KR20200041852A - Mollugin derivatives, and pharmaceutical composition for preventing or treating inflammatory bowel disease comprising the same - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treating inflammatory bowel diseases, comprising mollugin or a mollugin derivative applicable as a therapeutic agent for inflammatory bowel diseases, as an effective component. More specifically, the present invention relates to a mollugin derivative compound represented by chemical formula I. In the chemical formula I: X is a C_1-C_3 alkyl group-substituted or unsubstituted amine group, or oxygen; R_1 is a hydrogen group, a fluorine group-substituted or unsubstituted C_1-C_3 alkyl group, or a fluorine group; R_2 is a hydrogen group, a morpholine-substituted or unsubstituted C_1-C_3 alkyl group, or a N-(C_1-C_3 alkyl)-substituted or unsubstituted piperidine group; R_3 is a hydrogen group or a vinyl group; and R_4 is a hydrogen group (only when X is an amine group), or a C_1-C_3 alkyl group, wherein when R_3 is a vinyl group and R_4 is an alkyl group at the same time, R_3 binds to an adjacent R_4 to form a 6-membered unsaturated heterocycle.

Description

Molugin derivative compounds, and pharmaceutical compositions for the prevention or treatment of inflammatory bowel diseases comprising the same {MOLLUGIN DERIVATIVES, AND PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING INFLAMMATORY BOWEL DISEASE COMPRISING THE SAME}

The present invention relates to a pharmaceutical composition for the treatment of inflammatory bowel disease, which contains a molargin or a molulin derivative that can be usefully used as a therapeutic agent for inflammatory bowel disease.

Inflammatory bowel diseases (IBD), represented by ulcerative colitis (UC) and Crohn's disease (CD), are symptoms of necrosis of the intestinal mucosa, ulceration, and infiltration of inflammatory cells at the site of inflammation. It is a refractory disease that causes complications such as perforation, obstruction, bleeding, and colon cancer while chronically persisting.

In the United States, the number of IBD patients is estimated at about 1 million, and 30,000 new outbreaks are reported each year, and due to the nature of IBD disease that develops at a young age of 20 and repeats exacerbation and relief, effective, safe and inexpensive oral The demand for the development of solvent formulations is very high.

 Current inflammatory bowel treatments on the market include low molecular weight synthetic compounds aminosalicylate (5-ASA), steroid-based corticosteroids, immunosuppressive agents azathioprine, and antibody drug inflix Shimab (infliximab) and the like are used.

Among them, the TNF-a antibody represented by infliximab has been used as an agent for treating rheumatoid arthritis, an autoimmune disease, as an agent for treating enterocolitis, but is very expensive and disadvantageous as an injection. There is a discomfort in use, and there is a problem in that people with weak immunity can cause tuberculosis and pulmonary sepsis.

In addition, 5-ASA is a representative low-molecular compound drug, and is the most commonly used drug for the initial treatment and maintenance of ulcerative colitis, and is known to be effective in preventing recurrence. To do so, it is necessary to administer an excessive amount of drugs and various side effects such as nausea have been reported. That is true. In addition, sulfasalazine, a 5-ASA prodrug, is prone to side effects or adverse effects such as fullness, headache, rash, liver disease, leukopenia, agranulocytosis, and male infertility. In addition, it is unclear whether sulfasalazine has a sufficient effect of suppressing recurrence in patients with incisions of the intestine or patients with remission.

Immunosuppressive agents of steroids are adrenal cortical steroids, which are recognized for their short-term effects, but cannot improve their long-term prognosis, induced infectious diseases, secondary adrenal cortical insufficiency, peptic ulcers, diabetes, mental disorders, steroid kidney disease, etc. In terms of the same side effects, there are limits that should only be used in acute cases.

Accordingly, studies on components in natural extracts with less side effects or derivative compounds modified with these components are actively conducted, and mogulin is a representative component of these components.

Molugin and 3,4-dihydromolugin are separated from rubiaccordifolia, a medicinal plant used in China and India, and dried roots and rhizomes have been used medicinally for diseases such as arthritis and menstrual impurities.

Synthetic methods, such as electron cyclization reactions, have been reported in several papers in connection with the synthesis of this molugin and 3,4-dihydromolugin, and various molugin derivatives have been published in various documents.

For example, Korean Patent Publication No. 10-2017-0122970 A (Patent Document 1) improves solubility by substituting an ester group containing an amine capable of chlorinating the methyl ester of molugine derived from natural products having poor solubility in water. It has been disclosed in the molugin derivatives (therefore, all of the contents of Patent Document 1 are incorporated and cited as the prior art in this specification).

However, the exact active site and pharmacological mechanism for these various molugin derivatives have not yet been clarified, and development has been requested for various molugin derivatives having physiological activity.

KR 10-2017-0122970 A (2017.11.07.)

The present invention is to provide a variety of morugin derivative compounds useful for inflammatory bowel disease, which is not known in the art, and methods for synthesizing the compounds.

Particularly, in the present invention, a synthetic method of attaching various substituents such as F-, CF _3- , Me- to the aromatic ring of molugin was developed to obtain derivatives of various structures, and the activity was measured in an inflammatory bowel disease model using them. Improved drugs were obtained than 5-ASA, a therapeutic agent.

The present invention was made to solve the problems of the prior art,

It provides a mollugin derivative compound represented by the following formula (I).

[Formula Ⅰ]

X is a C ₁ -C ₃ alkyl group substituted or unsubstituted amine group, or oxygen;

R ₁ is a hydrogen group, a fluorine group substituted or unsubstituted C ₁ -C ₃ alkyl group, or fluorine group;

R ₂ is a hydrogen group, a morpholine substituted or unsubstituted C ₁ -C ₃ alkyl group, or an N- (C ₁ -C ₃ alkyl) substituted or unsubstituted piperidine group;

R ₃ is a hydrogen group or a vinyl group;

R ₄ is a hydrogen group, provided that X is an amine group, or a C ₁ -C ₃ alkyl group;

If R ₃ is a vinyl group and at the same time R ₄ is an alkyl group, it combines with adjacent R ₄ to form a 6-membered unsaturated hetero ring.

In addition, it provides a method for preparing a compound of a molugin derivative comprising the following scheme IV step.

[Scheme Ⅳ]

In addition, it provides a method for preparing an intermediate compound of a molugin derivative, comprising the following scheme V.

[Scheme Ⅴ]

In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of inflammatory bowel disease (inflammatory bowel disease) comprising the molulin derivative compound of the present invention as an active ingredient.

The molugin derivative compound of the present invention has a remarkable inhibitory activity on TNF-α, IL-6, and thus can be usefully used as a pharmaceutical composition for the prevention or treatment of inflammatory bowel disease.

1 is a graph showing the antioxidant activity of the present mollugin derivative compound.
Figure 2 shows the JAK-STAT gene expression and protein expression pattern according to IL-6 inhibition of the present invention molugin derivative compounds.
3, the NF-kb activity according to the TNF-α, and IL-6 inhibition of the present invention molugin derivative compounds.
Figure 4, tofacitinib and TNF-α, and IL-6-derived compounds of the present invention molulin derivative compounds to evaluate the inflammation-related genes (MCP-1, ICAM-1, IL-8) expression inhibitory activity in cells will be.

Hereinafter, the present invention will be described in detail.

One aspect of the present invention is a molulin derivative compound represented by the following formula (I).

[Formula Ⅰ]

X is a C ₁ -C ₃ alkyl group substituted or unsubstituted amine group, or oxygen;

R ₁ is a hydrogen group, a fluorine group substituted or unsubstituted C ₁ -C ₃ alkyl group, or fluorine group;

R ₂ is a hydrogen group, a morpholine substituted or unsubstituted C ₁ -C ₃ alkyl group, or an N- (C ₁ -C ₃ alkyl) substituted or unsubstituted piperidine group;

R ₃ is a hydrogen group or a vinyl group;

R ₄ is a hydrogen group, provided that X is an amine group, or a C ₁ -C ₃ alkyl group;

If R ₃ is a vinyl group and at the same time R ₄ is an alkyl group, it combines with adjacent R ₄ to form a 6-membered unsaturated hetero ring. In particular, R ₃ is a vinyl group, and R ₄ is an isopropyl group, which may be bonded to each other to form a 6-membered unsaturated hetero ring.

In the present invention, by attaching various substituents such as F-, CF _3- , Me- to the aromatic ring of molugine, an improved drug was obtained than 5-ASA, which is a conventional therapeutic agent. As a non-limiting example, And R ₁ is a trifluoromethyl group or a fluorine group.

In addition, the ester moiety may also affect activity, and non-limiting examples thereof include R ₂ being a morpholinoethyl group or an N- (methyl) piperidine group.

Here, 'substitution' means that hydrogen is replaced by one or more of the other, and the number is not particularly limited, and the alkyl group includes both straight and branched chains, unless otherwise specified.

Another aspect of the present invention relates to a method for synthesizing a molugin derivative compound of the present invention, such as attaching various substituents such as F-, CF _3- , Me- to an aromatic ring of molugin.

