS m/z (ESI): 282 [M-1]

the fifth step

3-amino-3'-(1H-tetrazol-5-yl)-biphenyl-2-ol hydrochloride

3-Nitro-3'-(1H-tetrazol-5-yl)-biphenyl-2-ol 8e (2.5 g, 8.83 mmol) was dissolved in 118 mL of ethanol and 78.6 mL of water, then sodium hydroxide solution was added (2.95 mL, 3 mol/L) and 313 mg of palladium-carbon were hydrogenated with hydrogen in a hydrogenation apparatus at 3 atm. and reacted at room temperature for 3 hours. The residue was removed by TLC, filtered, and then filtered, and then filtered, and then filtered, evaporated, evaporated, evaporated, evaporated, evaporated. -Amino-3'-(1H-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (2.33 g, red brown solid). MS m/z (ESI): 252 [M+1]

Step 6

1-(3,3-dimethylindan-5-yl)indolyl-1,2-dicarboxylic acid bis(t-butyl ester)

6-bromo-1,1-dimethylindane (WO2005066115) 8g (4.32g, 19.27mmol) was dissolved in 40mL of tetrahydrofuran, and butyl lithium (15.67mL, 1.6mol/L, 25.05) was added dropwise at -78 °C. Methyl), the reaction was carried out for 40 minutes, and a solution of di-tert-butyl azodicarboxylate (5.32 g, 23.12 mmol) in 30 mL of tetrahydrofuran was added, and the reaction was continued at -78 ° C for 3 hours. After the residue was traced to the disappearance of the starting material, 5 mL of methanol was added, and the reaction mixture was warmed to room temperature, and the mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the title product 1-(3,3-dimethylindole). -5-5-yl) decyl-1,2-dicarboxylic acid bis(t-butyl ester) 8 h (2.70 g, yellow solid). Yield: 37.2%.

Seventh step

2-(3,3-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazol-3-one

Dissolve 1-(3,3-dimethylindol-5-yl)indolyl-1,2-dicarboxylic acid bis(t-butyl ester) 8h (2.70g, 7.18mmol) in 100mL acetic acid, add 20 mL of trifluoroacetic acid was reacted at room temperature for 2 hours, and ethyl acetate (0.98 g, 7.54 mmol) was added, and the mixture was heated to 100 ° C for 2 hours. The mixture was traced by TLC until the material disappeared, cooled to room temperature and concentrated to remove acetic acid under reduced pressure. The acid in the reaction mixture was neutralized with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase was combined and washed with saturated sodium chloride solution. Drying over anhydrous sodium sulfate, EtOAc (EtOAc m.) 4-Dihydropyrazol-3-one 8i (1.0 g, light brown solid). Yield: 47.7%. MSm/z (ESI): 243 [M+1]

Eighth step

2-(3,3-Dimethylindan-5-yl)-4-{[2-hydroxy-3'-(1H-tetrazol-5-yl)-biphenyl-3-yl]-indole -5--5-methyl-2,4-dihydropyrazol-3-one

3-Amino-3'-(1H-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (290 mg, 1.0 mmol) was dissolved in hydrochloric acid (3.4 mL, 1 mol/L). Add 1.2 mL of sodium nitrite solution (73 mg, 1.05 mmol) dropwise, and react for 10 minutes, then add 2-(3,3-dimethylindol-5-yl)-5-methyl-2,4- Dihydropyrazol-3-one 8i (218 mg, 0.9 mmol) was added portionwise sodium bicarbonate (1.26 g, 15 mmol) and 4.4 mL of ethyl alcohol. The product disappeared by TLC, filtered, and the solid was washed with 20 mL of water, and then dissolved in 20 mL of water, adjusted to pH <5 with concentrated hydrochloric acid in an ice bath, filtered and dried to give the title product 2-(3,3-dimethyl Indole-5-yl)-4-{[2-hydroxy-3'-(1H-tetrazol-5-yl)-biphenyl-3-yl]-indenyl}-5-methyl-2, 4-Dihydropyrazol-3-one 8 (336 mg, yellow solid). Yield: 73.8%. MS m/z (ESI): 495 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.24 (m, 6H), 1.92 (t, J = 7.2 Hz, 2H), 2.36 (s, 3H), 2.87 (t, J = 7.2 Hz, 2H), 7.21 (m, 3H), 7.73 (m, 5H), 8.08 (d, J = 7.6 Hz, lH), 8.25 (s, 1H), 9.77 ( s, 1H), 13.80 (s, 1H)

Example 9

5-{2-hydroxy-3-"N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-oxime P-phenyl}-furan-2-carboxylic acid

first step

5-(2-methoxy-3-nitrophenyl)-furan-2-carboxylic acid

2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (10 g, 35.85 mmol), 5-bromo-furan-2-carboxylic acid (5.47 g, 28.66 mmol), tetrakis(triphenylphosphine)palladium (2.07 g, 1.79 mmol) and sodium carbonate (7.60 g, 71.66 mmol) dissolved in 200 mL 1,4- In a mixed solvent of dioxane and 30 mL of water, the mixture was heated under reflux for 2.5 hours. The mixture was traced by TLC until the material disappeared, filtered, and the filtrate was concentrated under reduced pressure. 150 mL of water was added to the residue, acidified to pH~3 with 1N hydrochloric acid, and filtered, and the mixture was mixed with 50 mL of n-hexane and ethyl acetate (1/1) Washing and drying gave the title product 5-(2-methoxy-3-nitrophenyl)-furan-2-carboxylic acid 9a (4.23 g, m. Yield: 56.1%. MS m/z (ESI): 262 [M-1]

Second step

5-(3-amino-2-methoxy-phenyl)-furan-2-carboxylic acid

5-(2-Methoxy-3-nitrophenyl)-furan-2-carboxylic acid 9a (4.23 g, 16.09 mmol) was dissolved in 125 mL of ethyl acetate and then 423 mg of palladium-carbon and ammonium formate ( 4.054 g, 64.35 mmol), heated to reflux for 3.5 hours. The residue was purified by EtOAc (EtOAc) eluting (2.79 g, pale green solid), Yield: 74.4%. MS m/z (ESI): 232 [M-1]

third step

5-(3-amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide

5-(3-Amino-2-methoxy-phenyl)-furan-2-carboxylic acid 9b (2.79 g, 11.97 mmol) was dissolved in 25 mL of dichloromethane, and boron tribromide (23.9 mL, 2.0 mol/L), reacted at room temperature for 1 hour. The title material was obtained as 5-(3-amino-2-hydroxybenzene). The title product was obtained after the residue was evaporated. Base)-furan-2-carboxylic acid hydrobromide 9c (1.24 g, yellow solid). Yield: 47.2%. MS m/z (ESI): 218 [M-1]

the fourth step

5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (300 mg, 1.0 mmol) was dissolved in hydrochloric acid (3.4 mL, 1 mol/L) and added dropwise. 1.2 mL of sodium nitrite solution (73 mg, 1.05 mmol), react for 10 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (193 mg, 0.9 (mmol), sodium hydrogencarbonate (1.26 g, 15 mmol) and 4.4 mL of ethanol were added portionwise and allowed to react at room temperature for 24 hours. The material disappeared by TLC, filtered, and the solid was washed with 20 mL of water, dissolved in 20 mL of water, adjusted to pH <5 with concentrated hydrochloric acid under ice-cooling, filtered and dried to give the title product 5-{2-hydroxy-3-[ N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl]-phenyl}-furan-2 - Carboxylic acid 9 (287 mg, yellow solid). Yield: 71.8%. MS m/z (ESI): 443 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 2.03 (m, 2H), 2.32 (s, 3H), 2.89) m, 4H), 7.15 ( m, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 3.6 Hz, 1H), 7.57 (m, 1H), 7.70 ( m, 2H), 7.78 (s, 1H), 9.97 (s, 1H), 13.73 (s, 1H)

Example 10

4-{"2-hydroxy-3'-(1H-tetrazol-5-yl)-biphenyl-3-yl]-arylene]-5-methyl-2-(5,6,7, 8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazol-3-one

3-Amino-3'-(1H-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (340 mg, 1.34 mmol) was dissolved in 3 mL of 1N hydrochloric acid, and 3 mL Sodium nitrate solution (98 mg, 1.41 mmol), reacted for 10 minutes, and then added 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazole- 3-keto 3i (276 mg, 1.21 mmol), sodium hydrogencarbonate (1.69 g, 20 mmol) and 3 mL of ethanol were added portionwise and reacted at room temperature for 18 hours. The product disappeared by TLC, filtered, and the solid was washed with 20 mL of water, dissolved in 20 mL of water, adjusted to pH = 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered and dried to give the title product 4-{[2-hydroxy-3 '-(1H-tetrazol-5-yl)-biphenyl-3-yl]-arylene}-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl -2,4-Dihydropyrazol-3-one 10 (208 mg, yellow solid). Yield: 31.6%. MS m/z (ESI): 491 [M-1] ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.19 (1H, s), 7.99 (1H, s), 7.69 (2H, t, J = 8.8 ), 7.49 (2H, d, J = 7.6), 7.I5 (3H, m), 2.75 (4H, m), 2.39 (3H, s), 1.75 (4H, m)

Example 11 2'-Hydroxy-5'-methyl-3'-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)- I,5-dihydropyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid

first step

2-bromo-4-methyl-6-nitrophenol

Sodium nitrate (28 g, 0.33 mmol) was dissolved in a mixed solvent of 70 mL of concentrated sulfuric acid and 210 mL of water at -5 ° C, and 2-bromo-4-methylphenol 11a (30.8 g, 0.165 mol) was slowly added dropwise thereto. After 2 hours, the reaction was allowed to rise to room temperature for 1 hour. The residue was purified by TLC. The title compound was obtained from ethyl acetate. EtOAc (EtOAc) 4-methyl-6-nitrophenol 11b (22.24 g, yellow solid). Yield: 58.1%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.29 (s, 3H), 7.81 (m, 2H), 10.76 (s, 1H)

Second step

1-bromo-2-methoxy-5-methyl-3-nitrobenzene

2-Bromo-4-methyl-6-nitrophenol 11b (22.24 g, 95.9 mmol) was dissolved in 150 mL of acetone, and potassium carbonate (15.9 g, 115 mmol) and methyl iodide (13.7 mL, 220.6 mmol) were added and heated. Reflux overnight. The title material was obtained by the residue eluting with EtOAc (EtOAc). - Nitrobenzene 11c (23.1 g, orange solid). Yield: 97.9%.

third step

2'-Methoxy-5'-methyl-3'-nitrobiphenyl-3-carboxylic acid

1-Bromo-2-methoxy-5-methyl-3-nitrobenzene 11c (15.0 g, 61 mmol) and m-carboxyphenylboronic acid (11.6 g, 70.1 mmol) were dissolved in 200 mL of 1,4-dioxane. Further, tetrakis(triphenylphosphine)palladium (2.8 g, 2.44 mmol) and 61 mL of sodium carbonate solution (12.9 g, 122 mmol) were added, and the mixture was heated to reflux overnight. The residue was evaporated to dryness with EtOAc (EtOAc) eluted eluted The pH was adjusted to 1-2, filtered, and the solid was dried to give the title product 2'-methoxy-5'-methyl-3'-nitrobiphenyl-3-carboxylic acid 11d (15.4 g, yellow solid) , Yield: 88.1%. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 2.40 (s, 3H), 3.42 (s, 3H), 7.58 (s, 1H), 7.58-7.75 (m, 1H), 7.75 (d, J = 1.6) Hz, lH), 7.82-7.84 (m, 1H), 8.02 (d, J = 8 Hz, 1H), 8.11 (d, J = 1.6 Hz, 1H), 13.12 (s, 1H)

the fourth step 2'-Hydroxy-5'-methyl-3'-nitrobiphenyl-3-carboxylic acid

2'-Methoxy-5'-methyl-3'-nitrobiphenyl-3-carboxylic acid 11d (11.2 g, 39.0 mmol) was dissolved in hydrobromic acid solution (250 mL, 40%) and heated Reflux overnight. The title material was washed with a small amount of water and n-hexane and dried to give the title product 2'-hydroxy-5'-methyl-3'-nitrobiphenyl. 3-carboxylic acid 11e (9.15 g, yellow solid). Yield: 85.9%. MS m/z (ESI): 272 [M-1] ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 2.36 (s, 3H), 7.60 (m, 2H), 7.78 (d, J = 8 Hz, 1H) ), 7.88 (d, J = 1.2 Hz, 1H), 7.97 (d, J = 8 Hz, 1H), 8.11 (s, 1H), 10.44 (s, 1H), 13.06 (s, 1H)

the fifth step 3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride

2'-Hydroxy-5'-methyl-3'-nitrobiphenyl-3-carboxylic acid 11e (9.15 g, 33.5 mmol) was dissolved in 200 mL of ethyl acetate, and 2 g of palladium-carbon and ammonium formate (8.45) were added. g, 134 mmol), heated to reflux for 30 minutes. The mixture was traced by TLC until the material disappeared, the reaction mixture was filtered, and the filtrate was acidified with hydrochloric acid, filtered and dried to give the title product 3'-amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride. Salt 11f (6.65 g, white solid). Yield: 71.0%. MS m/z (ESI): 242 [M-1] ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 2.29 (s, 3H), 7.09 (d, J = 1.6 Hz, 1H), 7.14 (d, J=1.6 Hz, lH), 7.59 (t, J=8 Hz, 1H), 7.74 (dd, J- ₁ = 6.4 Hz, J ₂ = 1.6 Hz, 1H), 7.94 (dd, J- ₁ = 6.4 Hz, J ₂ =1.6 Hz, 1H), 8.07 (s, 1H)

Step 6 2'-Hydroxy-5'-methyl-3'-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)- 1,5-dihydropyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid

3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride 11f (272 mg, 0.97 mmol) was dissolved in hydrochloric acid (3.3 mL, 1 mol/L). Add 1.3 mL of sodium nitrite solution (74 mg, 1.07 mmol) dropwise for 20 minutes, then add 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4- Dihydropyrazol-3-one 3i (200 mg, 0.88 mmol), sodium hydrogencarbonate (1.22 g, 14.6 mmol) and 2.1 mL of ethanol were added portionwise and allowed to react at room temperature for 4 hours. The material disappeared by TLC, filtered, and the solid was washed with 20 mL of water, and then dissolved in 20 mL of water, adjusted to pH <5 with concentrated hydrochloric acid in an ice bath, filtered and dried to give the title product 2'-hydroxy-5'-methyl. -3'-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4 - subunit]-mercapto}-biphenyl-3-carboxylic acid 11 (170 mg, red solid). Yield: 40.2%. MS m/z (ESI): 481 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.75 (m, 4H), 2.30 (s, 3H), 2.34 (s, 3H), 2.74 (m) , 4H), 7.00 (d, J = 1.2 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.62 (m, 3H), 7.80 (d, J = 7.6 Hz) , 1H), 7.95 (d, J = 7.6 Hz, 1H), 8.14 (s, 1H), 9.39 (s, 1H), 13.03 (s, 1H), 13.77 (s, 1H)

Example 12 5-(3-{N'-"1-(3,3-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4- Subunit]-mercapto}-2-hydroxyphenyl)-thiophene-2-carboxylic acid

first step 5-(2-methoxy-3-nitrophenyl)-thiophene-2-carboxylic acid

2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (10 g, 35.85 mmol), 5-bromo-thiophene-2-carboxylic acid (6.68 g, 32.2 mmol), tetrakis(triphenylphosphine)palladium (2.07 g, 1.79 mmol) and sodium carbonate (7.59 g, 71.6 mmol) dissolved in 200 mL 1,4- In a mixed solvent of dioxane and 30 mL of water, the mixture was heated under reflux for 1 hour. The mixture was traced by TLC until the material disappeared, filtered, and the filtrate was concentrated under reduced pressure. 150 mL of water was added to the residue, acidified to pH = 3 with 1N hydrochloric acid, filtered, and mixed with 50 mL of n-hexane and ethyl acetate (V:V = 1/1) Washing and drying gave the title product 5-(2-methoxy-3-nitrophenyl)-thiophene-2-carboxylic acid 12a (7.7 g, pale yellow solid). Yield: 77%. MS m/z (ESI): 277.9 [M-1]

Second step 5-(3-amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid

5-(2-Methoxy-3-nitrophenyl)-thiophene-2-carboxylic acid 12a (7.7 g, 27.6 mmol) was dissolved in 300 mL of ethyl acetate, followed by 500 mg of palladium-carbon and ammonium formate ( 6.96 g, 110 mmol), heated to reflux for 4 h. The residue was purified by TLC, EtOAc (EtOAc) eluted (6.2 g, gray solid), Yield: 90.1%. MS m/z (ESI): 248 [M-1]

third step 5-(3-amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide salt

Dissolve 5-(3-amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid 12b (2.2 g, 8.83 mmol) in 20 mL of dichloromethane and add boron tribromide (35 mL, 35.32) Mmmol/L), reacted at room temperature for 1.5 hours. The title material was obtained as 5-(3-amino-2-hydroxybenzene). The title product was obtained from the residue. Base)-thiophene-2-carboxylic acid hydrobromide 12c (1.2 g, grey solid). Yield: 57.1%. MS m/z (ESI): 234 [M-1]

the fourth step 5-(3-{N'-[1-(3,3-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4- Subunit]-mercapto}-2-hydroxyphenyl)-thiophene-2-carboxylic acid

5-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 12c (171 mg, 0.62 mmol) was dissolved in 3 mL of hydrochloric acid (1 N), and 1 mL of sodium nitrite was added dropwise. Solution (47 mg, 0.68 mmol), stirred for 20 minutes, then added 2-(3,3-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazol-3-one 8i (150 mg, 0.62 mmol), EtOAc (EtOAc m. The material disappeared by TLC, the solid was filtered, solid was dissolved in 20 mL of water, and concentrated hydrochloric acid was adjusted to pH = 3 to 4, filtered, dried, and the crude product was purified by HPLC to give the title product 5-(3-{N'- [1-(3,3-Dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}-2 -Hydroxyphenyl)-thiophene-2-carboxylic acid 12 (48 mg, orange solid). Yield: 15.9%. MS m/z (ESI): 487 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.24 (t, J = 8.6, 6H), 1.93 (t, J = 7.0, 2H), 2.87 ( t, J = 7.0, 2H), 7.16 (m, J = 6.0, 1H), 7.27 (d, J = 4.2, 2H), 7.57 (d, J = 8.0, 1H), 7.64 (d, J = 4.0, 1H), 7.70 (t, J = 8.4, 2H), 7.75 (d, J = 4.0, 1H)

