KR20110088737A - Novel oxazolidinone derivatives with cyclic amidrazone and pharmaceutical compositions thereof - Google Patents

Abstract

PURPOSE: A novel oxazolidinone derivative having cyclic amidrazone group and a pharmaceutical composition containing the same are provided to ensure strong antibacterial effect against gram positive and negative bacteria. CONSTITUTION: A novel oxazolidinone derivative is denoted by chemical formula 1. In chemical formula, X is chemical bond, -(CH_2)_n- or -(CH_2)_nC(=O)-; n is 0-2 integer; and R is 5-membered or 6-membered hetero cycle. A prodrug, hydrate, solvate, isomer, or pharmaceutically acceptable salt of the derivative is also denoted by chemical formula 1. A pharmaceutical composition for antibiotics contains the derivatives, prodrug, hydrate, solvate, isomer, or pharmaceutically acceptable salt thereof as an active ingredient.

Description

Novel Oxazolidinone derivatives with cyclic amidrazone and Pharmaceutical Compositions etc.

The present invention relates to novel oxazolidinone derivatives represented by the following general formula (1), in particular novel oxazolidinone derivatives comprising cyclic amidrazon groups.

[Formula 1]

The present invention also relates to a pharmaceutical composition for antibiotics containing a novel oxazolidinone derivative represented by Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. .

Since oxazolidinone antibiotic Lineezolide was first reported in 1984 (European Patent Publication No. 127,902), various oxazolidinone derivatives have been reported by several pharmaceutical companies. However, none of the drugs under development is less toxic and more potent than Linezolid (product name: XIVOX). This problem has been receiving attention by Linezolid as the best alternative to vancomycin in the treatment of MRSA. However, if more recently spread of Lineezolide resistant bacteria has been reported, there is a very serious problem that its treatment is almost eliminated. .

For this reason, it is very urgent to develop drugs that are superior to linezolide in terms of efficacy and toxicity, and are effective against linezolide resistant bacteria. The inventors of the Korean Patent No. 10-2008-0093712 filed Sep. 24, 2008 show that oxazolidinone antibiotics having a cyclic amidrazone or cyclic amidoxime group have superior properties to linezolid in terms of efficacy and toxicity. It has been reported that it has many advantages by introducing cyclic amidrazone groups.

In particular, the cyclic amidrazon group may have a weak basicity to form a salt, and in the case of hydrochloride, pKa is about 5, and has an acidity similar to acetic acid. Due to this weak acidic properties, the solubility in water can be greatly increased without degrading the antibacterial ability.

Accordingly, the present inventors have synthesized a novel oxazolidinone derivative to develop an antibiotic having a high solubility in order to facilitate the development of oral and injectables, and has a superior antimicrobial activity than conventional antibiotics, the novel oxa according to the present invention Zolidinone derivatives were confirmed that the antimicrobial effect is excellent and the antibacterial spectrum is significantly improved and completed the present invention.

In particular, cyclic amidrazone compounds such as the compounds of the present invention are new structures that have not been studied. Incorporation of cyclic amidrazon groups into the oxazolidinone antibiotics could greatly improve the absorbency and, with the proper basicity, could form salts, which greatly increased the solubility in water. The increased solubility in water makes it possible to make injections without taking the form of prodrugs and does not show much toxicity.

It is therefore an object of the present invention to provide novel oxazolidinone derivatives, in particular novel oxazolidinone compounds which have increased solubility by introducing cyclic amidrazone groups and methods for their preparation.

Another object of the present invention is to provide a pharmaceutical composition for antibiotics containing a novel oxazolidinone derivative, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The novel oxazolidinone derivatives according to the present invention are in vitro acquired pneumonia, socially acquired pneumonia, complex skin and soft tissue infections, simple skin and soft tissue infections, antibiotic resistant strains, in particular VRE (vancomycin resistant enterococcus fascium) or linezolide resistant It can be used as a therapeutic agent for infections such as sepsis caused by Enterococcus faecalis and combination therapy when gram (-) bacteria are included in pathogens.

The present invention relates to novel oxazolidinone derivatives represented by the following general formula (1), in particular novel oxazolidinone compounds having cyclic amidrazon groups. The present invention also relates to a pharmaceutical composition for antibiotics containing a novel oxazolidinone derivative of Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. .

[Formula 1]

[Wherein,

X is a chemical bond,-(CH ₂ ) _n -or-(CH ₂ ) _n C (= 0)-;

n is an integer from 0 to 2;

R is a 5 or 6 membered hetero ring selected from the structure:

R ₁ to R ₂₅ are each independently hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, -OH, -NR ₃₁ R ₃₂ , -C (= 0) R ₃₃ ,- (CH ₂ ) _m OH, —C═NOH, —CN, —NO ₂ or halogen;

R ₃₁ and R ₃₂ are independently of each other hydrogen, (C ₁ -C ₆ ) alkyl, or —C (═O) H;

R ₃₃ is hydrogen, —OH, —NH ₂ or (C ₁ -C ₆ ) alkyl;

m is an integer from 1 to 6;

Q is -OH, -NHC (= 0) R ₄₁ or -NHC (= 0) OR ₄₁ ;

R ₄₁ is (C ₁ -C ₆ ) alkyl.]

The term 'alkyl' as used herein includes both straight and branched chain structures. For example, (C ₁ -C ₆ ) alkyl includes all possible positions and geometric isomers such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.

Examples of (C ₃ -C ₆ ) cycloalkyl include the possible positions and geometric isomers of all ring forms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclopropylmethyl.

Preferred examples of the oxazolidinone derivative of Chemical Formula 1 according to the present invention are compounds selected from Chemical Formulas 2 to 4.

[Formula 2]

(3)

[Formula 4]

[In Formulas 2 to 4, R and Q are the same as defined in Formula 1 above.]

More preferred examples of the oxazolidinone derivative of Formula 1 according to the present invention are compounds selected from the following Formulas 5 to 10:

[Chemical Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

[R in Formulas 5 to 10 is the same as defined in Formula 1]

The novel oxazolidinone derivatives according to the present invention may be exemplified by the following compounds, but the following compounds do not limit the present invention.

The novel oxazolidinone derivatives according to the invention are made in the form of prodrugs, hydrates, solvates, isomers and pharmaceutically acceptable salts in order to enhance absorption in vivo or to increase solubility by having cyclic amidrazone groups. As such, prodrugs, hydrates, solvates, isomers and pharmaceutically acceptable salts thereof are also within the scope of the present invention.

The novel oxazolidinone derivatives according to the invention can be used in the form of pharmaceutically acceptable salts, the pharmaceutically acceptable salts being for example HCl, HBr, HI, sulfate, phosphate, acetate ), Propionate, lactate, mesylate, maleate, maleate, succinate, tartrate, citrate , Fumarate, 2-hydroxyethyl sulfonate, and the like. Such salts may also be in the form of baggage.

The oxazolidinone derivatives of the present invention may exist in solvated forms, for example hydrated forms and unsolvated forms, and solvates of the oxazolidinone derivative compounds according to the present invention are all solvated forms having pharmaceutical activity. It will include.

The oxazolidinone derivatives of the invention can be administered in the form of prodrugs that are degraded in the human or animal body to provide the compounds of the invention. Prodrugs can be used to alter or improve the physical and / or pharmacokinetic profile of the parent compound and can be formed if the parent compound contains suitable groups or substituents that can be induced to form the prodrug. Examples of prodrugs include in vivo hydrolyzable esters of the compounds according to the invention and pharmaceutically acceptable salts thereof.

Various forms of prodrugs are known in the art, for example:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic press, 1985);

b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); And

e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984)].

See et al.

Examples of prodrugs according to the present invention include the following compounds.

As in the above example, after being absorbed by attaching a phosphonate to an hydroxy group or by attaching an acetyl group, a form of returning to an active form, or adding an amino acid or a carbonate form is possible. These prodrugs are mainly used when the solubility is relatively low or the absorption is low, and the conversion to prodrug increases the solubility and absorption, as well as improves ADME (absorption, distribution, metabolism, excretion) and PK profile.

Compounds of the invention have a chiral center at the C-5 position of the oxazolidinone ring. Preferred diastereomers of the oxazolidinone derivative compounds according to the invention are as shown in [Formula 1] and exhibit a more favorable MAO profile compared to epimers such as Formula 1b.

[Chemical Formula 1b]

When any mixture of epimers on the oxazolidinone chiral center is used, its amount can be adjusted in consideration of the proportion of the diastereoisomers in order to obtain the same effect with pharmacological activity alone as with the enantiomer alone.

In the present invention, since the compound of Formula 1 or a salt thereof may exhibit tautomer phenomenon, although the formula or schemes in the present specification express only one possible tautomeric form, the present invention exhibits antimicrobial activity. It includes, but is not limited to, only one tautomeric form having any tautomeric form having it in the formula or scheme.

Certain compounds of the present invention may also exhibit polymorphisms, and any homogenous compounds having antimicrobial activity are also included in the present invention.

The novel oxazolidinone derivative compounds according to the present invention can be prepared by various known methods depending on the kind of substituents thereof, for example, can be prepared according to the methods illustrated in Schemes 1 and 2. The preparation method shown in Scheme 1 or 2 is only an example and can be easily modified by those skilled in the art according to specific substituents. Thus, the method illustrated in Scheme 1 or 2 is prepared to prepare an oxazolidinone compound according to the present invention. It does not limit the method, and unless otherwise stated, the definition of substituents in the following scheme is the same as defined in the formula (1).

The oxazolidinone derivative compounds of Chemical Formula 1 according to the present invention can be synthesized in different ways according to Q. In the case of Q is OH, a typical synthesis method is shown in Scheme 1 below, and Q is N-acetyl. In the case of is shown in Scheme 2.

As shown in Scheme 1 below, difluoronitrobenzene was reacted with ethanolamine to synthesize Compound I, and the alcohol and amine were protected with TBS (t-butyldimethylsilyl) and boc, respectively (Compound II), The group was reduced to an amine using Pd / C (Compound III), and the compound was synthesized by attaching a cbz group using Cbz-Cl. This compound was reacted with (Li) -glycidyl butyrate and BuLi to synthesize chiral compound V. In compound V, the alcohol group was first protected with benzoyl, and then boc and tbs protecting groups were removed with hydrochloric acid (compound VI), and mesolysis (mesylation) to synthesize compound VII. This compound was reacted with hydrazine and again with trimethylorthoformate to synthesize cyclic amidrazone compound VIII. By removing the formyl group (Compound IX) and introducing the linking portion X and various Rs, the compound of Formula 1 was obtained, and detailed examples of each were described in the Examples.

Scheme 1

In the case of Q in Formula 1, N-acetyl is shown in Scheme 2 below. Compound V synthesized in Scheme 1 was reacted with methanesulfonyl chloride (Ms-Cl), and then reacted with sodium azide (NaN ₃ ) to synthesize compound X. The compound was made of amine under Pd / C under hydrogen gas, and then cbz group was attached using Cbz-Cl to synthesize Compound XII. The compound was treated with hydrochloric acid to remove the protective groups boc and tbs, and then reacted with methanesulfonyl chloride (Ms-Cl) to synthesize Compound XIII. This compound was reacted with hydrazine and with trimethylorthoformate to synthesize cyclic amidrazone compound XIV. From this compound, the protective group cbz was removed, an acetyl group was introduced (Compound XV), a formyl group was removed, and various R groups were introduced to obtain a compound of Formula 1. Each detailed example is described in the Examples.

Scheme 2

Compositions of the present invention are suitable for oral use (e.g. tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), suitable for topical use. Forms (e.g. creams, ointments, gels or aqueous or oily solvents or suspensions), forms suitable for ophthalmic administration, forms suitable for inhalation administration (e.g. micronized powder or liquid aerosol), infusion administration Suitable forms for use (eg, undifferentiated powders) or suitable forms for parenteral administration (eg, as sterile aqueous or oily solvents for intravenous, subcutaneous, sublingual, intramuscular or intramuscular administration, or rectal As a suppository for administration).

In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may contain other clinically useful antibacterial agents (e.g., β-lactams, macrolides, quinolones or aminoglycosides) and / or other anti-infective agents (e.g., antifungal agents One or more known drugs selected from sexual triazoles or amphotericins) (ie, by formulating together) or co-administered with one or more known drugs. These may include carbapenems, for example meropenem or imipenem, to broaden the therapeutic efficacy. The compounds of the present invention may also be formulated or co-administered with bactericidal / permeable-increasing protein (BPI) products or effluent pump inhibitors to enhance activity against gram negative bacteria and bacteria that are resistant to antimicrobial agents. can do.