In order to introduce F- and CF ₃ -Me groups into the aromatic ring of molugine, a synthetic method represented by Scheme I was developed. First, a stilbene structure was introduced using a Pd catalyst, and methyl bromoacetate was added dropwise under indium conditions to synthesize a β-hydroxy ester intermediate. After oxidizing the hydroxy group to ketone using PCC, the cyclization reaction was further performed using Pd (O ₂ CCF ₃ ) ₂ and Cu (OAc) ₂ to introduce 1-hydroxy naphthalene with a substituent introduced at the 7-position. Was able to secure. Additionally, potassium persulfate was used to additionally introduce a hydroxy group at position 4 of the naphthalene ring. Afterwards, a desired final material could be obtained using a previously developed cyclization reaction and a transesterfication reaction using NaOMe.

[Scheme Ⅰ]

In addition, a method for synthesizing Reaction Scheme II was newly established to allow halogens and the like to be introduced into all parts of the aromatic ring. To explain the synthesis process, 2-bromine-dimethylbenzamide was lithiated using BuLi, and then DMF was administered to introduce aldehyde. KCN was added dropwise to prepare 3-oxo-1,3-dihydro isobenzofuran-1-carbonitrile intermediate. After it was secured, acrylate was added dropwise in the presence of a base of NaOtBu so that the Michael addition reaction proceeded to form a new benzene ring. Subsequently, under the conditions of phenylboronic acid, an additional ring was formed by reacting with butenal, and an excessive dose of MeONa and the desired alcohol group was induced to induce transesterfication, so that the desired final material could be obtained with good yield.

[Scheme Ⅱ]

Furthermore, in order to examine whether a substance having an intermediate structure of mollugen and 5-ASA is effective in an IBD bowel disease model, a hydroxylation reaction is performed using a methyl 1-hydroxy-7-alkyl-2-naphthoate intermediate in Scheme I. Instead, a nitridation reaction was performed, and then a material was synthesized by using a Pd / C catalyst under hydrogen gas conditions to obtain a new 1-hydroxy-4-aminonaphthalene material. The new substances also showed superior activity to 5-ASA at a concentration 2000-fold diluted 5-ASA in the inflammatory bowel disease model induced by IL-6.

[Scheme Ⅲ]

In addition, the method for synthesizing the molugin derivative compound of the present invention is characterized by including the following scheme IV.

[Scheme Ⅳ]

Here, R ₁ is a hydrogen group, a fluorine group substituted or unsubstituted C ₁ -C ₃ alkyl group, or a fluorine group, and non-limiting examples include -CF ₃ or a methyl group.

R ₂ is a hydrogen group, a morpholine substituted or unsubstituted C ₁ -C ₃ alkyl group, or an N- (C ₁ -C ₃ alkyl) substituted or unsubstituted piperidine group.

The method for preparing a molugine derivative compound comprising the step of the reaction scheme IV has a better yield than the conventional method for making a basic mollusk skeleton, and it is also advantageous to attach a substituent to the molugine derivative compound. This is because the substituents form a basic skeleton in a state, and there is an ease of not having to attach difficult substituents in a subsequent reaction, as well as an effect of improving the yield by the substituents.

In addition, the method for synthesizing the molugin derivative compound of the present invention is characterized by including the following scheme V.

[Scheme Ⅴ]

Here, R ₁ is a hydrogen group, a fluorine group substituted or unsubstituted C ₁ -C ₃ alkyl group, or a fluorine group, and non-limiting examples include -CF ₃ or a methyl group.

The molulin derivative intermediate compound can be used as a starting material of Scheme IV.

Another aspect of the present invention is a pharmaceutical composition for the prevention or treatment of inflammatory bowel disease (inflammatory bowel disease) comprising the above-described mollugin derivative compound of the present invention as an active ingredient.

The inflammatory bowel disease is, but is not particularly limited to, ulcerative colitis (ulcerative colitis), Crohn's disease, intestinal behcet's disease, indeterminate colitis, bacterial enteritis, viral enteritis, What is selected from the group which consists of amoebic enteritis and tuberculous enteritis can be illustrated.

The following is the structural formula and activity of the materials obtained in the present invention.

number name Compound name % inhibition at 10 μM TNF-alpha IL-6 One H1-23 Methyl 4-amino-1-hydroxy-2-naphthoate 48.8 36.2 2 H1-34 Methyl 6-hydroxy-2,2-dimethyl-1,2-dihydrobenzo [h] quinoline-5-carboxylate 42.1 2.2 3 DN201907 Methyl 4- (dimethylamino) -1-hydroxy-2-naphthoate 4 DN201908 Methyl 4- (methylamino) -1-hydroxy-2-naphthoate 5 DN201909 4-amino-1-hydroxy-2-naphthoic acid 6 DN201910 2- Morpholinoethyl 4- (dimethylamino) -1-hydroxy-2-naphthoate 9 DN202207 Methyl 4-amino-1-hydroxy-7-methyl-2-naphthoate 14.2 21.2 10 DN202355 Methyl 4-amino-1-hydroxy-7- (trifluoromethyl) -2-naphthoate 32.1 57.3 11 DN202357 Methyl 4-amino-1-hydroxy-7-fluoro-2-naphthoate 13.3 58.0 12 DN202203 Methyl 8-methyl-6-hydroxy-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate 29.8 23.4 13 DN202204 Methyl 6-hydroxy-2,2-dimethyl-8- (trifluoromethyl) -2H-benzo [h] chromene-5-carboxylate 63.2 39.3 14 DN202361 Methyl 8-fluoro-6-hydroxy-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate 36.1 59.4 15 DN202206 Methyl 9-fluoro-6-hydroxy-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate 24.9 28.0 16 DN202506 2-Morpholinoethyl 9-fluoro-6-hydroxy-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate 47.0 75.6 17 DN202507 2-Morpholinoethyl 6-hydroxy-2,2-dimethyl-8- (trifluoromethyl) -2H-benzo [h] chromene-5-carboxylate 46.0 50.3 18 DN202508 2-Morpholinoethyl 8-methyl-6-hydroxy-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate 24.9 54.3 19 DN202509 1-Methylpiperidin-4-yl 9-fluoro-6-hydroxy-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate 27.5 78.6 20 DN202604 2-Morpholinoethyl 8-fluoro-6-hydroxy-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate 36.6 61.1

The following is a method for synthesizing one type of materials of the present invention. Synthesis methods of various material types included in the claims of the present invention can be classified into several types according to types, and general synthesis according to types of distinct forms is described. From this general form of synthesis, a person skilled in the art will be able to understand the synthesis method of a specific compound, and thus the description of the synthesis method for individual compounds will be omitted.

Scheme  One. Molugin  Synthesis of Derivatives 9a-c

Reagents and conditions : (a) Pd (OAc) ₂ (0.1 eq), Tri (o-tolyl) phosphine (0.2 eq), TEA, 130 ° C., 15 h, yield: 68-75%; (b) zinc (1.5 eq), benzene, 110 ° C., 5 h, yield: 79-82%; (c) Dess-Martin periodinane (1.3 eq), DCM, room temperature, 2h, yield: 86-90%; (d) Pd (TFA) ₂ (0.2 eq), Cu (OAc) ₂ (1.0 eq), DCE, 100 ° C., 10 h, yield: 90-95%; (e) water phase KOH, THF, 95 ° C, 20 h, yield: 95-98% (f) K2S2O8 (1.5 eq) in water, 10% NaOH aqueous solution, 1,4-dioxane, 0 ° C to room temperature, overnight; (g) NaHCO ₃ (3eq), Iodomethane (3eq), DMF, 40 ° C., overnight, yield: 80-82%; (h) PhB (OH) ₂ (2.0 eq), AcOH (5.0 eq), toluene, 130 ° C., 6h, yield: 63-66%; (i) CH ₃ ONa (2.0 eq), toluene, microwave (150 ° C., 1 h), yield: 40-45%.

General procedure A-(4- methylstyryl ) benzaldehyde  Synthesis of derivatives 1a-c

Dissolve various 2-bormobenzaldehyde (ac), 4-methylstyrene (1.5 eq.), Palladium (II) acetate (0.1 eq.), And Tri ( o -tolyl) phosphine (0.2 eq.) In triethylamine (0.8 M), It was added to the pressure tube. The pressure tube was sealed and heated at 130 ° C. for 15 hours. The reactions were cooled in saturated aqueous ammonium chloride, and then the organics were extracted twice with dichloromethane. The composite organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The product was obtained by flash chromatography on silica gel using hexane / ethyl acetate (0% to 2% for 60 minutes) to obtain the desired product. Yield 65-75%; [ref: Eur . J. Org . Chem . 2011]

( E ) -5- Fluoro -2- (4- methylstyryl ) benzaldehyde (1a) : following general procedure A, 2-bromo-5-fluorobenzaldehyde (5.00 g, 24.63 mmol), 4-methylstyrene (1.5 eq, 4.87 ml , 36.9 mmol), 1a was synthesized from Palladium (II) acetate (0.1 eq, 0.55 g, 2.46 mmol), and Tri ( o -tolyl) phosphine (0.2 eq, 1.50 g, 4.93 mmol); Yield: 71% (3.85 g); ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.32 (s, 1H), 7.82 (d, J = 16.14 Hz, 1H), 7.65-7.70 (m, 1H), 7.50-7.85 (m, 1H), 7.42- 7.48 (m, 2H), 7.28-7.35 (m, 1H), 7.16-7.22 (m, 2H), 6.95 (d, J = 16.14 Hz, 1H), 2.38 (s, 3H); MS (ESI): m / z = 241.3 [M + H].