Example 13 3'-{N'-[1-(2,3-dihydrobenzofuran-5-yl)-3-methyl-5-sideoxy -1,5-dihydropyrazol-4-ylidene]-mercapto}-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid

3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride 11f (287 mg, 1.03 mmol) was dissolved in 3.5 mL of hydrochloric acid (1 N) and added dropwise 1.5 mL sodium nitrite solution (78 mg, 1.13 mmol), stirred for 20 minutes, then added 2-(2,3-dihydrobenzofuran-5-yl)-5-methyl-2,4-dihydropyrazole- 3-keto 7c (200 mg, 0.93 mmol), EtOAc (EtOAc m. The material disappeared by TLC, the solid was filtered, dissolved in 20 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and mixed with 10 mL of dichloromethane and methanol (V:V=1) :1) Washing, crude product was separated and purified by HPLC to give the title product 3'-{N'-[1-(2,3-dihydrobenzofuran-5-yl)-3-methyl-5-side oxygen Base-1,5-dihydropyrazol-4-ylidene]-mercapto}-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid 13 (100 mg, red solid). Yield: 23.0%. MS m/z (ESI): 469 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 2.34 (s, 3H), 2.36 (s, 3H), 3.24 (t, J = 8.8 Hz, 2H) ), 4.57 (t, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 1H), 7.00 (s, 1H), 7.54 (s, 1H), 7.61 (m, 2H), 7.74 (s) , 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 8.13 (s, 1H), 9.38 (s, 1H), 13.02 (s, 1H), 13.76 (s, 1H)

Example 14 3'-{N'-[1-(2,3-dihydrobenzofuran-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene ]-mercapto}-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid

3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid hydrochloride 2f (219 mg, 0.772 mmol) was dissolved in 3 mL of hydrochloric acid (1N), and 1 mL of nitrous acid was added dropwise. Sodium solution (59 mg, 0.85 mmol), stirred for 20 minutes, then added 2-(2,3-dihydrobenzofuran-5-yl)-5-methyl-2,4-dihydropyrazol-3-one 7c (150 mg, 0.69 mmol), EtOAc (EtOAc: m. The material disappeared by TLC, the solid was filtered, dissolved in 15 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 3'-{N'- [1-(2,3-Dihydrobenzofuran-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}-5 '-Fluoro-2'-hydroxybiphenyl-3-carboxylic acid 14 (65 mg, red solid). Yield: 20.0%. MS m/z (ESI): 473 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 2.33 (s, 3H), 3.23 (t, J = 8.8 Hz, 2H), 4.56 (t, J) = 8.8 Hz, 2H), 6.83 (d, J = 8.4 Hz, 1H), 7.03 (m, 1H), 7.48 (m, 1H), 7.60 (m, 2H), 7.65 (s, 1H), 7.83 (d) , J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 8.17 (s, 1H), 9.57 (s, 1H), 13.07 (s, 1H), 13.62 (s, 1H)

Example 15 5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-di Hydropyrazol-4-ylidene]-indenyl}-phenyl)-furan-2-carboxylic acid

5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (292 mg, 0.975 mmol) was dissolved in 3.3 mL of hydrochloric acid (1N), and then added dropwise Sodium nitrate solution (74 mg, 1.07 mmol), stirred for 20 minutes, then added 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazole- 3-ketone 3i (200 mg, 0.88 mmol) was added portionwise EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc The material disappeared by TLC, the solid was filtered, dissolved in 20 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 5-(2-hydroxyl -3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4- Subunit]-mercapto}-phenyl)-furan-2-carboxylic acid 15 (160 mg, red solid). Yield: 39.8%. MS m/z (ESI): 457 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.76 (m, 4H), 2.33 (s, 3H), 2.75 (m, 4H), 7.13 (m) , 2H), 7.22 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 3.2 Hz, 1H), 7.56 (d, J = 7.6 Hz, lH), 7.63 (m, 2H), 7.71 (d) , J=8.4Hz, 1H)

Example 16 3'-{N'-[1-(3.3-Dimethylindan-5-yl)-3-methyl-5-oxo-1.5-dihydropyrazole-4-ylidene]-indenyl }-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid

3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride 11f (257 mg, 0.92 mmol) was dissolved in 3.1 mL of hydrochloric acid (1 N), and then added dropwise. mL sodium nitrite solution (70 mg, 1.01 mmol), stirred for 20 minutes, then added 2-(3,3-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazole- 3-ketone 8i (200 mg, 0.83 mmol), EtOAc (EtOAc m. The material disappeared by TLC, the solid was filtered, dissolved in 30 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 3'-{N'. -[1-(3,3-dimethylindan-5-yl)-3-methyl-5-o-oxy-1,5-dihydropyrazole-4-ylidene]-indenyl}- 2'-Hydroxy-5'-methylbiphenyl-3-carboxylic acid 16 (160 mg, orange solid). Yield: 39.0%. MS m/z (ESI): 495 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.25 (s, 6H), 1.92 (t = 7.2 Hz, 2H), 2.35 (s, 3H), 2.86 (t, J = 7.6 Hz, 2H), 7.00 (s, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.54 (s, lH), 7.61 (t, J = 8.0 Hz, 1H), 7.69 (m, 2H), 7.80 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 8.14 (s, 1H), 9.41 (s, 1H), 13.05 (br, 1H) ), 13.77(s,1H)

Example 17 3'-{N'-"1-(3,3-Dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene ]-mercapto}-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid

3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid hydrochloride 2f (200 mg, 0.71 mmol) was dissolved in 2.4 mL of hydrochloric acid (1 N) and added dropwise to 1 mL. Sodium nitrate solution (54 mg, 0.78 mmol), stirred for 20 minutes, then added 2-(3,3-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazole-3- Ketone 8i (153 mg, 0.64 mmol) was added portionwise EtOAc EtOAc (EtOAc:EtOAc) The material disappeared by TLC, the solid was filtered, dissolved in 20 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 3'-{N'. -[1-(3,3-dimethylindan-5-yl)-3-methyl-5-o-oxy-1,5-dihydropyrazole-4-ylidene]-indenyl}- 5'-Fluoro-2'-hydroxybiphenyl-3-carboxylic acid 17 (120 mg, dark red solid). Yield: 38.0%. MSm / z (ESI): 499 [M-1] l HNMR (400MHz, DMSO- d6): δ1.25 (s, 6H), 1.92 (t, J = 7.2Hz, 2H), 2.34 (s, 3H) , 2.86 (t, J = 7.2 Hz, 2H), 7.03 (m, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.47 (m, 1H), 7.63 (m, 3H), 7.83 (d, J=7.6 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 8.18 (s, 1H), 9.60 (s, lH), 13.07 (br, 1H), 13.64 (s, 1H)

Example 18 5-{2-hydroxy-3-"N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-oxime "-phenyl}-thiophene-2-carboxylic acid

5-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 12c (380 mg, 1.2 mmol) was dissolved in 3.9 mL of hydrochloric acid (1 N), and 1.5 mL was added dropwise. Sodium nitrite solution (90 mg, 1.32 mmol), stirred for 20 minutes, then added 2-indane-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (210 mg, 1 mmol). The saturated sodium bicarbonate solution (1.51 g, 18 mmol) was added portionwise to adjust the pH to 8 to 9, and the mixture was quenched with 2 mL of ethanol and allowed to react to room temperature overnight. Followed by TLC until the disappearance of the starting material, the solid was filtered out, dissolved in 20 mL of 5% sodium hydroxide solution, the aqueous phase was extracted with dichloromethane (50 mL×3), the aqueous phase was adjusted to pH 3 to 4 with concentrated hydrochloric acid, filtered, dried, crude The product was isolated and purified by HPLC to give the title product 5-{2-hydroxy-3-[N'-(1-indane-5-yl-3-methyl-5-oxo-1,5-dihydropyridin. Azole-4-ylidene)-indenyl]-phenyl}-thiophene-2-carboxylic acid 18 (15 mg, orange solid). Yield: 3.3%. MSm / Z (ESI): 459 [M-1] l HNMR (400MHZ, DMS0-d 6): δ1.36-1.78 (m, 2H), 2.33 (s, 3H), 2.86-2.94 (m, 4H) , 7.17 (t, J = 8 Hz, 1H), 7.30 (d, J = 8 Hz, 1H), 7.56 (dd, J-1 = 8 Hz, J ₂ = 0.8 Hz, 1H), 7.56 (d, J = 4 Hz, 1H), 7.70 (m, 2H), 7.75 (d, J = 4 Hz, 1H), 7.79 (s, 1H)

Example 19 2'-Hydroxy-3'-{N'-[3-methyl-5-o-oxy-1-(1,1,3,3-tetramethylindan-5-yl)-1.5-dihydro Pyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid

first step 5-bromo-3,3-dimethylindan-1-one

6-bromo-1,1-dimethylindane 8 g (4 g, 17.8 mmol) was dissolved in 40 mL of re-distilled dichloromethane, chromium oxide (280 mg, 1.8 mmol) was added, and the third peroxide was slowly added dropwise. Alcohol (19 mL, 190 mmol), the reaction mixture was dark red, eluted with a gas, sealed, and stirred at room temperature overnight. The residue was evaporated to dryness eluting with EtOAc (EtOAc) (EtOAc) 3,3-Dimethylindan-1-one 19a (3.5 g, white solid), yield: 82.3%. MS m/z (ESI): 238 [M-1]

Second step 5-bromo-1,1,3,3-tetramethylindan

40 mL of dichloromethane was cooled to -40 ° C with acetonitrile-dry ice, titanium tetrachloride (2.7 mL, 24.6 mmol) was added by syringe, and stirred under cooling for 20 minutes, then dimethylzinc (29.3 mL, 35.1 mmol) in toluene was added. Control the reaction at -30 ° C, after the completion of the dropwise addition, react at low temperature for 30 minutes, and add 5-bromo-3,3-dimethylindan-1-one 19a (2.8 g, 11.7 mmol) in 10 mL of dichloromethane. The reaction was slowly warmed to room temperature and allowed to react overnight. The residue was evaporated to dryness under reduced pressure. (1.55 g, colorless oily liquid), yield: 52.3%. MS m/z (ESI): 252 [M-1]

third step 1-(1,1,3,3-tetramethyl-2,3-dihydro-1H-indan-5-yl)indenyl-1,2-dicarboxylic acid di-t-butyl ester

5-Bromo-1,1,3,3-tetramethylindan 19b (1.4g, 5.53mmol) was dissolved in 10mL of tetrahydrofuran, cooled to -78 ° C in acetone-dry ice bath, and added tributyllithium (4.4 mL, 11.1 mmol), stirring for 40 minutes, a solution of dibutyl azodicarboxylate (1.59 g, 6.92 mmol) in 10 mL of tetrahydrofuran was added dropwise to a constant pressure funnel, and the reaction was continued at -78 ° C for 3 hours. The mixture was traced by TLC until the disappearance of the material, and 5 mL of methanol was added. The reaction mixture was warmed to room temperature, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate. Purification by column chromatography to give the title product 1-(1,1,3,3-tetramethyl-2,3-dihydro-1H-indan-5-yl)indol-1,2-dicarboxylic acid Di-tert-butyl ester 19c (1.326 g, yellow oily liquid). Yield: 59.3%. MS m/z (ESI): 403 [M+1]

the fourth step 5-methyl-2-(1,1,3,3-tetramethylindan-5yl)-2,4-dihydropyrazol-3-one

1-(1,1,3,3-Tetramethyl-2,3-dihydro-1H-indan-5-yl)indolyl-1,2-dicarboxylic acid di-t-butyl ester 19c (2.70 g) , 7.18 mmol) was dissolved in 10 mL of acetic acid, and 13 mL of trifluoroacetic acid was added thereto, and the mixture was reacted at room temperature for 30 minutes, and ethyl acetate (502 mg, 3.86 mmol) was added thereto, and the mixture was heated to 100 ° C for 2 hours. The mixture was traced by TLC until the material disappeared, cooled to room temperature, and concentrated to remove acetic acid under reduced pressure. The acid in the reaction mixture was neutralized with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (20 mL×3). The sodium salt solution was washed with anhydrous sodium sulfate and filtered, and the filtrate was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjj Base-5-5-dihydropyrazol-3-one 19d (130 mg, pale yellow oily liquid). Yield: 13.6%. MS m/z (ESI): 269 [M+1]

the fifth step

2'-Hydroxy-3'-{N'-[3-methyl-5-o-oxy-1-(1,1,3,3-tetramethylindan-5-yl)-1,5- Dihydropyrazol-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid

3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 1f (172 mg, 0.56 mmol) was dissolved in 1.9 mL of 1N hydrochloric acid under ice bath, and 0.7 mL of sodium nitrite solution (42 mg) was added dropwise. , 0.61 mmol), further added 5-methyl-2-(1,1,3,3-tetramethylindan-5yl)-2,4-dihydropyrazol-3-one 19d (135 mg, 0.5 (mmol), sodium hydrogencarbonate (700 mg, 8.33 mmol) was added portionwise, the pH of the reaction mixture was adjusted to 8 to 9 and 2 mL of ethanol was added and the mixture was allowed to warm to room temperature overnight. The material disappeared by TLC, filtered, and the solid was dissolved in 20 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 2'-hydroxy-3. -{N'-[3-methyl-5-o-oxy-1-(1,1,3,3-tetramethylindan-5-yl)-1,5-dihydropyrazole-4- Subunit]-mercapto}-biphenyl-3-carboxylic acid 19 (75 mg, red solid). Yield: 29.4%. MS m / z (ESI): 509 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.30 (m, 12H), 1.92 (s, 2H), 2.35 (s, 3H), 7.14 (m, 2H) ), 7.23 (d, J = 8.0 Hz, 1H), 7.62 (m, 2H), 7.72 (m, 2H), 7.80 (d, J = 7.6 Hz, lH), 7.96 (d, J = 8.0 Hz, 1H) ), 8.14 (s, 1H), 9.68 (s, 1H), 13.10 (br, 1H), 13.78 (s, 1H)

Example 20

2'-Hydroxy-5'-methyl-3'-{N'-[3-methyl-5-oxo-l-(1,1,3,3-tetramethylindan-5-yl) )-1,5-dihydropyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid

3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride 11f (155 mg, 0.56 mmol) was dissolved in 1.9 mL of hydrochloric acid (1 N), and then added dropwise. mL sodium nitrite solution (42 mg, 0.61 mmol), stirred for 20 minutes, then added 5-methyl-2-(1,1,3,3-tetramethylindan-5-yl)-2,4-di Hydropyrazol-3-one 19d (135 mg, 0.5 mmol) was added portionwise with saturated sodium bicarbonate solution (700 mg, 8.33 mmol). The pH was adjusted to 8 to 9 and quenched with 2 mL of ethanol. . The material disappeared by TLC, the solid was filtered, dissolved in 30 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 2'-hydroxy-5. '-Methyl-3'-{N'-[3-methyl-5-o-oxy-1-(1,1,3,3-tetramethylindan-5-yl)-1,5- Dihydropyrazol-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid 20 (50 mg, red solid). Yield: 19.1%. MS m/z (ESI): 523 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ1.30 (m, 12H), 1.92 (s, 2H), 2.35 (m, 6H), 7.00 (m) , lH), 7.23 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.65 (m, 2H), 7.74 (m, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 8.14 (s, 1H), 9.41 (s, 1H), 13.05 (br, 1H), 13.78 (s, 1H)

Example 21

3'-"N'-(1-bicyclo"4.2.0]octane-1,3,5-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyridyl Azole-4-ylidene)-indenyl]-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid

3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride 11f (311 mg, 1.11 mmol) was dissolved in 3.7 mL of 1N hydrochloric acid and 1.5 mL of nitrous acid was added dropwise. Sodium solution (84 mg, 1.22 mmol) followed by 2-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-5-methyl-2,4-dihydropyr Zyridin-3-one 5d (200 mg, 1 mmol), sodium hydrogencarbonate (1.4 g, 16.7 mmol) was added portionwise, the pH of the reaction mixture was adjusted to 8 to 9, and 2 mL of ethanol was added and allowed to warm to room temperature overnight. The material disappeared by TLC, the solid was filtered, dissolved in 20 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 3'-[N'- (1-bicyclo[4.2.0]octane-1,3,5-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene) -mercapto]-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid 21 (330 mg, orange solid). Yield: 72.7%. MS m/z (ESI): 453 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 2.34 (m, 6H), 3.16 (m, 4H), 7.00 (s, 1H), 7.15 (d) , J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.62 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.95 (d , J=7.6Hz, 1H), 8.13(s,1H), 9.40(s,1H), 13.02(s,1H),13.75(s,1H)

Example 22

5-{3-[N'-(1-bicyclo[4.2.0]octane-1,3,5-trien-3-yl-3-methyl-5-oxo-1,5-di Hydropyrazol-4-ylidene-mercapto-2-furan-2-carboxylic acid

5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (333 mg, 1.11 mmol) was dissolved in 3.7 mL of 1N hydrochloric acid, and 1.5 mL of sodium nitrite solution was added dropwise. (84 mg, 1.22 mmol) followed by 2-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-5-methyl-2,4-dihydropyrazole- 3-ketone 5d (200 mg, 1 mmol), sodium bicarbonate (1.4 g, 16.7 mmol) was added portionwise, the pH of the reaction mixture was adjusted to 8 to 9 and 2 mL of ethanol was added and the mixture was allowed to warm to room temperature overnight. The material disappeared by TLC, the solid was filtered, dissolved in 20 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 5-{3-[N '-(1-Bicyclo[4.2.0]octane-1,3,5-trien-3-yl-3-methyl-5-oxo-oxy-1,5-dihydropyrazole-4-ya Base)-indenyl]-2-hydroxyphenyl}-furan-2-carboxylic acid 22 (275 mg, dark red solid). Yield: 63.9%. MS m/z (ESI): 429 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 2.31 (s, 3H), 3.15 (m, 4H), 7.15 (m, 2H), 7.20 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 3.6 Hz, 1H), 7.54 (m, 1H), 7.68 (m, 1H), 7.72 (m, 2H), 9.97 (z, 1H), 13.71 ( z,1H)

