KR20110046186A - Triazole compounds and pharmaceutical composition for treating tuberculosis comprising the same - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing triazole compounds for treating tuberculosis is provided to be used as an anti-tuberculosis therapeutic agent. CONSTITUTION: A triazole compound is denoted by chemical formula 1 or 2. In chemical formula 1 or 2, R1 is aryl or heteroaryl; R2 is hydroxy, keto, amino, azido, C1-16 alkyl amino, and C1-6 acyl amino group. A pharmaceutical composition for treating tuberculosis contains a triazole compound of chemical formula 1a or pharmaceutically acceptable salt thereof as an active ingredient.

Description

TRIAZOLE COMPOUNDS AND PHARMACEUTICAL COMPOSITION FOR TREATING TUBERCULOSIS COMPRISING THE SAME

The present invention relates to a triazole compound, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for treating tuberculosis containing the same as an active ingredient.

Econazole of Formula A, which is used as an antifungal agent, is known to have anti-tuberculosis activity and activity against non-replicating tuberculosis bacteria (Hugues Ouellet et al., JBC 2008, 283, 5069-5080). And Zahoor Ahmad et al., FEMS Microbiol Lett., 2006, 258, 200-203):

[Formula A]

Anti-tuberculosis activity of various triazole compounds has been published (Nilkanth G. Aher et al., BMCL, 2009, 19, 759-763; Yufeng Chen et al ., J. Med. Chem . 2008, 51, 3437- 3448; and Kadir Dabak et al ., Eur. J. Med. Chem . 2003, 38, 215-218).

In the present invention, a triazole-based compound having a structure in which an imidazole of econazol is substituted with triazole was designed and a similar synthesis method has been published (Haribabu Ankati et al ., J. Org. Chem . 2008, 73, 6433-6436). ).

Accordingly, the present inventors completed the present invention by discovering a novel triazole-based compound and performing an experiment for anti-tuberculosis effect, and discovering that there is an antituberculosis effect.

It is therefore an object of the present invention to provide triazole compounds and their pharmaceutically acceptable salts.

Still another object of the present invention is to provide a pharmaceutical composition for treating tuberculosis containing the triazole compound and its pharmaceutically acceptable salts as an active ingredient.

In order to achieve the above object, the present invention provides a triazole compound and a pharmaceutically acceptable salt thereof.

In order to achieve the above another object, it provides a pharmaceutical composition for treating tuberculosis containing the triazole compound and its pharmaceutically acceptable salts as an active ingredient.

Since the novel triazole-based compound of the present invention exhibits excellent anti-tuberculosis effect, it can be usefully used as an anti-tuberculosis therapeutic agent.

Hereinafter, the present invention will be described in detail.

The present invention provides a triazole compound represented by the following general formula (1) or (2) and a pharmaceutically acceptable salt thereof:

In the above equations,

R ₁ is aryl or heteroaryl;

R ₂ is hydroxy; Keto; Amino; Azido; C _1-6 alkylamino; C _1-6 acylamino group, C _1-3 arylalkyl or C _1-3 heteroarylalkyl unsubstituted or substituted with halogen, trifluoromethoxy;

R ₃ is C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl or hydroxyC _1-4 alkyl.

Preferably, in the above formula, R ₁ is phenyl, biphenyl, monohalophenyl or dihalophenyl; R ₂ is hydroxy, keto, amino, azido, C _1-6 alkylamino, acylamino, benzyl, monohalbenzyl, dihalbenzyl or trifluoromethoxy; R ₃ is monohalo, dihalo, carboxyl, alkyl, hydroxyl, amino or alkylamino.

Specific examples of the compounds which are more preferred as the triazole compound of Formula 1 or 2 according to the present invention are as follows:

1) 4-butyl-1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole;

2) 2- (1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) ethanol;

3) 4-butyl-1- (2- (2,4-dichlorophenyl) -2- (4- (trifluoromethoxy) benzyloxy) ethyl) -1H-1,2,3-triazole;

4) 2- (1- (2- (2,4-dichlorophenyl) -2- (4- (trifluoromethoxy) benzyloxy) ethyl) -1H-1,2,3-triazol-4-yl )ethanol;

5) 4-butyl-1- (2- (2,4-dichlorophenyl) -2- (2,4-difluorobenzyloxy) ethyl) -1H-1,2,3-triazole;

6) 2- (1- (2- (2,4-dichlorophenyl) -2- (2,4-difluorobenzyloxy) ethyl) -1H-1,2,3-triazol-4-yl) ethanol;

7) 1- (2,4-dichlorophenyl) -2- (1H-1,2,3-triazol-1-yl) ethanol;

8) 1- (2,4-dichlorophenyl) -2- (2H-1,2,3-triazol-2-yl) ethanol;

9) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole;

10) 2- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -2H-1,2,3-triazole;

11) 2- (2H-benzo [d] [1,2,3] triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol;

12) 2- (2H-benzo [d] [1,2,3] triazol-2-yl) -1- (2,4-dichlorophenyl) ethanol;

13) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-benzo [d] [1,2,3] triazole;

14) 2- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -2H-benzo [d] [1,2,3] triazole;

15) (1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) methanol;

16) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4-cyclopropyl-1H-1,2,3-triazole;

17) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4-cyclopentyl-1H-1,2,3-triazole;

18) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4-cyclohexyl-1H-1,2,3-triazole;

19) 4-tert-butyl-1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole;

20) 3- (1- (2- (4-chlorobenzyloxy) -2- (2,4-2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) Benzineamine;

21) 4- (1- (2- (4-chlorobenzyloxy) -2- (2,4-2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) Benzineamine;

22) 2- (1- (2- (4-chlorobenzyloxy) -2- (2,4-2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) Pyridine;

23) 3- (1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) phenol;

24) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4- (4-methoxyphenyl) -1H-1,2,3-triazole;

25) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4-propyl-1H-1,2,3-triazole;

26) ethyl 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole-4-carboxylate;

27) methyl 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole-4-carboxylate;

28) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4- (2,5-dimethylphenyl) -1H-1,2,3-triazole;

29) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4-m-tolyl-1H-1,2,3-triazole;

30) 1- (1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) ethanol;

31) 1- {1- [2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl] -1H- [1,2,3] triazol-4-yl} -hexane- 1-ol;

32) 2- (1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) propane-2- Come;

33) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole-4-carboxylic acid;

34) 1- (2,4-dichlorophenyl) -2- (4- (hydroxymethyl) -1H-1,2,3-triazol-1-yl) ethanol;

35) 2- (4-cyclopropyl-1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol;

36) 2- (4-cyclopentyl-1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol;

37) 2- (4-butyl-1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol;

38) 1- (2,4-dichlorophenyl) -2- (4- (2-hydroxyethyl) -1H-1,2,3-triazol-1-yl) ethanol;

39) 2- (4-cyclohexyl- [1,2,3] triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol;

40) 2- (4-tertiary-butyl-1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol;

41) 2- (4- (3-aminophenyl) -1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol;

42) 2- (4- (4-aminophenyl) -1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol; And

43) 1- (2,4-dichlorophenyl) -2- (4- (pyridin-2-yl) -1H-1,2,3-triazol-1-yl) ethanol.

The compounds of Formulas 1 and 2 according to the present invention include not only pharmaceutically acceptable salts thereof, but also all possible solvates, hydrates and stereoisomers that may be prepared therefrom.

As used herein, the term "halo" means fluoro, bromo, chloro or iodo.

As used herein, the term "alkyl" refers to a linear or branched saturated C ₁ to C ₆ hydrocarbon radical chain. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl and hexyl.

As used herein, the term "alkoxy" refers to the group -ORa, where Ra is alkyl as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, and the like.

The term "aryl" as used herein includes fused groups such as naphthyl, phenanthrenyl, and the like, as well as monocyclic or bicyclic aromatic rings such as phenyl, substituted phenyl, and the like. The aryl group optionally contains one or more substituents, ie halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, alkyl S (O) n ( n = 1,2,3) or thiol, but is not limited thereto.