( E ) -5-Methyl-2- (4- methylstyryl ) benzaldehyde (1b) : Following general procedure A, 2-bromo-5-methylbenzaldehyde (5.00 g, 25.1 mmol), 4-methylstyrene (1.5 eq, 4.97 ml , 37.70 mmol), 1b was synthesized from Palladium (II) acetate (0.1 eq, 0.56 g, 2.51 mmol), and Tri ( o -tolyl) phosphine (0.2 eq, 1.53 g, 5.01 mmol); Yellow oil; Yield: 73% (4.32 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.31 (s, 1H), 7.94 (d, J = 16.14 Hz, 1H), 7.58-7.65 (m, 2H), 7.42-7.49 (m, 2H), 7.35- 7.41 (m, 1H), 7.18 (m, J = 7.83 Hz, 2H), 6.99 (d, J = 16.14 Hz, 1H), 2.42 (s, 3H), 2.37 (s, 3H); MS (ESI): m / z = 237.3 [M + H].

( E ) -5- Trifluoromethyl -2- (4- methylstyryl ) benzaldehyde (1c) : Following general procedure A, 2-bromo-5- (trifluoromethyl) benzaldehyde (3.82 ml, 19.76 mmol), 4-methylstyrene (1.5 eq , 9.91 ml, 29.6 mmol), 1c was synthesized from Palladium (II) acetate (0.1 eq, 0.44 g, 1.98 mmol), and Tri ( o -tolyl) phosphine (0.2eq, 1.20 g, 3.95 mmol); Yellow oil; Yield: 75% (4.3 g); ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.32 (s, 1H), 7.81 (d, J = 16.14 Hz, 1H), 7.62-7.68 (m, 1H), 7.51-7.55 (m, 1H), 7.42- 7.45 (m, 2H), 7.26-7.31 (m, 1H), 7.13-7.24 (m, 2H), 6.97 (d, J = 16.14 Hz, 1H), 2.38 (s, 3H); MS (ESI): m / z = 291.3 [M + H].

General procedure B-methyl (4- methylstyryl ) phenyl) propanoate  Synthesis of derivatives 2a-c

(4-Methylstyryl) benzaldehyde 1a-c was dissolved in anhydrous benzene. Zinc powder (1.5 eq.) And methyl 2-bromoacetate (2.0 eq.) Were added to the solution to form a reaction mixture, and the reaction mixture was refluxed for 5 hours. The reaction was quenched with saturated aqueous ammonium chloride, and organics were extracted with diclomethane (2 times). The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The complex was purified by flash chromatography on silica gel using hexane / ethyl acetate (5% to 20% for 60 minutes) to obtain the desired product; Yield 79-82%;

Methyl ( E ) -3- hydroxy- 3- (5- fluoro -2- (4- methylstyryl ) phenyl) propionate (2a) : according to general procedure B, (E) -5-fluoro-2- (4-methylstyryl 2a was synthesized from benzaldehyde 1a (4.00 g, 15.61 mmol), zinc (1.5 eq, 1.53 g, 23.41 mmol) and methyl 2-bromoacetate (2.0 eq, 2.96 ml, 31.20 mmol); Yellow oil; Yield: 79% (4.05 g); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50 (dd, J = 8.68, 5.75 Hz, 1H), 7.36-7.47 (m, 2H), 7.30 (dd, J = 10.03, 2.69 Hz, 1H), 7.12 ( d, J = 16.14 Hz, 1H), 6.98 (td, J = 8.38, 2.81 Hz, 1H), 6.78-6.94 (m, 3H), 5.50 (dt, J = 9.23, 3.09 Hz, 1H), 3.83 (s , 3H), 3.73 (s, 3H), 3.37 (d, J = 3.18 Hz, 1H), 2.55-2.77 (m, 2H); MS (ESI): m / z = 331.4 [M + H].

Methyl ( E ) -3- hydroxy- 3- (5-methyl-2- (4- methylstyryl ) phenyl) propanoate (2b) : according to general procedure B, (E) -5-methyl-2- (4-methylstyryl 2b was synthesized from benzaldehyde 1b (4.00 g, 16.93 mmol), zinc (1.5 eq, 1.66 g, 25.41 mmol), and methyl 2-bromoacetate (2.0 eq, 3.20 ml, 33.90 mmol); Yellow oil; Yield: 80%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (d, J = 7.82 Hz, 1H); 7.36-7.43 (m, 3H), 7.32 (d, J = 15.89 Hz, 1H), 7.17 (d, J = 7.82 Hz, 2H), 7.08-7.13 (m, 1H), 6.91 (d, J = 15.89 Hz , 1H), 5.52 (ddd, J = 7.82, 4.89, 3.18 Hz, 1H), 3.72 (s, 3H), 3.21 (d, J = 2.93 Hz, 1H), 2.67-2.74 (m, 2H), 2.36 ( s, 6H); MS (ESI): m / z = 311.4 [M + H].

Methyl ( E ) -3- hydroxy- 3- (5- ( trifluoromethyl ) -2- (4-methylstyryl) phenyl) propanoate (2c) : According to general procedure B, (E) -5-trifluoromethyl-2- (4 2c was synthesized from -methylstyryl) benzaldehyde 1c (4.00 g, 13.78 mmol), zinc (1.5eq, 1.35 g, 20.67 mmol), and methyl 2-bromoacetate (2.0 eq, 2.61 ml, 27.60 mmol); Yellow oil; Yield: 82% (4.12 g); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (s, 1H) 7.66 (d, J = 8.31 Hz, 1H), 7.51-7.59 (m, 1H), 7.42 (m, J = 8.07 Hz, 2H), 7.30 (d, J = 15.89 Hz, 1H), 7.19 (m, J = 7.82 Hz, 2H), 7.02 (d, J = 15.89 Hz, 1H), 5.56 (dt, J = 8.13, 3.88 Hz, 1H), 3.73 (s, 3H), 3.47 (d, J = 3.18 Hz, 1H), 2.66-2.73 (m, 2H), 2.37 (s, 3H); MS (ESI): m / z = 365.4 [M + H].

General procedure C-methyl (4- methylstyryl ) phenyl) oxopropanoate  Synthesis of derivatives 3a-c

Various methyl (4-methylstyryl) phenyl) propanoate 2a-c And Dess-Martin periodinane (1.3equiv) was dissolved in anhydrous chloromethane and stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (2 times). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by silica gel flash chromatography using hexane / ethyl acetate (1% to 5% for 60 minutes). The product was obtained as a pale yellow oil; Yield 86-90%;

Methyl ( E ) -3- (5- Fluoro -2- (4- methylstyryl ) phenyl) -3- oxopropanoate (3a) : according to general procedure C, methyl ( E ) -3-hydroxy-3- (5-fluoro -2- (4-methylstyryl) phenyl) propanoate derivative (2a) (4.00 g, 12.72 mmol) and Dess-Martin periodinane (1.3eq, 7.02g, 16.54 mmol) were synthesized 3a; Yellow oil; Yield: 87% (3.45 g); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61-7.71 (m, 1H), 7.50 (d, J = 16.38 Hz, 1H), 7.40 (t, J = 8.44 Hz, 2H), 7.28-7.36 (m, 1H), 7.09-7.24 (m, 3H), 6.85-6.98 (m, 1H), 3.94 (s, 2H), 3.74-3.80 (m, 3H), 2.36 (s, 3H); MS (ESI): m / z = 313.4.

Methyl ( E ) -3- (5-methyl-2- (4- methylstyryl ) phenyl) -3- oxopropanoate (3b): according to general procedure C, methyl ( E ) -3-hydroxy-3- (5-methyl -2- (4-methylstyryl) phenyl) propanoate 2b (4.00 g, 12.89 mmol) and Dess-Martin pe riodinane (1.3eq, 7.11 g, 16.75 mmol), 3b were synthesized; Yellow oil; Yield: 86% (3.42 g); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50-7.67 (m, 2H), 7.27-7.44 (m, 4H), 7.16 (d, J = 8.07 Hz, 2H), 6.83-7.05 (m, 1H), 3.97 (s, 2H), 3.73-3.80 (m, 3H), 2.40 (s, 3 H), 2.35 (s, 3 H); MS (ESI): m / z = 309.4.

Methyl ( E ) -3- (5- ( trifluoromethyl ) -2- (4- methylstyryl ) phenyl) -3-oxopropanoate (3c) : according to general procedure C, methyl ( E ) -3-hydroxy-3- (5 -fluoro-2- (4-methylstyryl) phenyl) propanoate derivatives 2c (4.00 g, 10.98 mmol) and Dess-Martin periodinane (1.3eq, 6.05 g, 14.27 mmol) were synthesized 3c; Yellow oil; Yield: 90% (3.58 g); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70-7.89 (m, 2H), 7.66 (dd, J = 8.31, 1.96 Hz, 1H), 7.57 (d, J = 16.14 Hz, 1H), 7.35-7.48 ( m, 2H), 7.19 (d, J = 7.82 Hz, 2H), 7.08 (dd, J = 16.14, 13.45 Hz, 1H), 3.99 (s, 2H), 3.74-3.82 (m, 3H), 2.38 (s , 3H); MS (ESI): m / z = 363.3.