Example 23

2-bicyclo{4.2.0]octane-1,3,5-trien-3-yl-4-{[2-hydroxy-3'-(1H-tetrazol-5-yl)-biphenyl-3 -yl]-arylene-5-methyl-2,4-dihydropyrazol-3-one

3-Amino-3'-(1H-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (321 mg, 1.11 mmol) was dissolved in 3.7 mL of 1N hydrochloric acid and added dropwise 1.5 mL sodium nitrite solution (85 mg, 1.22 mmol), react for 20 minutes, then add 2-bicyclo[4.2.0]octane-1(6), 2,4-trien-3-yl-5-methyl- 2,4-Dihydropyrazol-3-one 5d (200 mg, 1 mmol), sodium bicarbonate (1.69 g, 20 mmol) and 3 mL of ethanol were added portionwise and allowed to react overnight at room temperature. The material disappeared by TLC, filtered, and the solid was washed with 20 mL of water, dissolved in 20 mL of water, adjusted to pH = 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered, and dried to give the title product 2-bicyclo[4.2.0] Octane-1,3,5-trien-3-yl-4-{[2-hydroxy-3'-(1H-tetrazol-5-yl)-biphenyl-3-yl]-anthracene} 5-5-Methyl-2,4-dihydropyrazol-3-one 23 (150 mg, red solid). Yield: 32.3%. MS m/z (ESI): 463 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 2.34 (s, 3H), 3.16 (m, 4H), 7.18 (m, 3H), 7.68 (s) , 1H), 7.73 (m, 4H), 8.08 (d, J = 7.6 Hz, 1H), 8.25 (d, J = 10 Hz, 1H), 9.71 (br, 1H), 13.77 (br, 1H)

Example 24

5-{2-hydroxy-3-"N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-oxime 5-methylphenyl}-thiophene-2-carboxylic acid

first step

2-(2-Methoxy-5-methyl-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

3-Bromo-2-methoxy-5-methyl-nitrobenzene 11c (20 g, 81.3 mmol) and 4,4,4',4',5,5,5',5'-octamethyl -2,2'-linked -1,3,2-boronic acid ethylene glycol ester (30.9 g, 112 mmol) was dissolved in 400 mL of dimethyl ether, and 1,1'-bis(diphenylphosphino)ferrocene dichloride was added. Palladium (3.3 g, 4.06 mmol) and potassium acetate (19.9 g, 203 mmol) were added and heated under reflux for 3 hours. The reaction solution was filtered to remove 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the title product 3-(4,5-dimethyl-[1,3,2]boronic acid benzoate-2-yl)-2-methoxy 5-methyl-nitrobenzene 24a (13.1 g, yellow oily liquid), yield 57.1%. MS m / z (ESI): 293.09 [M + 1] l HNMR (400MHz, CDCl 3): δ 1.16 (s, 12H), 2.39 (s, 3H), 3.5 (s, 3H), 7.53 (d, J =2Hz, lH), 7.83 (d, J=2Hz, 1H)

Second step

5-(3-nitro-2-methoxy-5-methylphenyl)-thiophene-2-carboxylic acid

3-(4,5-Dimethyl-[1,3,2]boronic acid pinacol-2-yl)-2-methoxy-5-methyl-nitrobenzene 24a (4.0 g, 14.5 Methyl), 5-bromo-thiophene-2-carboxylic acid (1.0 g, 4.8 mmol), tetrakis(triphenylphosphine)palladium (0.276 g, 0.24 mmol) and sodium carbonate (1.01 g, 9.6 mmol) were dissolved in 30 mL1. 4-Dioxanthracene and 10 mL of water, the reaction system was heated under reflux for 1 hour, and the mixture was traced by TLC until the disappearance of the starting material. The reaction mixture was concentrated under reduced pressure and then dissolved with water, and then filtered to remove tetras(triphenylphosphine)palladium. After the aqueous phase is acidified, a solid precipitates, the solid is dissolved in ethyl acetate, dried over anhydrous magnesium sulfate and filtered to remove the desiccant, and the filtrate is concentrated to give the title product 5-(3-nitro-2-methoxy-5- Phenyl)-thiophene-2-carboxylic acid 24b (1.03 g, yellow solid), yield: 73.6%. MS m/z (ESI): 291.7 [M-1] ¹ H NMR (400 MHz, CDCl ₃ ): δ 2.41 (s, 3H), 3.73 (s, 3H), 7.73-7.79 (m, 3H), 8.00 ( m, 1H), 13.20 (Br, 1H)

third step

5-(3-amino-2-methoxy-5-methylphenyl)-thiophene-2-carboxylic acid

Dissolve 5-(3-nitro-2-methoxy-5-methylphenyl)-thiophene-2-carboxylic acid 24b (0.29 g, 1 mmol) in 30 mL of ethyl acetate and add 0.06 g of palladium-carbon Ammonium formate (0.25 g, 4 mmol) was added and heated and refluxed for 45 minutes. The residue was removed by TLC, and the palladium-carbon was removed by filtration. The filtrate was concentrated under reduced pressure and dried to give the title product 5-(3-amino-2-methoxy-5-methylphenyl)-thiophene-2-carboxylic acid 24c (0.26 g, green solid). Yield: 99%. MS m/z (ESI): 261.7 [M-1] ¹ H NMR (400 MHz, CDCl ₃ ): δ 2.18 (s, 3H), 3.58 (s, 3H), 6.54 (d, J = 1.6 Hz, 1H) , 6.78 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 4 Hz, 1H), 7.68 (d, J = 4 Hz, 1H)

the fourth step

5-(3-amino-2-hydroxy-5-methylphenyl)-thiophene-2-carboxylic acid hydrobromide

Dissolve 5-(3-amino-2-methoxy-5-methylphenyl)-thiophene-2-carboxylic acid 24c (0.26 g, 1 mmol) in 20 mL of dichloromethane and add boron tribromide dropwise. 5 mL, 35.32 mmol/L), and reacted at room temperature for 1 hour. The title material was obtained as a title product 5-(3-amino-2-hydroxyl). -5-Methylphenyl)-thiophene-2-carboxylic acid hydrobromide 24d (0.15 g, m.p.). Yield: 45.5%. MS m/z (ESI): 247.8 [M-1] ¹ H NMR (400 MHz, CDCl ₃ ): δ 2.29 (s, 3H), 7.02 (d, J = 1.6 Hz, 1H), 7.41 (s, 1H) ), 7.59 (d, J = 4 Hz, 1H), 7.73 (d, J = 4 Hz, 1H)

the fifth step

5-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxooxy-1,5-dihydropyrazole-4-ylidene)- Mercapto]-5-methylphenyl}-thiophene-2-carboxylic acid

5-(3-Amino-2-hydroxy-5-methylphenyl)-thiophene-2-carboxylic acid hydrobromide 24d (138 mg, 0.42 mmol) was dissolved in 1.5 mL of 1N hydrochloric acid and added dropwise. 1.5mL sodium nitrite solution (85mg, 1.22mmol), reaction for 20 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (81mg, 0.38 Methyl) sodium hydrogencarbonate (527 mg, 6.27 mmol) and 2 mL of ethanol were added portionwise and allowed to react overnight at room temperature. The material disappeared by TLC, filtered, and the solid was washed with 20 mL of water, dissolved in 10 mL of water, adjusted to pH = 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered and dried to give the title product 5-{2-hydroxy-3. -[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indolyl]-5-methylbenzene }--thiophene-2-carboxylic acid 24 (30 mg, red solid). Yield: 16.7%. MS m/z (ESI): 473 [M-1] ¹ H NMR (400 MHz, DMS0- d6 ): δ 2.03 (m, 2H), 2.32 (s, 3H), 2.36 (s, 3H), 2.89 (m) , 4H), 7.29 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.50 (s, 1H), 7.63 (d, J = 4.0 Hz, 1H), 7.68 (d, J = 8.0 Hz) , 1H), 7.74 (m, 2H), 9.78 (s, 1H), 13.72 (br, 1H)

Example 25

5-(2-hydroxy-3-{N'-"3-methyl-5-oxo-l-(1,1,3,3-tetramethylindan-5-yl)-1,5 -dihydropyrazole-4-ylidene}-indenyl}-phenyl)-furan-2-carboxylic acid

5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (124 mg, 0.41 mmol) was dissolved in 1.4 mL of hydrochloric acid (1N), and 0.5 mL Sodium nitrate solution (32 mg, 0.45 mmol), stirred for 20 minutes, then added 5-methyl-2-(1,1,3,3-tetramethylindan-5yl)-2,4-dihydropyrazole 3-ketone 19d (100 mg, 0.37 mmol), the pH was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and the mixture was quenched with 2 mL of ethanol and allowed to react to room temperature overnight. The product disappeared by TLC, the solid was filtered, 10 mL of water was added to the solid, pH was adjusted to 3 to 4 with concentrated hydrochloric acid, filtered, and the solid was subjected to column chromatography and dried to give the title product 5-(2-hydroxy-3-{ N'-[3-Methyl-5-oxo-l-(1,1,3,3-tetramethylindan-5-yl)-1,5-dihydropyrazole-4-ylidene ]-Mercapto}-phenyl)-furan-2-carboxylic acid 25 (22 mg, red solid). Yield: 11.9%. ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.30 (m, 12H), 1.92 (s, 2H), 2.34 (s, 3H), 7, 15 (d, J = 3.6 Hz, 1H), 7.22 (m) , 2H), 7.36 (d, J = 3.2 Hz, 1H), 7.56 (dd, J1 = 8, 0 Hz, J2 = 1.2 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.75 (m, 2H)

Example 26

3'-[N'-(1-bicyclo[4.2.0]octane-1,3,5-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyridyl Azole-4-ylidene)-indenyl]-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid

first step

3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide salt The intermediate 3'-amino-5'-fluoro-2'-hydroxy group obtained in the fifth step of Example 2 Biphenyl-3-carboxylic acid 2f (500 mg '1.92 mmol) was added dropwise with 20 mL of hydrobromic acid, and a white turbid substance was formed. The mixture was heated and refluxed overnight, and the reaction was clarified to give a yellow-brown solution. The residue was evaporated to dryness, and the mixture was concentrated under reduced pressure. The solid brown solid was dissolved in ethyl acetate (20 mL), and stirred for 20 min, and filtered to give the title product 3'-amino-5'-fluoro-2'-hydroxybiphenyl. Base-3-carboxylic acid hydrobromide 26a (344 mg, off-white solid). Yield: 54.8%. MSm/z (ESI): 248 [M+1]

Second step

3'-[N'-(1-bicyclo[4.2.0]octane-1,3,5-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyridyl Azole-4-ylidene)-indenyl]-5'-fluoro-2'-hydroxy-diphenyl-3-carboxylic acid

3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 26a (328 mg, 1.11 mmol) was dissolved in 3.7 mL of 1N hydrochloric acid and added dropwise 1.5 mL. Sodium nitrate solution (84 mg, 1.22 mmol) followed by 2-bicyclo[4.2.0]octane-1(6), 2,4-trien-3-yl-5-methyl-2,4-dihydrogen Pyrazol-3-one 5d (200 mg, 1 mmol), sodium hydrogencarbonate (1.4 g, 16.7 mmol) was added portionwise, the pH of the reaction mixture was adjusted to 8 to 9 and 2 mL of ethanol was added and allowed to warm to room temperature overnight. The material disappeared by TLC, the solid was filtered, dissolved in 20 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 3'-[N'- (1-bicyclo[4.2.0]octane-1,3,5-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene) - mercapto]-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid 26 (335 mg, red solid). Yield: 73.1%. MS m/z (ESI): 457 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 2.32 (s, 3H), 3.22 (m, 4H), 7.02 (m, 1H), 7.14 (d) , J = 8.0 Hz, 1H), 7.46 (m, 1H), 7.61 (m, 2H), 7.69 (m, 1H), 7.82 (d, J = 7, 6 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 8.17 (s, 1H), 9.58 (s, 1H), 13.07 (s, 1H), 13.60 (s, 1H)

Example 27

4-{[2-hydroxy-3'-(1H-tetrazol-5-yl)-biphenyl-3-yl]-anthracene}-2-indan-5-yl-5-methyl-2, 4-dihydropyrazol-3-one

3-Amino-3'-(1H-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (188 mg, 0.74 mmol) was dissolved in 4 mL of 2N hydrochloric acid and added dropwise Sodium nitrate solution (57 mg, 0.82 mmol), reacted for 30 minutes, and then added 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (159 mg, 0.74 mmol). The pH was adjusted to 8 with saturated sodium bicarbonate, and 0.5 mL of ethanol was added and allowed to react at room temperature overnight. The material disappeared by TLC, filtered, and the solid was dissolved in sodium hydroxide solution (3N) and then washed three times with dichloromethane. The aqueous phase was adjusted to pH 3 with 2N hydrochloric acid, and a large amount of solid was precipitated and filtered. Chromatography gave the title product 4-{[2-hydroxy-3'-(1H-tetrazol-5-yl)-biphenyl-3-yl]-indole}-2-indan-5-yl-5- Methyl-2,4-dihydropyrazol-3-one 27 (67 mg, orange solid), yield: 18.8%. MS m/z (ESI): 477.2 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 2.03 (m, 2H), 2.33 (s, 3H), 2.89 (m, 4H), 7.17 (m) , 2H), 7.28 (d, J = 8.0 Hz, 1H), 7.71 (m, 5H), 8.08 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H), 9.73 (br, 1H), 13 ,77(s,1H)

Example 28

4-(2-hydroxy-3-{N'-"3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1, 5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-furan-2-carboxylic acid

first step

4-bromo-furan-2-carboxylic acid

4,5-dibromo-furan-2-carboxylic acid 28a (5.5 g, 20.3 mmol) and 18 mL of aqueous ammonia were added to 63 mL of water at room temperature, and zinc powder (1.46 g, 22.33 mmol) was added. After stirring for 6 hours, TLC was monitored until the starting material was completely reacted and the reaction was stopped. The pH of the reaction mixture was adjusted to 3 with hydrochloric acid (1N), and a large solid was precipitated, filtered, and the filter cake was washed with n-hexane (15 mL × 4) and dried to give the title product 4-bromo-furan-2-carboxylic acid 28b (3.2 g) , white solid), Yield: 83.1%. MS m/z (ESI): 188.7 [M-1]

Second step

4-(3-nitro-2-methoxy-phenyl)-furan-2-carboxylic acid

2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (4 g, 14.34 mmol), 4-bromo-furan-2-carboxylic acid 28b (2.18 g, 11.47 mmol), tetrakis(triphenylphosphine)palladium (829 mg, 0.717 mmol) and potassium carbonate (3.96 g, 28.68 mmol) dissolved in 80 mL 1,4- In a mixed solvent of dioxane and 30 mL of water, the mixture was heated under reflux for 2.5 hours. After the residue was traced to the disappearance of the starting material, the reaction mixture was acidified to pH 3 with 1N hydrochloric acid and ethyl acetate (EtOAc (EtOAc) Nitro-2-methoxy-phenyl)-furan-2-carboxylic acid 28c (3.42 g, brown oily). Yield: 90.7%. MS m/z (ESI): 261.8 [M-1]

third step

4-(3-amino-2-methoxy-phenyl)-furan-2-carboxylic acid

4-(3-Nitro-2-methoxy-phenyl)-furan-2-carboxylic acid 28c (500 mg, 1.9 mmol) was dissolved in 15 mL of ethyl acetate, and then 100 mg of palladium-carbon and ammonium formate ( 429 mg, 7.6 mmol), heated to reflux for 3 hours. The residue was removed by TLC, and the reaction mixture was filtered to remove palladium/carbon, and concentrated under reduced pressure to give the title product 4-(3-amino-2-methoxy-phenyl)-furan-2-carboxylic acid 28d (325 mg, yellow oil Liquid), yield: 73.4%. MS m/z (ESI): 231.8 [M-1]

the fourth step

4-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide

4-(3-Amino-2-methoxy-phenyl)-furan-2-carboxylic acid 28d (325 mg, 1.4 mmol) was dissolved in 5 mL dichloromethane, and boron tribromide (2.8 mL, 5.6) was added dropwise. Methyl), reacted at room temperature for 4.5 hours. The title material (4-amino-2-hydroxybenzene) was obtained after the residue was purified by chromatography. Base)-furan-2-carboxylic acid hydrobromide 28e (174 mg, gray solid). Yield: 57.1%. MS m/z (ESI): 217.7 [M-1]

the fifth step

4-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1, 5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-furan-2-carboxylic acid

4-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 28e (170 mg, 0.57 mmol) was dissolved in hydrochloric acid (1.9 mL, 1 mol/L). 0.7 mL of sodium nitrite solution (43 mg, 0.63 mmol), reacted for 20 minutes, and then added 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydrogen Pyrazol-3-one 3i (116 mg, 0.51 mmol) was adjusted to pH 8 to 9 with a saturated sodium hydrogen carbonate solution, and 2 mL of ethanol was added and allowed to react at room temperature for 24 hours. After the TLC was traced to the disappearance of the starting material, the mixture was filtered, and 15 mL of water was added to the solid. The mixture was adjusted to pH 2 to 3 with concentrated hydrochloric acid in an ice bath, filtered, and the filter cake was washed with ethyl acetate and dried to give the title product 4-(2-hydroxy- 3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole- 4-Subphenyl]-fluorenyl}-phenyl)-furan-2-carboxylic acid 28 (13 mg, red solid). Yield: 5.5%. MS m/z (ESI): 456.7 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.75 (m, 4H), 2.31 (s, 3H), 2.78 (m, 4H), 3.86 (s) , 3H), 7.13 (m, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.62 (m, 2H), 7.78 (s, 1H), 8.43 (s, 1H), 9.68 (br, 1H) , 13.73 (br, 1H)