As used herein, the term “heteroaryl” refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, Tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1 , 2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3- Triazineyl, 1,3,5-triazinyl, cinnolinyl, pterridylyl, purinyl, 6,7-dihydro-5H- [1] pyridinyl, or 5,6,7,8 as bicyclic Tetrahydro-quinolin-3-yl, benzooxazolyl, benzothiazolyl, benzo [b] thiophenyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, iso Thianaphthenyl, benzofuranyl, isobenzofuranyl, iso Dodol, indolyl, indolinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, pyrazolo [3,4-b] pyridinyl, or benzoxazineyl It is called.

As used herein, the term "alkenyl" refers to a linear or branched hydrocarbon radical chain having one or more carbon-carbon double bonds. Examples of "alkenyl" as used herein include, but are not limited to, ethenyl and propenyl.

As used herein, the term "alkynyl" refers to a linear or branched saturated hydrocarbon radical chain having one or more carbon-carbon triple bonds. Examples of "alkynyl" as used herein include, but are not limited to, acetylenyl and 1-propynyl.

"Pharmaceutically acceptable salts" of the compound of Formula 1 may be prepared by conventional methods in the art, for example, hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and the like. Salts with inorganic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestyic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid Salts with organic acids such as silicic acid (aspirin), salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, methanesulfonic acid , Salts with sulfonic acids such as ethanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid, metal salts by reaction with alkali metals such as sodium and potassium, or salts with ammonium ions. It should.

Compounds of Formula 1 or 2 according to the present invention may be prepared according to the synthetic route represented by Scheme 1 below:

Where

R ¹ is monohalo, dihalo, phenyl or nitro,

R ² is monohalo, dihalo or trifluoromethoxy,

R ³ is alkyl, hydroxyalkyl, cyclopropyl, cyclopentyl, cyclohexyl, aminophenyl, pyridyl, hydroxyphenyl, alkoxycarbonyl, alkylphenyl or carboxylic acid.

Referring to the preparation method of the compound of the present invention as shown in Scheme 1 in detail as follows.

Compound of Formula 1a, 1) heating the chlorohydrin compound of Formula 2 under azido sodium and dimethylformamide (DMF) to obtain the azido compound of Formula 3; And 2) various alkyne (e.g., C _1-6 alkylalkyne, C _1-6 hydroxide) using a click chemistry (cyclization reaction using base and copper catalyst of azide compound and alkyne compound). Oxyalkylalkyne, cyclopropylalkyne, cyclopropylalkyne, cyclopentylalkyne, cyclohexylalkyne, aminophenylalkyne, pyridylalkyne, hydroxyphenylalkyne, C _1-6 alkoxycarbonylalkyne, alkylphenylalkyne or carboxylic acid alkyne ) And a copper catalyst.

On the other hand, the compound of Formula 4 can be obtained by reacting the compound of Formula 3 obtained above with various benzyl bromide, sodium hydride (NaH) and tetrabutylammonium iodine (TBAI) under dimethylformamide. Compounds of Formula 1b can be prepared by reacting a compound of Formula 4 with various alkyne and copper catalysts using click chemistry.

Compounds of Formulas 1c and 1d can be prepared by reacting a chlorohydrin compound of Formula 2 with triazole.

In addition, the compound of formula 2 according to the present invention can also be prepared according to the synthetic route represented by Scheme 2:

Specifically, the compound of formula 1e or 1f of the present invention may be prepared by reacting the chlorohydrin compound of formula 2 with benzotriazole under microwaves.

In addition, the compound of Formula 1e or 1f prepared above may be prepared by benzylation at −78 ° C. to room temperature under DMF in the presence of sodium hydride (NaH) and tetrabutylammonium iodine (TBAI).

In addition, preferred embodiments of the present invention provide novel triazole compounds of Formulas 1a-1h:

In the above equations,

R ₁ and R ₂ are each independently C _1-6 alkyl, monohalo, dihalo, aryl or heteroaryl;

R ₃ is C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl or hydroxyC _1-4 alkyl.

On the other hand, the present invention provides a pharmaceutical composition for preventing or treating tuberculosis, which contains a triazole compound or a pharmaceutically acceptable salt thereof as an active ingredient.

A pharmaceutical composition comprising the triazole compound according to the present invention and a pharmaceutically acceptable salt thereof can be administered orally or parenterally during clinical administration and can be used in the form of general pharmaceutical formulations. It may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like.

Solid preparations for oral administration may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose or gelatin with at least one triazole compound according to the present invention. have. In addition to simple excipients, lubricants such as magnesium stearate or talc may also be used.

Liquid preparations for oral administration include suspensions, solutions, emulsions, or syrups, and various excipients such as wetting agents, sweeteners, fragrances, or preservatives can be used in addition to the commonly used simple diluents, water and liquid paraffin. have.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations or suppositories. The non-aqueous solvent or suspension may be a vegetable oil such as propylene glycol, polyethylene glycol, or olive oil, an injectable ester such as ethyl oleate, and the like. Cacao butter, laurin butter, glycerol or gelatin and the like can be used.

In addition, the human dosage of the pharmaceutical composition for preventing and treating tuberculosis according to the present invention may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is based on an adult patient having a weight of 70 kg. In general, the dosage is 0.1 to 1000 mg / day, preferably 1 to 500 mg / day, and may be dividedly administered once to several times a day at regular time intervals.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1: Preparation of 4-butyl-1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole

Step 1: Synthesis of 2-azido-1- (2,4-dichlorophenyl) ethanol

In a dried flask passed through argon, alpha- (chloromethyl) -2,4-dichlorobenzyl alcohol (5.00 g, 22.2 mmol) was diluted with dimethylformaldehyde, followed by sodium hydrogen (2.88 g, 44.3 mmol) and fluorinated tetra Butyl ammonium (0.41 g, 1.1 mmol) was added and reacted at 90 degreeC for 12 hours. The reaction was terminated by addition of water and extracted twice with ethyl acetate. The water of the obtained organic layer was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure, and then purified using a silica gel column (ethyl acetate / hexane = 1/5) to obtain 2-azido-1- (2,4-dichlorophenyl) ethanol. Was obtained as a pale yellow liquid in a yield of 69% (3.55 g).

¹ H NMR (CDCl ₃ ) δ 2.47-2.50 (m, 1H), 3.34 (dd, J = 12.6, 7.8 Hz, 1H), 3.57 (dd, J = 12.6, 3.0 Hz, 1H), 5.22-5.27 ( m, 1H), 7.32 (dd, J = 8.4, 2.1 Hz, 1H), 7.37 (d, J = 2.1 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H);

¹³ C NMR (CDCl ₃ ) δ 56.1, 69.7, 127.6, 128.4, 129.2, 132.1, 134.4, 136.4.

Step 2

The azide compound (500 mg, 2.15 mmol), 4-trifluoromethoxybenzyl bromide (659 mg, 2.59 mmol) and tetrabutylammonium iodide (159 mg, 0.43 mmol) synthesized in step 1 were placed in a dried flask passed through argon. ) Was diluted in anhydrous dimethylformaldehyde (5 mL) and 60% sodium hydride (95 mg, 2.4 mmol) was added at -78 ° C. After slowly raising the temperature of the reaction mixture to room temperature, the reaction mixture was reacted for 2.5 hours. Water was added to terminate the reaction, and the reaction mixture was extracted twice with ethyl acetate. The water of the obtained organic layer was removed with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and then purified using a silica gel column to obtain 1- (2-azido-1- (4-chlorobenzyloxy) ethyl) -2,4-dichlorobenzene Was obtained as a pale yellow liquid in a yield of 90% (790 mg).

¹ HNMR (CDCl ₃ ) δ 3.29 (dd, J = 12.9, 3.0 Hz, 1H), 3.40 (dd, J = 12.9, 7.8 Hz, 1H), 4.39 (d, J = 11.4, 1H), 4.48 (d , J = 11.4, 1H), 5.00 (dd, J = 7.5, 3.0 Hz, 1H), 7.25-7.35 (m, 5H), 7.40 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H);

¹³ CNMR (CDCl ₃ ) δ 54.8, 70.7, 77.2, 127.7, 128.6, 128.7, 128.8, 129.1, 129.2, 129.5, 133.5, 133.8, 134.4, 134.7, 135.6.