General procedure D-methyl hydroxy -2- naphthoate  Derivatives 4a-c:

Various methyl (4-methylstyryl) phenyl) oxopropanoate 3a-c was dissolved in anhydrous chloroethane. Palladium (II) trifluoroacetate (0.2equiv), copper (II) acetate (1.0equiv) and methyl acrylate (3.0equiv) were added to the reaction mixture and stirred at 100 ° C for 10 hours. The reaction was quenched with saturated ammonium chloride and extracted with dichloromethane (2 times). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel using hexane / ethyl acetate (0% to 2% for 60 minutes). The product was obtained as a white solid; Yield 90-95%;

Methyl 7- fluoro -1- hydroxy -2- naphthoate (4a) : methyl ( E ) -3- (5-fluoro-2- (4-methylstyryl) phenyl) -3-oxopropanoate 3a, according to general procedure D (3.4 g, 10.89 mmol), Palladium (II) trifluoroacetate (0.2eq, 0.72 g, 2.18 mmol), copper (II) acetate (1.0eq, 1.98 g, 10.89 mmol), and methyl acrylate (3.0 eq, 2.81 g, 32.70 mmol), 4a was synthesized; White solid, yield: 90%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.91 (s, 1H), 8.01 (dd, J = 10.03, 2.69 Hz, 1H), 7.65-7.83 (m, 2H) 7.37 (td, J = 8.68, 2.69 Hz , 1H), 7.28 (d, J = 8.80 Hz, 1H), 4.01 (s, 3H); MS (ESI): m / z = 221.2.

Methyl 7-methyl-1- hydroxy -2- naphthoate (4b) : methyl ( E ) -3- (5-methyl-2- (4-methylstyryl) phenyl) -3-oxopropanoate, according to general procedure D 3b (3.4 g, 11.03 mmol), Palladium (II) trifluoroacetate (0.2eq, 0.73 g, 2.21 mmol), copper (II) acetate (1.0eq, 2.00 g, 11.03 mmol), and methyl acrylate (3.0eq, 2.85 g ( 2.94 ml), 33.10 mmol), 4b was synthesized; White solid; Yield: 92%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.95 (s, 1H), 8.19 (s, 1H), 7.67 (d, J = 8.31 Hz, 1H), 7.70 (d, J = 8.80 Hz, 1H), 7.44 (dd, J = 8.31, 1.71 Hz, 1H), 7.24 (d, J = 9.05 Hz, 1H), 4.00 (s, 3H), 2.54 (s, 3H); MS (ESI): m / z = 217.3.

Methyl 7- ( trifluoromethyl ) -1- hydroxy -2- naphthoate (4c) : according to general procedure D, methyl ( E ) -3- (5- (trifluoromethyl) -2- (4-methylstyryl) phenyl) -3- oxopropanoate 3c (3.4g, 9.38 mmol), Palladium (II) trifluoroacetate (0.2eq, 0.62 g, 1.87 mmol), copper (II) acetate (1.0eq, 1.70 g, 9.38 mmol) and methyl acrylate (3.0eq, 2.42 g (2.50) ml), 28.20 mmol), 4C was synthesized; White solid, yield: 95%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.07 (s, 1H), 8.72 (s, 1H), 7.82-7.95 (m, 2H), 7.76 (dd, J = 8.56, 1.71 Hz, 1H), 7.33 ( d, J = 8.80 Hz, 1 H), 4.02 (s, 3 H); MS (ESI): m / z = 271.3

General procedure E-1- hydroxy -2- naphthoic  Synthesis of acid derivatives 5a-c:

Various methyl hydroxy-2-naphthoate 4a-c was dissolved in tetrahydrofuran and stirred at 25 ° C for 10 minutes. An aqueous potassium hydroxide solution was added to the reaction mixture and stirred at 90 ° C. for 20 hours. After the reaction was cooled, it was acidified with 6N hydrochloric acid solution and extracted with ethyl acetate (2 times). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel using dichloromethanol / methanol (10% to 30% for 60 minutes). The product was obtained as a yellow solid. Yield 95-98%;

From the general procedure, methyl 7-fluoro-1- hydroxy-2-naphthoate 4a (2.1g, 9.54 mmol) and excess aqueous potassium hydroxide solution according to E,: 7- Fluoro -1- hydroxy -2- naphthoic acid (5a) 5a was synthesized. Yellow solid; Yield: 95%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26-7.35 (m, 1H), 7.40 (td, J = 8.68, 2.69 Hz, 1H), 7.77-7.89 (m, 2H), 7.93 (dd, J = 10.27 , 2.45 Hz, 1H); MS (ESI): m / z = 207.18.

7-Methyl-1- hydroxy -2- naphthoic acid (5b) : according to General Procedure E, from methyl 7-methyl-1-hydroxy-2-naphthoate 4b (2.1 g, 9.71 mmol) and excess aqueous potassium hydroxide solution, 5b was synthesized. Yellow solid; Yield: 97%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20-7.27 (m, 1H), 7.44 (dd, J = 8.38, 1.41 Hz, 1H), 7.70 (d, J = 8.44 Hz, 1H), 7.75 (d, J = 8.80 Hz, 1H), 8.13 (s, 1 H); MS (ESI): m / z = 203.21.

7- (Trifluoromethyl) -1- hydroxy -2- naphthoic acid (5c): according to the general procedure E, methyl 7- (trifluoromethyl) -1 -hydroxy-2-naphthoate 4c (2.1g, 7.77 mmol) and excess hydroxide From the aqueous potassium solution, 5c was synthesized. Yellow solid; Yield: 98%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.24-7.33 (m, 1 H), 7.38 (td, J = 8.68, 2.69 Hz, 1H), 7.75-7.87 (m, 2H), 7.91 (dd, J = 10.27, 2.45 Hz, 1H); MS (ESI): m / z = 257.18.

General procedure F-methyl 1,4- dihydroxy -2- naphthoate  Synthesis of derivatives 6a-c:

Various 1-hydroxy-2-naphthoic acids 5a-c were dissolved in 10% sodium hydroxide solution and 1,4dioxane mixed solution. This was stirred at 0 ° C. for 1 hour. A saturated potassium persulfate (1.5 eq) aqueous solution was slowly added dropwise to the reaction mixture for 4-5 hours. The reaction mixture was stirred continuously at 20 ° C overnight.

Acidified with 6N hydrochloric acid solution and extracted with ethyl acetate (2 times). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The dried product was dissolved in N , N- dimethyl-formamide, 3.0 equivalent potassium hydrogencarbonate. This was stirred at 40 ° C. for 0.5 hour. 3.0 equivalents of Iodomethane were added to the reaction and stirred overnight at 40 ° C.

The product was purified by flash chromatography on silica gel using dichloromethanol / methanol (10% to 30% for 60 minutes). The product was obtained as a yellow solid. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (2 times). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel using hexane / ethyl acetate (5% to 10% for 60 minutes). The product was obtained as a pale yellow solid. Yield 80-82%.

Methyl 7- fluoro -1,4- dihydroxy -2- naphthoate ( 6a):, it was synthesized from 7-fluoro-1,4-dihydroxy- 2-naphthoic acid 5a, 6a from (6.5 mmol) according to general procedure F. Yellow solid; Yield: 81%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.61 (s, 1H), 8.71 (s, 1H), 8.27 (d, J = 8.80 Hz, 1H), 7.81 (dd, J = 8.93, 1.59 Hz, 1H) , 7.23 (s, 1H), 5.19 (s, 1H), 4.01 (s, 3H); MS (ESI): m / z = 237.2.

Methyl 7-methyl-1,4- dihydroxy -2- naphthoate (6b) : 6b was synthesized from 7-methyl-1,4-dihydroxy-2-naphthoic acid 5b (6.4 mmol) according to General Procedure F. Yellow solid; Yield: 80%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.54 (s, 1H), 8.18 (s, 1H), 8.02 (d, J = 8.56 Hz, 1H), 7.49 (dd, J = 8.44, 1.59 Hz, 1H) , 7.04 (s, 1H), 4.84 (s, 1H), 3.98 (s, 3H), 2.55 (s, 3H); MS (ESI): m / z = 233.2.

Methyl 7- ( trifluoromethyl ) -1,4- dihydroxy- 2-2- naphthoate (6c) : according to general procedure F, 7- (trifluoromethyl) -1,4-dihydroxy-2-naphthoic acid 5c (5.14 mmol), 6a was synthesized. Yellow solid; Yield: 82%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.60 (s, 1H), 8.70 (s, 1H), 8.26 (d, J = 8.56 Hz, 1H), 7.72-7.84 (d, J = 8.56 Hz, 1H) , 7.22 (s, 1H), 5.24 (s, 1H), 4.00 (s, 3H); ; MS (ESI): m / z = 286.2.