Example 29

2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl ]-5'-Methyl-biphenyl-3-carboxylic acid

3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride 11f (346 mg, 1.07 mmol) was dissolved in hydrochloric acid (5 mL, 2 mol/L). Add 2 mL of sodium nitrite solution (81 mg, 1.17 mmol), react for 30 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (229 mg, 1.07) (mmol), the pH was adjusted to 8 with saturated sodium bicarbonate solution, and 5 mL of ethanol was added and allowed to react overnight at room temperature. It was traced to the disappearance of the starting material by TLC, filtered, and the solid was washed with ethanol, and the filtrate was poured into ice water, and the pH was adjusted to 4 with 1N hydrochloric acid, and solids were precipitated, filtered, and the obtained solid was washed three times with ethyl acetate. 2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl ]-5'-Methyl-biphenyl-3-carboxylic acid 29 (75 mg, red solid). Yield: 15%. MS m/z (ESI): 467.2 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 2.01 (m, 2H), 2.35 (m, 6H), 2.88 (m, 4H), 6.97 ( S, 1H), 7.30 (s, 1H), 7.70 (m, 5H), 8.02 (s, 1H), 8.15 (s, 1H), 9.42 (br, 1H), 13.03 (br, 1H), 13.77 (s , 1H)

Example 30

3'-{N'-[1-(3,3-Dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene ]-mercapto}-2'-hydroxybiphenyl-3-carboxylic acid

3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 1f (310 mg, f. 0 mmol) was dissolved in hydrochloric acid (3.4 mL, 1 mol/L) under ice-cooling, and 1.2 mL was added dropwise. Sodium nitrite solution (73 mg, 1.05 mmol), reacted for 10 minutes, and then added 2-(3,3-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazole-3 - Ketone 8i (218 mg, 0.9 mmol), sodium bicarbonate (1.26 g, 15 mmol) and 4.4 mL of ethanol were added portionwise and reacted at room temperature for 10 hours. The material disappeared by TLC, filtered, and the solid was washed with 20 mL of water, dissolved in 20 mL of water, adjusted to pH <5 with concentrated hydrochloric acid in an ice bath, filtered and dried to give the title product 3'-{N'-[1- (3,3-Dimethylindan-5-yl)-3-methyl-5-oxooxy-1,5-dihydropyrazole-4-ylidene]-indenyl}-2'-hydroxyl Biphenyl-3-carboxylic acid 30 (500 mg, yellow solid). Yield: 94%. MS m/z (ESI): 509.1 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.24 (m, 6H), 1.92 (t, J = 7.2 Hz, 2H), 2.34 (s, 3H) ), 2.86 (t, J = 7.2 Hz, 2H), 7.16 (m, 2H), 7.25 (d, J = 8.8 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.70 (m, 3H) ), 7.80 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H), 8.14 (s, 1H), 9.68 (s, 1H)

Example 31

4-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-anthracene Benzene-furan-2-carboxylic acid

4-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 28e (170 mg, 0.57 mmol) was dissolved in hydrochloric acid (1.9 mL, 1 mol/L). 0.7mL sodium nitrite solution (43mg, 0.63mmol), reaction for 20 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (109mg, 0.51 Methyl), the pH was adjusted to 8 to 9 with a saturated sodium hydrogen carbonate solution, and 2 mL of ethanol was added thereto, and the mixture was reacted at room temperature for 24 hours. After the TLC was traced to the disappearance of the starting material, the mixture was filtered, and 15 mL of water was added to the solid. The mixture was adjusted to pH 2 to 3 with concentrated hydrochloric acid in an ice bath, filtered, and the filter cake was washed with ethyl acetate and dried to give the title product 4-{2-hydroxy- 3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl]-phenyl}-furan 2-carboxylic acid 31 (83 mg, black solid). Yield: 36.7%. MS m/z (ESI): 442.8 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 2.08 (m, 2H), 2.32 (s, 3H), 2.89 (m, 4H), 7.13 (t) , J = 8.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.65 (m, 3H), 7.75 (m, 1H), 8.37 (s , 1H), 9.68 (s, 1H), 13.22 (br, 1H), 13.74 (s, 1H)

Example 32

4-{[4'-(4,5-Dihydro-1H-imidazol-2-yl)-2-hydroxybiphenyl-3-yl]-anthracene}-2-indan-5-yl-5- Methyl-2,4-dihydropyrazol-3-one

first step

3'-Nitro-2'-methoxy-biphenyl-4-carbaldehyde

4-Methylphenylbenzeneboronic acid (3.0 g, 0.02 mol), 1-bromo-2-methoxy-3-nitrobenzene 1c (4.64 g, 0.02 mol), tetrakis(triphenylphosphine) at room temperature Palladium (1.15g, 1mmol) and sodium carbonate (4.24g, 0.04mol) were added to 60mL of 1,4-dioxane and 10mL of water. After the addition, it was heated and refluxed for 5 hours. TLC was monitored until the reaction of the starting material was complete, filtered and filtered. The cake was washed with ethyl acetate, and the filtrate was evaporated. mjjjjjjjjjjjj 80.4%.

Second step

2-(2'-methoxy-3'-nitro-biphenyl-4-yl)-4,5-dihydro-1H-imidazole

Add 3'-nitro-2'-methoxy-biphenyl-4-carbaldehyde 32a (4.0 g, 15.5 mmol) to 40 mL of dichloromethane under ice-cooling, stir until dissolved, then add 1,2- Aminoethane (981 mg, 16.3 mmol), stirring was continued for 0.5 h, 1-bromo-pyrrolidine-2,5-dione (2.91 g, 16.33 mmol) was added, and the ice bath was removed and stirred at room temperature overnight. The reaction to the starting material was completed, and the reaction mixture was concentrated under reduced pressure and then purified to give the title product 2-(2'-methoxy-3'-nitro-biphenyl-4-yl)-4,5-dihydro-1H. - Imidazole 32b (4.0 g, yellow solid), yield: 86.9%. MS m/z (ESI): 298.1 [M + 1] ¹ H NMR (400 MHz, DMSO - d ₆ ): δ 8.11 (2H, d, J = 8.4), 7.89 (1H, dd, J1 = 8.0, J2 = 1.6 ), 7.87 (2H, d, J = 8.4), 7.79 (1H, m), 7.49 (1H, t, J = 8.0), 4.04 (4H, m), 3.47 (3H, s)

third step

2-(2'-methoxy-3'-amino-biphenyl-4-yl)-4,5-dihydro-1H-imidazole

2-(2'-Methoxy-3'-nitro-biphenyl-4-yl)-4,5-dihydro-1H-imidazole 32b (1.5 g, 5.05 mmol) was added to 30 mL at room temperature After stirring in methanol, add formic acid amine (1.28 g, 20.2 mmol) and palladium-carbon (200 mg). After the addition, the mixture was heated to reflux for 1 hour. The reaction was completed by TLC until the reaction mixture was cooled to room temperature and then filtered. The title product 2-(2'-methoxy-3'-amino-biphenyl-4-yl)-4,5-dihydro-1H-imidazole 32c (1.1 g, yellow solid) : 81.5%. MS m/z (ESI): 268.2 [M + 1] ¹ H NMR (400 MH _Z , DMSO - d ₆ ): δ 8.42 (2H, s), 7.96 (2H, d, J = 8.0), 6.89 (1H, t , J=7.6), 6.75 (1H, m), 6.54 (1H, dd, J1=8.0, J2=1.6), 3.80 (4H, m), 3.47 (3H, s)

the fourth step

2-(2'-hydroxy-3'-amino-biphenyl-4-yl)-4,5-dihydro-1H-imidazole

2-(2'-Methoxy-3'-amino-biphenyl-4-yl)-4,5-dihydro-1H-imidazole 32c (1.1 g, 4.1 mmol) was dissolved in 50 mL at room temperature To the methyl chloride, a solution of boron bromide in dichloromethane (1N, 16.5 mL) was added, and the mixture was stirred at room temperature for 4 hrs, and the mixture was monitored by TLC until the reaction mixture was completed. The reaction was quenched with methanol. The ethyl acetate was dissolved and stirred for 0.5 hours, filtered, and the filter cake was washed with ethyl acetate (5mL×2), and dried to give the title product 2-(2'-hydroxy-3'-amino-biphenyl-4-yl)- 4,5-Dihydro-1H-imidazole 32d (900 mg, gray solid), yield: 89.6%. Msm/z(EsI): 254.3 [M1 1] ^l HNMR (400 MHz, DMSO- d ₆ ): δ 7.23 (2H, m), 7.01 (2H, t, J = 6.8), 6.65 (1H, m) , 6.62 (1H, dd, J = 8.0, J2 = 1.6), 6, 36 (1H, t, J = 7.6), 4.03 (4H, m)

the fifth step

4-{[4'-(4,5-Dihydro-1H-imidazol-2-yl)-2-hydroxybiphenyl-3-yl]-anthracene}-2-indan-5-yl-5- Methyl-2,4-dihydropyrazol-3-one

2-(2'-Hydroxy-3'-amino-biphenyl-4-yl)-4,5-dihydro-1H-imidazole 32d (334 mg, 1.11 mmol) was dissolved in hydrochloric acid (3.7 mL, 1 mol). In /L), 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol) was added dropwise, and the reaction was carried out for 20 minutes, followed by the addition of 2-indan-5-yl-5-methyl-2,4-dihydropyrazole-3. - Ketone 1i (214 mg, 1 mmol), adjusted to pH 8 with saturated sodium bicarbonate solution, and 5 mL of ethyl alcohol. The material disappeared by TLC, filtered, and the obtained solid was added to 30 mL of water. The mixture was stirred and concentrated with concentrated hydrochloric acid to adjust pH to 4, and solids were precipitated and filtered. The obtained solid was subjected to column chromatography to give the title product 4-{[4'-( 4,5-dihydro-1H-imidazol-2-yl)-2-hydroxybiphenyl-3-yl]-purine}-2-indan-5-yl-5-methyl-2,4-di Hydropyrazol-3-one 32 (145 mg, red solid). Yield: 30.3%. MS m/z (ESI): 476.9 [M-1] ¹ H NMR (400 MHz, DMSO - d ₆ ): δ 2.02 (m, 2H), 2.34 (s, 3H), 2.87 (m, 4H), 4.00 (s, 4H), 6.88 (m, 1H), 7.18 (m, 2H), 7.49 (m, 1H), 7.90 (m, 5H), 8.18 (s, 1H)

Example 33

5-(2-hydroxy-5-methyl-3-{N'-"3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)- 1,5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-thiophene-2-carboxylic acid

5-(3-Amino-2-hydroxy-5-methylphenyl)-thiophene-2-carboxylic acid hydrobromide 24d (366 mg, 1.11 mmol) was dissolved in 3.7 mL of 1N hydrochloric acid and added dropwise. 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol), reacted for 20 minutes, and then added 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydrogen Pyrazol-3-one 3i (228 mg, 1 mmol) was added portionwise sodium bicarbonate (1. 4 g, 16.67 mmol) and 2 mL of ethyl alcohol. The product disappeared by TLC, filtered, and the solid was added to 30 mL of water, and then adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried and dried to give the title product 5-(2-hydroxy-5-methyl- 3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4-ya Benzyl)-phenyl)-thiophene-2-carboxylic acid 33 (88 mg, red solid). Yield: 18.09%. MS m/z (ESI): 486.7 [M-1] ¹ H NMR (400 MHz, DMS0- d6 ): δ 1.75 (m, 4H), 2.31 (s, 3H), 2.36 (s, 3H), 2.73 (m) , 4H), 7.12 (d, J = 8.4 Hz, lH), 7.37 (s, 1H), 7.56 (s, 1H), 7.63 (m, 3H), 7.74 (d, J = 3.6 Hz, 1H), 9.77 (s, 1H), 13.07 (br, 1H), 13.70 (s, 1H)

Example 34

5-(3-{N'-"1-(3,3-dimethylindan-5-yl)-3-methyl-5-oxo-1.5-dihydropyrazole-4-subunit ]-mercapto}-2-hydroxy-5-methylphenyl)-thiophene-2-carboxylic acid

5-(3-Amino-2-hydroxy-5-methylphenyl)-thiophene-2-carboxylic acid hydrobromide 24d (366 mg, 1.11 mmol) was dissolved in 3.7 mL of 1N hydrochloric acid and added dropwise. 1.5mL sodium nitrite solution (85mg, 1.22mmol), reaction for 20 minutes, then add 2-(3,3-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazole 3-ketone 8i (242 mg, 1 mmol) was adjusted to pH 8 with saturated sodium bicarbonate solution, 2 mL of ethanol was added, and the ice bath was removed and allowed to react overnight at room temperature. The product disappeared by TLC, filtered, solid was added to 30 mL of water, and then adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, and dried to give the title product 5-(3-{N'-[1-(3,3) -Dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}-2-hydroxy-5-methyl Benzene)-thiophene-2-carboxylic acid 34 (308 mg, red solid). Yield: 61.4%. MS m/z (ESI): 500.8 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.25 (s, 6H), 1.93 (m, 2H), 2.36 (s, 3H), 2.38 (s) , 3H), 2.87 (t, J = 7.2 Hz, 2H), 7.27 (d, 1 = 8.8 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 1.2 Hz, 1H) ), 7.65 (m, 1H), 7.71 (m, 2H), 7.74 (d, J = 4.0 Hz, 1H), 9.82 (br, 1H), 13.06 (s, 1H), 13.71 (br, 1H)

Example 35

5-{3-[N'-(1-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-3-methyl-5-oxo-1, 5-dihydropyrazole-4-ylidene)-indenyl]-2-hydroxy-5-methylphenyl}-thiophene-2-carboxylic acid

5-(3-Amino-2-hydroxy-5-methylphenyl)-thiophene-2-carboxylic acid hydrobromide 24d (366 mg, 1.11 mmol) was dissolved in 3.7 mL of 1N hydrochloric acid and added dropwise. 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol), react for 20 minutes, then add 2-bicyclo[4.2.0]octane-1(6), 2,4-trien-3-yl-5-methyl -2,4-Dihydropyrazol-3-one 5d (200 mg, 1 mmol), the pH was adjusted to 8 with a saturated sodium hydrogen carbonate solution, 2 mL of ethanol was added, the ice bath was removed, and the reaction was carried out at room temperature for 5 hours. The material disappeared by TLC, filtered, and the solid was added to 30 mL of water, then adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, and the filter cake was washed with 6 mL of dichloromethane and dried to give the title product 5-{3-[N'- (1-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4- Subunit)-indenyl]-2-hydroxy-5-methylphenyl}-thiophene-2-carboxylic acid 35 (306 mg, red solid). Yield: 66.5%. MS m/z (ESI): 459.2 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 2.33 (s, 3H), 2.36 (s, 3H), 3.16 (m, 4H), 7.16 (d) , J=8.0Hz, 1H), 7.38(s,1H), 7.49(s,1H), 7.62(m,2H),7.73(m,2H)

Example 36

5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-di Hydropyrazol-4-ylidene]-indenyl}-phenyl)-thiophene-2-carboxylic acid

5-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 12c (351 mg, 1.11 mmol) was dissolved in 3.7 mL of hydrochloric acid (1 N) and added dropwise 1.5 mL. Sodium nitrate solution (85 mg, 1.22 mmol), stirred for 20 minutes, then added 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazole- 3-ketone 3i (228 mg, 1 mmol) was adjusted to pH 8 with a saturated aqueous sodium hydrogen carbonate solution, and the mixture was quenched with 2 mL of ethanol and allowed to react at room temperature for 3 hours. The material disappeared by TLC, the solid was filtered, 30 mL of water was added to the solid, pH was adjusted to 3 to 4 with concentrated hydrochloric acid, filtered, and dried, and then subjected to column chromatography to give the title product 5-(2-hydroxy-3-{N '-[3-Methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4-ylidene]-oxime }-Benzene)-thiophene-2-carboxylic acid 36 (30 mg, red solid). Yield: 6.3%. MS m/z (ESI): 472.8 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.74 (m, 4H), 2.30 (s, 3H), 2.73 (m, 4H), 7.12 (d) , J = 8.0 Hz, 1H), 7.17 (m, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.62 (m, 3H), 7.67 (d, J = 8.0 Hz, lH), 7.74 (d , J=4.0Hz, 1H)

Example 37

5-{3-"N'-(1-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-3-methyl-5-sideoxy-1, 5-dihydropyrazole-4-ylidene)-indolyl]-2-hydroxyphenyl}-thiophene-2-carboxylic acid

5-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 12c (298 mg, 0.94 mmol) was dissolved in 3.1 mL of hydrochloric acid (1 N) and added dropwise Sodium nitrate solution (72 mg, 1.04 mmol), stirred for 20 minutes, then added 2-bicyclo[4.2.0]octane-1 (6), 2,4-trien-3-yl-5-methyl-2, 4-Dihydropyrazol-3-one 5d (170 mg, 0.85 mmol) was adjusted to pH 8 using a saturated sodium hydrogen carbonate aqueous solution, and the mixture was quenched with 2 mL of ethanol and allowed to react at room temperature for 3 hours. The material disappeared by TLC, the solid was filtered, 30 mL of water was added to the solid, pH was adjusted to 3 to 4 with concentrated hydrochloric acid, filtered, and the solid was dried and then subjected to column chromatography to obtain the title product 5-{3-[N'-(1 -bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-subunit )-Mercapto]-2-hydroxyphenyl}-thiophene-2-carboxylic acid 37 (57 mg, red solid). Yield: 15.01%. MS m/z (ESI): 444.5 [M-1] 1H NMR (400 MHz, DMSO- d6 ): δ 2.31 (s, 3H), 3.15 (m, 4H), 7.15 (m, 2H), 7.54 (d, J = 7.6 Hz, lH), 7.63 (m, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.73 (m, 2H).