The compounds of the present invention may also be formulated with or coadministered with vitamins such as vitamin B such as vitamin B2, vitamin B6, vitamin B12 and folic acid. The compounds of the present invention may also be formulated or co-administered with cyclooxygenase (COX) inhibitors, in particular COX-2 inhibitors. The compounds of the invention can also be formulated and coadministered with antimicrobial agents active against Gram-positive bacteria, Gram-negative bacteria.

The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients which are well known in the art. Thus, a composition intended for oral administration may contain, for example, one or more colorants, sweeteners, flavors and / or preservatives. Pharmaceutical compositions to be administered intravenously may advantageously contain (eg, to enhance stability) suitable bactericides, antioxidants or reducing agents, or suitable sequestrants.

Compositions for oral administration may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient in water or oil such as peanut oil, liquid paraffin or olive oil. It may be in the form of a soft gelatin capsule mixed with.

Aqueous suspending agents generally include one or more suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, tragacand gum and acacia gum; Dispersing or wetting agents, for example lecithin or condensation products of alkylene oxides with fatty acids (eg polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadeca Condensation products of ethyleneoxycetanol or partial esters derived from fatty acids and hexitols, for example polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example , Heptadecaethyleneoxycetanol, or a condensation product of ethylene oxide with partial esters derived from fatty acids and hexitol, for example polyoxyethylene sorbitol monooleate, or ethylene oxide derived from fatty acids and hexitol anhydrides Condensation products with partial esters, for example polyethylene sorbbi Together with tan monooleate, it contains the active ingredient in micronized form. Aqueous suspending agents include one or more preservatives (eg, ethyl or propyl p-hydroxybenzoate), antioxidants (eg, ascorbic acid), colorants, flavors, and / or sweetening agents (eg, shoe Cross, saccharin or aspartame).

Oily suspensions can be formulated by suspending the active ingredient in vegetable oils (eg arachis oil, olive oil, sesame oil or coconut oil) or mineral oils (eg liquid paraffin). Oily suspensions may contain thickening agents, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents as mentioned above, and flavoring agents may be added to provide a delicious oral preparation. These compositions can be preserved by adding antioxidants such as ascorbic acid.

Dispersible powders and granules suitable for preparing an aqueous suspending agent by adding water contain the active ingredient together with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified as mentioned above. Additional excipients may also be present, such as sweetening, flavoring and coloring agents.

For further information regarding formulations, reference may be made to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient combined with one or more excipients to produce a single dosage form will of course vary depending upon the host being treated and the particular route of administration. For example, formulations intended for oral administration to humans generally contain 50 mg to 5 g of active compound with a convenient suitable amount of excipient, which may be about 5 to about 98% based on the total weight of the composition. can do. Dosage unit forms will generally contain about 200 mg to about 2 g of active ingredient. For further information regarding the route of administration and dosage regimen, reference may be made to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

Suitable pharmaceutical compositions of the invention are tablets or capsules containing 0.1 mg to 1 g, preferably 100 mg to 1 g of a compound of the invention, in a form suitable for oral administration in unit dosage form. Especially preferred are tablets or capsules containing 50 mg to 800 mg, in particular 100 mg to 500 mg of the compounds of the invention.

In addition, the pharmaceutical composition of the present invention may be in a form suitable for intravenous, subcutaneous or intramuscular injection, for example 0.1% w / v to 50% w / v (1 mg / ml to 500 mg / ml) injection.

Each patient may be administered intravenously, subcutaneously or intramuscularly, for example, from 0.1 mg / kg to 20 mg / kg of a compound of the invention, and the composition is administered once to four times daily. In another embodiment, the compound of the present invention is administered 1 mg / kg to 20 mg / kg per day. Intravenous, subcutaneous and intramuscular doses can be given by bolus injection. Alternatively, intravenous doses can be given by continuous infusion over time. Alternatively, each patient may be administered a daily oral dose, which may be approximately equivalent to a daily parenteral dose, and the composition is administered 1 to 4 times per day.

The oxazolidinone derivatives of the present invention are Gram-positive bacteria and Haemophilus influenza, such as Staphylococcus aureus and Enterococcus faecalis, which are resistant to conventional antibiotics at much lower concentrations than commercially available linezolids. It shows antimicrobial activity against Gram-negative bacteria such as Moraxella catarrhalis, and especially against linezolide resistant enterococcus fascia.

As described above, the novel oxazolidinone derivative of the present invention has a broad antimicrobial spectrum against resistant bacteria including MRSA and VRE, and also shows activity against Gram-negative bacteria such as Haemophilus influenza and is a second-generation oxazolidinone-based antibiotic. It can be usefully used. In addition, the compounds of the present invention contain cyclic amidrazon groups, which can form salts, so that the solubility in water is higher than that of the conventionally known compounds, so it is easy to develop oral or injectables.

Hereinafter, preferred examples and experimental examples are presented to help understand the present invention. However, the following examples and experimental examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.

Preparation Example 1 Preparation of Compound I

3,4-Difluoronitrobenzene (158 g, 0.99 mol) was dissolved in acetonitrile (800 mL), ethanolamine (117 g, 1.9 mol) was added thereto, and the mixture was stirred under reflux for 4 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, triturated with diethylether and filtered to obtain yellow Compound I (199 g, 0.99 mol, 100%).

¹ H NMR (400 MHz, chloroform-d ₁ ) δ 7.97 (d, 1H, J = 8.8 Hz), 7.87 (dd, 1H, J ₁ = 11.6 Hz, J ₂ = 2.4 Hz), 6.65 (t, 1H, J = 8.8 Hz), 5.10-4.87 (bs, 1H), 3.97-3.83 (m, 2H), 3.43-3.37 (m, 2H).

Preparation Example 2 Preparation of Compound II

Compound I (100 g, 0.5 mol), TBS-Cl (t-butyldimethylsilyl chloride, 97g, 0.65 mol) and imidazole (51 g, 0.75 mol) were dissolved in dichloromethane (700 mL) at 0 ° C and then slowly cooled to room temperature. Raised and stirred overnight. The reaction product was concentrated under reduced pressure, and then dissolved in ethyl acetate, washed with 0.5 N HCl, washed sequentially with saturated sodium bicarbonate solution and saturated sodium chloride solution (brine), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to attach a tbs group to alcohol. The compound was obtained quantitatively. After dissolving the compound in THF (500 mL), 1.2 equivalents of Boc ₂ O and 0.1 equivalents of DMAP (4-dimethylaminopyridine) were added thereto, stirred at room temperature for 3 hours, and ammonia water (30 mL) was added thereto. The mixture was stirred for 5 minutes and concentrated under reduced pressure. The concentrated solution was again dissolved in ethyl acetate, washed sequentially with 0.5 N HCl, saturated sodium bicarbonate solution and saturated sodium chloride solution (brine), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Compound II quantitatively.

¹ H NMR (600 MHz, chloroform-d ₁ ) δ 8.06-7.98 (m, 1H), 7.95 (dd, 1H, J ₁ = 10.2 Hz, J ₂ = 2.4 Hz), 7.57 (t, 1H, J = 7.8 Hz), 3.80 (t, 2H, J = 5.4 Hz), 3.73 (t, 2H, J = 4.8 Hz), 1.42 (s, 9H), 0.81 ( s, 9H), 0.01 (s, 6H).

Preparation Example 3 Preparation of Compound III

Compound II (92 g, 0.22 mol) was dissolved in methanol (600 mL) and Pd / C (6 g) was added thereto, and the mixture was stirred for 4 hours under a hydrogen gas balloon. The mixture was filtered through celite, concentrated under reduced pressure, and colorless. Oil compound III (86 g) was obtained quantitatively.

¹ H NMR (400 MHz, chloroform-d ₁ ) δ 6.99 (t, 1H, J = 12.0 Hz), 6.44-6.30 (m, 2H), 3.81-3.63 (m, 4H), 3.63-3.52 (m, 2H ), 1.50 (s, 3H), 1.35 (s, 6H), 0.86 (s, 9H), 0.03 (s, 6H).

Preparation Example 4 Preparation of Compound IV

Compound III (86 g, 0.22 mol) was dissolved in dichloromethane (300 mL), 1N NaOH aqueous solution (300 mL) was added thereto, and slowly added dropwise Cbz-Cl (benzyl chloroformate, 38 mL, 0.27 mol) while stirring. After stirring for 1 hour at room temperature, the organic layer was separated, washed twice with water, dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to yield yellow oil compound IV (116 g) quantitatively.

¹ H NMR (600 MHz, chloroform-d ₁ ) δ 7.44-7.32 (m, 6H), 7.18 (t, 1H, J = 8.1 Hz), 6.96 (d, 1H, J = 8.4 Hz), 6.84-6.66 ( bs, 1H), 5.20 (s, 2H), 3.82-3.63 (m, 2H), 3.63-3.58 (m, 2H), 1.51 (s, 3H), 1.35 (s, 6H), 0.86 (s, 9H) , 0.02 (s, 6H).

Preparation Example 5 Preparation of Compound V

Compound IV (116 g, 0.22 mol) was dissolved in THF (400 mL), then n-butyllithium (2.5M solution in n-Hexane) (90 mL, 0.23 mol) was slowly added dropwise at -78 ° C and 20 Stirred for a minute. After adding (R) -glycidyl butyrate ((R) -Glycidyl butyrate, 31.5 mL, 0.23 mol), the mixture was slowly raised to room temperature, stirred for 3 hours, adjusted to pH 6 with aqueous ammonium chloride solution, and concentrated under reduced pressure. The concentrated solution was dissolved in 80% ethyl acetate / hexane, washed sequentially with water and saturated aqueous sodium chloride (brine), and concentrated under reduced pressure by dehydration using anhydrous sodium sulfate. This concentrate was separated by column chromatography using 40% ethyl acetate / hexane solution to give a colorless oil compound V (45 g, 0.093 mol, 42%).

¹ H NMR (600 MHz, CDCl 3) δ 7.50-7.48 (m, 1H), 7.30-7.28 (m, 1H), 7.17-7.16 (m, 1H), 4.74-4.70 (m, 1H), 4.03-4.02 (m , 1H), 3.98 (m, 2H), 3.75 (m, 3H), 3.65 (m, 2H), 1.51 (s, 3H), 1.36 (s, 6H), 0.85 (s, 9H), 0.02 (s, 6H).

Preparation Example 6 Preparation of Compound VI

Compound V (26 g, 0.053 mol) was dissolved in dichloromethane (180 mL), and then DIPEA (diisopropylethylamine, 13 mL, 0.079 mol) and benzoyl chloride (Bz-Cl, 7.4 mL, 0.064 mol) were added sequentially at 0 ° C. It was slowly added dropwise and stirred for 10 minutes. After raising to room temperature, a small amount of DMAP (4-dimethylaminopyridine) was added thereto, followed by stirring for 2 hours. The solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution (brine), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to give benzoyl compound. (31 g, 0.053 mol) was obtained quantitatively. The compound was dissolved in dichloromethane (100 mL), 4N HCl in dioxane solution (130 mL) was added thereto, stirred at room temperature for 3 hours, and concentrated under reduced pressure to obtain Compound VI quantitatively.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.88 (d, J = 7.8 Hz, 2H), 7.63 (t, 1H, J = 7.2 Hz), 7.46 (t, 2H, J = 7.2 Hz), 7.41 (dd, 1H, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz), 7.11 (d, 1H, J = 9.0 Hz), 6.88 (t, 1H, J = 9.0 Hz), 5.02 (m, 1H), 4.54 -4.45 (m, 2H), 4.16 (t, 1H, J = 9.0 Hz), 3.88 (m, 1H), 3.54 (t, 2H, J = 6.0 Hz), 3.13 (t, 2H, J = 6.0 Hz) .

Preparation Example 7 Preparation of Compound VII

Compound VI (19.8 g, 0.053 mol) was dissolved in dichloromethane (300 mL), and then triethylamine (17.3 mL, 0.123 mol) and methanesulfonyl chloride (MsCl, 4.8 mL, 0.062 mol) were added slowly at 0 ° C. It was added dropwise and stirred for 10 minutes. After raising to room temperature, the mixture was stirred for 2 hours, diluted with dichloromethane, washed sequentially with water, saturated sodium bicarbonate solution and saturated sodium chloride solution (brine), and concentrated under reduced pressure by dehydration using anhydrous sodium sulfate. The solid thus obtained was triturated again with diethylether solvent and filtered to give white solid Compound X (18.6 g, 0.041 mol, 77%).

¹ H NMR (600 MHz, CDCl ₃ ) δ 8.02-8.00 (m, 2H), 7.58 (m, 1H), 67.44-7.40 (m, 3H), 7.05 (m, 1H), 6.70 (t, 1H, J = 9.0 Hz), 4.99 (m, 1H), 4.62-4.54 (m, 2H), 4.39 (t, 2H, J = 5.4 Hz), 4.18 (br s, 1H), 4.15 (t, 1H, J = 9.0 Hz ), 3.86 (m, 1 H), 3.55 (br t, 2 H), 3.02 (s, 3 H).