Step 3: Click chemistry (Vsevolod V. Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-2599)

The compound obtained in step 2 (107 mg, 0.30 mmol) was diluted in t-butanol / water (1 mL: 1 mL), and then 1-hexine (46.0 mg, 0.60 mmol) and 0.03 mL of 1M aqueous sodium L-ascorbate solution ( 5.94 mg, 0.030 mmol) and copper pentasulphate (0.75 mg, 0.0030 mmol) are added, followed by stirring at room temperature for 72 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and purified using a silica gel column (EA / Hex = 1/3-> 1/1) to give the compound of Example 1 as a white solid in a yield of 68% (90.0 mg).

Mp = 78.9-80.2 ° C.;

¹ HNMR (CDCl ₃ ) δ 0.95 (t, J = 7.2Hz, 3H), 1.34-.1.42 (m, 2H), 1.58-1.66 (m, 2H), 2.72 (t, J = 8.1, 7.2Hz, 2H ), 4.17 (d, J = 11.7, 1H), 4.36-4.46 (m, 2H), 4.36-4.46 (m, 2H), 4.60 (dd, J = 14.1, 3.0 Hz, 1H), 5.14 (dd, J = 8.4, 3.0 Hz, 1H), 7.04 (d, J = 8.4 Hz, 2H), 7.25-7.33 (m, 4H), 7.38-7.44 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 13.8, 22.2, 25.2, 31.6, 54.0, 70.6, 76.2, 121.7, 127.9, 128.5, 128.6, 129.1, 129.7, 133.67, 133.7, 133.8, 135.0, 135.2, 148.2; HRMS (ESMS) calcd for C ₂₁ H ₂₂ Cl ₃ N ₃ O ₃ [M ⁺ ] 437.0828, found 437.0802.

Example 2: of 2- (1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) ethanol Produce

Step 2 of Example 1 was diluted with starting material (50 mg, 0.140 mmol) in acetonitrile (1.5 mL), followed by but-3-tin-1-ol (11.8 mg, 0.168 mmol), 2,6- Lutidine (30 mg, 0.25 mmol), diisopropylethylamine (36.2 mg, 0.280 mmol) and copper iodide (I) (2.66 mg, 0.014 mmol) were added and stirred. The reaction mixture was reacted for 15 minutes at 60 ° C. in a microwave reactor (Rotor: 4 × 48MC) for 15 minutes (ramp time: 5 minutes). After completion of the reaction, the mixture was extracted with ethyl acetate, and the compound of Example 2 was obtained as a yellow liquid in 63% (38 mg) yield by prep TLC.

Example 3: 4-butyl-1- (2- (2,4-dichlorophenyl) -2- (4- (trifluoromethoxy) benzyloxy) ethyl) -1H-1,2,3-triazole Produce

Step 1:

Example 1 step 1 compound was used as starting material, instead of 4-chlorobenzyl bromide of step 2 of Example 1 using 4-trifluoromethoxybenzyl bromide as starting material, In the same manner, 1- (2-azido-1- (4- (trifluoromethoxy) benzyloxy) ethyl) -2,4-thichlorobenzene was obtained in a yellow liquid at a yield of 90%.

¹ H NMR (CDCl ₃ ) δ 3.31 (dd, J = 12.9, 7.8 Hz, 1H), 3.42 (dd, J = 12.9, 7.8 Hz, 1H), 4.45 (d, J = 11.7, 1H), 4.51 (d , J = 11.7, 1H), 5.03 (dd, J = 7.8, 3.3 Hz, 1H), 7.21 (d, J = 8.7 Hz, 2H), 7.31-7.41 (m, 4H), 7.50 (d, J = 8.4 Hz, 1H);

¹³ C NMR (CDCl ₃ ) δ 54.8, 70.7, 77.2, 118.7, 121.0, 122.2, 127.8, 128.8, 129.1, 129.6, 133.5, 134.4, 134.8, 135.9, 148.9.

Step 2:

Step 1 After diluting the compound (50 mg, 0.12 mmol) in acetonitrile (1.5 mL), 1-hexine (10.1 mg, 0.123 mmol), 2,6-lutidine (26.4 mg, 0.246 mmol), diiso Propylethylamine (31.8 mg, 0.246 mmol) and copper iodide (I) (2.34 mg, 0.0123 mmol) were added and stirred. The reaction mixture was reacted for 15 minutes at 60 ° C. in a microwave reactor (Rotor: 4 × 48MC) for 15 minutes (ramp time: 5 minutes). After completion of the reaction, the mixture was extracted with ethyl acetate, and the compound of Example 3 was obtained as a yellow liquid by 58% (35 mg) yield by prep TLC.

¹ H NMR (CDCl ₃ ) δ 0.94 (t, J = 7.2 Hz, 3H), 1.34-1.44 (m, 2H), 1.56-1.69 (m, 2H), 2.72 (t, J = 8.1, 7.2 Hz, 2H ), 4.23 (d, J = 11.7, 1H), 4.38-4.48 (m, 2H), 4.62 (dd, J = 14.1, 3.0 Hz, 1H), 5.17 (dd, J = 8.4, 3.0 Hz, 1H), 7.15 (s, 4H), 7.26-7.33 (m, 2H), 7.39-7.45 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 13.8, 22.2, 25.3, 31.6, 54.0, 70.7, 120.9, 121.8, 127.9, 128.5, 129.1, 129.8, 133.7, 133.8, 135.1, 135.6, 148.4, 148.9;

HRMS (ESMS) calcd for C ₂₂ H ₂₂ Cl ₂ F ₃ N ₃ O ₂ [M ⁺ ] 487.1041, found 487.1044.

Example 4: 2- (1- (2- (2,4-dichlorophenyl) -2- (4- (trifluoromethoxy) benzyloxy) ethyl) -1H-1,2,3-triazole-4 Preparation of Ethanol

In the same manner as in Example 2, Step 2, using but-3-tin-1-ol as the starting material instead of 1-hexyne of Step 2 of Example 3, the compound of Example 4 was obtained as a pale yellow solid. mg) yield.

¹ H NMR (CDCl ₃ ) δ 2.61 (s, br, 1H), 2.95 (t, J = 6.0 Hz, 2H), 3.93-3.97 (m, 2H), 4.24 (d, J = 11.7, 1H), 4.40 -4.48 (m, 2H), 4.64 (dd, J = 14.1, 3.0 Hz, 1H), 5.18 (dd, J = 8.4, 3.0 Hz, 1H), 7.16 (s, 4H), 7.32 (dd, J = 8.5 , 1.9 Hz, 1H), 7.39-7.45 (m, 3H);

¹³ C NMR (CDCl ₃ ) δ 28.6, 54.1, 61.7, 70.7, 76.4, 121.1, 128.0, 128.5, 129.1, 129.8, 133.6, 133.7, 135.2, 135.5, 148.9;

HRMS (ESMS) calcd for C ₂₀ H ₁₈ Cl ₂ F ₃ N ₃ O ₃ [M ⁺ ] 475.0677, found 475.0649.

Example 5: Preparation of 4-butyl-1- (2- (2,4-dichlorophenyl) -2- (2,4-difluorobenzyloxy) ethyl) -1H-1,2,3-triazole

Step 1:

Example 1 step 1 compound was used as starting material, and 1- (bromomethyl) -2,4-difluorobenzene was used as starting material instead of 4-chlorobenzyl bromide of step 2 of Example 1 In the same manner as in Step 2 of Example 1, 94% of 1-((2-azido-1- (2,4-dichlorophenyl) ethoxy) methyl) -2,4-difluorobenzene as a yellow liquid Obtained in yield.