Example 38

2'-Hydroxy-3'-{N'-[3-methyl-1-(3-methylindan-5-yl)-5-o-oxy-1,5-dihydropyrazole-4- Subunit]-mercapto}-biphenyl-3-carboxylic acid

first step

6-bromo-indan-1-one

Add 3-(4-bromophenyl)-propionic acid 38a (20.6 g, 90 mmol, ABCR) to a 250 mL single-necked flask, dry in vacuo for 20 min, then add 110 mL of re-distilled methylene chloride. Arsenic chloride (20 mL, 276 mmol) was heated to reflux overnight. Most of the solvent was removed under reduced pressure, and 100 mL of dichloromethane was added, and aluminum chloride (24.5 g, 25.8 mmol) was added portionwise with stirring, and a large amount of gas was released, and the reaction was refluxed overnight. The reaction mixture was poured into 200 g of crushed ice, and a large amount of solid was precipitated, which was filtered with EtOAc (EtOAc). - Indan-1-one 38b (18.34 g, yellow solid). Yield: 96.6%. MS m/z (ESI): 210 [M-1]

Second step

6-bromo-1-methylene-indane

Methyltriphenylphosphonium bromide (4.56 g, 12.76 mmol) was dissolved in 25 mL of tetrahydrofuran, and potassium t-butoxide (1.5 g, 13.4 mmol) was added in one portion, and the mixture was stirred at room temperature for 35 minutes.

6-Bromo-indan-1-one 38b (898 mg, 4.25 mmol) was dissolved in 5 mL of tetrahydrofuran, and the above solution was added dropwise with stirring. The resulting solution was stirred at room temperature for 1 hour, and quenched by adding 25 mL of water. The reaction mixture was extracted with EtOAc (EtOAc) (EtOAc) Further isolation and purification gave the title product 6-bromo-1-methylene-indane 38c (830 mg,yield of yellow oil). Yield: 93.4%. MS m/z (ESI): 208 [M-1]

third step

6-bromo-1-methylindole

6-Bromo-1-methylene indane 38c (4.91 g, 23.5 mmol) was dissolved in ethyl acetate, palladium-carbon (0.98 g) was added, and reacted under a hydrogen atmosphere at room temperature for 4 hours, followed by TLC to The disappearance of the starting material, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, and then purified to give the title product 6-bromo-1-methylindane 38d (3.1 g, colorless oily liquid), yield: 62.7%. MS m/z (ESI): 209.8 [M-1]

the fourth step

1-(3-methylindan-5-yl)indole-1,2-dicarboxylic acid di-t-butyl ester

Under an argon atmosphere, n-butyllithium (8.6 mL, 13.76 mmol) was added to a three-necked flask, and 8 mL of tetrahydrofuran was added under cooling in a dry ice-acetone bath, and 6-bromo-1-methylindane 38d (1.32 g) was added with stirring. , 6.26 mmol), the obtained solution was reacted in a dry ice-acetone bath for 2 hours, and a solution of dibutyl azodicarboxylate (1.87 g, 8.14 mmol) in 10 mL of tetrahydrofuran was added dropwise, stirring was continued for 30 minutes, the ice bath was removed, and the temperature was raised. The reaction was completed by stirring for 20 hours at room temperature. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc) Concentration under reduced pressure, the residue was purified mjjjjjjjjjjjjjj Liquid). Yield: 46.7%. MS m/z (ESI): 362.6 [M+1]

the fifth step

5-methyl-2-(3-methylindan-5-yl)-2,4-dihydropyrazol-3-one

Dissolving 1-(3-methylindan-5-yl)indole-1,2-dicarboxylic acid di-t-butyl ester 38e (1.05 g, 2.9 mmol) in 16 mL of a mixed solvent of ethanol and water (V: V=5) In 3), ethyl acetate (0.377 mL, 2.9 mmol) and 1.45 mL of 6N hydrochloric acid were successively added under stirring, and the reaction was heated under reflux for 1.5 hours under nitrogen. The mixture was cooled to room temperature, and the mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjj Chromatography of the title compound gave 5-methyl-2-(3-methylindan-5-yl)-2,4-dihydropyrazol-3-one 38f (103 mg, m. Yield: 15.6%. MS m/z (ESI): 229.3 [M+1]

Step 6

2'-Hydroxy-3'-{N'-[3-methyl-1-(3-methylindan-5-yl)-5-o-oxy-1,5-dihydropyrazole-4- Subunit]-mercapto}-biphenyl-3-carboxylic acid

3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 1f (344 mg, 1.11 mmol) was dissolved in 3.7 mL of hydrochloric acid (1 N) under ice bath, and 1.5 mL of sodium nitrite solution was added dropwise. (85 mg, 1.22 mmol), followed by addition of 5-methyl-2-(3-methylindan-5-yl)-2,4-dihydropyrazol-3-one 38f (228 mg, 1 mmol). The pH of the reaction solution was adjusted to 8 with sodium bicarbonate solution, 2 mL of ethanol was added, and the mixture was allowed to warm to room temperature overnight. The material disappeared by TLC, the solid was filtered, 30 mL of water was added to the solid, and the mixture was adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, and the solid was dried, and then 10 mL of a mixed solution of dichloromethane and methanol (V:V=50: 1), after stirring for 1 hour, filtering, the filter cake was washed with dichloromethane (2 mL×3), and dried to give the title product 2'-hydroxy-3'-{N'-[3-methyl-1-( 3-methylindan-5-yl)-5-sideoxy-1,5-dihydropyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid 38 (300 mg, yellow solid ). Yield: 64.1%. MS m/z (ESI): 466.9 [M-1] ¹ H NMR (400 MHz, DMS0- d6 ): δ 1.25 (m, 3H), 1.58 (m, 1H), 2.30 (m, 1H), 2.33 (s) , 3H), 2.80 (m, 2H), 3.19 (m, 1H), 7.13 (m, 2H), 7.26 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.69 (m, 3H), 7.80 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 8.43 (s, 1H), 9.69 (br, 1H), 13.06 (s, 1H) , 13.76(s,1H)

Example 39

2'-Hydroxy-5'-methyl-3'-{N'-"3-methyl-1-(3-methylindan-5-yl)-5-sideoxy-1,5-di Hydropyrazol-4-ylidene]-mercapto}-biphenyl-3-carboxylic acid

3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride 11f (360 mg, 1.11 mmol) was dissolved in 3.7 mL of hydrochloric acid (1N) and added dropwise 1.5 mL sodium nitrite solution (85 mg, 1.22 mmol) was stirred for 20 minutes, then 5-methyl-2-(3-methylindan-5-yl)-2,4-dihydropyrazol-3-one was added. 38f (228 mg, 1.0 mmol), the pH of the reaction mixture was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and 2 The material disappeared by TLC, the solid was filtered out, dissolved in 30 mL of water, stirred uniformly, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and then added to 10 mL of dichloromethane and stirred for 1 hour, and the solid was filtered and dried. The title product 2'-hydroxy-5'-methyl-3'-{N'-[3-methyl-1-(3-methylindol-5-yl)-5-sideoxy-1 was obtained. , 5-dihydropyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid 39 (240 mg, red solid). Yield: 49.8%. MS m/z (ESI): 480.9 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.29 (m, 3H), 1.56 (m, 1H), 2.28 (m, 1H), 2.34 (s, 3H), 2.36 (s, 3H), 2.80 (m, 2H), 3.18 (m, 1H), 7.00 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.70 (m, 2H), 7.80 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 4.4) Hz, 1H), 9.40 (br, 1H), 13.03 (s, 1H), 13.76 (s, 1H)

Example 40

5-(2-hydroxy-3-{N'-[3-methyl-1-(3-methylindan-5-yl)-5-oxo-1,5-dihydropyrazole-4 -subunit]-mercapto}-phenyl)-thiophene-2-carboxylic acid

5-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 12c (351 mg, 1.11 mmol) was dissolved in 3.7 mL of hydrochloric acid (1 N) and added dropwise 1.5 mL. Sodium nitrate solution (85 mg, 1.22 mmol), stirred for 20 minutes, then added 5-methyl-2-(3-methylindan-5-yl)-2,4-dihydropyrazol-3-one 38f ( 228 mg, 1 mmol), the pH was adjusted to 8 with a saturated sodium bicarbonate solution, and the mixture was quenched with 2 mL of ethanol and allowed to react to room temperature for 3 hours. The product disappeared by TLC, the solid was filtered out, 30 mL of water was added to the solid, and the mixture was adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, and dried, and then subjected to column chromatography to give the title product 5-(2-hydroxy-3-{ N'-[3-Methyl-1-(3-methylindan-5-yl)-5-o-oxy-1,5-dihydropyrazole-4-ylidene]-indenyl}-benzene )-thiophene-2-carboxylic acid 40 (90 mg, red solid). Yield: 19.0%. MS m/z (ESI): 472.8 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.26 (m, 3H), 1.58 (m, lH), 2.30 (m, 1H), 2.32 (s) , 3H), 2.82 (m, 2H), 3.18 (m, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.6 Hz) , 1H), 7.70 (m, 5H), 10.09 (br, 1H), 13.71 (br, 1H)

Example 41

3'-{N'-"1-(3-Ethyl-indan-5-yl)-3-methyl-5-o-oxy-1,5-dihydropyrazole-4-ylidene]- Mercapto}-2'-hydroxybiphenyl-3-carboxylic acid

first step

6-bromo-1-ethylidene-indane

Ethyltriphenylphosphonium bromide (14.5 g, 39.1 mmol) was dissolved in 75 mL of tetrahydrofuran at room temperature, and potassium butoxide (5.29 g, 47.3 mmol) was added, and the mixture was stirred at room temperature for 1 hour. 6-Bromo-indan-1-one 38b (3.39 g, 18.6 mmol) was dissolved in 25 mL of tetrahydrofuran, and the above solution was added dropwise with stirring, and the mixture was further stirred at room temperature for 1 hour. TLC was monitored until the reaction of the starting material was complete. The reaction was quenched by the addition of 150 mL of water. The mixture was extracted with dichloromethane (50 mL×4). The organic phase was combined and washed with brine (45 mL×2) The sodium was dried, and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure, and then purified to give the title product 6-bromo-1-ethylidene-yield 41a (3.07 g, yellow oily liquid). MS m/z (ESI): 221.8 [M-1]

Second step

6-bromo-1-ethyl-indane

6-Bromo-1-ethylidene-indan 41a (3.07 g, 13.7 mmol) was dissolved in 80 mL of ethyl acetate at room temperature, palladium-carbon (0.61 g) was added, in a hydrogenation apparatus in 3 Hydrogenation with hydrogen at atmospheric pressure, reaction at room temperature for 5 hours, the reaction of the starting material was completely monitored by TLC, the reaction mixture was filtered to remove palladium-carbon, and the filter cake was washed with ethyl acetate (10 mL×3), and the filtrate was concentrated under reduced pressure and then subjected to column chromatography. The title product 6-bromo-1-ethyl-indan 41b (2.75 g, pale yellow liquid) was obtained, yield: 88.7%. MSm/z (ESI): 224 [M-1]

third step

1-(3-ethyl-2,3-dihydro-1H-indan-5-yl)-1-tert-butoxycarbonyl-2-tert-butoxycarbonyl-indole

6-Bromo-1-ethyl-indan 41b (2.52 g, 11.2 mmol) was dissolved in 15 mL of tetrahydrofuran under argon, and added dropwise to a solution of dry butyl-acetone-cooled tributyllithium in cyclohexane. (18.1 mL, 1.3 N), stirring was continued for 2 hours in a dry ice-acetone bath. Dissolve ditributyl azodicarboxylate in 15 mL of tetrahydrofuran, add dropwise to the above reaction solution, continue to stir in a dry ice-acetone bath for 0.5 hour, remove the dry ice-acetone bath, and the reaction solution naturally rises to room temperature. After stirring for 18 hours, the reaction of the starting material was completed by TLC. The reaction mixture was quenched by the addition of 25 mL of a saturated aqueous solution of ammonium chloride. The reaction mixture was extracted with ethyl acetate (30 mL×3). The desiccant was removed, and the filtrate was concentrated under reduced pressure and then purified by column chromatography to give the title product 1-(3-ethyl-2,3-dihydro-1H-indane-5-yl)-1-t-butoxycarbonyl-2 - Third butoxycarbonyl-oxime 41c (3.43 g, brownish yellow oily liquid), yield: 81.5%.

the fourth step

2-(3-ethyl-indan-5-yl)-5-methyl-2,4-dihydropyrazol-3-one

1-(3-Ethyl-2,3-dihydro-1H-indan-5-yl)-1-tert-butoxycarbonyl-2-tert-butoxycarbonyl-indole 41c (3.43) at room temperature g, 9.1 mmol) was dissolved in 50 mL of a mixed solvent of ethanol and water (V:V=3:2), and 3-ethyloxy-butyric acid ethyl ester (1.18 g, 9.1 mmol) and 4.55 mL of hydrochloric acid (6N) were added. After the reaction was completed, the reaction solution was refluxed for 1 hour, and the reaction of the reaction mixture was completed by TLC. The reaction mixture was evaporated to remove ethanol, and then extracted with dichloromethane (15mL×3). The organic phase was combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and purified by column chromatography to give the title product 2-(3-ethyl-indane-5-yl)-5-methyl-2,4-dihydropyrazol-3-one 41d (0.712 g, yellow oily liquid), yield: 39.8%. MS m/z (ESI): 243.2 [M+1]

the fifth step

3'-{N'-[1-(3-ethyl-indan-5-yl)-3-methyl-5-o-oxy-1,5-dihydropyrazole-4-ylidene]- Mercapto}-2'-hydroxybiphenyl-3-carboxylic acid

3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 1f (285 mg, 0.92 mmol) was dissolved in 3.1 mL of hydrochloric acid (1 N) under ice bath, and 1.2 mL of sodium nitrite solution was added dropwise. (70 mg, 1.01 mmol), stirring was continued for 20 minutes, and 2-(3-ethyl-indan-5-yl)-5-methyl-2,4-dihydropyrazol-3-one 41d (200 mg, 0.83 mmol), the pH of the reaction mixture was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and 2 mL of ethanol was added, and the mixture was allowed to warm to room temperature overnight. The product disappeared by TLC, filtered, solid was added to 20 mL of water, and the pH was adjusted to 3 to 4 with concentrated hydrochloric acid. The solid was filtered and dried to give the title product 3'-{N'-[1-(3-ethyl -indol-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}-2'-hydroxybiphenyl-3-carboxylic acid 41 (145 mg, red solid), Yield: 36.4%. MS m/z (ESI): 480.9 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 0.95 (m, 3H), 1.43 (m, 1H), 1.65 (m, 1H), 1.83 (m) , 1H), 2.23 (m, 1H), 2.34 (s, 3H), 2.92 (m, 2H), 3.05 (m, 1H), 7.15 (s, 2H), 7.27 (d, J = 8.0 Hz, 1H) , 7.62 (t, J = 8.0 Hz, 1H), 7.72 (m, 3H), 7.80 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 8.14 (s, 1H) , 9.66(s,1H), 13.04(s,1H),13.76(s,1H)

Example 42

3'-{N'-[1-(3-ethyl-indan-5-yl)-3-methyl-5-o-oxy-1,5-dihydropyrazole-4-ylidene]- Mercapto}-2'-hydroxy-5'-methyl-biphenyl-3-carboxylic acid

3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride 11f (298 mg, 0.92 mmol) was dissolved in 3.1 mL of hydrochloric acid (1 N), and then added dropwise. mL sodium nitrite solution (70 mg, 1.01 mmol), stirring was continued for 20 minutes, and 2-(3-ethyl-indan-5-yl)-5-methyl-2,4-dihydropyrazole-3- The ketone 41d (200 mg, 0.83 mmol) was adjusted to pH 8 with saturated sodium bicarbonate solution, and 2 mL of ethanol was added and allowed to warm to room temperature overnight. The product disappeared by TLC, filtered, solid was added to 20 mL of water, and the pH was adjusted to 3 to 4 with concentrated hydrochloric acid. The solid was filtered and dried to give the title product 3'-{N'-[1-(3-ethyl -Indolyl-5-yl)-3-methyl-5-o-oxy-1,5-dihydropyrazole-4-ylidene]-indenyl}-2'-hydroxy-5'-methyl- Biphenyl-3-carboxylic acid 42 (290 mg, red solid), yield: 70.7%. MS m/z (ESI): 494.9 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 0.95 (m, 3H), 1.43 (m, 1H), 1.65 (m, 1H), 1.83 (m) , 1H), 2.23 (m, 1H), 2.34 (s, 3H), 2.92 (m, 2H), 3.05 (m, 1H), 6.99 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H) , 7.53 (s, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.68 (m, 1H), 7.75 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 8.14 (s, 1H), 9.39 (s, 1H), 13.03 (s, 1H), 13.76 (s, 1H)

Example 43

5-(3-{N'-"1-(3,3-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4- Subunit]-mercapto}-2-hydroxyphenyl)-furan-2-carboxylic acid

5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (333 mg, 1.1 mmol) was dissolved in hydrochloric acid (3.7 mL, 1 mol/L) and added dropwise. 1.5mL sodium nitrite solution (85mg, 1.22mmol), reaction for 20 minutes, then add 2-(3,3-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazole 3-ketone 8i (242 mg, 1.0 mmol), sodium hydrogencarbonate (1.4 g, 16.67 mmol) and 3 mL of ethanol were added portionwise and allowed to react overnight at room temperature. The material disappeared by TLC, filtered, and the solid was added to 20 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid, and the solid was filtered. The solid was dried and then subjected to column chromatography to give the title product 5-(3-{N'-[1 -(3,3-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}-2-hydroxyl Benzene)-furan-2-carboxylic acid 43 (190 mg, red solid), yield: 40.3%. MS m/z (ESI): 470.9 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.26 (s, 6H), 1.92 (t, J = 7.2 Hz, 2H), 2.33 (s, 3H) ), 2.86 (t, J = 7.2 Hz, 2H), 7.15 (m, 1H), 7.20 (m, 2H), 7.37 (d, J = 3.6 Hz, 1H), 7.55 (d, J = 6.8 Hz, 1H) ), 7.71 (m, 3H), 9.99 (br, 1H), 13.15 (br, 1H), 13.74 (br, 1H)

Example 44

5-(2-hydroxy-3-{N'-[3-methyl-1-(3-methylindan-5-yl)-5-oxo-1,5-dihydropyrazole-4 -subunit]-mercapto}-phenyl)-furan-2-carboxylic acid