Preparation Example 8 Preparation of Compound VIII

Compound VII (18.6 g, 0.041 mol) was added to ethanol (100 mL) and hydrazine monohydrate (H ₂ NNH ₂ -H ₂ O, 50 mL) was added and stirred at 60 ° C. for 2 hours. The solution was concentrated under reduced pressure to quantitatively obtain an oily compound.

The compound thus obtained was added to acetic acid (200 mL), trimethylorthoformate (100 mL) was added and refluxed for 8 hours. After distilling under reduced pressure, the solution was dissolved in dichloromethane, washed sequentially with a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution (brine), and then dehydrated using anhydrous sodium sulfate and concentrated under reduced pressure. This concentrate was separated by column chromatography with 5% methanol / dichloromethane solution to give white solid compound VIII (4.2 g, 0.013 mol, 32%).

¹ H NMR (600 MHz, CDCl ₃ ) δ = 8.55 (s, 1H), 7.61 (dd, J ₁ = 13 Hz, J ₂ = 2.4 Hz, 1H), 7.25 (dd, J ₁ = 9.0 Hz, J ₂ = 2.7 Hz, 1H), 7.14 (t, J = 8.4 Hz, 1H), 6.90 (s, 1H), 4.79 (m, 1H), 4.04-3.99 (m, 5H), 3.79- 3.73 (m, 3 H), 2.58 (br s, 1 H); LCMS: 323 (M + H ⁺ ) for C ₁₄ H ₁₅ -FN ₄ O ₄

Preparation Example 9 Preparation of Compound IX

Compound VIII (8.8 g, 27 mmol) was dissolved in methanol (150 mL), and then 4N-hydrochloric acid (15 mL) dissolved in 1,4-dioxane was added thereto, followed by stirring for 2 hours. The reaction mass was concentrated under reduced pressure and triturated with diethylether to give a pale yellow solid. Compound was obtained quantitatively (8.72 g, 27 mmol, 100%).

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.73 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.60 (t, J = 9 Hz, 1H), 7.45 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 4.75 (m, 1H), 4.11 (t, J = 9.0 Hz, 1H), 3.88 (m, 1H), 3.78 (t, J = 4.8 Hz, 2H) , 3.70-3.55 (m, 2H), 3.36 (t, J = 4.8 Hz, 2H); LCMS: 295 (M + H ⁺ ) for C ₁₃ H ₁₅ -FN ₄ O ₃

This compound was reacted with TBS-Cl again in the same manner as in Preparation Example 2 to obtain compound IX quantitatively.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.53 (dd, J ₁ = 13.6 Hz, J ₂ = 2.4 Hz, 1H), 7.21 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 6.89 (br s, 1H), 4.89 (br S, 1H), 4.69 (m, 1H), 4.03- 3.78 (m, 6H), 3.31 (t, J = 4.6 Hz, 2H), 0.85 (s, 9H), 0.09 (s, 6H)

Preparation Example 10 Preparation of Compound X

Compound V (45 g, 0.093 mol) was dissolved in dichloromethane (300 mL), then triethylamine (26 mL, 0.186 mol) and methanesulfonyl chloride (MsCl, 10.9 mL, 0.14 mol) were added sequentially at 0 ° C. It was slowly added dropwise and stirred for 20 minutes. After raising to room temperature, the mixture was stirred for 1 hour and concentrated under reduced pressure. The concentrated solution was dissolved in ethyl acetate, washed sequentially with 0.5 N HCl, saturated sodium bicarbonate solution and saturated sodium chloride solution (brine), dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow oil compound X (50 g, 0.089 mol, 96%). %) Was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 (dd, 1H, J ₁ = 11.6 Hz, J ₂ = 2.4 Hz), 7.29 (m, 1H), 7.13 (m, 1H), 4.94-4.88 (m, 1H ), 4.50-4.39 (m, 2H), 4.12 (m, 1H), 3.92 (m, 1H), 3.72 (m, 2H), 3.64-3.62 (m, 2H), 3.08 (s, 3H), 1.49 ( s, 3H), 1.34 (s, 6H), 0.83 (s, 9H), 0.00 (s, 6H).

Preparation Example 11 Preparation of Compound XI

Compound X (50 g, 0.089 mol) was dissolved in DMF (200 mL), NaN ₃ (7.16 g, 0.11 mol) was added thereto, and the mixture was stirred at 80 ° C. for 3 hours. After cooling to room temperature, diluted with ethyl acetate, washed sequentially with water, saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution (brine), dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to give a colorless oily solid compound XI (47 g, 0.089 mol). ) Was obtained quantitatively.

¹ H NMR (600MHz, CDCl ₃ ) δ 7.48 (dd, J ₁ = 8.2 Hz, J ₂ = 1.4 Hz) 7.30 (m, 1H), 7.16 (m, 1H), 4.81-4.79 (m, 1H), 4.09-4.08 (m, 1H), 3.86 ( m, 1H), 3.74 (m, 2H), 3.62-3.59 (m, 1H), 1.51 (s, 3H), 1.36 (s, 6H), 0.85 (s, 9H), 0.02 (s, 6H).

Preparation Example 12 Preparation of Compound XII

Compound XI (47 g, 0.089 mol) was dissolved in methanol (400 mL), Pd / C (3.5 g) was added thereto, and the mixture was stirred for 4 hours under a hydrogen gas balloon. The mixture was filtered using celite and concentrated under reduced pressure. The concentrate was dissolved in dichloromethane (130 mL), 1N NaOH aqueous solution (130 mL) was added thereto, and Cbz-Cl (15.5 mL, 0.11 mol) was slowly added dropwise with stirring. After stirring for 2 hours at room temperature, the organic layer was separated, washed with water and saturated aqueous sodium chloride (brine), dehydrated using anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography was performed with 20% ethyl acetate / hexane solution. It was separated to give a light yellow oil compound XII (50.5 g, 0.082 mol, 92%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.43 (m, 1H), 7.36-7.35 (m, 1H), 7.31 (s, 6H), 7.11 (m, 1H), 5.09 (s, 2H), 4.75 (m, 1H), 4.01 (t, 1H, J = 8.4 Hz), 3.76-3.50 (m, 1H), 1.49 (s, 3H), 1.34 (s, 6H), 0.83 (s, 9H), 0.01 ( s, 6H).

Preparation Example 13 Preparation of Compound XIII

Compound XII Dissolve (50.5 g, 0.082 mol) in dichloromethane (100 mL), add 4N HCl in dioxane solution (130 mL), stir at room temperature for 3 hours, and concentrate under reduced pressure to give a white solid compound (36 g, 0.082 mol). Obtained quantitatively.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.69 (t, 1H, J = 6.0 Hz), 7.44-7.40 (m, 1H), 7.32 (s, 6H), 7.09-7.07 (m, 1H), 6.88 (t, 1H, J = 9.2 Hz), 5.03 (s, 2H), 4.71-4.68 (m, 1H), 4.08-4.03 (m, 2H), 3.73-3.69 (m, 1H), 3.60-3.57 (m , 3H), 3.39-3.34 (m, 2H), 3.18-3.15 (m, 2H).

Thus obtained compound (36 g, 0.082 mol) was dissolved in dichloromethane (300 mL), triethylamine (34.5 mL, 0.245 mol) and methanesulfonyl chloride (MsCl, 9.5 mL, 0.123 mol) were added at 0 ° C. The mixture was slowly added dropwise and stirred for 10 minutes. After raising to room temperature, the mixture was stirred for 2 hours, diluted with dichloromethane, washed sequentially with water, saturated sodium bicarbonate solution and saturated sodium chloride solution (brine), and concentrated under reduced pressure by dehydration using anhydrous sodium sulfate. The solid thus obtained was triturated again with a diethylether solvent and filtered to give a white solid compound XIII. (30.5 g, 0.063 mol, 77%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.39-7.32 (m, 6H), 7.01 (m, 1H), 6.68 (t, 1H, J = 9.0 Hz), 5.24 (t, 1H, J = 6.0 Hz), 5.11 (s, 2H), 4.75 (m, 1H), 4.40 (t, 2H, J = 5.4Hz), 4.17 (br t, 1H), 3.99 (t, 1H, J = 8.7 Hz), 3.75-3.52 ( m, 5H), 3.03 (s, 3H).

Preparation Example 14 Preparation of Compound XIV

Compound XIII (20 g, 0.042 mol) was added to ethanol (100 mL) and hydrazine monohydrate (H ₂ NNH ₂ -H ₂ O, 50 mL) was added and stirred at 60 ° C for 2 h. The solution was concentrated under reduced pressure to give an oil compound. (17.4 g, 0.042 mol) was obtained.

The compound thus obtained was added to acetic acid (200 mL), trimethylorthoformate (100 mL) was added and refluxed for 8 hours. After distilling under reduced pressure, the solution was dissolved in dichloromethane, washed sequentially with a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution (brine), and then dehydrated using anhydrous sodium sulfate and concentrated under reduced pressure. This concentrate was separated by column chromatography with 5% methanol / dichloromethane solution to give white solid compound XIV (5.8 g, 0.013 mol, 31%).

¹ H NMR (600 MHz, CDCl ₃ ) δ = 8.52 (s, 1H), 7.55-7.53 (m, 1H), 7.30-7.28 (m, 6H), 7.19-7.18 (m, 1H), 7.11-7.08 (m , 1H), 6.86 (s, 1H), 5.27 (t, J = 6 Hz, 1H), 5.08 (s, 2H), 4.77 (m, 1H), 4.03-4.00 (m, 1H), 3.97 (t, J = 4.8 Hz, 2H), 3.81-3.76 (m, 1H), 3.70 (t, J = 5.1 Hz, 2H), 3.65-3.60 (m, 1H), 3.59-3.54 (m, 1H).

Preparation Example 15 Preparation of Compound XV

Compound XIV (5 g, 0.011 mol) was dissolved in methanol (100 mL), Pd / C (0.5 g) was added thereto, and the mixture was stirred for 4 hours under a hydrogen gas balloon. Filtration using celite followed by concentration under reduced pressure afforded an oily solid compound (3.2 g, 0.010 mol, 91%).

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 8.43 (s, 1H), 7.65-7.63 (m, 1H), 7.40-7.36 (m, 2H), 7.12 (s, 1H), 4.65-4.62 (m , 1H), 4.09-4.06 (m, 1H), 3.89-3.86 (m, 1H), 3.85 (t, J = 5.1 Hz, 2H), 3.70 (t, J = 4.8 Hz, 2H), 2.88-2.85 ( m, 1H), 2.82-2.79 (m, 1H).

So obtained Compound (0.1 g, 0.31 mmol) was dissolved in dichloromethane (3 mL), and then DIPEA (0.1 mL, 0.6 mmol) and Ac ₂ O (0.06 mL, 0.6 mmol) were added dropwise sequentially and stirred at room temperature for 2 hours. After concentration under reduced pressure, compound XV was obtained as a white solid using column chromatography. (0.098 g, 0.27 mmol, 87%) was obtained.

¹ H NMR (400 MHz, chloroform-d ₄ ) δ = 8.54 (s, 1H), 7.59 (dd J = 13.6, 2.4 Hz, 1H), 7.20 (dd, J = 13.6, 2.4 Hz, 1H), 7.13 (t J = 8.8, Hz, 1H), 6.88 (s, 1H), 6.19 (t, J = 6.0 Hz, 1H), 4.81 (m, 1H), 4.05 (t, J = 8 Hz, 1H), 3.99 (t, J = 4.8 Hz, 2H), 3.80 (dd, J = 8.8, 6.8 Hz, 1H), 3.73 (t, J = 4.8 Hz, 2H), 3.69 (m, 2H), 2.03 (s, 3H); LCMS: 364 (M + H ⁺ ) for C ₁₆ H ₁₈ FN ₅ O ₄

Preparation Example 16 Preparation of Compound XVI

Compound XV (0.7 g, 1.93 mmol), 4N-hydrochloric acid (3 mL, 12 mmol) dissolved in 1,4-dioxane, Pd / C (70 mg) was added to THF (20 mL), followed by 2 hours under hydrogen gas. After stirring for a while, the reaction mixture was filtered through celite and concentrated under reduced pressure to yield compound XVI as a white solid. (0.72 g, 1.93 mmol, 100%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.34-8.31 (m, 2H), 7.68 (dd J = 13.6, 2.4 Hz, 1H), 7.56 (t, J = 8.8 Hz, 1H), 7.41 (dd J = 13.6, 2.4 Hz, 1H), 4.76 (m, 1H), 4.15 (t, J = 8.8 Hz, 1H), 3.78 (m, 3H), 3.46 (m, 2H), 3.35 (t, J = 8.4 Hz, 2H), 1.83 (s, 3H)

LCMS: 336 (M + H ⁺ ) for C ₁₅ H ₁₈ FN ₅ O ₃

Synthesis of the final compounds from the intermediates prepared in Preparation Examples 1 to 16 is shown in the following Examples.