¹ H NMR (CDCl ₃ ) δ 3.29 (dd, J = 13.2, 3.3Hz, 1H), 3.39 (dd, J = 12.9, 7.8Hz, 1H) 4.44 (d, J = 11.7Hz, 1H), 4.54 (d , J = 11.7 Hz, 1H), 5.03 (dd, J = 7.8, 3.3 Hz, 1H), 6.77-6.93 (m, 2H), 7.33 (dd, J = 8.4, 2.1 Hz, 1H), 7.39-7.47 ( m, 2H), 7.58 (d, J = 8.4 Hz, 1H);

¹³ CNMR (CDCl ₃ ) δ 54.6, 64.6, 77.3, 103.7, 111.2, 111.3, 120.2, 120.4, 127.7, 128.6, 129.5, 131.1, 133.3, 134.3, 134.6, 159.9, 160.0, 161.6, 161.9, 162.0, 163.5, 163.6 .

Step 2:

Step 1 Compound (5 mg, 0.12 mmol) was used as a starting material, and the compound of Example 5 was obtained as a pale yellow solid in a yield of 54% (33 mg) using the same method as in Step 2 of Example 3.

¹ H NMR (CDCl ₃ ) δ 0.94 (t, J = 7.2 Hz, 3H), 1.34-1.42 (m, 2H), 1.58-1.68 (m, 2H), 2.71 (t, J = 8.1, 7.2 Hz, 2H ), 4.25 (d, J = 11.7, 1H), 4.37 (dd, J = 14.1, 8.7 Hz, 1H), 4.47 (d, J = 11.4 Hz, 1H), 4.62 (dd, J = 14.1, 3.0 Hz, 1H), 5.15 (dd, J = 8.4, 3.0 Hz, 1H), 6.74-6.86 (m, 2H), 7.08-7.16 (m, 1H), 7.30-7.33 (m, 2H), 7.40-7.45 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 13.8, 22.2, 25.3, 31.6, 54.0, 64.9, 76.6, 103.9, 111.3, 111.4, 119.9, 121.8, 127.9, 128.4, 129.7, 133.3, 133.7, 135.1, 148.3, 160.1, 160.2, 161.8, 161.9, 162.1, 163.7, 163.8;

HRMS (ESMS) calcd for C ₂₁ H ₂₁ Cl ₂ F ₂ N ₃ O [M ⁺ ] 439.1030, found 439.1026.

Example 6: 2- (1- (2- (2,4-dichlorophenyl) -2- (2,4-difluorobenzyloxy) ethyl) -1H-1,2,3-triazole-4- Production of Ethanol

Example 1 Compound 1 was obtained as a pale yellow liquid in 56% (34 mg) yield in the same manner as in Example 4, using the compound of Step 1 of Example 5 as a starting material (50 mg, 0.140 mmol).

Mp = 99.3-100.1 ° C;

¹ HNMR (CDCl ₃ ) δ 2.52 (s, br, 1H), 2.94 (t. J = 6.0 Hz, 2H), 3.95 (s, br, 2H), 4.25 (d, J = 11.7, 1H), 4.37 ( dd, J = 14.1, 8.7 Hz, 1H), 4.47 (d, J = 11.4, 1H), 4.64 (dd, J = 14.1, 3.0 Hz, 1H), 5.15 (dd, J = 8.4, 3.0 Hz, 1H) , 6.74-6.87 (m, 2H), 7.08-7.16 (m, 1H), 7.37 (dd, J = 8.5, 1.9 Hz, 1H), 7.40 (s, 1H), 7.43-7.45 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 28.6, 54.2, 61.7, 64.9, 76.4, 103.9, 111.3, 111.4, 119.9, 127.9, 128.4, 129.8, 131.4, 133.5, 133.7, 135.2, 160.2, 161.8, 161.9, 162.1, 162.2, 163.7, 163.8;

HRMS (ESMS) calcd for C ₁₉ H ₁₇ Cl ₂ F ₂ N ₃ O ₂ [M ⁺ ] 427.0666, found 427.0656.

Example 7: Preparation of 1- (2,4-dichlorophenyl) -2- (1H-1,2,3-triazol-1-yl) ethanol

Alpha- (chloromethyl) -2,4-dichlorobenzyl alcohol (500 mg, 2.22 mmol) diluted in acetonitrile (5 mL), hydrogen 1,2,3-triazole (306.3 mg, 4.434 mmol ), Potassium carbonate (612.8 mg, 4.434 mmol) is added and stirred. The reaction mixture was reacted in a microwave reactor (Rotor: MF100) at 600W for 80 minutes for 50 minutes (ramp time 5 minutes). After completion of the reaction, the mixture was extracted with ethyl acetate and separated by silica gel column with ethyl acetate / hexane = 1: 3 to give the compound of Example 7 as a white solid in a yield of 43% (245.1 mg).

Mp = 127.2-128.0 ° C .;

¹ HNMR (CDCl ₃ ) δ 3.77 (d, J = 3.3 Hz, 1H), 4.42 (dd, J = 14.1, 7.8 Hz, 1H), 4.75 (dd, J = 14.1, 2.7 Hz, 1H), 5.50-5.54 (m, 1H), 7.26-7.30 (m, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 0.9, 1H), 7.67 (d, J = 0.9, 1 H);

¹³ C NMR (CDCl ₃ ) δ 55.2, 63.3, 69.3, 124.9, 127.7, 128.4, 129.3, 132.1, 133.5, 134.6, 136.0;

HRMS (ESMS) calcd for C ₁₀ H ₉ Cl ₂ N ₃ O [M ⁺ ] 257.0123, found 257.0108.

Example 8: Preparation of 1- (2,4-dichlorophenyl) -2- (2H-1,2,3-triazol-2-yl) ethanol

Example 7 80.6 mg (14%) of the compound of Example 8 was obtained as a white solid as a by-product during the synthesis process.

Mp = 93.0-93.9 ° C .;

¹ HNMR (CDCl ₃ ) δ 4.05 (d, J = 4.2 Hz, 1H), 4.41 (dd, J = 13.8, 7.8 Hz, 1H), 4.75 (dd, J = 14.1, 2.4 Hz, 1H), 5.52-5.55 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 5.4 Hz, 2H);

¹³ C NMR (CDCl ₃ ) δ 55.4, 69.2, 125.2, 127.8, 128.6, 129.3, 132.3, 133.4, 134.6, 136.5;

HRMS (ESMS) calcd for C ₁₀ H ₉ Cl ₂ N ₃ O [M ⁺ ] 257.0123, found 257.0120.

Example 9: Preparation of 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole

Example 7 compound (50 mg, 0.19 mmol) and 4-chloro instead of 4-trifluoromethoxybenzyl bromide and 2-azido-1- (2,4-dichlorophenyl) ethanol in step 2 of Example 1 Example 9 compound was obtained as a pale yellow liquid in 77% yield using the same method as step 2 of Example 1 using benzyl bromide as a starting material.

¹ H NMR (CDCl ₃ ) δ 4.19 (d, J = 11.7 Hz, 1H), 4.41-4.52 (m, J = 12.1H), 4.71 (dd, J = 14.1, 3.0H), 5.17 (dd, J = 8.1, 3.0 Hz, 1H), 7.04 (d, J = 8.4 Hz, 2H), 7.26-7.33 (m, 2H), 7.38 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 1.8, 1H ), 7.61 (d, J = 0.9, 1H), 7.70 (d, J = 0.9, 1H);

¹³ C NMR (CDCl ₃ ) δ 53.9, 70.7, 76.2, 124.6, 127.9, 128.4, 128.6, 129.0, 129.8, 133.5, 133.6, 133.7, 133.9, 135.1, 135.14; LC / MS [M + H ⁺ ] 382.97.

Example 10 Preparation of 2- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -2H-1,2,3-triazole

Example 2 compound (50 mg, 0.19 mmol) was used as starting material instead of 2-azido-1- (2,4-dichlorophenyl) ethanol in Step 2 of Example 1, and was the same as Step 2 of Example 1 The compound of Example 9 was obtained as a pale yellow liquid in 49% yield by the method.