5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (333 mg, 1.1 mmol) was dissolved in hydrochloric acid (3.7 mL, 1 mol/L) and added dropwise. 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol), reacted for 20 minutes, and then added 5-methyl-2-(3-methylindan-5-yl)-2,4-dihydropyrazole-3- Ketone 38c (228 mg, 1.0 mmol) was added portionwise sodium bicarbonate (1.4 g, 16.67 mmol) and 3 mL of ethyl alcohol. The product disappeared by TLC, filtered, and the solid was added to 20 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid, and the solid was filtered. The solid was dried and then subjected to column chromatography to give the title product 5-(2-hydroxy-3-{N '-[3-Methyl-1-(3-methylindan-5-yl)-5-o-oxy-1,5-dihydropyrazole-4-ylidene]-indenyl}-benzene) - furan-2-carboxylic acid 44 (110 mg, red solid), yield: 24.0%. MS m/z (ESI): 457.0 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.25 (m, 3H), 1.59 (m, 1H), 2.29 (m, 1H), 2.33 (s) , 3H), 2.84 (m, 2H), 3.17 (m, 1H), 7.14 (d, J = 3.2 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz) , 1H), 7.36 (d, J = 3.2 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.71 (m, 3H) 9.96 (br, 1H) 13.75 (br, 1H)

Example 45

5-(3-{N'-[1-(2,2-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4- Subunit]-mercapto}-2-hydroxyphenyl)-furan-2-carboxylic acid

first step

6-bromo-2,2-dimethylindan-1-one

6-Bromo-indan-1-one 38b (6.02 g, 28.5 mmol) and iodomethane (4.4 mL, 70 mmol) were dissolved in 200 mL of tetrahydrofuran (dry), stirred at room temperature for 15 min, and sodium hydride (2.73 g, 68.2 mmol), stirring for 2 hours, TLC was carried out until the reaction of the starting material was completed, 150 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL × 2), the organic phase was combined, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure, and then purified to give the title product 6-bromo-2,2-dimethylindan-1-one 45a (5.36 g, brown solid). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.918 (d, J = 1. 6 Hz, 1H), 7.725 (dd, J ₁ = 8 Hz, J ₂ = 2 Hz, 1H), 7.352 (d, J = 8 Hz, 1H) ), 2.979(s, 2H), 1.273(s, 6H)

Second step

5-bromo-2,2-dimethylindole

6-Bromo-2,2-dimethylindan-1-one 45a (7.23 g, 30.3 mmol) was dissolved in 150 mL of trifluoroacetic acid, and triethyl decane (12.1 mL, 75.6 mmol) was added and stirred at room temperature. After overnight, TLC monitored the reaction until the reaction of the starting material was complete, and the reaction was quenched with water. The reaction mixture was concentrated under reduced pressure to remove trifluoroacetic acid. The mixture was adjusted to pH with saturated sodium carbonate and extracted with ethyl acetate (50mL×3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Liquid), directly to the next reaction. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.335 (s, 1H), 7.281 (d, J + 8 Hz, 1H), 7.063 (s, J = 8 Hz, 1H), 2.749 (s, 2H), 2.702 (s) , 2H), 1.188 (s, 6H)

third step

1-(2,2-dimethylindan-5-yl)indole-1,2-dicarboxylic acid di-t-butyl ester

Dissolve 5-bromo-2,2-dimethylindane 45b (2.4g, 10.7mmol) in 20mL tetrahydrofuran (dry), cool to -78 ° C with dry ice / ethanol bath, add n-butyl lithium (12.1 mL, 30.2 mmol), stirring for 2 hours, dissolving dibutyl azodicarboxylate (3.27 g, 14.2 mmol) in 20 mL of tetrahydrofuran (dry), adding to the above reaction solution, and continuing the low temperature reaction for 3 hours. TLC was monitored until the reaction of the starting material was completed. The reaction was quenched with 50 mL of water. The mixture was evaporated to ethyl acetate (50 mL×2). The organic phase was combined and washed with brine, dried over anhydrous sodium sulfate After concentration under reduced pressure, the title product was obtained from the title product 1-(2,2-dimethylindan-5-yl)indole-1,2-dicarboxylic acid di-t-butyl ester 45c (2.68 g, yellow oily liquid ), yield: 66.8%.

the fourth step

2-(2,2-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazol-3-one

Dissolve 1-(2,2-dimethylindan-5-yl)indole-1,2-dicarboxylic acid di-t-butyl ester 45c (3.3 g, 8.78 mmol) in 12 mL of acetic acid, add 6 mL of trifluoroacetic acid And methyl 3-butoxy-butyrate (1.5 mL, 13.8 mmol), and the mixture was stirred at 90 ° C for 2 hours. The reaction was monitored by TLC until the reaction mixture was completed. The reaction mixture was concentrated under reduced pressure. And 30 mL of ethyl acetate, and the mixture was stirred, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Methyl indane-5-yl)-5-methyl-2,4-dihydropyrazol-3-one 45d (464 mg, yellow oily). Yield: 22.1%. MS m/z (ESI): 243.3 [M+1]

the fifth step

5-(3-{N'-[1-(2,2-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4- Subunit]-mercapto}-2-hydroxyphenyl)-furan-2-carboxylic acid

5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (150 mg, 0.5 mmol) was dissolved in hydrochloric acid (1.7 mL, 1 mol/L) and added dropwise. 0.6 mL of sodium nitrite solution (38 mg, 0.55 mmol), react for 20 minutes, then add 2-(2,2-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazole 3-ketone 45d (109 mg, 0.45 mmol), sodium bicarbonate (630 mg, 7.5 mmol) and 1 mL of ethanol were added portionwise and allowed to react overnight at room temperature. The product disappeared by TLC, filtered, and the solid was added to 15 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid, filtered, and the filter cake was washed with ethyl acetate (1 mL×3) and dried to give the title product 5-(3-{ N'-[1-(2,2-Dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl "-2-Hydroxybenzene)-furan-2-carboxylic acid 45 (67 mg, yellow solid), yield: 31.6%. MS m/z (ESI): 470.7 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.13 (s, 6H), 2.32 (s, 3H), 2.70 (m, 4H), 7.14 (d) , J = 3.6 Hz, 1H), 7.21 (m, 2H), 7.36 (d, J = 3.6 Hz, 1H), 7.54 (m, 1H), 7.62 (m, 1H), 7.69 (m, 2H)

Example 46

5-{2-hydroxy-3-[N'-(1-indan-5-yl-3methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl ]-5-methylphenyl}-furan-2-carboxylic acid

first step

5-(3-nitro-2-methoxy-5-methylphenyl)-furan-2-carboxylic acid

3-(4,5-Dimethyl-[1,3,2]boronic acid pinacol-2-yl)-2-methoxy-5-methyl-nitrobenzene 24a (3.lg, 7.5 mmol), 5-bromo-furan-2-carboxylic acid (1.3 g, 6.8 mmol), tetrakis(triphenylphosphine)palladium (0.43 g, 0.4 mmol) and sodium carbonate (1.6 g, 15.1 mmol) were added to 30 mL1 The reaction system was heated under reflux for 1 hour, and the reaction mixture was heated to reflux for 1 hour. The residue was evaporated to dryness eluted with EtOAc. 50 mL of water, adjusted to pH 3 with brine, filtered, washed with ethyl acetate and dried to give the title product 5-(3-nitro-2-methoxy-5-methylphenyl)-furan- 2-carboxylic acid 46a (522 mg, yellow solid), yield: 29%. MS m/z (ESI): 275.7 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 13.31 (1H, br), 7.90 (1H, s), 7.78 (1H, s), 7.39 (1H) , d, J = 3.2 Hz), 7.16 (1H, d, J = 3.6 Hz), 3.80 (3H, s), 2.42 (3H, s)

Second step

5-(3-amino-2-methoxy-5-methylphenyl)-furan-2-carboxylic acid

Dissolve 5-(3-nitro-2-methoxy-5-methylphenyl)-furan-2-carboxylic acid 46a (410 mg, 1.48 mmol) in 28 mL of ethyl acetate and add 61 mg of palladium-carbon and Ammonium formate (658 mg, 10.44 mmol) was heated and refluxed for 3 hours. The residue was removed by TLC, and the palladium-carbon was removed by filtration. The filtrate was concentrated under reduced pressure and dried to give the title product 5-(3-amino-2-methoxy-5-methylphenyl)-furan-2-carboxylic acid 46b (356 mg, white solid). Yield: 97.3%. Ms m/z (ESI): 246.0 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 7.18 (1H, s), 6.98 (1H, m), 6.80 (1H, s), 6.56 (1H) , s), 3.62 (3H, s), 2.20 (3H, s)

third step

5-(3-amino-2-hydroxy-5-methylphenyl)-furan-2-carboxylic acid hydrobromide

Dissolve 5-(3-amino-2-methoxy-5-methylphenyl)-furan-2-carboxylic acid 46b (248 mg, 1 mmol) in 20 mL of dichloromethane and add dropwise boron tribromide The methyl chloride solution (3 mL, 1 mmol/L) was reacted at room temperature for 2 hours. The residue was purified by EtOAc (EtOAc) eluting 2-carboxylic acid hydrobromide 46c (172 mg, white solid). Yield: 54.7%. MS m/z (ESI): 231.8 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 7.46 (1H, m), 7.34 (1H, m), 7.10 (2H, m), 2.31 (3H, s)

the fourth step

5-{2-hydroxy-3-[N'-(1-indan-5-yl-3methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl ]-5-methylphenyl}-furan-2-carboxylic acid

5-(3-Amino-2-hydroxy-5-methylphenyl)-furan-2-carboxylic acid hydrobromide 46c (219 mg, 0.70 mmol) was dissolved in 2.3 mL of 1N hydrochloric acid and added dropwise. 1.0 mL of sodium nitrite solution (53 mg, 0.77 mmol), reacted for 20 minutes, and then added 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (134 mg, 0.63) Methyl) sodium hydrogencarbonate (878 mg, 10.45 mmol) and 2 mL of ethanol were added portionwise and allowed to react overnight at room temperature. The material disappeared by TLC, filtered, and the solid was added to 20 mL of water, adjusted to pH + 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered, and the filter cake was washed with 6 mL of dichloromethane and dried to give the title product 5-{2- Hydroxy-3-[N'-(1-indan-5-yl-3methyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-indenyl]-5-A Benzo}-furan-2-carboxylic acid 46 (170 mg, red solid). Yield: 59.2%. Ms m/z (ESI): 456.8 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 2.05 (m, 2H), 2.32 (s, 3H), 2.37 (s, 3H), 2.88 (m, 4H), 7.13 (d, J = 3.6 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.35 (m, 2H), 7.51 (s, lH), 7.68 (d, J + 7.6 Hz, 1H), 7.78 (s, lH)

Example 47

2-{2-hydroxy-3-"N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-oxime Base]-benzene}-5-methyl-thiazole-4-carboxylic acid

first step

2-(2-methoxy-3-nitrophenyl)-5-methyl-thiazole-4-carboxylic acid

2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (1.7 g, 6.08 mmol) 2-Bromo-5-methyl-thiazole-4-carboxylic acid (900 mg, 4.05 mmol), tetrakis(triphenylphosphine)palladium (233 mg, 0.2 mmol) and sodium carbonate (1.29 g, 12.16 mmol) dissolved in 30 mL In 1,4-dioxane, the mixture was heated under reflux for 4 hours. After the residue was traced by TLC, the mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added 20 mL of hydrochloric acid (1N) and 30 mL of ethyl acetate. After stirring, the mixture was separated and the organic phase was washed with saturated sodium chloride solution. The sodium salt was dried, and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure and then recrystallized from ethyl acetate and n-hexane, and the obtained solid was dried to give the title product 2-(2-methoxy-3-nitrophenyl)- 5-Methyl-thiazole-4-carboxylic acid 47a (310 mg, yellow solid). Yield: 26%. MS m/z (ESI): 292.6 [M-1] ¹ H NMR (400 MHz, DMSO - d ₆ ): δ 13.45 (br, 1H), 8.58 (dd, J = 8.0, 1H), 8.14 (dd, J =8.0,1H), 7.52 (t, J=8.0, 1H), 3.93 (s, 3H), 2.71 (s, 3H)

Second step

2-(2-methoxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid

2-(2-Methoxy-3-nitrophenyl)-5-methyl-thiazole-4-carboxylic acid 47a (300 mg, 1.02 mmol) was dissolved in 15 mL of methanol, and 30 mg of palladium-carbon was added to hydrogen. Stir for 24 hours under the atmosphere. The residue was removed by TLC, the reaction mixture was filtered to remove palladium-carbon, and the filtrate was concentrated under reduced pressure to give the title product 2-(2-methoxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid. 47b (250 mg, yellow solid). Yield: 92%. MS m/z (ESI): 262.8 [M-1]

third step

2-(2-hydroxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid hydrobromide

2-(2-Methoxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid 47b (280 mg, 0.94 mmol) was dissolved in 5 mL of hydrogen hydrogen chloride and stirred at 80 ° C overnight. . It was traced by TLC until the disappearance of the starting material, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate and dried to give the title product 2-(2-hydroxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid Hydrobromide 47c (200 mg, yellow solid). Yield: 64%. MS m/z (ESI): 262.7 [M-1] ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.78 (d, J = 8.0, 1H), 7.51 (d, J = 8.0, 1H), 7.09 (t, J=8.0, 1H), 2.73 (s, 3H)

the fourth step

2-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-anthracene Base]-benzene}-5-methyl-thiazole-4-carboxylic acid

2-(2-Hydroxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid hydrobromide 47c (200 mg, 0.60 mmol) was dissolved in 2 mL hydrochloric acid (1 N). 0.82 mL of sodium nitrite solution (46 mg, 0.66 mmol) was added dropwise, stirred for 20 minutes, and then 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (116 mg) was added. , 0.544 mmol), a saturated sodium hydrogencarbonate solution (781 mg, 9.3 mmol) was added portionwise to adjust the pH to 8 to 9, and the mixture was quenched with 2 mL of ethanol and allowed to react to room temperature overnight. The product disappeared by TLC, the solid was filtered, solid was dissolved in 20 mL of water, and concentrated hydrochloric acid was adjusted to pH = 3 to 4, filtered, dried, and the crude product was purified by HPLC to give the title product 2-{2-hydroxy-3- [N'-(1-indan-5-yl-3-methyl-5-oxooxy-1,5-dihydropyrazol-4-ylidene)-indenyl]-phenyl}-5-A Base-thiazole-4-carboxylic acid 47 (195 mg, red solid). Yield: 75.9%. MS m/z (ESI): 473.7 [M-1] ¹ H NMR (400 MHz, D ₂ O): δ 1.97 (m, 2H), 2.31 (s, 3H), 2.53 (s, 3H), 2.80 (m, 4H), 6.52 (t, J = 8.0 Hz, 1H), 7.23 (m, 4H), 7.84 (d, J + 8.0 Hz, 1H)

Example 48

5-{2-hydroxy-3-"N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-oxime Ethyl]-phenyl}-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester

Ethyl 5-(3-amino-2-hydroxyphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate hydrobromide 6h (180 mg, 0.66 mmol) Dissolved in 2.2 mL of hydrochloric acid (1N), added 0.8 mL of sodium nitrite solution (50 mg, 0.72 mmol), stirred for 20 minutes, and then added 2-indan-5-yl-5-methyl-2,4-di Hydropyrazol-3-one 1i (126 mg, 0.59 mmol) was adjusted to a pH of 8 to 9 using a saturated sodium hydrogen carbonate solution, and the mixture was quenched with 2 mL of ethanol and allowed to react at room temperature overnight. After the residue was traced to the disappearance of the material, the solid was filtered, and 20 mL of dichloromethane and 20 mL of water were added, and the mixture was stirred and concentrated to pH = 3 to 4 with concentrated hydrochloric acid, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure, and then purified by column chromatography to give the title product 5-{2-hydroxy-3-[N'-(1-indane-5-yl-3-methyl-5-s. -1,5-Dihydropyrazole-4-ylidene)-indolyl]-phenyl}-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 48 (80 mg, red solid) . Yield: 25.8%. MS m/z (ESI): 514.0 [M+1] ¹ H NMR (400 MHz, DMSO - d ₆ ): δ 1.30 (m, 3H), 2,01 (m, 2H), 2.23 (s, 3H), 2.50 (s, 3H), 2.95 (m, 4H), 3.32 (s, 3H), 4.33 (m, 2H), 6.63 (m, 1H), 7.00 (m, 1H), 7.12 (m, 1H), 7.28 (m, 1H), 7.73 (m, 2H), 13.91 (br, 1H)

Example 49 5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(1,1,3,3-tetramethylindan-5-yl)-1,5 -dihydropyrazole-4-ylidene]-indenyl}-phenyl)-thiophene-2-carboxylic acid

5-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 12c (260 mg, 0.823 mmol) was dissolved in 2.7 mL of hydrochloric acid (1 N) and added dropwise to 1.1 mL. Sodium nitrate solution (62 mg, 0.91 mmol), stirred for 20 minutes, then added 5-methyl-2-(1,1,3,3-tetramethylindan-5yl)-2,4-dihydropyrazole 3-ketone 19d (200 mg, 0.74 mmol), the pH was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and the mixture was quenched with 2 mL of ethanol and allowed to react at room temperature for 3 hours. The material disappeared by TLC, the solid was filtered, 20 mL of water was added to the solid, and the mixture was adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and then subjected to column chromatography to give the title product 5-(2-hydroxy-3-{ N'-[3-Methyl-5-oxo-l-(1,1,3,3-tetramethylindan-5-yl)-1,5-dihydropyrazole-4-ylidene ]-Mercapto}-phenyl)-thiophene-2-carboxylic acid 49 (216 mg, red solid). Yield: 56.5%. ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.30 (m, 12H), 1.93 (s, 2H), 2.34 (s, 3H), 7.19 (t, J = 8.0 Hz, 1H), 7.25 (d, J) = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.66 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.77 (m, 2H), 10.10 (s, fH ), 13.06 (br, 1H), 13.72 (br, 1H)

Example 50 5-(2-hydroxy-5-methyl-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)- 1,5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-furan-2-carboxylic acid