Example 1 Preparation of Compound 1

Compound VIII made in Preparation Example 8 (4.4 g, 0.013 mol) is dissolved in dichloromethane (60 mL) with DIPEA (4.3 ml, 0.024 mol) and DMAP (0.15 g), and then benzoyl chloride (1.37 ml, 0.020 mol) is dropwise at 0 ° C. and room temperature The mixture was stirred for 1 hour, dissolved in dichloromethane, washed sequentially with 0.5N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride (brine), and concentrated under reduced pressure by using anhydrous sodium sulfate. This concentrate was separated by column chromatography with 100% ethyl acetate solution to obtain a white solid compound XVII. (3.2 g, 0.007 mol, 55%) was obtained.

This compound XVII Dissolve (3.2 g, 0.007 mol) in 40 mL methanol, add 8 mL of 4 M HCl in dioxane solution, stir at room temperature for 1 hour, concentrate and triturate with diethylether to give white solid compound XVIII (3.35 g, quantitative).

The obtained compound compound XVIII (1 g, 2.30 mmol) and saturated aqueous sodium bicarbonate solution (20 ml) were added to chloroform (20 ml), and then thiophosgen (0.2 mL, 2.6 mmol) was dropwise at 0 ° C., and then stirred at room temperature for 1 hour. Aqueous ammonia solution (8 ml) was added at room temperature, stirred for 2 hours, and triturated with diethyl ether (100 ml) to obtain an ivory solid compound XIX (0.8 g, 1.75 mmol, 76%).

Thus obtained compound XIX (0.2 g, 0.43 mmol) was dissolved in 4 mL ethanol, and 50% aqueous chloroacetaldehyde solution (0.11 ml, 0.87 mmol) was added and refluxed for 12 hours. The solution was concentrated under reduced pressure, column chromatography (eluent: 5% MeOH / MC) to obtain a benzoyl compound, dissolved in 5 mL ethanol, 2 ml of aqueous ammonia solution and refluxed for 90 minutes to remove the benzoyl group. The solution was concentrated under reduced pressure and column chromatography (eluent: 5% MeOH / MC) afforded the title compound 1 (23 mg, 0.06 mmol, 14%).

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.41 (t, J = 9 Hz, 1H), 7.37 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.21 (d, J = 3.6 Hz, 1H), 7.18 (d, J = 1.8 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H), 5.23 (br s, 1H), 4.72 (m, 1H), 4.09 (t, J = 9.0 Hz, 1H), 4.02 (t, J = 4.8 Hz, 2H), 3.86-3.83 (m, 3H), 3.68 (dd , J ₁ = 12.6 Hz, J ₂ = 3.0 Hz, 1H), 3.56 (dd, J ₁ = 12.6 Hz, J ₂ = 3.8 Hz, 1H)

LCMS: 378 (M + H ⁺ ) for C ₁₆ H ₁₆ -FN ₅ O ₃ S

Example 2 Preparation of Compound 2

The title compound 2 (66 mg, 0.17 mmol, 40%) was obtained in the same manner as in Example 1, using chloroacetone instead of chloroacetaldehyde from compound XIX .

¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.61 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.36 (t, J = 9 Hz, 1H), 7.33 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.11 (s, 1H), 6.38 (s, 1H), 5.20 (t, J = 5.4 Hz, 1H), 4.68 (m, 1H), 4.05 (t, J = 9.0 Hz, 1H), 3.96 (t, J = 4.8 Hz, 2H), 3.81-3.78 (m, 3H), 3.66-3.51 (m, 2H)

LCMS: 392 (M + H ⁺ ) for C ₁₇ H ₁₈ -FN ₅ O ₃ S

Example 3 Preparation of Compound 3

The title compound 3 (53 mg, 0.13 mmol, 30%) as a pale yellow solid was obtained from the compound XIX using ethyl bromoacetate instead of chloroacetaldehyde in the same manner as in Example 1.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.67 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.47 (s, 1H), 7.44 (t, J = 9 Hz, 1H), 7.39 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 5.22 (t, J = 5.6 Hz, 1H), 4.73 (m, 1H), 4.22 (t, J = 5.6 Hz, 2H), 4.10 (t, J = 8.8 Hz, 1H), 3.87 (s, 2H), 3.85-3.82 (m, 3H), 3.71-3.53 (m, 2H)

LCMS: 394 (M + H ⁺ ) for C ₁₆ H ₁₆ -FN ₅ O ₄ S

Example 4 Preparation of Compound 4

The title compound 4 (53 mg, 0.13 mmol, 30%) was obtained as a light brown solid, in the same manner as in Example 1, using ethyl bromopyruvate instead of chloroacetaldehyde from compound XIX .

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.45-7.23 (m, 6H), 5.26 (br s, 1H), 4.73 (m, 1H), 4.10-3.57 (m, 8H)

LCMS: 421 (M + H ⁺ ) for C ₁₇ H ₁₇ -FN ₆ O ₄ S

Example 5 Preparation of Compound 5

Made in Preparation Example 8 Compound VIII (8.8 g, 27 mmol) was dissolved in methanol (150 mL), and then 4N-hydrochloric acid (15 mL) dissolved in 1,4-dioxane was added thereto, followed by stirring for 2 hours. The reaction was concentrated under reduced pressure and triturated with diethyl to quantitatively obtain a pale yellow solid compound XX (8.72 g, 27 mmol, 100%).

Compound XX thus obtained (100 mg, 0.30 mmol) was dissolved in 3 mL dichloromethane, and chloroacetyl chloride (0.048 ml, 0.6 mmol) and triethylamine (0.127 ml, 0.9 mmol) were added and stirred at room temperature for 30 minutes. The solution was diluted with 50 mL dichloromethane, washed with saturated aqueous sodium bicarbonate solution and concentrated again. The mixture was dissolved in 5 mL ethanol, thiourea (0.068 g, 0.9 mmol) was added thereto, and the mixture was stirred under reflux for 3 hours and then concentrated again. The solution was diluted with 50 mL dichloromethane, washed with saturated aqueous sodium bicarbonate solution, separated by column chromatography (eluent: 10% MeOH / MC) to give the title compound 5 as a yellow solid (0.01 g, 0.021 mmol, 8%). Got.

¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.63 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.29 (m, 1H), 7.16 (t, J = 9 Hz, 1H), 7.08 (s, 1H), 5.0 (br s, 1H), 4.78 (m , 1H), 4.36-4.34 (m, 2H), 4.07-4.02 (m, 3H), 3.88 (s, 2H), 3.84-3.75 (m, 3H)

LCMS: 394 (M + H ⁺ ) for C ₁₆ H ₁₆ -FN ₅ O ₄ S

Example 6 Preparation of Compound 6

Made in Preparation Example 9 Compound IX Dissolve (100mg, 0.24mmol) in dichloromethane (5ml), add diisopropylamine (0.06ml, 0.36mmol), and add ethyl malonyl chloride (0.037ml, 0.29mmol) at 0 ℃. Diluted in chlormethane (3ml). After stirring for 10 minutes, the temperature was raised to room temperature and stirred for another 20 minutes at room temperature. 50 ml of dichloromethane was added to the solution, diluted with water, washed with 50 ml of water, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to give a pale yellow oil. This was triturated with diethyl to give a pale yellow solid compound XXI (90 mg 71.7%).

Compound XXI thus obtained Toluene (3ml) was added to (160mg, 0.306mmol), Lawesson's reagent (148.6mg, 0.367mmol) was added thereto, and the mixture was stirred under reflux for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure and separated by column chromatography with 3% methanol / dichloromethane solution to obtain a pale yellow solid compound XXII (104 mg, 63%).

The compound XXII (50 mg, 0.093 mmol) thus obtained was suspended in ethanol (1 ml), hydrazine (0.48 ml, 0.093 mmol) was diluted in ethanol (10 ml), and stirred at 60 ° C for 1 hour. The resulting solid was filtered under reduced pressure, washed with ethanol and dried under reduced pressure to obtain a white solid compound XXIII (35mg, 76.7%).

Thus obtained compound XXIII (35mg, 0.07mmol) was dissolved in dichloromethane (3ml) and 4M HCl in dioxane solution (0.2ml, 0.8mmol) was added. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to obtain the title compound 6 as a white solid.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.66 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.44 (t, J = 9 Hz, 1H), 7.39 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.26 (s, 1H), 5.34 (s, 1H), 4.73 (m, 1H), 4.09 (t, J = 9.0 Hz, 1H), 3.86-3.55 ( m, 9H)

LCMS: 377 (M + H ⁺ ) for C ₁₆ H ₁₇ -FN ₆ O ₄

Example 7 Preparation of Compound 7

Compound XX (500mg, 1.50mmol) prepared in Example 5 was dissolved in dichloromethane (30mL), and then saturated sodium bicarbonate solution (10mL) was added and thiophosgene (thiophosgene, 0.14mL, 1.80mmol) at 0 ° C. The mixture was slowly added thereto, stirred for 40 minutes, and the organic layers were collected and dehydrated using anhydrous sodium sulfate. The solution was distilled under reduced pressure, dissolved in THF (30 mL), hydrazine (H ₂ NNH ₂ .H ₂ O, 31 mL, 6.25 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The solution was distilled under reduced pressure, triturated with diethyl and filtered to give white solid compound XXIV (520 mg, 83%).

Thus obtained compound XXIV (260mg, 0.71mmol) was added to formic acid (formic acid, 5mL), trimethyl ortho formate (TMOF, 2.5mL) and refluxed for 9 hours. To cool to room temperature and concentrated under reduced pressure, the solvent dichloromethane after diluted with (60mL) and washed with saturated aqueous sodium bicarbonate solution (50mL) was dehydrated over anhydrous sodium sulfate, and purified by column chromatography (eluent: 5% MeOH / MC ) to separate the title Compound 7 (66.5 mg, 25%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.85 (s, 1H), 7.66 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.43 (t, J = 9 Hz, 1H), 7.38 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.25 (s, 1H), 5.24 (t, J = 5.6 Hz, 1H), 4.73 (m, 1H), 4.12-3.52 (m, 8H)

LCMS: 379 (M + H ⁺ ) for C ₁₅ H ₁₅ -FN ₆ O ₃ S

Example 8 Preparation of Compound 8

Compound XXIV (260 mg, 0.71 mmol), acetic acid (5 mL) and triethyloacetate (TEOA, 2.5 mL) prepared in Example 7 were mixed and stirred at reflux for 9 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, diluted with dichloromethane (60 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL), and dehydrated with anhydrous sodium sulfate. The solution was distilled under reduced pressure and triturated with diethyl to give the title compound 8 (51 mg, 19%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.66 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.42 (t, J = 9 Hz, 1H), 7.37 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.21 (s, 1H), 5.24 (t, J = 5.6 Hz, 1H), 4.72 (m, 1H), 4.12-3.52 (m, 8H), 2.52 ( s, 3 H)

LCMS: 393 (M + H ⁺ ) for C ₁₆ H ₁₇ -FN ₆ O ₃ S

Example 9 Preparation of Compound 9

Compound XXIV (0.3 g, 0.63 mmol) prepared in Example 7 was dissolved in THF (10 mL), and carbonyldiimidazole (CDI, 0.12 g, 0.73 mmol) was added thereto, followed by stirring at room temperature for 5 hours. The solution was concentrated, dissolved in dichloromethane, solidified with diethyl ether, filtered, and triturated with methanol and diethyl to give the white solid title compound 9 (240 mg, 0.61 mmol, 97%).

^OneH NMR (600MHz, DMSO-d₆) δ = 11.81 (s, 1 H), 7.64 (dd, J _One = 13.8 Hz,J ₂ = 2.4 Hz, 1H), 7.39 (t,J = 9 Hz, 1H), 7.36 (dd, J _One = 9.0 Hz,J ₂ = 2.4 Hz, 1H), 7.12 (s, 1H), 5.24 (t,J= 5.6 Hz, 1H), 4.72 (m, 1H), 4.09 (t,J = 9.0 Hz, 1H), 3.84-3.54 (m, 7H)

LCMS: 395 (M + H ⁺ ) for C ₁₅ H ₁₅ -FN ₆ O ₄ S

Example 10 Compound 10 , Manufacture of 11

Dissolve compound XXIV (100mg, 0.21mmol) prepared in Example 7 in DMF (3 mL), slowly add ethyl chlorooxoacetate (0.05 mL, 0.41 mmol), and stir at room temperature for 1 hour to 80 ° C. Heated and stirred for 14 h. Lowered to room temperature, diluted with ethyl acetate (60mL) and washed three times with water (50mL). The organic layer was dehydrated using anhydrous sodium sulfate and separated by column chromatography (eluent: ethyl acetate) to obtain a yellow solid (55 mg, 47%).