General procedure G-methyl 6- hydroxy -2H- benzo [h] chromene -5- carboxylate  Synthesis of derivatives 7a-c:

Dissolve various methyl 1,4-dihydroxy-2- naphthoate derivatives 6a-c, phenylboronic acid (2.0 eq), glacial acetic acid (5.0 eq), and 3-methylbut-2-enal (3.0 eq) in anhydrous toluene and Dean Stark In a device equipped with a trap (Dean-Stark trap), reflux was performed for 6 hours under nitrogen gas. The reaction was cooled, quenched with saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane (2 times). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel using hexane / ethyl acetate (5% to 20% for 60 minutes). The product was obtained as a pale yellow solid. Yield 63-66%;

Methyl 8- fluoro -6- hydroxy- 2,2- dimethyl- 2 H - benzo [ h ] chromene -5-carboxylate (7a) : according to general procedure G, methyl 7-fluoro-1,4-dihydroxy-2- naphthoate 6a (1.19 g, 5.04 mmol), 7a was synthesized from phenylboronic acid (1.23 g, 10.08 mmol), glacial acetic acid (1.51 g, 25.20 mmol), and 3-methylbut-2-enal (1.27 g, 15.11 mmol). Yellow solid; Yield: 63%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.10 (s, 1H), 8.16 (d, J = 8.56 Hz, 1H), 7.39 (td, J = 8.07, 4.65 Hz, 1H), 7.22 (ddd, J = 12.72, 7.70, 1.10 Hz, 1H), 7.05 (d, J = 10.03 Hz, 1H), 5.67 (d, J = 10.03 Hz, 1H), 4.03 (s, 3H), 1.51 (s, 6H); MS (ESI): m / z = 303.29

Methyl 6- hydroxy- 2,2,8- trimethyl - 2H - benzo [ h ] chromene -5- carboxylate (7b) : according to general procedure G, methyl 7-methyl-1,4-dihydroxy-2-naphthoate 6b , (1.19 g, 5.12 mmol), 7b was synthesized from phenylboronic acid (1.29 g, 10.25 mmol), glacial acetic acid (1.25 g, 25.60 mmol), and 3-methylbut-2-enal (1.29 g, 15.37 mmol). Yellow solid; Yield: 65%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.13 (s, 1H), 8.14 (s, 1H), 8.07 (d, J = 8.56 Hz, 1H), 7.39-7.52 (d, J = 8.56 Hz, 1H) , 7.10 (d, J = 10.03 Hz, 1H), 5.65 (d, J = 10.03 Hz, 1H), 4.01 (s, 3H), 2.53 (s, 3H), 1.48 (m, 6H); MS (ESI): m / z = 299.3.

Methyl 6- hydroxy- 2,2- dimethyl -8- ( trifluoromethyl ) -2 H - benzo [ h ] chromene -5-carboxylate (7c) : according to general procedure G, methyl 7- (trifluoromethyl) -1,4- dihydroxy-2-2-naphthoate 6c, (1.19 g, 4.16 mmol), 7c was synthesized from phenylboronic acid (1.01 g, 8.32 mmol), glacial acetic acid (1.25 g, 20.79 mmol), and 3-methylbut-2-enal (1.05 g, 12.48 mmol). Yellow solid; Yield: 66%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.21 (s, 1H), 8.67 (s, 1H), 8.27 (d, J = 8.80 Hz, 1H), 7.75 (dd, J = 8.80, 1.71 Hz, 1H) , 7.13 (d, J = 10.03 Hz, 1H), 5.74 (d, J = 10.03 Hz, 1H), 4.04 (s, 3H), 1.50 (s, 6H); MS (ESI): m / z = 353.3.

General procedure H-2- morpholinoethyl -6- hydroxy -2 H - benzo [ h ] chromene Synthesis of -5-carboxylate derivatives (8a-c):

Various methyl 6-hydroxy-2 H- benzo [ h ] chromene-5-carboxylate (7a-c), sodium methoxide (2.0 eq) and 2-morpholinoethanol (7.0 eq) were dissolved in anhydrous toluene and placed on a microwave cavity. It was added to the microwave vial and stirred at 150 ° C. for 1.5 hours. After cooling, 1.0 equivalent of 6N hydrochloric acid solution was added dropwise to neutralize, and the mixture was concentrated in vacuo. The product was purified by flash chromatography on silica gel using hexane / ethyl acetate (30% to 100% for 20 minutes). The product was obtained as a pale yellow oil. Yield 40-45%;

2- Morpholinoethyl 8- fluoro -6- hydroxy- 2,2- dimethyl- 2 H - benzo [ h ] chromene- 5-carboxylate (8a) : methyl 8-fluoro-6-hydroxy-2, according to general procedure H, 2-dimethyl-2 H -benzo [ h ] chromene-5-carboxylate 7a, (0.90 g, 2.98 mmol), 8a was synthesized from sodium methoxide (2.0eq, 0.32 g, 5.95 mmol) and 2-morpholinoethanol (2.73 g, 20.84 mmol). Yellow oil; Yield: 40%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.46 (s, 1H), 8.15 (d, J = 8.31 Hz, 1H), 7.38 (td, J = 8.01, 4.77 Hz, 1H), 7.15-7.24 (m, 1H), 7.08 (d, J = 10.03 Hz, 1H), 5.66 (d, J = 10.03 Hz, 1H), 4.56 (t, J = 5.50 Hz, 2H), 3.76 (t, J = 4.40 Hz, 4H) , 2.79 (t, J = 5.62 Hz, 2H), 2.59 (s, 4H), 1.50 (s, 6H); MS (ESI): m / z = 402.1.

2- Morpholinoethyl 6- hydroxy -2,2,8- trimethyl -2 H - benzo [ h ] chromene -5-carboxylate (8b) : According to the general procedure H, methyl 6-hydroxy-2,2,8-trimethyl- 2 H -benzo [ h ] chromene-5-carboxylate 7b, (0.90 g, 3.02 mmol), From Sodium methoxide (0.33 g, 6.05 mmol) and 2-morpholinoethanol (2.77 g, 21.12 mmol), 8b Synthesized. Yellow oil; Yield: 41%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (s, 1H), 8.07 (d, J = 8.56 Hz, 1H), 7.48 (dd, J = 8.44, 1.34 Hz, 1H), 6.93 (d, J = 10.03 Hz, 1H), 5.65 (d, J = 10.03 Hz, 1H), 4.81-4.91 (m, 2H), 3.97 (d, J = 4.16 Hz, 4H), 3.68 (s, 2H), 3.47-3.58 ( m, 4H), 2.54 (s, 3H), 1.47 (s, 7H); MS (ESI): m / z = 398.5.

2- Morpholinoethyl 6- hydroxy -2,2- dimethyl -8- ( trifluoromethyl) -2 H -benzo [h] chromene-5-carboxylate (8c): according to general procedure H, methyl 6-hydroxy-2,2- dimethyl-8- (trifluoromethyl) -2 H -benzo [ h ] chromene-5-carboxylate 7c, 8c was synthesized from (0.90 g, 2.55 mmol), s sodium methoxide (0.28 g, 5.11 mmol) and 2-morpholinoethanol (2.35 g, 17.88 mmol). Yellow oil, yield: 45%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.65 (s, 1H), 8.26 (d, J = 8.80 Hz, 1H), 7.73 (dd, J = 8.68, 1.59 Hz, 1H), 7.17 (d, J = 10.03 Hz, 1H), 5.73 (d, J = 10.03 Hz, 1H), 4.58 (t, J = 5.62 Hz, 2H), 3.71-3.84 (m, 4H), 2.80 (t, J = 5.62 Hz, 2H) , 2.53-2.66 (m, 4H), 1.50 (s, 6H); MS (ESI): m / z = 452.4.

Synthesis of 8a and 8b

Reagents and conditions : (a) oxalyl chloride; (b) HN (Et) ₂ ; (c) BuLi, DMF; (d) 18-crown ether, KCN, TMSC; (e) methyl acrylate, LiO t Bu, THF, 8h; (f) PhB (OH) ₂ , AcOH, toluene, 130 ° C., 6h; (g) 2-morpholinoethan-1-ol, CH ₃ ONa, toluene, microwave (150 ° C., 1 h); (h) 1-methylpiperidin-4-ol, CH ₃ ONa, toluene, microwave (150 ° C., 1h);

2- Bromo - N, N -diethyl- fluorobenzamide (10a-b): Benzoic acid (9, 2.19 g, 10 mmol) was suspended in CH ₂ Cl ₂ (20 mL), and SOCl ₂ (5 mL) was added by syringe. After adding DMF (3 drops), the reaction mixture was stirred at room temperature for 5 hours, then dried under reduced pressure and concentrated. The resulting chloride was dissolved in CH ₂ Cl ₂ (30 mL) and cooled in an ice bath. Diethylamine (2.58 ml, 25 mmol) was added dropwise and the resulting colorless suspension was stirred at room temperature for 3 hours. After adding brine (80 ml) and CH ₂ Cl ₂ (50 mL), the organic layer was separated, washed with brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain diethylamide, and purified by flash chromatography to obtain the title compound.

2- Bromo - N, N -diethyl- 4- fluorobenzamide (10a): Yield: 94%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32 (dd, J = 8.3, 2.5 Hz, 1H), 7.26-7.22 (m, 1H), 7.08 (td, J = 8.3, 2.4 Hz, 1H), 3.82 ( dd, J = 13.7, 7.0 Hz, 1H), 3.33 (dd, J = 13.7, 6.9 Hz, 1H), 3.14 (dq, J = 9.9, 7.2 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H ), 1.07 (t, J = 7.1 Hz, 3H); MS (ESI) [M + H] ⁺ = 274.

2- Bromo - N, N -diethyl- 5- fluorobenzamide (10b): Yield: 97%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.53 (m, 1H), 7.00-6.95 (m, 2H), 3.82 (q, J = 6.8 Hz, 1H), 3.33 (q, J = 7.2 Hz, 1H) , 3.20-3.12 (m, 2H), 1.27 (t, J = 6.8 Hz, 3H), 1.09 (t, J = 7.2 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 167.0 (d, J = 1.0 Hz), 161.7 (d, J = 247 Hz), 140.3 (d, J = 7.0 Hz), 134.3 (d, J = 8.0 Hz) , 117.2 (d, J = 22 Hz), 114.7 (d, J = 24 Hz), 113.5 (d, J = 3.0 Hz), 42.7, 39.0, 13.8, 13.6; MS (ESI) [M + H] ⁺ = 274.