5-(3-Amino-2-hydroxy-5-methylphenyl)-furan-2-carboxylic acid hydrobromide 46c (120 mg, 0.38 mmol) was dissolved in 1.3 mL of 1N hydrochloric acid and added dropwise. 0.5 mL of sodium nitrite solution (29 mg, 0.42 mmol), reacted for 20 minutes, and then added 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydrogen Pyrazol-3-one 3i (78 mg, 0.34 mmol) was adjusted to pH 8 with saturated sodium bicarbonate solution, and 2 mL of ethanol was added and allowed to react overnight at room temperature. The product disappeared by TLC, filtered, and the solid was added to 20 mL of water, and then adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and then subjected to column chromatography to give the title product 5-(2-hydroxy-5-methyl -3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4- Subunit]-mercapto}-phenyl)-furan-2-carboxylic acid 50 (56 mg, red solid). Yield: 34.8%. MS m/z (ESI): 470.8 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.75 (m, 4H), 2.31 (s, 3H), 2.37 (s, 3H), 2.73 (m) , 4H), 7.13 (m, 2H), 7.35 (m, 2H), 7.50 (s, 1H), 7.62 (m, 2H)

Example 51 4-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-di Hydropyrazol-4-ylidene]-indenyl}-phenyl)-thiophene-2-carboxylic acid

first step 4-(3-nitro-2-methoxy-phenyl)-thiophene-2-carboxylic acid

Ethylene 2-(2-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (0.81 g, 2.9 mmol) 4-bromo-thiophene-2-carboxylic acid (0.3 g, 1.45 mmol), tetrakis(triphenylphosphine)palladium (80 mg, 0.073 mmol) and sodium carbonate (0.31 g, 2.9 mmol) dissolved in 20 mL of 1,4- In a mixed solvent of dioxane and 10 mL of water, the mixture was heated under reflux for 0.5 hour. The title material (4-nitro-nitro) was obtained by the TLC. The residue was evaporated to dryness eluted with 1N hydrochloric acid to pH 3 and ethyl acetate (20 mL×3). 2-methoxy-phenyl)-thiophene-2-carboxylic acid 51a (0.54 g, brown oily liquid) was directly subjected to the next reaction. MS m/z (ESI): 277.6 [M-1]

Second step 4-(3-Amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid

4-(3-Nitro-2-methoxy-phenyl)-thiophene-2-carboxylic acid 51a (400 mg, 1.45 mmol) was dissolved in 30 mL of ethyl acetate, and then 100 mg of palladium-carbon and amine formate ( 360 mg, 5.8 mmol), heated to reflux for 3 hours. The residue was removed by TLC, and the reaction mixture was filtered to remove palladium/carbon, and concentrated under vacuo to give the title product 4-(3-amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid 51b (410 mg, brown oil Liquid)) directly to the next reaction. MS m/z (ESI): 247.8 [M-1]

third step 4-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide salt

4-(3-Amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid 51b (360 mg, 1.45 mmol) was dissolved in 5 mL of dichloromethane, and boron tribromide (2.8 mL, 5.6) was added dropwise. Methyl), reacted at room temperature for 4.5 hours. The title material (4-amino-2-hydroxybenzene) was obtained after the residue was purified by chromatography. Base)-thiophene-2-carboxylic acid hydrobromide 51c (80 mg, grey solid). Yield: 17.5%. MS m/z (ESI): 236.1 [M+1]

the fourth step 4-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-di Hydropyrazol-4-ylidene]-indenyl}-phenyl)-thiophene-2-carboxylic acid

4-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 51c (80 mg, 0.25 mmol) was dissolved in 1 mL of 1N hydrochloric acid, and 0.3 mL of sodium nitrite solution was added dropwise. (19 mg, 0.28 mmol), react for 20 minutes, then add 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazol-3-one 3i (52 mg, 0.23 mmol), the pH was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and 2 mL of ethanol was added and allowed to react overnight at room temperature. The product disappeared by TLC, filtered, and the solid was added to 20 mL of water, and then adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, and 4 mL of ethyl acetate was added to the solid for 2 hours, filtered, and the obtained solid was dried to give the title product 4 -(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro Pyrazole-4-ylidene]-indenyl}-phenyl)-thiophene-2-carboxylic acid 51 (11 mg, mp. Yield: 10.2%. MS m/z (ESI): 472.8 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.76 (m, 4H), 2.33 (s, 3H), 2.74 (m, 4H), 7.13 (m) , 2H), 7.33 (m, 1H), 7.65 (m, 3H), 8.06 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 1.6 Hz, .1H), 9.68 (s, 1H), 13.75(s,1H)

Example 52 4-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-anthracene Benzene-thiophene-2-carboxylic acid

4-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 51c (120 mg, 0.38 mmol) was dissolved in 2.7 mL of 1N hydrochloric acid and 0.45 mL of sodium nitrite was added dropwise. Solution (29 mg, 0.42 mmol), react for 20 min, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (73 mg, 0.34 mmol). The sodium hydrogencarbonate solution was adjusted to pH 8, and 2 mL of ethanol was added and allowed to react at room temperature overnight. The product disappeared by TLC, filtered, and the solid was added to 20 mL of water, then adjusted to pH 3 to 4 with concentrated hydrochloric acid, filtered, and 5 mL of ethyl acetate was added to the solid for 1 hour, filtered, and the obtained solid was dried to give the title product 4- {2-Hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-l,5-dihydropyrazole-4-ylidene)-indenyl] -Benzene-thiophene-2-carboxylic acid 52 (45 mg, yellow solid). Yield: 28.7%. MS m/z (ESI): 458.8 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 2.05 (m, 2H), 2.32 (s, 3H), 2.87 (m, 4H), 7.13 (t) , J = 8.0 Hz, 1H), 7.32 (m, 2H), 7.67 (m, 2H), 7.78 (s, 1H), 8.05 (d, J = 1.6 Hz, 1H), 8.13 (d, J = 1.2 Hz) , 1H), 9.68 (s, 1H), 13.79 (s, 1H)

Example 53 5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-di Hydropyrazol 1-4-ylidene]-mercapto}-phenyl)-2-methylfuran-3-carboxylic acid

first step Methyl 5-bromo-2-methylfuran-3-carboxylate

Methyl 2-methylfuran-3-carboxylate (2.0 g, 14.3 mmol) was dissolved in benzene, azobisisobutyronitrile (10 mg, 0.06 mmol) was added, cooled to 0 ° C in ice bath, and N-bromine was added. The amber succinimide (2.8 g, 15.7 mmol) was added to the ice bath. The reaction mixture was stirred at room temperature overnight. The product, methyl 5-bromo-2-methylfuran-3-carboxylate, 53a (1.9 g, mp.

Second step Methyl 5-(2-methoxy-3-nitrophenyl)-2-methylfuran-3-carboxylate

Methyl 5-bromo-2-methylfuran-3-carboxylate 53a (0.65 g, 3.0 mmol) and 2-(2-methoxy-3-nitrophenyl)-4,4,5,5 Tetramethyl-[1,3,2]ethylene glycolate 6a (1.0 g, 3.58 mmol) was dissolved in 1,4-dioxane (15 mL), and tetrakis(triphenylphosphine)palladium ( 173 mg, 0.15 mmol) and sodium carbonate (636 mg, 6.0 mmol) were added to reflux at 100 ° C for 3 hours, followed by TLC until the disappearance of the starting material, the reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. Methyl 5-(2-methoxy-3-nitrophenyl)-2-methylfuran-3-carboxylate 53b (659 mg, white solid). Yield: 75%.

third step 5-(2-methoxy-3-nitrophenyl)-2-methylfuran-3-carboxylic acid

Methyl 5-(2-methoxy-3-nitrophenyl)-2-methylfuran-3-carboxylate 53b (650 mg, 2.23 mmol) was dissolved in methanol and sodium hydroxide (268 mg, 6.7) After stirring for 3 hours at 50 ° C, the mixture was traced by TLC until the disappearance of the starting material. The reaction mixture was concentrated under reduced pressure. The pH was adjusted to 3 to 4 with 1N hydrochloric acid, and a large amount of solid was precipitated and filtered. The mixed solvent of ethyl acetate (V: V = 5:1) was recrystallized to give the titled product 5-(2-methoxy-3-nitrophenyl)-2-methylfuran-3-carboxylic acid 53c ( 450 mg, white solid), yield: 84%. MS m/z (ESI): 275.7 [M-1] ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.80 (s, 1H), 8.03 (dd, J = 8.0, 1H), 7.87 (dd, J = 8.0, 1H), 7.44 (t, J = 8.0, 1H), 7.13 (s, 1H), 3.83 (s, 3H), 2.64 (s, 3H)

the fourth step 5-(2-methoxy-3-amino-phenyl)-2-methylfuran-3-carboxylic acid

5-(2-Methoxy-3-nitrophenyl)-2-methylfuran-3-carboxylic acid 53c (450 mg, 1.62 mmol) was dissolved in methanol, and 45 mg of palladium/carbon was added under hydrogen atmosphere. After stirring under reflux for 4 hours, the residue was evaporated to dryness eluted with EtOAc (EtOAc). 53d (370 mg, white solid), yield: 92%. MS m/z (ESI): 245.8 [M-1] ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.97 (s, 1H), 6.87 (m, 2H), 6.68 (m, 1H), 5.06 (br, 2H), 3.63 (s, 3H), 2.59 (s, 3H)

the fifth step 5-(2-hydroxy-3-amino-phenyl)-2-methylfuran-3-carboxylic acid hydrobromide

5-(2-Methoxy-3-amino-phenyl)-2-methylfuran-3-carboxylic acid 53d (370mg, 1.5mmol) was dissolved in dichloromethane, cooled to 0 ° C in ice bath, drip Add a solution of boron tribromide in dichloromethane (1N, 3.6 mL), and add the reaction at room temperature for 2 hours. The mixture was traced by TLC until the disappearance of the starting material. The reaction mixture was quenched by adding 0.5 mL of methanol. The reaction mixture was stirred for 30 minutes. Concentration, the obtained solid was added with 10 mL of ethyl acetate and stirred for 30 min, filtered, and the obtained solid was dried to give the title product 5-(2-hydroxy-3-amino-phenyl)-2-methylfuran-3-carboxylic acid hydrobromide. Acid salt 53e (240 mg, gray solid), yield: 46%. MS m/z (ESI): 231.7 [M-1] ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.57 (dd, J = 6.0, 1H), 7.24 (dd, J = 8.0, 1H), 7.05 (t) , J=8.0, 1H), 2.61(s, 3H)

Step 6 5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-di Hydropyrazol 1-4-ylidene]-mercapto}-phenyl)-2-methylfuran-3-carboxylic acid

5-(2-Hydroxy-3-amino-phenyl)-2-methylfuran-3-carboxylic acid hydrobromide 53e (200 mg, 0.64 mmol) was dissolved in 2.2 mL of 1N hydrochloric acid and added dropwise. 0.9mL sodium nitrite solution (48mg, 0.7mmol), reaction for 20 minutes, then add 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydrogen Pyrazol-3-one 3i (131 mg, 0.57 mmol) was adjusted to pH 8 with saturated sodium bicarbonate solution, and 2 mL of ethanol was added and allowed to react overnight at room temperature. The product disappeared by TLC, filtered, and the solid was added to 20 mL of water, and then adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, and 8 mL of ethyl acetate was added to the solid for 1 hour, filtered, and the obtained solid was dried to give the title product 5 -(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro Pyrazole 1-4-ylidene]-mercapto}-phenyl)-2-methylfuran-3-carboxylic acid 53 (200 mg, red solid). Yield: 73.8%. ^{1 HNMR (400MHz, DMSO- d6)} : δ1.75 (m, 4H), 2.31 (s, 3H), 2.62 (s, 3H), 2.77 (m, 4H), 7.14 (m, 3H), 7.47 (d , J=7.6Hz, 1H), 7.65 (m, 3H), 9.79 (s, 1H), 12.73 (br, 1H), 13.76 (br, 1H)

Example 54 5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1, Methyl 5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-furan-2-carboxylate

first step Methyl 5-(2-methoxy-3-nitrophenyl)-furan-2-carboxylate

2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (3.6 g, 12 mmol), Methyl 5-bromo-furan-2-carboxylate (2.05 g, 10 mmol), tetrakis(triphenylphosphine)palladium (1.55 g, 0.5 mmol) and sodium carbonate (2.12 g, 20 mmol) were dissolved in 1,4-di In the oxygen earth mash, it was heated to reflux for 3 hours. The residue was removed by TLC, filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Methyl 5-(2-methoxy-3-nitrophenyl)-furan-2-carboxylate 54a (500 mg, yellow solid). Yield: 18%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.23 (dd, J = 7.6, 1H), 7.83 (dd, J = 7.6, 1H), 7.35 (m, .2H), 7.16 (d, J = 4.0, 1H) ), 3.98 (s, 3H), 3.94 (s, 3H)

Second step Methyl 5-(3-amino-2-methoxy-phenyl)-furan-2-carboxylate

Methyl 5-(2-methoxy-3-nitrophenyl)-furan-2-carboxylate 54a (500 mg, 1.8 mmol) was dissolved in methanol, then 50 mg palladium-carbon was added and heated under hydrogen atmosphere Reflux for 4 hours. The residue was traced to dryness by EtOAc (EtOAc) eluted eluted Methyloxy-phenyl)-furan-2-carboxylate 54b (370 mg, white solid), yield: 83%.

third step Methyl 5-(3-amino-2-hydroxyphenyl)-furan-2-carboxylate

Methyl 5-(3-amino-2-methoxy-phenyl)-furan-2-carboxylate 54b (350 mg, 1.42 mmol) was dissolved in dichloromethane, and boron tribromide (3.3 mL, 2.0 mol/L), reacted at room temperature for 2 hours. The mixture was traced by TLC until the material disappeared, and the reaction was quenched with methanol. The mixture was adjusted to pH 5 to 6 with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography to give the title product 5-- 3- Methylamino-2-hydroxyphenyl)-furan-2-carboxylate 54c (170 mg, gray solid). Yield: 451%. MS m / z (ESI): 232.0 [M-1] 1 HNMR (400MHz, DMSO- d 6): δ7.32 (d, J = 7.6,1H), 7.05 (d, J = 7.6,1H), 6.82 (m, 3H), 3.96 (s, 3H)

the fourth step 5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1, Methyl 5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-furan-2-carboxylate

5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid methyl ester 54c (110 mg, 0.47 mmol) was dissolved in hydrochloric acid (1.6 mL, 1 mol/L), and 0.6 mL was added dropwise. Sodium nitrite solution (36 mg, 0.52 mmol), react for 10 minutes, then add 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazole 3-ketone 3i (97 mg, 0.43 mmol) was adjusted to pH 8 to 9 with saturated sodium bicarbonate solution and allowed to react at room temperature for 24 hours. The title material was obtained by the TLC. {N'-[3-Methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalenylene-2-yl)-1,5-dihydropyrazole-4- Subunit]-mercapto}-phenyl)-furan-2-carboxylic acid methyl ester 54 (48 mg, red solid). Yield: 23.9%. MS m/z (ESI): 470.7 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 1.76 (m, 4H), 2.31 (s, 3H), 2.73 (m, 4H), 3.86 (s) , 3H), 7.12 (m, 1H), 7.17 (m, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.46 (m, 1H), 7.56 (m, 1H), 7.65 (m, 2H) , 7.72 (m, 1H), 10.02 (s, 1H), 13.72 (br, 1H)

Example 55 5-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-anthracene Methyl]-phenyl}-furan-2-carboxylate

5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid methyl ester 54c (110 mg, 0.47 mmol) was dissolved in hydrochloric acid (1.6 mL, 1 mol/L), and 0.6 mL was added dropwise. Sodium nitrite solution (36 mg, 0.52 mmol), react for 20 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (91 mg, 0.43 mmol) The pH was adjusted to 8 to 9 with a saturated sodium hydrogencarbonate solution and allowed to react at room temperature for 24 hours. The material disappeared by TLC, the reaction was quenched with ethanol, filtered, and the solid was dissolved in 15 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered, and the solid was dried by column chromatography to give the title product 5-- 2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-indenyl]- Phenyl}-furan-2-carboxylic acid methyl ester 55 (137 mg, red solid). Yield: 70.3%. MS m/z (ESI): 456.7 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 2.05 (m, 2H), 2.33 (s, 3H), 2.89 (m, 4H), 3.86 (s) , 3H), 7.18 (m, 2H), 7.30 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 3.6 Hz, 1H), 7.56 (m, 1H), 7.71 (m, 2H), 7.78 (s, 1H)

Example 56 3'-{N'-[1-(2,2-Dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene ]-mercapto}-2'-hydroxybiphenyl-3-carboxylic acid

2'-hydroxy-3'-aminobiphenyl-3-carboxylic acid hydrobromide salt 1f (150 mg, 0.5 mmol) was dissolved in hydrochloric acid (1.7 mL, 1 mol/L) under ice bath, and 0.6 mL was added dropwise. Sodium nitrate solution (38 mg, 0.55 mmol), reacted for 20 minutes, and then added 2-(2,2-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazole-3- Ketone 45d (109 mg, 0.45 mmol), the pH was adjusted to 8 to 9 with saturated sodium bicarbonate solution, and the solvent was quenched with ethanol and allowed to react overnight at room temperature. The product disappeared by TLC, filtered, and the solid was added to 15 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid, filtered, and the filter cake was washed with ethyl acetate (1mL×3) and dried to give the title product 3'-{N' -[1-(2,2-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}- 2'-Hydroxybiphenyl-3-carboxylic acid 56 (16 mg, yellow solid), yield: 7.6%. MS m/z (ESI): 480.7 [M-1] ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 1.13 (s, 6H), 2.32 (s, 3H), 2.70 (m, 4H), 7.14 m, 2H), 7.22 (d, J = 8.8 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.70 (m, 2H), 7.80 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 8.13 (s, 1H)