Thus obtained compound (50mg, 0.09mmol) was dissolved in a mixed solvent of THF (1mL) and MeOH (2mL) and ammonia water (4mL) was added and stirred under reflux for 14 hours. The solvent was concentrated under reduced pressure and separated by column chromatography (eluent: water / AN = 2/8) to obtain the title compound 10 (3.8 mg) and the title compound 11 (11 mg), respectively.

< Compound 10>

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 8.20 (s, 1H), 7.80 (s, 1H), 7.67 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.43 (t, J = 9 Hz, 1H), 7.38 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.35 (s, 1H), 5.26 (br t, 1H), 4.73 (m, 1H), 4.16 (t, J = 4.8 Hz, 2H), 4.10 (t , J = 9.0 Hz, 1H), 3.88-3.55 (m, 5H)

LCMS: 422 (M + H ⁺ ) for C ₁₆ H ₁₆ FN ₇ O ₄ S

<Compound 11>

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.41 (t, J = 9 Hz, 1H), 7.37 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.21 (s, 1H), 5.25 (t, J = 5.6 Hz, 1H), 4.72 (m, 1H), 4.09 (t, J = 9.0 Hz, 1H) , 4.03 (t, J = 5.2 Hz, 2H), 3.87-3.51 (m, 5H)

LCMS: 423 (M + H ⁺ ) for C ₁₆ H ₁₅ -FN ₆ O ₅ S

Example 11 Compound 12 , 13 , manufacturing

Compound XVIII made in Example 1, above (1 g, 2.30 mmol) was dissolved in dichloromethane (5 mL), triethylamine (0.97 mL, 6.9 mmol) and cyanogen bromide (0.3 mL, 3 mmol) were added and stirred at 0 ° C. for 90 minutes. It was. The solution was diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL) and dehydrated with anhydrous sodium sulfate. The solution was concentrated under reduced pressure and separated by column chromatography (eluent: 50% EA / Hex) to give a pale yellow solid compound XXV (0.21 g, 0.5 mmol, 22%).

The obtained compound compound XXV (0.21 g, 0.5 mmol) was dissolved in DMF (3 mL), followed by ammonium chloride (80 mg, 1.5 mmol), NaN ₃ (48 mg, 0.75 mmol) was added thereto and stirred at 120 ° C. for 2.5 hours. The solution was diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL) and dehydrated with anhydrous sodium sulfate. The solution was concentrated under reduced pressure and triturated with diethyl to afford the white solid compound XXVI (0.08 g, 0.18 mmol, 36%).

The obtained compound compound XXVI (0.08 g, 0.18 mmol) was dissolved in DMF (1 mL), KOH (25 mg, 0.45 mmol) and iodine methane (0.045 mL, 0.73 mmol) were added thereto, and the resultant was stirred at room temperature for 2 hours. The solution was diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL) and dehydrated with anhydrous sodium sulfate. The solution was concentrated under reduced pressure, dissolved in ethanol, ammonia water (2 mL) was added, and the mixture was stirred under reflux for 1 hour. The solution was concentrated under reduced pressure and separated by column chromatography to obtain a pale yellow solid title compound 12 (23 mg, 0.06 mmol, 33%) and an ivory solid title compound 13 (23 mg, 0.06 mmol, 33%), respectively.

<Compound 12>

LCMS: 377 (M + H ⁺ ) for C ₁₅ H ₁₇ -FN ₈ O ₃

<Compound 13>

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.64 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.40 (t, J = 9 Hz, 1H), 7.36 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.10 (s, 1H), 5.24 (br t, 1H), 4.73 (m, 1H), 4.21 (s, 3H), 4.09 (t, J = 9.0 Hz , 1H), 3.86-3.55 (m, 7H)

LCMS: 377 (M + H ⁺ ) for C ₁₅ H ₁₇ -FN ₈ O ₃

Example 12 Preparation of Compound 14

Made in Preparation Example 9 Compound IX (140mg, 0.34mmol) was dissolved in DMF (5 mL), and then diisopropylamine (DIEA, 0.11 mL, 0.68 mmol) and 2-chloro-5-nitropyridine (81.5 mg, 0.51 mmol) were added thereto. After stirring for 12 hours at room temperature, 100 mL of 10% hexane / ethyl acetate was added to the mixture, and the mixture was diluted with water, washed twice with 50 mL of water, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow solid compound (140mg 77.6%). .

Methanol (2 mL) was added to the compound (90 mg, 0.17 mmol), and Pd / C (36 mg) was added thereto. The mixture was stirred under a hydrogen gas balloon for 4 hours. Filtration using celite followed by concentration under reduced pressure gave a yellow oil compound (40 mg, 47%).

The compound thus obtained (40 mg, 0.079 mmol) was dissolved in THF (2 mL), and nitrosyl tetrafluoroborate (10 mg, 0.087 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, diethyl ether was added, and the resulting solid was filtered under reduced pressure, and then poured into toluene (3 mL), followed by stirring under reflux for 12 hours. Concentration under reduced pressure and then separated by column chromatography in 10% methanol / dichloromethane solution to give the yellow solid title compound 14 (4mg, 14%).

¹ H NMR (600 MHz, acetone-d ₆ ) δ = 8.17 (s, 1H), 7.76-7.73 (m, 2H), 7.45-7.38 (m, 3H), 7.19 (br s, 1H), 6.83 (br s , 1H), 4.81 (m, 1H), 4.40 (br s, 1H), 4.26-3.28 (m, 8H)

LCMS: 372 (M + H ⁺ ) for C ₁₈ H ₁₈ -FN ₅ O ₃

Example 13 Preparation of Compound 15

Compound XX (60 mg, 0.18 mmol) prepared in Example 5 was dissolved in dichloroethane (3 mL), followed by triethylamine (0.02 mL, 0.18 mmol) and 5-methyl furfural (0.02 mL). , 0.22 mmol), acetic acid (0.01 mL, 0.18 mmol) and sodium triacetoxyborohydride (46 mg, 0.22 mmol) were added thereto, and the resultant was stirred at room temperature for 2 hours. 2 mL of water was added to the reaction mixture, followed by stirring. 20 mL of saturated aqueous sodium hydrogen carbonate solution was added thereto, and extracted twice with 20 mL of dichloromethane. Dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography with 7% methanol / dichloromethane solution to give a pale yellow solid title compound 15 (43mg, 61%).

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.58 (d, J = 15 Hz, 1H), 7.31-7.28 (m, 2H), 6.87 (br s, 1H), 6.18 (br d, 1H), 6.00 (br s, 1H), 5.23 (t, J = 5.4 Hz, 1H), 4.70 (m, 1H), 4.07 (t, J = 9.0 Hz, 1H), 3.91 (s, 2H), 3.82-3.54 ( m, 5H), 2.91 (br t, 2H), 2.24 (s, 3H)

LCMS: 389 (M + H ⁺ ) for C ₁₉ H ₂₁ -FN ₄ O ₄

Example 14 Preparation of Compound 16

Compound XX (50 mg, 0.17 mmol) and 5-nitro-furan-2-carbaldehyde (29 mg, 0.20 mmol) prepared in Example 5 were dissolved in DCE (dichloroethane, 3 mL) and dissolved in AcOH (0.01 mL, 0.17 mmol) was added and NaBH (OAc) ₃ was added thereto and stirred at room temperature for 2 hours. Dilute with dichloromethane (50 mL), wash sequentially with saturated sodium bicarbonate solution (40 mL), saturated aqueous sodium chloride solution (40 mL), dehydrate with anhydrous sodium sulfate, and use column chromatography with 5% MeOH / MC. Isolate to give a yellow solid title compound 16 (44mg, 62%).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.54 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 7.20 (dd, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 7.10 (t, J = 8.8 Hz, 1H), 6.89 (s, 1H), 6.62 (d, J = 3.6 Hz, 1H), 4.77 (m, 1H) , 4.18 (s, 2H), 4.04-3.96 (m, 3H), 3.84 (t, J = 4.8 Hz, 2H), 3.77 (m, 1H), 3.11 (t, J = 4.8 Hz, 2H), 2.04 ( t, J = 6.6 Hz, 1H)

LCMS: 420 (M + H ⁺ ) for C ₁₈ H ₁₈ FN ₅ O ₆

Example 15 Preparation of Compound 17

Compound XX (100 mg, 0.30 mmol) prepared in Example 5 was dissolved in dichloroethane (5 mL), and triethylamine (0.04 mL, 0.30 mmol) was added thereto, and furan-2,5-dicarbaldehyde (75 mg) was used. , 0.36 mmol), acetic acid (0.02 mL, 0.30 mmol) and sodium triacetoxyborohydride (77 mg, 0.36 mmol) were added thereto, and the resulting mixture was stirred at room temperature for 2 hours. 2 mL of water was added to the reaction mixture, followed by stirring. 20 mL of saturated aqueous sodium hydrogen carbonate solution was added thereto, and extracted twice with 20 mL of dichloromethane. Dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography with 7% methanol / dichloromethane solution to give a yellow solid title compound 17 (55mg, 45%).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.61 (s, 1H), 7.53 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.24 (d, J = 3.6 Hz, 1H), 7.20 (dd, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 7.09 (t, J = 8.8 Hz, 1H), 6.90 (s, 1H), 6.59 (d, J = 3.6 Hz, 1H), 4.77 (m, 1H) , 4.20 (s, 2H), 4.04-3.96 (m, 3H), 3.83 (t, J = 4.8 Hz, 2H), 3.77 (m, 1H), 3.09 (t, J = 4.8 Hz, 2H), 2.17 ( br t, 1H)

LCMS: 403 (M + H ⁺ ) for C ₁₉ H ₁₉ FN ₄ O ₅

Example 16 Preparation of Compound 18

Compound XX (100 mg, 0.30 mmol) prepared in Example 5 was dissolved in dichloroethane (5 mL), and triethylamine (0.04 mL, 0.30 mmol) was added thereto, and 5- (hydroxymethyl) furfural (46 mg , 0.36 mmol), acetic acid (0.02 mL, 0.30 mmol) and sodium triacetoxyborohydride (77 mg, 0.36 mmol) were added thereto, followed by stirring at room temperature for 1 hour. 2 mL of water was added to the reaction mixture, followed by stirring. 20 mL of saturated aqueous sodium hydrogen carbonate solution was added thereto and extracted twice with 20 mL of dichloromethane. Dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography with 7% methanol / dichloromethane solution to give a yellow solid title compound 18 (95mg, 78%).

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.58 (d, J = 15 Hz, 1H), 7.31-7.28 (m, 2H), 6.87 (br s, 1H), 6.24 (d, J = 3.0 Hz , 1H), 6.21 (d, J = 3.0 Hz, 1H), 5.22 (t, J = 5.4 Hz, 1H), 5.18 (t, J = 5.4 Hz, 1H), 4.70 (m, 1H), 4.35 (d , J = 5.4 Hz, 2H), 4.07 (t, J = 9.0 Hz, 1H), 3.95 (s, 2H), 3.82-3.53 (m, 5H), 2.93 (t, J = 4.8 Hz, 2H)

LCMS: 405 (M + H ⁺ ) for C ₁₉ H ₂₁ -FN ₄ O ₅

Example 17 Preparation of Compound 19

Compound XX (100 mg, 0.30 mmol) prepared in Example 5 was dissolved in dichloroethane (5 mL), and triethylamine (0.04 mL, 0.30 mmol) was added thereto, and 5-nitrile-2-thiophencarbaldehyde (57 mg, 0.36 mmol), acetic acid (0.02 mL, 0.30 mmol) and sodium triacetoxyborohydride (49 mg, 0.36 mmol) were added thereto, followed by stirring at room temperature for 1 hour. 2 mL of water was added to the reaction mixture, followed by stirring. 20 mL of saturated aqueous sodium hydrogen carbonate solution was added thereto, and extracted twice with 20 mL of dichloromethane. Dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography with 10% methanol / dichloromethane solution to give a yellow solid title compound 19 (92.3mg, 73%).

¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.55 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.51 (d, J = 3.6 Hz, 1H), 7.19 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.12 (t, J = 9 Hz, 1H), 7.00 (d, J = 3.6 Hz, 1H), 6.94 (s, 1H), 4.77 (m, 1H) , 4.32 (s, 2H), 4.04-3.96 (m, 3H), 3.83 (t, J = 4.8 Hz, 2H), 3.77 (dd, J ₁ = 12.6 Hz, J ₂ = 3.6 Hz, 1H), 2.99 (t, J = 4.8 Hz, 2H)

LCMS: 416 (M + H ⁺ ) for C ₁₉ H ₁₈ -FN ₅ O ₃ S

Example 18 Preparation of Compound 20

Compound XX (100 mg, 0.30 mmol) prepared in Example 5 was dissolved in dichloroethane (5 mL), and triethylamine (0.04 mL, 0.30 mmol) was added thereto to give 2,5-thiophendicarbaldehyde (85 mg). , 0.36 mmol), acetic acid (0.02 mL, 0.30 mmol) and sodium triacetoxyborohydride (77 mg, 0.36 mmol) were added thereto, and the resulting mixture was stirred at room temperature for 2 hours. 2 mL of water was added to the reaction mixture, followed by stirring. 20 mL of saturated aqueous sodium hydrogen carbonate solution was added thereto, and extracted twice with 20 mL of dichloromethane. Dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography with 7% methanol / dichloromethane solution to give the title compound 20 (95 mg, 75%).

¹ H NMR (600 MHz, CDCl ₃ ) δ = 9.88 (s, 1H), 7.67 (d, J = 3.6 Hz, 1H), 7.55 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.19 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.13-7.10 (m, 2H), 6.94 (s, 1H), 4.77 (m, 1H), 4.35 (s, 2H), 4.04-3.96 (m, 3H ), 3.82 (t, J = 4.8 Hz, 2H), 3.77 (dd, J ₁ = 12.6 Hz, J ₂ = 3.6 Hz, 1H), 3.01 (t, J = 4.8 Hz, 2H)

LCMS: 419 (M + H ⁺ ) for C ₁₉ H ₁₉ FN ₄ O ₄ S

Example 19 Preparation of Compound 21

Compound XX (100 mg, 0.30 mmol) prepared in Example 5 was dissolved in dichloroethane (5 mL), and triethylamine (0.04 mL, 0.30 mmol) was added thereto, and 5-nitro-2-thiophencarbaldehyde (57 mg, 0.36 mmol), acetic acid (0.02 mL, 0.30 mmol) and sodium triacetoxyborohydride (77 mg, 0.36 mmol) were added thereto, followed by stirring at room temperature for 1 hour. 2 mL of water was added to the reaction mixture, followed by stirring. 20 mL of saturated aqueous sodium hydrogen carbonate solution was added thereto and extracted twice with 20 mL of dichloromethane. Dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography with 5% methanol / dichloromethane solution to give a yellow solid title compound 21 (68mg, 51%).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.82 (d, J = 4.4 Hz, 1H), 7.56 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.20 (dd, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 7.13 (t, J = 8.8 Hz, 1H), 6.95-6.94 (m, 2H), 4.77 (m, 1H), 4.29 (s, 2H), 4.05- 3.96 (m, 3H), 3.84 (t, J = 4.8 Hz, 2H), 3.76 (m, 1H), 3.03 (t, J = 4.8 Hz, 2H), 2.01 (t, J = 6.0 Hz, 1H)

LCMS: 436 (M + H ⁺ ) for C ₁₈ H ₁₈ FN ₅ O ₅ S

Example 20 Preparation of Compound 22

Compound 20 (60 mg, 0.14 mmol) prepared in Example 18 was dissolved in methanol (3 mL), and then hydroxylamine hydrochloride (15 mg, 0.21 mmol) and triethylamine (0.1 mL, 0.67 mmol) were added thereto. Stir at 12 h. The reaction mixture was concentrated under reduced pressure, and the solid was washed with water, diethyl ether and dichloroethane to give a pale yellow solid, the title compound 22 (30.3 mg, 35%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.76 (s, 0.5H), 11.1 (s, 0.5H), 8.26 (s, 0.5H), 7.76 (s, 0.5H), 7.59 (d, J = 14 Hz, 1H), 7.31-6.93 (m, 4H), 5.23 (t, J = 5.6 Hz, 1H), 4.70 (m, 1H), 4.29-4.05 (m, 3H), 3.83-3.53 (m, 5H), 2.89 (br t, 2H)

LCMS: 434 (M + H ⁺ ) for C ₁₉ H ₂₀ -FN ₅ O ₄ S

Example 21 Preparation of Compound 23

Made in Preparation Example 9 Compound IX (80 mg, 0.20 mmol) was dissolved in DMF (2 mL), 5- (chloromethyl) -1-methyl-1H-tetrazole (78 mg, 0.59 mmol) and DIEA (0.1 mL, 0.59 mmol) were added thereto. Stir at 60 ° C. for 7 hours. The solution was diluted with ethyl acetate (50 mL), washed twice with water (40 mL), dehydrated with anhydrous sodium sulfate and separated by column chromatography with 80% EA / Hexane (20 mg). , 20%).

After dissolving this compound (20 mg, 0.04 mmol) in THF (2 mL), TBAF (0.06 mL, 0.06 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure, diluted with dichloromethane (20 mL), washed with water (20 mL), dehydrated with anhydrous sodium sulfate, separated by column chromatography with 10% MEOH / EA, and the title compound 23 (9 mg, 58%).

¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.52 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.17 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.07 (t, J = 9 Hz, 1H), 6.89 (s, 1H), 4.76 (m, 1H), 4.39 (s, 2H), 4.37 (s, 3H), 4.02-3.96 (m, 3H), 3.84 (t, J = 4.8 Hz, 2H), 3.76 (dd, J ₁ = 12.2 Hz, J ₂ = 3.0 Hz, 1H), 3.17 (t, J = 4.8 Hz, 2H)

LCMS: 391 (M + H ⁺ ) for C ₁₆ H ₁₉ -FN ₈ O ₃

Example 22 Preparation of Compound 24

After dissolving Compound XX (100mg, 0.34mmol) prepared in Example 5 in DMF, DIEA (0.65 mL, 0.34 mmol) and chloromethylcyclic amidoxime (56 mg, 0.37 mmol) were added and stirred at room temperature for 5 hours. Stirred at 80 ° C for 13 h. After cooling to room temperature, dilute with dichloromethane (50 mL), wash with distilled water (40 mL), dehydrate with anhydrous sodium sulfate, and column chromatography with 10% MeOH / MC to separate ivory-colored solid title compound 24 (56mg, 41). %) Was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.54 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.19 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.87 (s, 1H), 4.77 (m, 1H), 4.04-4.00 (m, 5H), 3.79- 3.62 (m, 5H) 3.34 (t, J = 4.8 Hz, 2H), 3.10 (s, 3H), 3.08-3.04 (m, 2H), 2.80 (br s, 1H)

LCMS: 407 (M + H ⁺ ) for C ₁₈ H ₂₃ -FN ₆ O ₄

Example 23 Preparation of Compound 25

Made in Preparation Example 9 Compound IX AcOH (0.01 mL, 0.17 mmol) and NaBH (OAc) ₃ (43 mg, 0.20 mmol) were added to the mixture (70 mg, 0.17 mmol) and aldehyde in dichloromethane (4 mL), followed by stirring. The solution was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, dehydrated with anhydrous sodium sulfate and separated by column chromatography with 10% MeOH / MC to give a brown solid (60 mg, 68%).

This compound (60mg, 0.12mmol) was added dichloromethane (3mL) and 4M HCl (0.5mL) and stirred for 40 minutes at room temperature. The solvent was concentrated under reduced pressure, triturated with dichloromethane and filtered to obtain a brown solid title compound 25 (49 mg, 96%).

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 9.31 (br s, 2H), 7.67 (d, J = 14 Hz, 1H), 7.47-7.39 (m, 2H), 7.31 (s, 1H), 4.73 (m, 1H), 4.13 (s, 2H), 4.09 (t, J = 9.0 Hz, 1H), 3.86-3.55 (m, 5H), 3.12 (br t, 2H)

LCMS: 407 (M + H ⁺ ) for C ₁₇ H ₁₉ -FN ₆ O ₃ S

Example 24 Preparation of Compound 26

Made in Preparation Example 9 Compound IX (100 mg, 0.24 mmol) and aminothiazole (68 mg, 0.37 mmol) were added to acetonitrile (4 mL), and DIPEA (0.13 mL, 0.72 mmol) was added and stirred under reflux for 9 hours. After cooling to room temperature, the solvent was concentrated under reduced pressure, diluted with dichloromethane, washed sequentially with water and brine, dehydrated with anhydrous sodium sulfate, separated by column chromatography with 10% MeOH / MC, and brown solid (40mg, 32%). Got.

This compound (40mg, 0.08mmol) was added dichloromethane (2.5mL) and 4M HCl (0.4mL) and stirred for 40 minutes at room temperature. The solvent was concentrated under reduced pressure, triturated with dichloromethane, the filtered solid was dissolved in MeOH, concentrated under reduced pressure, triturated with EA, and filtered to obtain a brown solid title compound 26 (24 mg, 70%).

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 9.17 (br s, 2H), 7.72 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.60 (t, J = 9.0 Hz, 1H), 7.44 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 6.90 (s, 1H), 4.74 (m, 1H), 4.11 (t, J = 9.0 Hz, 1H), 4.06 (s, 2H), 3.89-3.55 ( m, 5H), 3.29 (br t, 2H)

LCMS: 407 (M + H ⁺ ) for C ₁₇ H ₁₉ -FN ₆ O ₃ S

Example 25 Preparation of Compound 27

Compound XX (100mg, 0.34mmol) prepared in Example 5 was added to DMF, followed by stirring with formylthiazolacetic acid (127mg, 0.68mmol), DIPEA (0.12mL, 0.68mmol), and PyBoP (265mg, 0.51mmol). Stir for 3 hours. Dilute with dichloromethane (70mL), wash three times with water (70mL), wash with saturated aqueous sodium bicarbonate solution, dehydrate with anhydrous sodium sulfate, concentrate under reduced pressure and separate by column chromatography with 10% MeOH / MC to give the title compound. 27 (22 mg, 14%) was obtained.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 12.20 (s, 1H), 8.45 (s, 1H), 7. 65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.40-7.36 (m, 2H), 7.11 (d, J = 1.8 Hz, 1H), 6.94 (s, 1H), 5.23 (t, J = 5.4 Hz, 1H), 4.72 (m, 1H), 4.09 (t, J = 9.0 Hz, 1H), 4.00 (s, 2H), 3.92 (t, J = 4.8 Hz, 2H), 3.83 (m, 1H), 3.71 ( t, J = 4.8 Hz, 2H), 3.69-3.54 (m, 2H)

LCMS: 463 (M + H ⁺ ) for C ₁₉ H ₁₉ -FN ₆ O ₅ S

Example 26 Preparation of Compound 28

Compound 27 (30mg, 0.06mmol) prepared in Example 25 was dissolved in MeOH (6mL), 4M HCl (0.4mL) was added thereto, and the resultant was stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure, triturated with diethyl ether and filtered to obtain an ivory-colored solid title compound 28 (20 mg, 66%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.19 (br s, 2H), 7. 65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.40-7.38 (m, 2H), 7.18 (d, J = 2.0 Hz, 1H), 6.71 (s, 1H), 4.73 (m, 1H), 4.09 ( t, J = 9.0 Hz, 1H), 4.00 (s, 2H), 3.93 (t, J = 4.8 Hz, 2H), 3.84 (m, 1H), 3.71 (t, J = 4.8 Hz, 2H), 3.69- 3.54 (m, 2 H)

LCMS: 435 (M + H ⁺ ) for C ₁₈ H ₁₉ -FN ₆ O ₄ S

Example 27 Preparation of Compound 29

The compound XVI prepared in Preparation Example 16 was reacted in the same manner as in Example 7, to obtain an ivory-colored solid title compound 29 (158 mg, 77%).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.54 (s, 1H), 7.59 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.21 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.15 (t, J = 9 Hz, 1H), 6.98 (s, 1H), 5.99 (t, J = 6.0 Hz, 1H), 4.80 (m, 1H) , 4.26 (t, J = 4.8 Hz, 2H), 4.06 (t, J = 9.0 Hz, 1H), 3.90 (t, J = 4.8 Hz, 2H), 3.82-3.61 (m, 3H), 2.03 (s, 3H)

LCMS: 420 (M + H ⁺ ) for C ₁₇ H ₁₈ -FN ₇ O ₃ S

Example 28 Preparation of Compound 30

From the compound XVI prepared in Preparation Example 16, the reaction was carried out as in Example 10, to obtain a yellow solid title compound 29 (19 mg, 16%).