Mp = 204.1-204.3 ° C.;

¹ HNMR (CDCl ₃ ) δ 4.15 (d, J = 12.0 Hz, 1H), 4.44 (d, J = 12.0 Hz, 1H), 4.63-4.65 (m, 2H), 5.33-5.37 (m, 2H), 6.95 (d, J = 8.1 Hz, 2H), 7.20-7.26 (m, 2H), 7.33 (dd, J = 8.4, 1.8 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1 H), 7.62 (s, 2 H); LC / MS [M + H ⁺ ] 382.91.

Example 11: Preparation of 2- (2H-benzo [d] [1,2,3] triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol

The compound of Example 11 was white in the same manner as in Example 7, using 1-hydrogen-1,2,3-benzotriazole as a starting material instead of 1-hydrogen-1,2,3-triazole of Example 7. Obtained as a solid in 25% yield.

Mp = 204.3-206.1 ° C .;

¹ HNMR (CDCl ₃ ) δ 4.72 (dd, J = 14.1, 8.1 Hz, 1H), 4.96 (dd, J = 14.1, 2.7 Hz, 1H), 5.63-5.68 (m, 1H), 7.30 (dd, J = 1.8 Hz, 1H), 7.35-7.40 (m, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.47-7.58 (m, 3H), 8.02 (d, J = 8.4 Hz, 1H);

¹³ C NMR (CDCl ₃ ) δ 53.4, 69.7, 109.5, 119.9, 124.2, 127.7, 127.8, 128.5, 129.3, 132.2, 133.6, 134.7, 136.1, 145.6;

HRMS (ESMS) calcd for C ₁₄ H ₁₁ Cl ₂ N ₃ O [M ⁺ ] 307.0279, found 307.0271.

Example 12: 2- (2H-benzo [d] [1,2,3] triazol-2-yl) -1- (2,4-dichlorophenyl) ethanol

Example 11 51.9 mg (8%) of the compound of Example 12 was obtained as a white solid as a by-product during the synthesis process.

Mp = 152.7-153.0 ° C .;

¹ HNMR (CDCl ₃ ) δ 4.31 (d, J = 3.3 Hz, 1H), 4.73 (dd, J = 13.8, 8.7 Hz, 1H), 5.09 (dd, J = 13.8, 2.4 Hz, 1H), 5.67-5.71 (m, 1H), 7.29 (dd, J = 8.4, 2.1 Hz, 1H), 7.41-7.46 (m, 3H), 7.61 (d, J = 8.4 Hz, 1H), 7.87-7.91 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 60.9, 69.4, 117.5, 118.0, 126.9, 127.7, 128.5, 129.4, 132.4, 134.6, 135.6, 144.2;

HRMS (ESMS) calcd for C ₁₄ H ₁₁ Cl ₂ N ₃ O [M ⁺ ] 307.0279, found 307.0267.

Example 13: Preparation of 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-benzo [d] [1,2,3] triazole

Example 2 step 2 of Example 1 using the compound of Example 11 (50 mg, 0.16 mmol) as starting material instead of 2-azido-1- (2,4-dichlorophenyl) ethanol. In the same manner, Example 13 compound was obtained as a white solid in 73% yield.

Mp = 98.6-100.2 ° C .;

¹ HNMR (CDCl ₃ ) δ 4.04 (d, J = 12.0 Hz, 1H), 4.40 (d, J = 12.0 Hz, 1H), 4.80-4.83 (m, 2H), 5.25 (dd, J = 7.5, 3.9 Hz , 1H), 6.73 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 7.27-7.51 (m, 7H), (dd, J = 8.4, 2.1 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1 H);

¹³ C NMR (CDCl ₃ ) δ 52.4, 70.5, 75.5, 109.8, 119.8, 123.8, 127.2, 128.0, 128.3, 128.7, 129.0, 129.7, 133.4, 133.6, 133.7, 134.0, 134.9, 135.1, 145.9;

LC / MS [M + H ⁺ ] 432.82

Example 14 Preparation of 2- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -2H-benzo [d] [1,2,3] triazole

Example 2 step 2 of Example 1 using the compound of Example 12 (50 mg, 0.16 mmol) as starting material instead of 2-azido-1- (2,4-dichlorophenyl) ethanol. In the same manner, Example 14 compound was obtained as a colorless liquid in 57% yield.

¹ H NMR (CDCl ₃ ) δ 4.07 (d, J = 12.3, 1H), 4.45 (d, J = 12.3, 1H), 4.83-4.92 (m, 2H), 5.49 (dd, J = 8.7, 3.91H) , 6.72 (d, J = 8.1, 2H), 6.96 (d, J = 8.1 Hz, 2H), 7.35-7.46 (m, 4H), 7.62 (d, J = 8.4 Hz, 1H), 7.86-7.89 (m , 2H);

¹³ C NMR (CDCl ₃ ) δ 60.3, 70.6, 75.9, 118.1, 126.5, 128.0, 128.3, 128.9, 129.7, 133.6, 133.8, 134.2, 135.1, 135.2, 144.5; LC / MS [M + H ⁺ ] 433.90;

LC / MS [M + H ⁺ ] 431.93.

Example 15 Preparation of (1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) methanol

Step 2 compound of Example 1 (50 mg, 0.140 mmol) was diluted in methylene chloride (1.5 mL) using starting material, followed by propazyl alcohol (11.8 mg, 0.210 mmol), diisopropylethylamine (90.6 mg, 0.700 mmol) and copper iodide (I) (53.3 mg, 0.280 mmol) were added and stirred. The reaction mixture was reacted at 600 ° C. in a microwave reactor (Rotor: 4 × 48MC) for 10 minutes at 150 ° C. (ramp time: 5 minutes). After completion of the reaction, the resultant was filtered through celite, extracted with ethyl acetate, and the compound of Example 15 was obtained as a yellow solid in 72% (42 mg) yield by prep TLC (ethyl acetate / hexane = 3/1).

Mp = 95.6-96.7 ° C .;

¹ HNMR (CDCl ₃ ) δ 2.30-2.32 (m, 1H), 4.28 (d, J = 11.7 Hz, 1H), 4.40-4.48 (m, 2H), 4.65 (dd, J = 14.1, 3.0 Hz, 1H) , 4.80 (d, J = 5.7 Hz, 2H), 5.13-5.16 (m, 1H), 7.05 (d, J = 8.1 Hz, 2H), 7.26-7.33 (m, 3H), 7.39-7.45 (m, 2H ), 7.58 (s, 1 H);

¹³ C NMR (CDCl ₃ ) δ 54.1, 56.2, 70.7, 76.1, 123.0, 127.9, 128.4, 128.7, 129.1, 129.8, 133.5, 133.6, 133.9, 135.1, 147.6;

HRMS (ESMS) calcd for C ₁₈ H ₁₆ Cl ₃ N ₃ O ₂ [M ⁺ ] 411.0308, found 411.0309.

Example 16: Preparation of 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4-cyclopropyl-1H-1,2,3-triazole

Using the same method as in Example 15, using cyclopropylacetylene as the starting material instead of the propazyl alcohol of Example 15, the Example 16 compound was obtained as a yellow liquid in 76% yield.

¹ H NMR (CDCl ₃ ) δ 0.80-0.88 (m, 2H), 0.95-1.01 (m, 2H), 1.93-1.99 (m, 1H), 4.16 (d, J = 11.7, 1H), 4.32-4.46 ( m, 2H), 4.58 (dd, J = 14.1, 3.0 Hz, 1H), 4.80 (d, J = 5.7 Hz, 2H), 5.11 (dd, J = 8.7, 3.0 Hz, 1H), 7.03 (d, J = 8.1 Hz, 2H), 7.24-7.34 (m, 4H), 7.40-7.45 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 6.8, 7.7, 54.1, 70.7, 76.1, 120.7, 127.9, 128.5, 128.7, 129.0, 129.2, 129.7, 133.7, 133.9, 135.1, 135.2, 150.2; HRMS (ESMS) calcd for C ₂₀ H ₁₈ Cl ₃ N ₃ O [M ⁺ ] 421.0515, found 421.0508.