N, N -Diethyl-5- fluoro - formylbenzamide (11a-b): To a solution of amide (2.5 g, 9.1 mmol) in dry THF (30 mL) at -78 ° C, BuLi (11.85 mL, 1.6 M, 11.83 mmol) Dropwise. The resulting pale yellow solution was stirred at the same temperature for 15 minutes. DMF (2.5eq) was added dropwise, and the reaction mixture was stirred for 30 minutes, before slowly warming at room temperature for 2 hours or more.

The reaction mixture was quenched with saturated NH ₄ Cl (50 mL) solution, and extracted with CH ₂ Cl ₂ (3 × 35 mL). The combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a yellow crude oil. The crude oil was purified by flash chromatography to obtain the target compound.

N, N -Diethyl-4- fluoro -2- formylbenzamide (11a) : yield = 74%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.02 (s, 1H), 7.68-7.60 (m, 1H), 7.43-7.30 (m, 2H), 3.62 (q, J = 7.1 Hz, 2H), 3.14 ( q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H); MS (ESI) [M + H] ⁺ = 224.

N, N -Diethyl-5- fluoro -2- formylbenzamide (11b) : Yield = 42%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.37 (s, 1H), 7.62 (dd, J = 5.2, 3.2 Hz, 1H), 7.20 (dd, J = 8.8, 5.6 Hz, 2H), 7.10 (d, J = 7.6 Hz, 1H), 3.60 (q, J = 7.2 Hz, 2H), 3.08 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.2 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 186.6 (d, J = 8.0 Hz), 168.2 (d, J = 3 Hz), 164.7 (d, J = 259 Hz), 139.6, 136.1 (d, J = 10 Hz), 122.9 (d, J = 4.0 Hz), 120.9 (d, J = 8.0 Hz), 116.7 (d, J = 21 Hz), 42.6, 38.9, 13.6, 12.2; MS (ESI) [M + H] ⁺ = 224.

Fluoro- 3- oxo -1,3- dihydroisobenzofuran -1- carbonitrile (12a-b): 18-crown-6 in a solution of formylarylamide (0.85 g, 4.80 mmol) in 0-5 ° C CH ₂ Cl ₂ (20 mL) 127 mg, 0.48 mmol) and KCN (31 mg, 0.48 mmol) were added. After 10 minutes, TMSCN (667 mg, 6.7 mmol) was added dropwise and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure and AcOH (5 mL) was added to the residue.

After stirring at room temperature for 12 hours, the reaction mixture was poured into saturated NaHCO ₃ (100 mL) solution with slow stirring. After 30 minutes (no more gas generation), the organics were extracted with ethyl acetate (50 ml), washed with brine, dried with MgSO ₄ , filtered, and dried under reduced pressure. The crude product was purified by flash chromatography to obtain a white solid.

6- Fluoro- 3- oxo -1,3- dihydroisobenzofuran -1- carbonitrile (12a) : yield = 75%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (m, 1H), 7.45-7.40 (m, 2H), 6.08 (s, 1H); MS (ESI) [M + H] ⁺ = 178.

5- Fluoro- 3- oxo -1,3- dihydroisobenzofuran -1- carbonitrile (12b) : yield = 42%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83 (d, J = 7.7 Hz, 1H), 7.76 (m, 1H), 7.5 (m, 1H), 6.17 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.2 (d, J = 2.0 Hz), 156.8 (d, J = 255 Hz), 134.2 (d, J = 6.0 Hz), 127.8 (d, J = 17 Hz) , 127.3 (d, J = 3.0 Hz), 122.6 (d, J = 4.0 Hz), 122.4 (d, J = 18 Hz), 112.5, 63.1; MS (ESI) [M + H] ⁺ = 178.

* Methyl fluoro -1,4- dihydroxy -2- naphthoate (13a-b) . Under inert gas, LiOtBu (6 ml. 1M in THF, 6.0 mmol) was added as a stirred solution of phthalide (0.35 g, 2.0 mmol) in dry THF (10 mL) at -60 ° C. To the obtained solution, a solution of methyl acrylate (0.362 mL, 4.0 mmol) in dry THF (10 mL) was added, followed by stirring at the same temperature for 30 minutes. The reaction mixture was further stirred at -60 ° C for 30 minutes followed by stirring at room temperature for 8 hours. The reaction was quenched with saturated ammonium chloride solution (20 mL), and THF was evaporated under reduced pressure. And the residue was extracted with ethyl acetate (2 x 20 mL). The complex extract was washed with brine, dried (Na ₂ SO ₄ ), filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain a pure compound.

Methyl 6- fluoro -1,4- dihydroxy -2- naphthoate (13a) : yield = 56%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.59 (s, 1H), 8.40 (dd, J = 9.2, 5.7 Hz, 1H), 7.31 (dd, J = 10.2, 2.6 Hz, 1H), 7.31 (td, J = 8.7, 2.6 Hz, 1H), 7.13 (s, 1H), 4.97 (s, 1H), 3.98 (s, 3H); MS (ESI) [M + H] ⁺ = 237.1.

Methyl 7- fluoro- 1,4- dihydroxy -2- naphthoate (13b) : Yield = 95%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.80 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 4.4 Hz, 2H), 7.40 (m, 1H), 7.14 (s, 1H), 3.96 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 170.5, 158.8 (d, J = 255 Hz), 152.0 (d, J = 4.0 Hz), 145.3 (d, J = 3.0 Hz), 127.9 (d, J = 4.0 Hz), 127.3 (d, J = 9.0 Hz), 120.4, 119.9 (d, J = 5.0 Hz), 119.0, 115.0 (d, J = 21 Hz), 106.4 (d, J = 9 Hz), 53.2; MS (ESI) [M + H] ⁺ = 237.

Methyl fluoro -6- hydroxy- 2,2- dimethyl- 2 H - benzo [ h ] chromene -5-carboxylate (14a-b) . Glacial acetic acid in a mixture of phenylboronic acid (0.207 g, 1.7 mmol), methyl-naphthoate ( 13a-b , 0.4g, 1.7 mmol), and 3-methyl-2-butenal (1.63 ml, 17 mmol) in toluene (30 mL) (3 mL) was added and refluxed for 14 hours in a device equipped with a Dean Stark trap. After cooling to room temperature, the reaction mixture was quenched by adding saturated sodium bicarbonate (30 mL) and the organics were extracted with ethyl acetate (30 mL × 3). The combined organic extract was washed with water, dried over MgSO ₄ , filtered, and evaporated in vacuo. The desired compound was obtained by flash chromatography on silica gel.

Methyl 9- fluoro -6- hydroxy- 2,2- dimethyl- 2 H - benzo [ h ] chromene -5-carboxylate (14a) : Yield = 71%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.23 (s, 1H), 8.37 (dd, J = 9.05, 5.62 Hz, 1H), 7.75 (dd, J = 10.51, 2.45 Hz, 1H), 7.18-7.32 ( m, 1H), 7.11 (d, J = 10.03 Hz, 1H), 5.70 (d, J = 10.03 Hz, 1H), 4.02 (s, 3H), 1.48 (s, 6H); MS (ESI) [M + H] ⁺ = 303.

Methyl 8- fluoro -6- hydroxy- 2,2- dimethyl- 2 H - benzo [ h ] chromene -5-carboxylate (14b) : yield = 68%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.09 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.36 (m, 1H), 7.20 (m, 1H), 7.02 (d, J = 10 Hz, 1H), 5.64 (d, J = 10 Hz, 1H), 4.00 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.1, 158.8 (d, J = 257 Hz), 155.5 (d, J = 4.0 Hz), 141.3 (d, J = 5.0 Hz), 129.1 (d, J = 1.0 Hz), 127.5 (d, J = 4.0 Hz), 126.2 (d, J = 9.0 Hz), 122.0, 120.0 (d, J = 5.0 Hz), 119.1 (d, J = 10 Hz), 115.3 (d, J = 22 Hz), 114.1 (d, J = 2.0 Hz), 103.2, 74.5, 52.5, 26.6; MS (ESI) [M + H] ⁺ = 303.

Aminoalkyl fluoro -6- hydroxy -2,2- dimethyl -2 H - benzo [ h ] chromene -5-carboxylate (8a-c): fluorinated mollugin ( 14a-b , 302 mg, 1.0 mmol), aminoalkyl alcohol (7.0 mmol), NaOMe (27 mg, 0.5 mmmol), and toluene (5 ml) in a microwave vial. After sealing, it was placed in a microwave cavity and stirred at 150 ° C. for 75 minutes. After cooling to room temperature and neutralizing by adding 1 equivalent of HCl, the mixture was rotary evaporated to dryness. Silica gel flash chromatography using hexane / ethyl acetate (30% to 100% 20 min) gave the title product.

2- Morpholinoethyl 9- fluoro -6- hydroxy- 2,2- dimethyl- 2 H - benzo [ h ] chromene- 5-carboxylate (8a) : Yield = 55%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (dd, J = 9.05, 5.62 Hz, 1H), 7.75 (dd, J = 10.27, 2.45 Hz, 1H), 7.22-7.32 (m, 2H), 6.95 ( d, J = 9.78 Hz, 1H), 5.71 (d, J = 10.03 Hz, 1H), 4.81-4.93 (m, 2H), 3.98 (d, J = 4.40 Hz, 4H), 3.33-3.57 (m, 2H) ), 2.6 (d, J = 4.40 Hz, 4H), 1.48 (s, 6H); MS (ESI) [M + H] ⁺ = 402.