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 8.23 (t, J = 5.4 Hz, 1H), 8.16 (s, 1H), 7.76 (s, 1H), 7.60 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.40 (t, J = 9 Hz, 1H), 7.32-7.30 (m, 2H), 4.71 (m, 1H), 4.13-4.08 (m, 3H), 3.84-3.69 (m, 3H), 3.38 (t, J = 5.6 Hz, 2H), 1.80 (s, 3H)

LCMS: 463 (M + H ⁺ ) for C ₁₈ H ₁₉ FN ₈ O ₄ S

Example 29 Preparation of Compound 31

Compound XVI prepared in Preparation Example 16 was reacted in the same manner as in Example 3, to obtain a yellow solid title compound 31 (63 mg, 21%).

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 8.23 (t, J = 5.8 Hz, 1H), 7.64 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.48 (s, 1H), 7.45 (t, J = 9.0 Hz, 1H), 7.35 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 4.75 (m, 1H), 4.22 (t, J = 5.2 Hz, 2H), 4.13 (t, J = 9.0 Hz, 1H), 3.87 (s, 2H) , 3.84-3.73 (m, 3H), 3.42 (t, J = 5.2 Hz, 2H), 1.83 (s, 3H)

LCMS: 435 (M + H ⁺ ) for C ₁₈ H ₁₉ FN ₆ O ₄ S

Example 30 Preparation of Compound 32

Compound XVI (100 mg, 0.27 mmol) prepared in Preparation Example 16 was dissolved in chloroform (3 mL), and then saturated aqueous sodium bicarbonate solution (3 mL) was added thereto and thiophosgene (0.021 mL, 0.27 mmol) at 0 ° C. ) Was slowly added and stirred for 30 minutes. The organic layer was collected using a separating funnel, ammonia water (3 mL) and THF (5 mL) were added thereto, and the organic solvent was distilled under reduced pressure after stirring at room temperature for 12 hours. The mixture was triturated with diethyl and filtered to give a white solid (80 mg, 76%).

The solid (37 mg, 0.09 mmol) was added to EtOH (2 mL), and chloroacetaldehyde (0.024 mL, 0.18 mmol) was added and stirred under reflux for 12 hours. The solvent was distilled under reduced pressure to triturate with diethyl to give the title compound 32 (33 mg, 89%) as a light brown solid.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 8.30 (t, J = 5.4 Hz, 1H), 7.65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.45 (t, J = 9.0 Hz, 1H), 7.37 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 7.30 (s, 1H), 6.96 (d, J = 3.6 Hz, 1H), 4.77 (m, 1H) , 4.16 (t, J = 9.0 Hz, 1H), 4.09 (t, J = 4.8 Hz, 2H), 3.90-3.75 (m, 3H), 3.44 (t, J = 4.8 Hz, 2H), 1.86 (s, 3H)

LCMS: 419 (M + H ⁺ ) for C ₁₈ H ₁₉ FN ₆ O ₃ S

Example 31 Preparation of Compound 33

The white solid title compound 33 (148 mg, 84%) was obtained by the same method as in Example 30, using ethyl bromopyruvate instead of chloroacetaldehyde from Compound XVI prepared in Preparation Example 16.

¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.56 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.54 (s, 1H), 7.18 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.13 (t, J = 9 Hz, 1H), 6.95 (s, 1H), 5.98 (t, J = 6.0 Hz, 1H), 4.78 (m, 1H) , 4.35 (q, J = 7.2 Hz, 2H), 4.22 (t, J = 4.8 Hz, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.84 (t, J = 4.8 Hz, 2H), 3.79 -3.60 (m, 3H), 2.01 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H)

LCMS: 491 (M + H ⁺ ) for C ₂₁ H ₂₃ -FN ₆ O ₅ S

Example 32 Preparation of Compounds 34 and 35

Compound 33 (140mg, 0.29mmol) prepared in Preparation Example 16 was dissolved in MeOH (7 mL), and ammonia water (14 mL) was added thereto, and the mixture was stirred under reflux for 12 hours. The solvent was concentrated under reduced pressure and separated by column chromatography (eluent: 7% MeOH in MC) to give a pale yellow solid title compound 34 (30.2mg, 0.06mmol, 22%), title compound 35 (19.7mg, 0.04mmol, 15%) Were obtained respectively.

<Title Compound 34>

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.24 (t, J = 5.6 Hz, 1H), 7.61 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.44-7.40 (m, 4H), 7.33 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.22 (d, J = 1.6 Hz, 1H), 4.73 (m, 1H), 4.14-4.08 (m, 3H), 3.87-3.71 (m, 3H), 3.41 (t, J = 5.6 Hz, 2H), 1.82 (s, 3H)

LCMS: 462 (M + H ⁺ ) for C ₁₉ H ₂₀ FN ₇ O ₄ S

<Title Compound 35>

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.22 (t, J = 5.6 Hz, 1H), 7.57 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.38 (t, J = 9.2 Hz, 1H), 7.31-7.28 (m, 2H), 7.14 (d, J = 2.0 Hz, 1H), 4.70 (m, 1H), 4.11-3.97 (m, 3H), 3.80-3.68 (m, 3H), 3.37 (t, J = 5.6 Hz, 2H), 1.79 (s, 3H)

LCMS: 463 (M + H ⁺ ) for C ₁₉ H ₁₉ FN ₆ O ₅ S

Example 33 Preparation of Compound 36

Compound XVI prepared in Preparation Example 16 was reacted in the same manner as in Example 10 using ethyl bromoacetate instead of ethylchlorooxoacetate to obtain a pale yellow solid title compound 36 (11 mg, 0.025 mmol, 23%).

^OneH NMR (600MHz, DMSO-d₆) δ = 10.59 (s, 1H), 8.25 (t,J = 5.8 Hz, 1H), 7.59 (dd, J _One = 13.8 Hz,J ₂ = 2.4 Hz, 1H), 7.37 (t,J = 9.0 Hz, 1H), 7.31 (dd, J _One = 9.0 Hz,J ₂ = 2.4 Hz, 1H), 7.06 (s, 1H), 4.73 (m, 1H), 4.12 (t,J = 9.0 Hz, 1H), 3.77-3.7 (m, 5H), 3.41 (t,J = 5.4 Hz, 2H), 3.39 (s, 2H), 1.83 (s, 3H)

LCMS: 450 (M + H ⁺ ) for C ₁₈ H ₂₀ FN ₇ O ₄ S

Example 34 Preparation of Compound 37

The compound XVI prepared in Preparation Example 16 was reacted with CNBr as in Example 11, treated with hydrazine, and reacted in the same manner as in Example 9, to obtain a white solid title compound 37 (10 mg, 0.02 mmol, 16%). Got it.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.17 (s, 1H), 10.61 (s, 1H), 8.25 (t, J = 5.6 Hz, 1H), 7.64-7.01 (m, 4H), 4.74 ( m, 1H), 4.12 (t, J = 8.8 Hz, 1H), 3.86-3.37 (m, 7H), 1.83 (s, 3H)

LCMS: 419 (M + H ⁺ ) for C ₁₇ H ₁₉ FN ₈ O ₄

Example 35 Preparation of Compound 38

The compound XVI prepared in Preparation Example 16 was reacted with CNBr as in Example 11, treated with hydroxylamine, and reacted in the same manner as in Example 9 to give a white solid title compound 38 (10 mg, 0.02 mmol, 24%). )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.28 (s, 1H), 8.20 (t, J = 5.6 Hz, 1H), 7.56 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.37 (t, J = 9.2 Hz, 1H), 7.29 (dd, J ₁ = 9.2 Hz, J ₂ = 2.4 Hz, 1H), 7.13 (s, 1H), 4.70 (m, 1H), 4.08 (t, J = 8.8 Hz, 1H), 3.77-3.36 (m, 7H), 1.71 ( s, 3 H)

LCMS: 420 (M + H ⁺ ) for C ₁₇ H ₁₈ FN ₇ O ₅

Example 36 Preparation of Compound 39

The white solid title compound 39 (0.048 g, 0.11 mmol, 83%) was obtained by reaction in the same manner as in Example 17 from compound XVI prepared in Preparation Example 16.

¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.51 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.31-7.16 (m, 3H), 7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.09 (t, J = 9 Hz, 1H), 6.93 (s, 1H), 5.97 (t, J = 6.0 Hz, 1H), 4.79 (m, 1H) , 4.03 (t, J = 9.0 Hz, 1H), 3.79-3.61 (m, 5H), 2.93 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H)

LCMS: 432 (M + H ⁺ ) for C ₂₀ H ₂₂ -FN ₅ O ₃ S

Example 37 Preparation of Compound 40

Compound XVI prepared in Preparation Example 16 was reacted in the same manner as in Example 13, to obtain white solid title compound 40 (0.021 g, 0.05 mmol, 37%).

¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.51 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.09 (t, J = 9 Hz, 1H), 6.93 (s, 1H), 6.49 (s, 1H), 5.94 (t, J = 6.0 Hz, 1H) , 4.79 (m, 1H), 4.03 (t, J = 9.0 Hz, 1H), 3.98 (s, 2H), 3.79 (t, J = 4.8 Hz, 2H), 3.78-3.60 (m, 3H), 2.95 ( t, J = 4.8 Hz, 2H), 2.03 (s, 3H)

LCMS: 416 (M + H ⁺ ) for C ₂₀ H ₂₂ -FN ₅ O ₄

Example 38 Preparation of Compound 41

The white solid title compound 41 (0.044 g, 0.10 mmol, 76%) was obtained by reaction in the same manner as in Example 13 from compound XVI prepared in Preparation Example 16.

¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.76 (d, J = 3.0 Hz, 1H), 7.52 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.33 (d, J = 3.0 Hz, 1H), 7.15 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.11 (t, J = 9 Hz, 1H), 6.96 (s, 1H), 5.97 (t, J = 6.0 Hz, 1H), 4.79 (m, 1H) , 4.50 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.83 (t, J = 4.8 Hz, 2H), 3.78-3.60 (m, 3H), 3.08 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H)

LCMS: 433 (M + H ⁺ ) for C ₁₉ H ₂₁ -FN ₆ O ₃ S

Example 39 Preparation of Compound 42

The white solid title compound 42 (0.043 g, 0.10 mmol, 74%) was obtained by reaction in the same manner as in Example 13 from compound XVI prepared in Preparation Example 16.

¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.51 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.08 (t, J = 9 Hz, 1H), 6.98 (s, 1H), 6.89 (s, 1H), 6.88 (s, 1H), 5.98 (t, J = 6.0 Hz, 1H), 4.79 (m, 1H), 4.21 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.79 (s, 3H), 3.78-3.60 (m, 5H), 3.01 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H)

LCMS: 430 (M + H ⁺ ) for C ₂₀ H ₂₄ -FN ₇ O ₃

Example 40 Preparation of Compound 43

The white solid title compound 43 (0.004 g, 0.01 mmol, 7%) was obtained from the compound XVI prepared in Preparation Example 16 in the same manner as in Example 23.

¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.51 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.14-7.09 (m, 4H), 6.94 (s, 1H), 6.23 (s, 1H), 4.79 (m, 1H), 4.20 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.78-3.60 (m, 5H), 3.10 (t, J = 4.8 Hz, 2H), 2.73 (s, 3H), 2.03 (s, 3H)

LCMS: 447 (M + H ⁺ ) for C ₂₀ H ₂₃ -FN ₆ O ₃ S

Example 41 Preparation of Compound 44

Compound XVI (150 mg, 0.40 mmol) prepared in Preparation Example 16 was dissolved in acetonitrile (5 mL), and then DIPEA (0.22 mL, 0.61 mmol) was added to the trityl-aminothiazole compound (237 mg, 0.61 mmol). The mixture was refluxed for 5 hours. The solution was cooled to room temperature, the solvent was distilled under reduced pressure, diluted with dichloromethane (40 mL), washed with water (40 mL), and the organic layer was dehydrated with anhydrous titanium sulfate, followed by column chromatography with 5% MeOH / MC. The chromatography separated to give a brown solid (8 2 mg, 30%). The compound (80 mg, 0.12 mmol) was added to TFA (8 mL), stirred at reflux for 3 hours, cooled to room temperature, the solvent was concentrated under reduced pressure, and the residue was concentrated by column chromatography with water: acetonitrile = 3: 7 to give a brown solid title. Compound 44 (40 mg, 60%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.26 (t, J = 5.6 Hz, 1H), 7.57 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.36 (t, J = 9.2 Hz, 1H), 7.30 (dd, J ₁ = 9.2 Hz, J ₂ = 2.4 Hz, 1H), 7.12 (s, 1H), 6.56 (s, 1H), 4.73 (m, 1H), 4.11 (t, J = 8.8 Hz, 1H), 3.86 (s, 2H), 3.74-3.01 (m, 7H), 1.83 (s, 3H)

LCMS: 448 (M + H ⁺ ) for C ₁₉ H ₂₂ -FN ₇ O ₃ S

Example 42 Preparation of Compound 45

The white solid title compound 45 (0.003 g, 0.01 mmol, 4%) was obtained from the compound XVI prepared in Preparation Example 16 in the same manner as in Example 22.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.26 (t, J = 5.6 Hz, 1H), 7.57 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.34 (t, J = 9.2 Hz, 1H), 7.29 (dd, J ₁ = 9.2 Hz, J ₂ = 2.4 Hz, 1H), 6.91 (s, 1H), 4.73 (m, 1H), 4.11 (t, J = 8.8 Hz, 1H), 3.83 (t, J = 4.8 Hz, 2H) , 3.73-3.28 (m, 7H), 2.97 (s, 3H), 2.93 (t, J = 4.8 Hz, 2H), 1.83 (s, 3H)

LCMS: 448 (M + H ⁺ ) for C ₂₀ H ₂₆ -FN ₇ O ₄ S

Example 43 Preparation of Compound 46

Compound XVI (0.2 g, 0.54 mmol), chloroacetonitrile (0.07 mL, 1.08 mmol), potassium carbonate (0.074 g, 0.54 mmol), NaI (0.081 g, 0.54 mmol) prepared in Preparation Example 16 was added to DMF (6 mL). After the reaction was carried out for 3 hours at 60 ° C., the organic layer was extracted and the column chromatography was separated to give an intermediate compound. (0.141 g, 0.38 mmol, 70%) was obtained. This compound (0.124 g, 0.33 mmol) was dissolved in DMF (3 mL) with ammonium chloride solution (0.089 mL, 1.65 mmol) and sodium azide (0.108 g, 1.65 mmol), and then stirred under reflux for 12 hours to solidify ( trituration) gave the title compound 46 (0.074 g, 0.146 mmol, 44%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.25 (t, J = 5.6 Hz, 1H), 7.55 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.35-7.27 (m, 2H), 6.87 (s, 1H), 4.72 (m, 1H), 4.13-2.92 (m, 10H), 1.83 (s, 3H )

LCMS: 418 (M + H ⁺ ) for C ₁₇ H ₂₀ -FN ₉ O ₃ S

Example 44 Preparation of Compound 47

The white solid title compound 47 (0.030 g, 0.07 mmol, 54%) was reacted with furan-2-carbaldehyde instead of 5-methylfurfural in the same manner as in Example 13 from compound XVI prepared in Preparation Example 16. Got it.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.51 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.41 (m, 1H) 7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.08 (t, J = 9 Hz, 1H), 6.92 (s, 1H), 6.36-6.33 (m, 2H), 5.93 (t, J = 6.0 Hz, 1H), 4.78 (m, 1H), 4.12 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.81 (t, J = 4.8 Hz, 2H), 3.78-3.56 (m, 3H) 3.02 (t, J = 4.8 Hz, 2H), 2.02 (s, 3H)

LCMS: 416 (M + H ⁺ ) for C ₂₀ H ₂₂ -FN ₅ O ₄

Example 45 Preparation of Compound 48

Compound XVI prepared in Preparation Example 16 was reacted with 5-nitrofuran-2-carbaldehyde instead of 5-methylfurfural in the same manner as in Example 13, to obtain a white solid title compound 48 (0.040 g, 0.08 mmol, 64 %) Was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.53 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 7.15 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.10 (t, J = 9 Hz, 1H), 6.89 (s, 1H), 6.62 (d, J = 3.6 Hz, 1H), 5.92 (t, J = 6.0 Hz, 1H), 4.79 (m, 1H), 4.18 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.84 (t, J = 4.8 Hz, 2H), 3.78-3.61 (m, 3H) 3.11 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H)

LCMS: 461 (M + H ⁺ ) for C ₂₀ H ₂₁ -FN ₆ O ₆

Example 46 Preparation of Compound 49

The pale yellow solid title compound 49 (44 mg, 72%) was reacted with 5-chlorofuran-2-carbaldehyde instead of 5-methylfurfural by the same method as Example 13 from compound XVI prepared in Preparation Example 16. Got.

¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.53 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.10 (t, J = 9 Hz, 1H), 6.94 (s, 1H), 6.35 (d, J = 2.4 Hz, 1H), 6.13 (d, J = 2.4 Hz, 1H), 5.99 (t, J = 6.0 Hz, 1H), 4.79 (m, 1H), 4.07 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.82 (t, J = 4.8 Hz, 2H), 3.78-3.60 (m, 3H) 3.15 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H)

LCMS: 450 (M + H ⁺ ) for C ₂₀ H ₂₁ -ClFN ₅ O ₄

Example 47 Preparation of Compound 50

The white solid title compound was reacted by using 2,4-dihydroxy-6-methylpyrimidine-5-carbaldehyde instead of 5-methylfurfural in the same manner as in Example 13 from compound XVI prepared in Preparation Example 16. 50 (33 mg, 52%) was obtained.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 10.81 (s, 1H), 8.27 (t, J = 6.0 Hz, 1H), 7.55 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.32 (t, J = 9.0 Hz, 1H), 7.27 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 6.85 (s, 1H), 4.73 (m, 1H), 4.11 (t, J = 9.0 Hz, 1H), 3.74-3.67 (m, 5H), 3.41 ( t, J = 4.8 Hz, 2H), 2.87 (t, J = 4.8 Hz, 2H), 2.20 (s, 3H), 1.84 (s, 3H)

LCMS: 474 (M + H ⁺ ) for C ₂₁ H ₂₄ -ClFN ₇ O ₅

Example 48 Preparation of Compound 51

The white solid title compound 51 (0.039 g, 0.09 mmol, 68%) was reacted by using picolinaldehyde instead of 5-methylfurfural in the same manner as in Example 13 from compound XVI prepared in Preparation Example 16. Got

¹ H NMR (600 MHz, CDCl ₃ ) δ = 8.59 (d, J = 4.8 Hz, 1H), 7.69 (m, 1H), 7.53-7.50 (m, 2H), 7.20 (m, 1H), 7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.10 (t, J = 9 Hz, 1H), 6.93 (s, 1H), 5.94 (t, J = 6.0 Hz, 1H), 4.78 (m, 1H) , 4.24 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.83 (t, J = 4.8 Hz, 2H), 3.77-3.59 (m, 3H), 3.09 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H)

LCMS: 427 (M + H ⁺ ) for C ₂₁ H ₂₃ -FN ₆ O ₃

Example 49 Preparation of Compound 52

The white solid title compound 52 (3.2 mg, 6%) was obtained by reacting the same method as in Example 9 from Compound XVI prepared in Preparation Example 16.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 11.80 (s, 1H), 8.26 (t, J = 5.8 Hz, 1H), 7.61 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.39 (t, J = 9.0 Hz, 1H), 7.33 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.12 (s, 1H), 4.74 (m, 1H), 4.12 (t, J = 9.0 Hz, 1H), 3.80-3.71 (m, 5H), 3.41 ( t, J = 5.2 Hz, 2H), 1.83 (s, 3H)

LCMS: 436 (M + H ⁺ ) for C ₁₇ H ₁₈ FN ₇ O ₄ S

Experimental Example 1 Measurement of In Vitro Antimicrobial Activity

In order to determine the antimicrobial activity of the oxazolidinone derivatives synthesized in Examples 1 to 48 in vitro activity test was carried out in the following manner.

In vitro antimicrobial activity of the oxazolidinone derivatives of Examples 1 to 48 of the present invention is 90% inhibition, which is the minimum concentration of antibiotic that can inhibit the growth of bacteria by 90% compared to drug-untreated control growth by spectroscopic measurements. The concentration (MIC ₉₀ , ug / mL) was evaluated by measuring. MIC ₉₀ is a CLSI standard [Clinical and Laboratory Standards Institute Document. (2000) Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically-Fifth Edition: M7-A5. CLSI, Villanova, PA] was measured by the Broth microdilution method.

1) test strain

Methicillin susceptible Staphylococcus aureus (MSSA, methicillin susceptible Staphylococcus aureus ), methicillin resistant Staphylococcus aureus (MRSA, methicillin resistant Staphylococcus aureus ), vancomycin-resistant enterocokai (VRE, Vancomycin) resistant Enterococci ), vancomycin-linezolide resistant enterococcus faecalis (VLRE, Vancomycin - Linezolid Resistant Enterococcus faecalis ), Haemophilus Influenzae and moraxella were all 14 strains ( S. aureus , S. aureus ^MR , S. epidermidis , S.epidermidis ^MR , E. faecalis , E.faecalis ^VanA , E. faecalis ^VanA LR , E. faecium ^VanA , E. faecium , E. coli , P. aeruginosa , K.pneumoniae, H. influenzae , M. catarrhalis ) were used to determine the antimicrobial activity. Shown in

2) Test substance manufacturing method

The test substance (oxazolidinone derivative compounds 1 to 51 according to the present invention synthesized in Examples 1 to 48) was dissolved in DMSO at a concentration of 10240 ug / mL, and then diluted twice by fold to sterilized tertiary distilled water. Diluted 20fold. In the antimicrobial experiment, the final concentration was from 128 ug / mL to 0.0625 ug / mL, and the concentration of DMSO used as excipient was 2.5% (V / V). As a control material, the antibacterial activity was compared using the compound of Pharmazolide (Formula B) of Pharmacia & Upzone and the results are shown in Table 1 below.

[Formula B]

Table 1 Antimicrobial activity of compounds of formula 1 (MIC ₉₀ , ug / mL)

1.Staphylococcus aureus

2. Methicillin Resistant Staphylococcus aureus

3. Staphylococcus epidermidis

4. Methicillin Resistant Staphylococcus epidermidis

5. Enterococcus faecalis

6. Vancomycin Resistant Enterococcus faecalis

7. Linezolid and Vancomycin Resistant Enterococcus faecalis

8. Enterococcus faecium

9. Vancomycin Resistant Enterococcus faecium

10. Haemophilus influenzae

11.Moraxella catarrhalis

As shown in Table 1, the oxazolidinone derivatives of the present invention are effective against Gram-positive bacteria, particularly Gram-positive bacteria (MRSA, VRE, etc.), which are resistant to gram-positive bacteria, especially existing antibiotics, at much lower concentrations than the control linerazole. Haemophilus It is also effective for Gram-negative bacteria such as Influenzae ) and moraxella . In particular, it shows high antimicrobial activity against Linezolide resistant Enterococcus faecalis, which shows that it can be useful for Linezolide resistant bacteria that can start to manifest recently and become a big problem in the future.

Therefore, it can be seen that the oxazolidinone derivative of the present invention can be usefully used as an antibiotic having a broad spectrum for Gram-positive bacteria.

Claims (5)

A novel oxazolidinone derivative represented by the following formula (1), a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof.
[Formula 1]

[Wherein,
X is a chemical bond,-(CH ₂ ) _n -or-(CH ₂ ) _n C (= 0)-;
n is an integer from 0 to 2;
R is a 5 or 6 membered hetero ring selected from the structure:

R ₁ to R ₂₅ are each independently hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, -OH, -NR ₃₁ R ₃₂ , -C (= 0) R ₃₃ ,- (CH ₂ ) _m OH, —C═NOH, —CN, —NO ₂ or halogen;
R ₃₁ and R ₃₂ are independently of each other hydrogen, (C ₁ -C ₆ ) alkyl, or —C (═O) H;
R ₃₃ is hydrogen, —OH, —NH ₂ or (C ₁ -C ₆ ) alkyl;
m is an integer from 1 to 6;
Q is -OH, -NHC (= 0) R ₄₁ or -NHC (= 0) OR ₄₁ ;
R ₄₁ is (C ₁ -C ₆ ) alkyl.] The method of claim 1,
A novel oxazolidinone derivative represented by the following Chemical Formulas 2 to 4, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof.
(2)

(3)

[Chemical Formula 4]

[In Formulas 2 to 4, R and Q are the same as defined in claim 1.] The method of claim 2,
Novel oxazolidinone derivatives represented by the formulas 5 to 10, prodrugs thereof, hydrates thereof, solvates thereof, isomers thereof or pharmaceutically acceptable salts thereof.
[Chemical Formula 5]

[Formula 6]

[Formula 7]

[Chemical Formula 8]

[Formula 9]

[Formula 10]

[In Formulas 5 to 10, R is the same as defined in claim 1] The method of claim 3, wherein
An oxazolidinone derivative, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from the following compounds.

Antibiotics comprising the novel oxazolidinone derivatives, prodrugs thereof, hydrates thereof, solvates thereof, isomers thereof or pharmaceutically acceptable salts thereof according to any one of claims 1 to 4 as an active ingredient. Pharmaceutical composition for.