Example 17 Preparation of 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4-cyclopentyl-1H-1,2,3-triazole

Using the same procedure as in Example 15, using cyclopentylacetylene as the starting material instead of the propazyl alcohol of Example 15, the compound of Example 17 was obtained as a yellow liquid in 78% yield.

¹ H NMR (CDCl ₃ ) δ 1.59-1.75 (m, 6H), 2.10 (s, br, 2H), 3.18-3.24 (m, 1H), 4.16 (d, J = 11.7, 1H), 4.34-4.46 ( m, 2H), 4.60 (dd, J = 14.1, 3.0 Hz, 1H), 5.12-5.15 (m, 1H), 7.03 (d, J = 8.1 Hz, 2H), 7.26-7.34 (m, 4H), 7.40 -7.45 (m, 2 H);

¹³ C NMR (CDCl ₃ ) δ 25.1, 33.2, 33.3, 36.8, 54.2, 70.7, 76.1, 120.7, 127.9, 128.5, 128.7, 129.2, 129.7, 133.7, 133.8, 133.9, 135.1, 135.3, 152.7;

HRMS (ESMS) calcd for C ₂₂ H ₂₂ Cl ₃ N ₃ O [M ⁺ ] 449.0828, found 449.0818.

Example 18 Preparation of 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4-cyclohexyl-1H-1,2,3-triazole

Using the same method as in Example 15, using cyclohexylacetylene as the starting material instead of the propazyl alcohol of Example 15, the Example 18 compound was obtained as a yellow liquid in 84% yield.

¹ H NMR (CDCl ₃ ) δ 1.29-1.45 (m, 5H), 1.71-1.85 (m, 3H), 2.05 (s, br, 2H), 2.74-2.84 (m, 1H), 4.16 (d, J = 11.7, 1H), 4.34-4.46 (m, 2H), 4.60 (dd, J = 14.1, 3.0 Hz, 1H), 5.12-5.15 (m, 1H), 7.03 (d, J = 8.1 Hz, 2H), 7.26 -7.34 (m, 4H), 7.40-7.45 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 26.1, 33.1, 35.2, 54.1, 70.7, 76.3, 120.6, 127.9, 128.5, 128.6, 129.1, 129.7, 133.7, 133.8, 133.9, 135.1, 135.2, 153.7;

HRMS (ESMS) calcd for C ₂₃ H ₂₄ Cl ₃ N ₃ O [M ⁺ ] 463.0985, found 463.0988.

Example 19 Preparation of 4-tert-butyl-1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole

Using the same method as in Example 15, using cyclohexylacetylene as the starting material instead of the propazyl alcohol of Example 15, the Example 19 compound was obtained as a yellow liquid in 84% yield.

¹ H NMR (CDCl ₃ ) δ 1.36 (s, 9H), 4.16 (d, J = 11.7, 1H), 4.33-4.46 (m, 2H), 4.60 (dd, J = 14.1, 3.0 Hz, 1H), 5.15 (dd, J = 8.7, 3.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 2H), 7.26-7.34 (m, 4H), 7.40-7.45 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 30.2, 30.5, 30.7, 54.2, 70.7, 76.2, 119.8, 127.9, 127.5, 128.6, 129.0, 129.2, 129.7, 133.8, 133.9, 135.1, 135.3, 157.5;

HRMS (ESMS) calcd for C ₂₁ H ₂₂ Cl ₃ N ₃ O [M ⁺ ] 437.0828, found 437.0838.

Example 20: 3- (1- (2- (4-chlorobenzyloxy) -2- (2,4-2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole-4- I) Preparation of Benzineamine

Example 20 compound was obtained in 84% yield as a brown solid by the same method as Example 15 using 3-ethynylaniline as a starting material instead of the propazyl alcohol of Example 15.

Mp = 109.6-110.4 ° C .;

¹ HNMR (CDCl ₃ ) δ 3.78 (s, 2H), 4.18 (d, J = 11.4 Hz, 1H), 4.23-4.50 (m, 2H), 4.68 (dd, J = 14.4, 3.0 Hz, 1H), 5.17 (dd, J = 8.4, 2.7Hz, 1H), 6.69 (d, J = 7.5Hz, 1H), 7.04 (d, J = 8.1Hz, 2H), 7.11 (d, J = 7.5Hz, 1H), 7.20 -7.25 (m, 4H), 7.33 (dd, J = 8.4, 1.8 Hz, 2H), 7.41-7.47 (m, 2H), 7.73 (s, 1H);

HRMS (ESMS) calcd for C ₂₃ H ₁₉ Cl ₃ N ₄ O [M ⁺ ] 472.0624, found 427.0628.

Example 21: 4- (1- (2- (4-chlorobenzyloxy) -2- (2,4-2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole-4- I) Preparation of Benzineamine

In the same manner as in Example 15 using 4-ethynylaniline as a starting material instead of the propazyl alcohol of Example 15, the compound of Example 21 was obtained in a brown liquid in a 79% yield.

¹ H NMR (CDCl ₃ ) δ 3.78 (s, br, 2H), 4.18 (d, J = 11.7 Hz, 1H), 4.41-4.49 (m, 2H), 4.67 (dd, J = 14.4, 3.0 Hz, 1H ), 5.17 (dd, J = 8.4, 2.7 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.1 Hz, 2H), 7.22-7.26 (m, 2H), 7.31 -7.34 (m, 1H), 7.42-7.46 (m, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.65 (s, 1H);

HRMS (ESMS) calcd for C ₂₃ H ₁₉ Cl ₃ N ₄ O [M ⁺ ] 472.0624, found 427.0621.

Example 22: 2- (1- (2- (4-chlorobenzyloxy) -2- (2,4-2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole-4- I) Preparation of Pyridine

Example 22 compound was obtained as a white solid in 74% yield in the same manner as in Example 15, using 2-ethynylpyridine as a starting material instead of the propazyl alcohol of Example 15.

Mp = 122.9-124.2 ° C .;

¹ HNMR (CDCl ₃ ) δ 4.19 (d, J = 12.0 Hz, 1H), 4.45-4.56 (m, 2H), 4.68 (d, J = 13.8 Hz, 1H), 5.18-5.20 (m, 1H), 7.05 (d, J = 7.8 Hz, 2H), 7.18-7.27 (m, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.78-7.83 (m, 1H), 8.20 (s, 2 H), 8.62 (s, 1 H);

HRMS (ESMS) calcd for C ₂₂ H ₁₇ Cl ₃ N ₄ O [M ⁺ ] 458.0468, found 458.0459.

Example 23) of 3- (1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) phenol Produce

Example 23 compound was obtained as a yellow solid in 93% yield in the same manner as in Example 15, using 3-hydroxyphenylacetylene as a starting material instead of the propazyl alcohol of Example 15.

Mp = 116.2-116.7 ° C .;

¹ HNMR (CDCl ₃ ) δ 4.18 (d, J = 12.0 Hz, 1H), 4.44-4.51 (m, 2H), 4.70 (dd, J = 14.4, 2.7 Hz, 1H), 5.18 (dd, J = 8.4, 3.0 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 8.1 Hz, 2H), 7.22-7.35 (m, 5H), 7.42-7.46 (m, 3H), 7.77 ( s, 1 H);

HRMS (ESMS) calcd for C ₂₃ H ₁₈ Cl ₃ N ₃ O ₂ [M ⁺ ] 473.0465, found 473.0464.

Example 24 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4- (4-methoxyphenyl) -1H-1,2,3-triazole Manufacture

In the same manner as in Example 15, using 1-ethynyl-4-methoxybenzene as a starting material instead of the propazyl alcohol of Example 15, the compound of Example 24 was obtained in a white solid in 87% yield.