2- Morpholinoethyl 8- fluoro -6- hydroxy- 2,2- dimethyl- 2 H - benzo [ h ] chromene- 5-carboxylate (8b) : yield = 59%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.46 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.38 (m, 1H), 7.20 (m, 1H), 7.08 (d, J = 10 Hz, 1H), 5.66 (d, J = 10 Hz, 1H), 4.56 (t, J = 5.6 Hz, 2H), 3.76 (t, J = 4.4 Hz, 4H), 2.79 (t, J = 5.6 Hz , 2H), 2.59 (m, 4H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.8, 158.9 (d, J = 257 Hz), 153.1 (d, J = 4.0 Hz), 141.3 (d, J = 5.0 Hz), 129.28, 127.6 (d, J = 4.0 Hz), 126.1 (d, J = 8.0 Hz), 121.7, 119.9 (d, J = 5.0 Hz), 118.8 (d, J = 10 Hz), 114.8 (d, J = 21 Hz), 114.3, 104.9 , 74.8, 66.8, 61.6, 56.5, 53.5, 26.7; MS (ESI) [M + H] ⁺ = 402.

1- Methylpiperidin -4- yl 9- fluoro -6- hydroxy- 2,2- dimethyl- 2 H- benzo [ h ] chromene-5-carboxylate (8c) : ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 ( dd, J = 9.29, 5.62 Hz, 1H), 7.67-7.82 (m, 1H), 7.26 (m, 1 H), 6.97 (d, J = 10.03 Hz, 1H), 5.64-5.78 (m, 1H), 5.54 (s, 1H), 2.83 (s, 3H), 2.46 (d, J = 14.43 Hz, 1H), 2.39 (s, 1H), 2.27 (d, J = 16.38 Hz, 2H), 1.91 (m, 4H ), 1.52 (s, 6H); MS (ESI) [M + H] ⁺ = 386.

Synthesis of 17a-d

Scheme 3. Reagents and conditions: (a) acetic acid, 70% nitric acid (1: 1 v / v), acentonitrile, 0 ° C to room temp., 2 h, yield: 56-60%; (b) 10% Pd / C, H ₂ gas ethanol and ethyl acetate (1: 5 v / v), 2 h, yield: 79-85%

General procedure I-methyl 1- hydroxy -4-nitro-2- naphthoate  Synthesis of (16a-d)

Various methyl hydroxy-2-naphthoate 15a-c was dissolved in acetonitrile and stirred at 0 ° C for 10 minutes. Excess acetic acid and nitric acid (1: 1 volume mixing) were added to the reaction mixture and stirred for 2 hours. The reaction mixture was quenched with saturated sodium hydrogen carbonate and extracted with dichlrormethane (2 times). The composite organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by haxanes / ethyl acetate silica gel flash chromatography (10% to 50% 60 minutes). The product was obtained as a yellow solid. Yield 56-60%;

Methyl 1- hydroxy- 4-nitro-2- naphthoate (16a) : commercially available.

Methyl 1- hydroxy- 7- fluoro- 4-nitro-2- naphthoate (16b) : General procedure I follow, 16b was synthesized from methyl 7-fluoro-1-hydroxy-2-naphthoate 15b (0.2 g, 0.908 mmol) and excess acetic acid and nitric acid (1: 1 volume mixing). Yellow solid; Yield: 56%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.59 (s, 1H), 8.69-8.90 (m, 2H), 8.14 (dd, J = 9.41, 2.81 Hz, 1H), 7.61 (ddd, J = 9.54, 7.83 , 2.69 Hz, 1H), 4.08 (s, 3H); MS (ESI): m / z = 262.3.

* Methyl 1- hydroxy- 7-methyl-4-nitro-2- naphthoate (16c) : General procedure I Accordingly, 16c was synthesized from methyl 7-methyl-1-hydroxy-2-naphthoate 15c (0.2 g, 0.925 mmol) and excess acetic acid and nitric acid (1: 1 volume mixing). Yellow solid; Yield: 60%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.58 (s, 1H), 8.72-8.84 (m, 1H), 8.66 (d, J = 8.80 Hz, 1H), 8.31 (s, 1H), 7.69 (d, J = 7.58 Hz, 1H), 4.06 (s, 3H), 2.58 (s, 3H); MS (ESI): m / z = 266.2.

Methyl 1- hydroxy- 4-nitro-7- ( trifluoromethyl ) -2- naphthoate (16d) : General procedure I Accordingly, 16d was synthesized from methyl 7- (trifluoromethyl) -1-hydroxy-2-naphthoate 15d (0.2g, 0.925 mmol) and excess acetic acid and nitric acid (1: 1 volume mixing). Yellow solid; Yield: 58%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.90-9.06 (m, 2H), 8.86 (s, 1H), 7.99-8.10 (m, 1H), 4.11 (s, 3H); MS (ESI): m / z = 316.3.

General procedure J-methyl  One- hydroxy -4-amino-2- naphthoate  Synthesis of (17a-d)

Various methyl 1-hydroxy-4-nitro-2-naphthoate 16a-d was dissolved in methanol and ethyl acetate, and a reduction reaction was performed in 10% palladium on carbon and hydrogen gas. Palladium on carbon was filtered through celite. The organic layer was concentrated in vacuo. The product was purified by silica gel flash chromatography (10% to 30% 60 minutes) using dichloromethanol / methanol. The product was obtained as a yellow solid. Yield 79-85%

Methyl 4-amino-1- hydroxy -2- naphthoate (17a ): from methyl 1-hydroxy-4-nitro-2-naphthoate 16a (0.1g, 0.401 mmol) according to general procedure J, by general palladium reduction reaction , 17a was synthesized. Yellow solid; Yield: 86%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.45 (s, 1H), 8.43 (dd, J = 8.31, 0.73 Hz, 1H), 7.82 (d, J = 8.31 Hz, 1H), 7.64 (ddd, J = 8.31, 6.85, 1.47 Hz, 1H), 7.50-7.59 (m, 1H), 7.09 (s, 1H), 3.98 (s, 3H); MS (ESI): m / z = 220.2.

Methyl 4-amino-1- hydroxy -7- fluoro -2- naphthoate (17b): according to the general procedure J, methyl 1-hydroxy-7 -fluoro-4-nitro-2-naphthoate 16b From (0.1 g, 0.374 mmol), 17b was synthesized by a general palladium reduction reaction. Yellow solid; Yield: 79%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J = 10.03 Hz, 1H), 7.83 (dd, J = 9.05, 5.14 Hz, 1H), 7.32-7.47 (m, 1H), 7.05 (s, 1H), 3.97 (s, 3H); MS (ESI): m / z = 238.3.

Methyl 4-amino-1- hydroxy- 7-methyl-2- naphthoate (17c) : according to general procedure J, methyl 1-hydroxy-7-methyl-4-nitro-2-naphthoate 16c (0.1 g, 0.380 mmol) From, 17c was synthesized by a general palladium reduction reaction. Yellow solid; Yield: 85%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.44 (s, 1H), 8.22 (s, 1H), 7.73 (d, J = 8.56 Hz, 1H), 7.48 (dd, J = 8.50, 1.65 Hz, 1H) , 7.03 (s, 1H), 3.98 (s, 1H), 2.56 (s, 1H); MS (ESI): m / z = 235.3.

Methyl 4-amino-1- hydroxy- 7- ( trifluoromethyl ) -2- naphthoate (17d) : according to general procedure J, methyl 1-hydroxy-4-nitro-7- (trifluoromethyl) -2-naphthoate 16d (0.1 g , 0.315 mmol), 17d was synthesized by a general palladium reduction reaction. Yellow solid; Yield: 84%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.74 (s, 1H), 7.94 (d, J = 8.80 Hz, 1H), 7.80 (dd, J = 8.80, 1.71 Hz, 1H), 7.22 (s, 1H) , 4.01 (s, 3H); MS (ESI): m / z = 288.2.

Synthesis of 18

Scheme 3. Reagents and conditions: (a) CuCl, 3-chloro-3-methylbut-1-yne, toluene, 120 ° C., 5 h, yield: 37%

Methyl 6- hydroxy -2,2- dimethyl -1,2- dihydrobenzo [ h ] quinoline -5-carboxylate (18) : methyl 4-amino-1-hydroxy-2-naphthoate ( 17a ), 3-chloro-3- Methylbut-1-yne and copper (I) chloride were dissolved in toluene and stirred at 120 ° C for 5 hours. The reaction mixture was quenched with saturated sodium hydrogen carbonate water and extracted with diclomethane (2 times). The composite organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by silica gel flash chromatography (10% to 50% 60 minutes) using haxanes / ethyl acetate. The product was obtained as a yellow solid. Yield 37%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.93 (s, 1H), 8.30-8.48 (m, 1H), 7.75 (d, J = 8.56 Hz, 1H), 7.57 (td, J = 7.70, 1.22 Hz, 1H), 7.43-7.54 (m, 1H), 7.05 (d, J = 9.78 Hz, 1H), 5.54 (d, J = 9.78 Hz, 1H), 3.99 (s, 3H), 1.34 (s, 6H); MS (ESI): m / z = 284.3.