Example 57 4-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1, 5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-1H-pyrrole-2-carboxylic acid

first step 2,2,2-trichloro-1-(1H-pyrrol-2-yl)-acetamidine

Trichloroethane chloride (45 g, 247 mmol) was dissolved in 100 mL of diethyl ether, and pyrrole (15.4 g, 230 mmol) was dissolved in 100 mL, added dropwise to the above solution, and 200 mL of potassium carbonate solution (20 g, 145 mmol) was added thereto. After stirring at room temperature for 1 hour, the reaction was monitored by TLC until the reaction mixture was completed. The reaction mixture was partitioned, and the organic phase was dried over anhydrous magnesium sulfate and filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to give the title product 2, 2, 2 Trichloro-1-(1H-pyrrol-2-yl)-acetamidine 57b (38 g, white solid), yield: 77.8%. MS m/z (ESI): 210.3 [M-1]

Second step 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)-acetamidine

2,2,2-Trichloro-1-(1H-pyrrol-2-yl)-acetamidine 57b (32 g, 151.8 mmol) was dissolved in dichloromethane (250 mL), and iodine chloride (25 g, 153 mmol) was dissolved in In 125 mL of dichloromethane, it was added dropwise to the above solution, and after stirring, the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until the reaction of the starting material was complete. The reaction mixture was successively saturated sodium carbonate solution, sodium thiosulfate solution (2M) and saturated salt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered, evaporated, evaporated, evaporated. - acetamidine 57c (47 g, yellow solid), yield: 92%. MS m/z (ESI): 336.4 [M-1]

third step Methyl 4-iodo-1H-pyrrole-2-carboxylate

Dissolve 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)-acetam 57c (47 g, 136 mmol) in 265 mL of methanol and dissolve sodium methoxide (17.23 g, 163 mmol). The mixture was added dropwise to 200 ml of methanol, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC until the reaction was completed. The mixture was concentrated under reduced pressure. The organic phase was combined, and the organic layer was evaporated, evaporated, evaporated, evaporated Solid), Yield: 92.5%. MS m/z (ESI): 250.1 [M-1]

the fourth step Methyl 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylate

Methyl 4-iodo-1H-pyrrole-2-carboxylate 57d (25.1 g, 100 mmol) was dissolved in 150 mL of dichloromethane, then triethylamine (30.6 mL, 220 mmol), 4-dimethylaminopyridine (1.22 g) , 10 mmol) and p-toluenesulfonic acid (21 g, 110 mmol) were reacted at 20 ° C overnight. The reaction was monitored by TLC until the starting material was completely reacted, and the reaction was quenched by adding 30 mL of hydrochloric acid (1 N). The reaction mixture was extracted with methylene chloride (50 mL×3). The organic phase was washed with saturated sodium carbonate and brine, and dried over anhydrous sodium sulfate. 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57e (32.5 g, white solid), yield: 80.2%. MS m/z (ESI): 405.8 [M+1]

the fifth step Methyl 4-(3-nitro-2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylate

2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (2.05 g, 5.5 mmol) , 4-iodo-1-(toluene-4-sulfonium)-1H-pyrrole-2-carboxylic acid methyl ester 57e (2.03 g, 5 mmol), potassium carbonate (1.38 g, 10 mmol) and tetrakis(phenylphosphine)palladium (144 mg, 0.125 mmol) was added to a mixed solvent of 15 mL of 1,4-dioxane and 5 mL of water, and subjected to microwave reaction at 80 ° C for 30 minutes. The reaction of the reaction was completed by TLC, and the reaction mixture was concentrated under reduced pressure. After stirring, the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was combined and evaporated. Methyl (3-nitro-2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylate 57f (1.04 g, m. 48%. MS m/z (ESI): 431.0 [M + 1] ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.225~8.231 (m, 1H), 7.79~8.00 (m, 2H), 7.710~7.765 (m, 1H) ), 7.452~7.457(m,1H), 7.389~7.409(m,2H), 7.271~7.311(m,2H),3.839(s,3H),3.829(s,2H),2.488(s,3H)

Step 6 4-(3-nitro-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid

4-(3-Nitro-2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57f (1.04 g, 2.42 mmol) and one Lithium hydroxide hydrate (1.01 g, 24.19 mmol) was added to a mixed solvent of 10 mL of N,N-dimethylformamide and 5 mL of water, and microwave-reacted at 100 ° C for 30 minutes. The reaction of the reaction material was completely monitored by TLC. Hydrochloric acid (1N) was adjusted to pH 3, a large amount of solid was precipitated, filtered, and filtered to give the title product 4-(3-nitro-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid 57 g. (350 mg, yellow solid), yield: 50%. MS m/z (ESI): 260.8 [M-1]

Seventh step 4-(3-Amino-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid

57 g (633 mg, 2.41 mmol) of 4-(3-nitro-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid was dissolved in 15 mL of ethyl acetate, and 127 mg of palladium/carbon and ammonium formate were added. (609 mg, 9.66 mmol), after heating and refluxing for 2 hours, the reaction was monitored by TLC until the starting material was completely reacted, and the mixture was filtered to remove palladium/carbon. The filtrate was concentrated under reduced pressure and purified by column chromatography to give the title product 4-(3-amino-2). -Methoxy-phenyl)-1H-pyrrole-2-carboxylic acid 57 h (130 mg, m.p.). MS m/z (ESI): 230.8 [M-1] ¹ H NMR (400 MHz, DMSO- d6 ): δ 11.631 (s, 1H), 7.305 (s, 1H), 7.025 (s, 1H), 6.712~6.798 (m, 2H), 6.524~6.543 (m, 1H), 3.514 (s, 3H)

Eighth step 4-(3-Amino-2-hydroxyphenyl)-1H-pyrrole-2-carboxylic acid

4-(3-Amino-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid 57h (130mg, 0.56mmol) was added to 2mL of dichloromethane, then boron bromide (1.12mL, 2.24mmol) After stirring at room temperature for 6 hours, the reaction was monitored by TLC until the reaction mixture was completed. The reaction was quenched with methanol, and the mixture was concentrated under reduced pressure to give the title product 4-(3-amino-2-hydroxyphenyl)-1H. Pyrrole-2-carboxylic acid 57i (140 mg, gray solid), yield: 99%. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.312 (s, 1H), 7.178 (s, 1H), 7.06 to 7.028 (m, 1H), 6.822 to 6.837 (m, 2H)

Step 9 4-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1, 5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-1H-pyrrole-2-carboxylic acid

4-(3-Amino-2-hydroxyphenyl)-1H-pyrrole-2-carboxylic acid 57i (130 mg, 0.43 mmol) was dissolved in hydrochloric acid (1.5 mL, 1 mol/L), and 0.6 mL was added dropwise. Sodium nitrite solution (33 mg, 0.47 mmol), react for 10 minutes, then add 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazole 3-ketone 3i (89 mg, 0.3 mmol) was adjusted to pH 8 to 9 with a saturated sodium hydrogen carbonate solution and allowed to react at room temperature for 24 hours. The title material (4-hydroxy-) was obtained by the TLC. 3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole- 4-Mercapto]-indenyl}-phenyl)-1H-pyrrole-2-carboxylic acid 57 (38 mg, m.p.). Yield: 21.3%. ^{1 HNMR (400MHz, DMSO- d6)} : δ11.74 (1H, br), 11.64 (1H, br), 7.60 (1H, d J = 8.2), 7.49 (1H, d J = 8.0), 7.32 (3H, m), 7.05 (3H, m), 2.67 (4H, m), 1.95 (3H, s), 1.13 (4H, m)

Example 58 4 -{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl ]-Benzene}-1H-pyrrole-2-carboxylic acid

4-(3-Amino-2-hydroxyphenyl)-1H-pyrrole-2-carboxylic acid 57i (240 mg, 0.8 mmol) was dissolved in hydrochloric acid (3 mL, 1 mol/L) under ice-cooling, and 1.1 mL was added dropwise. Sodium nitrate solution (61 mg, 0.88 mmol), reacted for 20 minutes, then added 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (154 mg, 0.72 mmol). The pH was adjusted to 8 to 9 with a saturated sodium hydrogencarbonate solution and allowed to react at room temperature for 24 hours. The mixture was traced to disappearance by TLC, quenched with ethanol, filtered, and the solid was dissolved in 15 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered, and the solid was subjected to column chromatography and dried to give the title product 4-{ 2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-indenyl]- Benzene}-1H-pyrrole-2-carboxylic acid 58 (101 mg, red solid), yield: 28.4%. ^{1 HNMR (400MHz, DMSO- d6)} : δ11.83 (1H, br), 11.77 (1H, br), 7.57 (1H, d, J = 7.2), 7.50 (1H, s), 7.37 (4H, m) , 7.26 (1H, m), 7.10 (1H, m), 2.87 (4H, m), 2.32 (3H, s), 2.04 (2H, m)

Test case: Biological evaluation Test Example 1 Proliferation of BAF3-TPOR cells by TPO series compounds 1. Materials and methods:

a.RPM1 Medium 1640, Powder, 10*1L, with HEPES (Gibco Catalog no. 23400021)

b. FBS fetal bovine serum (Gibco Catalog no. 10099-141)

c.PENICILLIN STREPTOMYCIN SOL (Gibco Catalog no. 15140-122)

d.Geneticin(G418)(Gibco Catalog no. 11811-098)

E.recombinant mouse IL-3(chemicon Catalog no. IL015)

f.Human Thrombopoietin R Mab(TPO)(R&D Catalog no. MAB1016)

g.DMSO (AppliChem Catalog no. A3672)

h. Multi Site Directed Mutagenesis Kit, 10 Runs (Stratagene ST200515)

i.Cell Counting Kit-8 (Tongren Chemical Institute Catalog no. CK04-13)

j.Ba/F3 cells (Concord Cell Bank Catalog no. 0095)

k.EX-EGFP-M02 (FulenGen Catalog no. EX-EGFP-M02 Control)

l.EX-B0010-M02 (FulenGen Catalog no. EX-B0010-M02)

2. Operation steps:

(1) plastid construction: According to the TPOR gene sequence provided by Entrez Gene ID: 4325, Refseq: NM_005373, the purchased EX-B0010-M02 plastid (FulenGen) was utilized. The Multi Site Directed Mutagenesis Kit (Stratagene) kit performs a 2-point mutation. The multi-point mutation primer sequences were: g491a: 5'-gggaacttcagatcagctgggaggagccg-3', g491a_antisense: 5'-cggctcctcccagctgatctgaagttccc-3'; c965t: 5'-caggaccatgctagctcccaaggcttcttct-3', c965t_antisense: 5'-agaagaagccttgggagctagcatggtcctg-3'. After the mutation, the plastid was transformed into E. coli DH5α, and the positive clone was screened by Amp, and the mutation result was confirmed by sequencing.

(2) Construction of BAF3-TPOR cell line: A BaF3 cell line stably constructing a highly functional TPO receptor was constructed. 25 μg of the human TPO receptor and the EX-B0010-M02 plastid of the screening gene neomycin were transfected into wild-type BaF3 cells (1× ^{10 7} ), and the instrument used for transfection was Electro Square Porator ECM830 (BTX Division of Genetronic). , Inc. US), the transfection conditions are: 250V, 18ms. The BAF3-TPOR stable cell line was obtained by G418 (Gibco, US) screening. BAF3-TPOR was cultured in RPMI 1640 (Gibco, US) medium, 10% FB (Gibco, US) S, 800 ng/ml G418, 5 ng/ml, rmIL-3 (Chemicon, US).

3. Compound screening:

(1) Centrifugal washing of cells: take appropriate amount of cell suspension at 1000 rpm, centrifuge for 5 minutes, discard the supernatant, resuspend the cells with 10 ml of cell culture medium without IL3, centrifuge at 1000 rpm for 5 minutes, discard the supernatant. ;

(2) Add 1 ml of cell culture medium containing no IL3 to blow the cells evenly, and take appropriate amount of cell suspension to dilute and count;

(3) preparing a cell suspension having a density of 100,000 / ml according to the cell counting result;

(4) Add 100 μl of cell suspension to each well of 96-well plate, set 3 replicate wells, and set blank control group (B), negative control group (N), TPO positive control group (P) and test compound Group (S);

(5) The test compound powder was formulated into 10 mM stock solution in DMSO, and diluted to different concentrations with RPM11640: 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM. ;

(6) Add 10 μl of the corresponding concentration of the drug solution to each well, and add 1 μl of rhTPO (10 μg/mL) to the positive control well;

(7) placed in a 5% CO 2, 37 ° C cell culture incubator for 24 hours;

(8) 10 μl of CCK-8 was added to each well, and cultured in a cell culture incubator for 4 hours;

(9) The OD value was measured at 450 nm using a VICTOR 3 (Perkin Elmer 1420-120) instrument.

4. Results analysis and calculation:

(1) Value-added rate definition: [(S-B)/(P-B)]*100%S: sample; B: blank control; P: positive control

(2) Calculate EC ₅₀ by Origin 7.0.

5. Results:

Pharmacokinetic test Test Example 1 Pharmacokinetic test of the present invention 1. Purpose of the test

Rats were used as test animals, and the concentrations of the drugs in plasma at different times after administration of Example 1, Example 15, and Example 29 by intragastric administration were determined by LC/MS/MS method. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.

2, the test plan 2.1, test drugs Example 1, Example 15, and Example 29 2.2, test animals

24 healthy adult SD rats, male and female, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2003-0002.

2.3, equipment

TSQ Quantum Ultra AM Triple Quadrupole Mass Spectrometer, Thermo Finnigan, USA;

Agilent 1200 High Performance Liquid Chromatography System, Agilent, USA.

2.4, drug preparation

An appropriate amount of the sample was weighed and added with 1% sodium carboxymethylcellulose to prepare a 0.5 mg/ml (as prototype) suspension, which was prepared immediately.

2.5, administration

Twenty-four healthy adult SD rats, half male and half female, were divided into 5 groups on average. After fasting overnight, the rats were intragastrically administered at a dose of 5.0 mg/kg (in original form) at a dose of 10 ml/kg.

2.6, sample collection

Twenty-four SD rats, half male and half female, were intragastrically administered overnight after fasting for a dose of 5 mg/kg. 0.2 ml of blood was collected from the eyelids before and after administration and 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 11.0, 14.0, 24.0, 36.0, 48.0 hours after administration, placed in heparinized tubes, centrifuged at 3500 rpm for 10 min. Plasma was separated and stored at 20 °C.

2.7, analytical methods

Rat plasma 501 at each time after administration, adding internal standard solution 201, methanol: water (80:20, v/v) 201, mixing, adding methanol 1501 precipitation protein, vortex mixing for 1 min, centrifugation at 13000 rpm for 10 min, 201 was subjected to LC/MS/MS analysis.

2.8, standard curve preparation

Rat blank plasma 501 was taken and added to the standard series solution to make the plasma concentration of 1.0, 5.0, 25.0, 50.0, 100.0, 250.0, 500.0 ng/ml, and the internal standard solution 201 was added, according to the "pretreatment of plasma samples". Take action. Taking the plasma concentration as the abscissa, the ratio of the peak area of the sample to the internal standard is the ordinate, and the linear regression is performed by the weighted least squares method (w=1/x ² ) to obtain the typical standard curve equation.

2.9, calculation of pharmacokinetic parameters

The pharmacokinetic behavior of the test compound was fitted to the atrioventricular model, and the main pharmacokinetic parameters were calculated, wherein C _max and t _{max were} measured.

3, pharmacokinetic parameters results

The test results showed that each of the compounds was well absorbed after the rats were intragastrically administered with the above compounds of the present invention.

Claims (12)

A compound of the formula (I) or a pharmaceutically acceptable salt thereof: Wherein: A is selected from a carbon atom or an oxygen atom; R, R ₂ and R ₄ are a hydrogen atom; and R _{1 is} selected from a phenyl group, a furyl group, a pyrrolyl group, a thienyl group or a thiazolyl group, wherein each group may be further one or Substituted with a plurality of substituents of an alkyl group having 1 to 4 carbon atoms, a halogen, a hydroxyl group, a tetrazolyl group, an imidazole, a dihydroimidazole, a carboxylic acid or a carboxylate; R _{3 is} selected from a hydrogen atom and contains 1 to 4 An alkyl group or a halogen of one carbon atom; R ₅ , R ₆ and R ₇ are each independently selected from a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxylic acid or a carboxylate; R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently selected from a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; and n is 0, 1 or 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: A compound of the formula (IA) which is an intermediate for the synthesis of a compound of the formula (I) in claim 1 of the patent application: Wherein: A is selected from a carbon atom or an oxygen atom; and R ₅ , R ₆ and R ₇ are each independently selected from a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, Halogen, hydroxy, amino, nitro, cyano, carboxylic acid or carboxylic acid ester; R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently selected from a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; n is 0 or 1. A compound as claimed in claim 3, wherein the compound is selected from the group consisting of: A method of preparing a compound of the general formula (IA) of claim 3, the method comprising: The amino-substituted benzopolycyclic ring is diazotized with sodium nitrite in an acidic solution, and then reduced by stannous chloride to obtain hydrazine, and hydrazine is condensed with a carbonyl compound in a solvent to obtain a general formula (IA). a compound wherein: A, n and R ₅ to R ₁₁ are as defined in Patent Application No. 1. A method of preparing a compound of the general formula (I) of claim 1 of the patent, the method comprising: The substituted aniline compound is subjected to a diazotization reaction with sodium nitrite in an acidic solution, and a coupling reaction with a compound of the formula (IA) in an alkaline solution is carried out to obtain a compound of the formula (I). Wherein: A, n and R ₅ to R ₁₁ are as defined in Patent Application No. 1. A compound or a salt thereof according to any one of claims 1 to 4 The use thereof is for the preparation of a thrombopoietin (TPO) receptor agonist. Use of a compound of any one of claims 1 to 4, or a salt thereof, for the manufacture of a medicament for treating thrombocytopenia. The use of claim 8 wherein the drug is further combined with a drug selected from the group consisting of: colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor agonist or antagonist, A soluble receptor, receptor agonist or antagonist antibody or a peptide or small molecule substance having one or more of the same mechanisms of action as the drug. A pharmaceutical composition comprising an effective amount of the compound of any one of claims 1 to 4, and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 10, wherein the composition further comprises a therapeutically effective amount of a drug selected from the group consisting of: colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor Agonist. A use of a pharmaceutical composition according to claim 10 for the preparation of a medicament for treating thrombocytopenia.