Mp = 128.5-129.7 ° C .;

¹ HNMR (CDCl ₃ ) δ 3.87 (s, 3H), 4.18 (d, J = 11.7 Hz, 1H), 4.42-4.50 (m, 2H), 4.67 (dd, J = 14.4, 3.0 Hz, 1H), 5.18 (dd, J = 8.4, 3.0Hz, 1H), 6.99 (d, J = 8.4Hz, 2H), 7.04 (d, J = 8.1Hz, 2H), 7.23 (d, J = 8.1Hz, 2H), 7.34 (d, J = 8.4, 1.8 Hz, 1H), 7.42-7.47 (m, 2H), 7.70-7.75 (m, 3H);

HRMS (ESMS) calcd for C ₂₄ H ₂₀ Cl ₃ N ₃ O ₂ [M ⁺ ] 487.0621, found 487.0615.

Example 25 Preparation of 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4-propyl-1H-1,2,3-triazole

Example 25 compound was obtained in a white solid at 90% yield in the same manner as in Example 15, using 1-pentine as a starting material instead of the propazyl alcohol of Example 15.

¹ H NMR (CDCl ₃ ) δ 0.97 (t, J = 7.2 Hz, 3H), 1.65-1.75 (m, 2H), 2.70 (t, J = 7.8, 7.2 Hz, 2H), 4.18 (d, J = 11.7 , 1H), 4.37-4.46 (m, 2H), 4.61 (dd, J = 14.1, 3.0 Hz, 1H), 5.15 (dd, J = 8.1, 2.7 Hz, 1H), 7.04 (d, J = 8.1 Hz, 2H), 7.25-7.33 (m, 4H), 7.38-7.44 (m, 2H);

¹³ C NMR (CDCl ₃ ) δ 13.8, 22.2, 25.2, 31.6, 54.0, 70.6, 76.2, 121.7, 127.9, 128.5, 128.6, 129.1, 129.7, 133.67, 133.7, 133.8, 135.0, 135.2, 148.2; HRMS (ESMS) calcd for C ₂₀ H ₂₀ Cl ₃ N ₃ O [M ⁺ ] 423.0672, found 423.0680.

Example 26 Preparation of ethyl 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole-4-carboxylate

The compound of Example 26 was obtained in 86% yield as a yellow solid in the same manner as in Example 15, using ethyl propiolate as a starting material instead of the propazyl alcohol of Example 15.

Mp = 136.2-138.4 ° C .;

¹ HNMR (CDCl ₃ ) δ 1.44 (t, J = 7.2 Hz, 3H), 4.18 (d, J = 11.7 Hz, 1H), 4.42-4.52 (m, 4H), 4.70 (dd, J = 14.1, 3.0 Hz , 1H), 5.15 (dd, J = 8.1, 2.7 Hz, 1H), 7.05 (d, J = 8.4 Hz, 2H), 7.26-7.38 (m, 4H), 7.46 (d, J = 1.8 Hz, 1H) , 8.12 (s, 1 H);

HRMS (ESMS) calcd for C ₂₀ H ₁₈ Cl ₃ N ₃ O ₃ [M ⁺ ] 453.0414, found 453.0426.

Example 27 Preparation of Methyl 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole-4-carboxylate

In the same manner as in Example 15, using methyl propiorate as a starting material instead of the propazyl alcohol of Example 15, the compound of Example 27 was obtained in a white solid at 82% yield.

Mp = 113.4-114.8 ° C .;

¹ HNMR (CDCl ₃ ) δ 3.98 (s, 3H), 4.21 (d, J = 11.7 Hz, 1H), 4.44-4.53 (m, 2H), 4.71 (dd, J = 14.1, 3.0 Hz, 1H), 5.15 (dd, J = 8.1, 2.7Hz, 1H), 7.05 (d, J = 8.4Hz, 2H), 7.26-7.38 (m, 4H), 7.46 (d, J = 1.8Hz, 1H), 8.13 (s, 1H);

LC / MS [M + H ⁺ ] 439.87

Example 28: 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4- (2,5-dimethylphenyl) -1H-1,2,3- Preparation of Triazole

In the same manner as in Example 15, using the 2-ethynyl-1,4-dimethylbenzene as a starting material instead of the propazyl alcohol of Example 15, the compound of Example 28 was obtained in a white solid in 85% yield.

Mp = 110.6-111.5 ° C .;

¹ HNMR (CDCl ₃ ) δ 2.36 (s, 3H), 2.38 (s, 3H), 4.22 (d, J = 11.7 Hz, 1H), 4.44-4.55 (m, 2H), 4.73 (dd, J = 14.1, 3.0 Hz, 1H), 5.23 (dd, J = 8.1, 3.0 Hz, 1H), 7.05-7.10 (m, 3H), 7.17 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.40-7.46 (m, 2H), 7.60 (s, 1H), 7.67 (s, 1H); HRMS (ESMS) calcd for C ₂₅ H ₂₂ Cl ₃ N ₃ O [M ⁺ ] 485.0828, found 485.0826.

Example 29 Preparation of 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4-m-tolyl-1H-1,2,3-triazole

Example 29 compound was obtained in a 77% yield as a white solid in the same manner as in Example 15, using 3-ethynyltoluene as a starting material instead of the propazyl alcohol of Example 15.

Mp = 112.1-112.3 ° C .;

¹ HNMR (CDCl ₃ ) δ 2.43 (s, 3H), 4.18 (d, J = 11.7 Hz, 1H), 4.43-4.51 (m, 2H), 4.69 (dd, J = 14.1, 3.0 Hz, 1H), 5.23 (dd, J = 8.4, 3.0 Hz, 1H), 7.04 (d, J = 8.1 Hz, 2H), 7.17-7.24 (m, 3H), 7.26-7.36 (m, 2H), 7.41 (s, 1H), 7.45-7.47 (m, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.66 (s, 1H), 7.77 (s, 1H);

HRMS (ESMS) calcd for C ₂₄ H ₂₀ Cl ₃ N ₃ O [M ⁺ ] 471.0672, found 471.0662.

Example 30: 1- (1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) ethanol Produce

In the same manner as in Example 15, using 3-butyn-2-one as a starting material in place of the propazyl alcohol of Example 15, the compound of Example 30 was obtained as a colorless liquid in 93% yield.

¹ H NMR (CDCl ₃ ) δ 1.60 (s, 3H), 2.33 (dd, J = 13.8, 4.2 Hz, 1H), 4.17 (d, J = 11.7 Hz, 1H), 4.32-4.47 (m, 2H), 4.64 (dd, J = 14.1, 3.0 Hz, 1H), 5.15 (dd, J = 8.4, 2.7 Hz, 1H), 7.05 (d, J = 8.1 Hz, 2H), 7.26-7.34 (m, 3H), 7.40 -7.46 (m, 2H), 7.52 (d, J = 3.0 Hz, 1H);

HRMS (ESMS) calcd for C ₁₉ H ₁₈ Cl ₃ N ₃ O ₂ [M ⁺ ] 425.0465, found 425.0486.

Example 31: 1- {1- [2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl] -1H- [1,2,3] triazol-4-yl}- Preparation of Hexane-1-ol

In the same manner as in Example 15, using 1-octin-3-ol as a starting material instead of the propazyl alcohol of Example 15, the compound of Example 31 was obtained as a white solid in 70% yield.

Mp = 127.1-128.9 ° C .;

¹ HNMR (CDCl ₃ ) δ 0.91 (s, 3H), 1.26-1.49 (m, 6H), 1.81-1.86 (m, 2H), 2.53 (s, br, 1H), 4.18 (d, J = 11.7 Hz, 1H), 4.38-4.48 (m, 2H), 4.64 (dd, J = 14.1, 3.0 Hz, 1H), 5.15 (dd, J = 8.4, 2.7 Hz, 1H), 7.05 (d, J = 8.4 Hz, 2H ), 7.26-7.38 (m, 3H), 7.39-7.45 (m, 2H), 7.51 (s, 1H);

HRMS (ESMS) calcd for C ₂₃ H ₂₆ Cl ₃ N ₃ O ₂ [M ⁺ ] 481.1091, found 481.1080.

Example 32: 2- (1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) propane- Preparation of 2-ol

In the same manner as in Example 15 using 2-methyl-3-butyn-2-ol as a starting material instead of the propazyl alcohol of Example 15, the Example 32 compound was obtained as a white solid in 93% yield.