Synthesis of 19-21

Scheme 3. Reagents and conditions: (a) LiOH (3 eq), THF: Water = 1: 1, room temperature, 4h, yield: 4-5%; (b) NaH (1eq), MeI (1.5eq), DMF, room temperature, 1h, yield: 12-18%; (c) p-TsOH (0.1eq), 4-2-hydroxyethylmorpholine (10eq), toluene, microwave (160 ℃, 3h)

4-Amino-1- hydroxy -2- naphthoic acid (19) : lithium hydroxide (0.033 g, 1.381 mmol) and methyl 4-amino-1-hydroxy-2-naphthoate (0.1 g, 0.460 mmol) in THF (2.5 ml) ) And water (2.5 ml) were stirred at room temperature for 4 hours. The reaction was quenched with ice water. The cold aqueous layer was acidified with 1N HCl, extracted with diethyl ether, washed with brine, dried over Na ₂ SO ₄ and silica gel flash chromatography gave the desired product as a white solid (4 mg, 5%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, J = 8 Hz, 2H), 7.81 (t, J = 8 Hz, 1H), 7.73 (t, J = 8 Hz, 1H), 7.35 (s , 1H), 6.37 (s, 1H); MS (ESI) [M + H] ⁺ = 204.

Methyl 1- hydroxy -4- ( methylamino ) -2- naphthoate (20a) and Methyl 4- (dimethylamino) -1-hydroxy-2-naphthoate (20b) : iodomethane (0.043 ml, 0.691 mmol) in DMF (4.60 ml) , methyl 4-amino-1-hydroxy-2-naphthoate (0.1 g, 0.460 mmol), and a mixture of sodium hydride (0.011 g, 0.460 mmol) were stirred at room temperature for 1 hour. The reaction mixture was quenched with NH ₄ Cl and the organic layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo. Silicagel flash chromatography gave the desired products 20a (13 mg, 12%) and 20b (20 mg, 17%). 20a: ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.47 (s, 1H), 8.44 (dd, J = 4, 8 Hz, 1H), 7.80 (d, J = 8 Hz, 1H), 7.62 (dd, J = 4, 8 Hz, 1H), 7.55 (dd, J = 4, 8 Hz, 1H), 6.85 (s, 1H), 4.00 (s, 3H), 3.00 (s, 3H); MS (ESI) [M + H] ⁺ = 232. 20b: ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.73 (s, 1H), 8.43 (d, J = 8 Hz, 1H), 8.21 (d, J = 8 Hz, 1H), 7.64 (t, J = 4 Hz , 1H), 7.54 (t, J = 4 Hz, 1H), 7.36 (s, 1H), 4.00 (s, 3H). 2.83 (s, 6 H); MS (ESI) [M + H] ⁺ = 246

2- Morpholinoethyl 4- ( dimethylamino ) -1- hydroxy -2- naphthoate (21) : 4-2-Hydroxyethylmorpholine (0.248 ml, 2.039 mmol) in toluene (2.039 ml), Methyl 4- (dimethylamino) -1-hydroxy- 2-naphthoate (0.05 g, 0.204 mmol), and p-toluenesulfonic acid monohydrate (3.88 mg, 0.020 mmol) were placed in a microwave vial. After sealing, it was placed on a microwave cavity and stirred at 160 ° C. for 3 hours. After cooling to room temperature, the mixture was evaporated to dryness. Silicagel flash chromatography gave the desired product as a white solid (24 mg, 34%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.52 (d, J = 8 Hz, 1H), 8.22 (d, J = 8 Hz, 1H), 7.84 (t, J = 8 Hz, 1H), 7.78 (s , 1H), 7.70 (t, J = 8 Hz, 1H), 4.87 (t,, J = 8 Hz, 2H), 4.03-4.08 (m, 4H), 3.99 (d,, J = 8 Hz, 2H) , 3.76-3.79 (m. 4H), 3.13 (s, 6H); MS (ESI) [M + H] ⁺ = 345.

Experimental example

Topacitinib Molugin  Derivative DPPH  Evaluation of antioxidant efficacy by radical scavenging activity

1 shows the antioxidant effect of the molugin derivatives. As can be seen in FIG. 1, in free radical scavenging, it was observed that molugin and its derivatives according to the treatment of DPPH were significantly better than tofacitinib used as a JAK inhibitor. That is, it can be confirmed that the antioxidant activity of the molugin and molugin derivatives is concentration-dependent, but the antioxidant effect of tofacitinib is somewhat weak, and 5-ASA shows excellent antioxidant effect at the concentration treated with 20 mM, whereas it has a high concentration. It was observed to be relatively reduced at 200 mM.

Mollugin  According to IL-6 inhibition of derivatives JAK -STAT gene expression and protein expression pattern

IL-6-induced JAK-STAT cell signaling was evaluated for the activity of JAK inhibitors, molugin and molugin derivatives, and the results are shown in FIG. 2.

As can be seen in Figure 2, as a result of observing the expression of STAT3 Down-signaling in JAK-STAT signaling, it was observed that the HT-29 cell line was not significantly affected except the Jak inhibitor tofacitinib.

Mollugin  Derivative TNFα  And IL-6 inhibition NF -kb activity evaluation

Whether TNF-alpha or IL-6 activity was inhibited for the JAK inhibitor, molugin and molugin derivatives was confirmed by a report assay system of NF-kb, and the results were as shown in FIG. 3.

* As can be seen in Figure 3, NF-kb expressed by STAT3 through NF-kb report assay, DN202604 was confirmed to inhibit both TNFα and NF-kb induced by IL-6, anti-inflammatory effect Is predicted.

Tofacitinib  And Molugin  Derivative TNFα  And IL-6 induced cells in inflammation-related genes ( MCP -One, ICAM -1, IL-8) Expression inhibition evaluation

In the cells induced by TNF-alpha, IL-6, the effect of inhibiting the expression of the JAK inhibitors, mogulin and mogulin derivatives of inflammation-related genes (MCP-1, ICAM-1, IL-8) was confirmed, and the results are shown in FIG. 4. It was as shown in.

Inflammation suppression efficacy was evaluated by efficacy through TNF-α (10 ng / ml) and IL-6 (10 ng / ml) induced monocyte-intestinal epithelial cell adhesion test. Was used. It was confirmed that the newly synthesized substances were effective in the degree of suppressing the activity of TNF-α and IL-6 even at a concentration diluted by 2000 times or more compared to the control drug, or more effective than the control drug.

In particular, as can be seen in Figure 4, TNF-α and IL-6 related to the inflammatory response by genes MCP-1, ICAM-1, IL-8 expression is increased, but in the case of DN202604 TNF-α and IL-6 induction Showed the effect of inhibiting both ICAM-1 and IL-8.

In addition to the above experimental examples, substances in which functional groups of F-, CF _3- , and Me- were introduced were confirmed by evaluating in vitro ADME to improve metabolic stability, and most of these substances were also effective CYP inhibition and hERG inhibition. , It was confirmed that it has plasma stability (Table 2).

DN # CYP  inhibition ( %  of control) MS ( %  remain, after 30 min) PS (after 2h) 1A2 2A6 2B6 3C8 2C9 2C19 2D6 2E1 3A4 human rat human rat Molugin 41.2 86.3 93.7 100 93.0 67.5 98.9 100 98.1 32.7 19.0 92.0 16.4 DN202204 45.3 100 96.6 53.5 98.9 86.2 100 100 91.6 100.0 89.6 97.1 10.0 DN202507 66.5 97.5 97 89.8 100 96.7 100 58.4 89.8 84.0 51.6 100 51.1

Claims (7)

A mollugin derivative compound represented by the following formula (I), characterized in that it has an IL-6 cytokine inhibitory effect.
[Formula Ⅰ]

X is oxygen;
R ₁ is a fluorine group substituted or unsubstituted C ₁ -C ₃ alkyl group, or fluorine group;
R ₂ is a morpholine substituted C ₁ -C ₃ alkyl group;
R ₃ is a vinyl group;
R ₄ is an isopropyl group;
R ₃ combines with adjacent R ₄ to form a 6-membered unsaturated hetero ring. The method according to claim 1, R ₁ is a trifluoromethyl group, or a fluorine derivative compound that is a fluorine group. The method according to claim 1, R ₂ is a morpholine derivative compound that is a morpholinoethyl group. Method of producing a molargin derivative compound comprising the following scheme IV step.
[Scheme Ⅳ]

Here, R ₁ is a fluorine group substituted or unsubstituted C ₁ -C ₃ alkyl group, or fluorine group;
R ₂ is a morpholine substituted or unsubstituted C ₁ -C ₃ alkyl group, or an N- (C ₁ -C ₃ alkyl) substituted or unsubstituted piperidine group. Method for preparing a compound of an intermediate of a molugin derivative, comprising the following scheme V.
[Scheme Ⅴ]

Here, R ₁ is a fluorine group substituted or unsubstituted C ₁ -C ₃ alkyl group, or a fluorine group. A pharmaceutical composition for the prevention or treatment of inflammatory bowel disease, comprising the molugin derivative compound of claim 1 as an active ingredient. The method according to claim 6, The inflammatory bowel disease (ulcerative colitis), Crohn's disease (crohn's disease), intestinal behcet's disease (intestinal behcet's disease), indeterminate colitis (indeterminate colitis), bacterial enteritis, viral enteritis, amoebic enteritis And Pharmacological composition for the prevention or treatment of inflammatory bowel disease, characterized in that selected from the group consisting of tuberculous enteritis.

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