Mp = 84.1-85.4 ° C .;

¹ HNMR (CDCl ₃ ) δ 1.64 (s, 6H), 2.53 (s, 1H), 4.17 (d, J = 11.7 Hz, 1H), 4.36-4.72 (m, 2H), 4.63 (dd, J = 14.1, 2.7 Hz, 1H), 5.15 (dd, J = 8.1, 2.7 Hz, 1H), 7.04 (d, J = 8.1 Hz, 2H), 7.26-7.35 (m, 3H), 7.41-7.49 (m, 3H);

HRMS (ESMS) calcd for C ₂₀ H ₂₀ Cl ₃ N ₃ O ₂ [M ⁺ ] 439.0621, found 439.0623.

Example 33 Preparation of 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole-4-carboxylic acid

Example 33 compound was obtained as a white solid in 81% yield in the same manner as in Example 15, using propionic acid as a starting material instead of the propazyl alcohol of Example 15.

¹ H NMR (CDCl ₃ ) δ 4.19 (d, J = 11.7 Hz, 1H), 4.41-4.52 (m, 2H), 5.18 (dd, J = 8.4, 2.7 Hz, 1H), 7.04 (d, J = 8.1 Hz, 2H), 7.26-7.33 (m, 3H), 7.38 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.63 (s, 1H), 7.73 (s, 1H );

HRMS (ESMS) calcd for C ₁₈ H ₁₄ Cl ₃ N ₃ O ₃ [M ⁺ ] 425.0101, found 425.0132.

Example 34 Preparation of 1- (2,4-dichlorophenyl) -2- (4- (hydroxymethyl) -1H-1,2,3-triazol-1-yl) ethanol

Example 34 compound was obtained as a yellow solid in 89% yield in the same manner as in Example 15, using the compound of Step 1 of Example 1 (50 mg, 0.19 mmol) as a starting material.

Mp = 103.5-104.2 ° C;

¹ HNMR (CDCl ₃ ) δ 2.25 (s, br, 1H), 4.24-4.32 (m, 1H), 4.74 (d, J = 8.7 Hz, 3H), 5.42-5.45 (m, 1H), 7.26-7.33 ( m, 1H), 7.41-7.42 (m, 1H), 7.57 (dd, J = 8.4, 3.6 Hz, 1H), 7.72 (s, 1H);

HRMS (ESMS) calcd for C ₁₁ H ₁₁ Cl ₂ N ₃ O ₂ [M ⁺ ] 287.0228, found 287.0202.

Example 35 Preparation of 2- (4-cyclopropyl-1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol

In the same manner as in Example 34, using cyclopropylacetylene instead of the propazyl alcohol of Example 34, the compound of Example 35 was obtained in a yellow solid in 74% yield.

Mp = 158.2-158.9 ° C .;

¹ HNMR (CDCl ₃ ) δ 0.76-0.79 (m, 2H), 0.89-0.97 (m, 2H), 1.86-1.92 (m, 1H), 4.26 (dd, J = 14.1, 8.4 Hz, 1H), 4.60- 4.64 (m, 1H), 5.49-5.51 (m, 1H), 7.27-7.30 (m, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H);

HRMS (ESMS) calcd for C ₁₃ H ₁₃ Cl ₂ N ₃ O [M ⁺ ] 297.0436, found 297.0438.

Example 36 Preparation of 2- (4-cyclopentyl-1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol

In the same manner as in Example 34 using cyclopentylacetylene as a starting material instead of the propazyl alcohol of Example 34, the compound of Example 36 was obtained in a yellow solid in 86% yield.

Mp = 148.1-149.7 ° C .;

¹ HNMR (CDCl ₃ ) δ 1.59-1.78 (m, 6H), 2.05 (s, br, 2H), 3.14-3.19 (m, 1H), 3.75 (d, J = 3.6 Hz, 1H), 4.35 (dd, J = 14.1, 8.1 Hz, 1H), 4.62-4.67 (m, 1H), 5.48-5.51 (m, 1H), 7.26-7.29 (m, 2H), 7.40 (s, 1H), 7.49 (d, J = 8.4 Hz, 1 H);

HRMS (ESMS) calcd for C ₁₅ H ₁₇ Cl ₂ N ₃ O [M ⁺ ] 325.0749, found 325.0741.

Example 37 Preparation of 2- (4-butyl-1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol

Example 37 compound was obtained in a white solid at 90% yield in the same manner as in Example 34, using 1-hexine as a starting material instead of the propazyl alcohol of Example 34.

Mp = 101.5-102.6 ° C .;

¹ HNMR (CDCl ₃ ) δ 0.93 (t, J = 7.2 Hz, 3H), 1.36 (q, J = 11.1, 7.2 Hz, 2H), 1.60-1.68 (m, 2H), 2.70 (t, J = 7.8, 7.5 Hz, 2H), 4.37 (dd, J = 14.1, 7.8 Hz, 1H), 4.67 (dd, J = 13.8, 2.4 Hz, 1H), 5.48-5.50 (m, 1H), 7.26-7.29 (m, 2H ), 7.40 (d, J = 1.5 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H);

HRMS (ESMS) calcd for C ₁₄ H ₁₇ Cl ₂ N ₃ O [M ⁺ ] 313.0749, found 313.0731.

Example 38 Preparation of 1- (2,4-dichlorophenyl) -2- (4- (2-hydroxyethyl) -1H-1,2,3-triazol-1-yl) ethanol

The compound of Example 38 was obtained in 86% yield as a white solid by the same method as in Example 34, using 3-butyn-1-ol as a starting material instead of the propazyl alcohol of Example 34.

Mp = 120.1-120.5 ° C .;

¹ HNMR (CDCl ₃ ) δ 2.91 (t, J = 6.0 Hz, 2H), 3.91 (s, br, 2H), 4.30 (dd, J = 14.1, 8.4 Hz, 1H), 4.38 (d, J = 3.6 Hz , 1H), 4.68 (dd, J = 14.1, 2.4 Hz, 1H), 5.47-5.49 (m, 1H), 7.30 (dd, J = 8.4, 2.1 Hz, 2H), 7.41 (d, J = 1.8 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H); HRMS (ESMS) calcd for C ₁₂ H ₁₃ Cl ₂ N ₃ O ₂ [M ⁺ ] 301.0385, found 301.0406.

Example 39 Preparation of 2- (4-cyclohexyl- [1,2,3] triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol

In the same manner as in Example 34, using cyclohexylacetylene as a starting material instead of the propazyl alcohol of Example 34, the compound of Example 39 was obtained in a yellow solid at a yield of 89%.

Mp = 168.7-169.6 ° C .;

¹ HNMR (CDCl ₃ ) δ 1.30-1.42 (m, 5H), 1.71-1.19 (m, 3H), 2.02-2.03 (m, 2H), 2.72-2.74 (m, 1H), 3.90 (d, J = 3.9 Hz, 1H), 4.34 (dd, J = 14.1, 7.8 Hz, 1H), 4.65 (dd, J = 14.1, 2.4 Hz, 1H), 5.50-5.52 (m, 1H), 7.25-7.30 (m, 2H) , 7.40 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H);

HRMS (ESMS) calcd for C ₁₆ H ₁₉ Cl ₂ N ₃ O [M ⁺ ] 339.0905, found 339.0906.

Example 40 Preparation of 2- (4-tertiary-butyl-1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol

Example 40 compound was obtained in a 94% yield as a white solid in the same manner as in Example 34, using 3,3-dimethyl-1-butyne as the starting material instead of the propazyl alcohol of Example 34.

Mp = 160.8-161.8 ° C;

¹ HNMR (CDCl ₃ ) δ 1.33 (s, 9H), 4.01 (s, 1H) 4.34 (dd, J = 14.1, 7.8 Hz,, 1H), 4.64 (dd, J = 13.8, 1.8 Hz, 1H), 5.50 -5.53 (m, 1H), 7.25-7.30 (m, 2H), 7.40 (d, J = 1.2 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H);

HRMS (ESMS) calcd for C ₁₄ H ₁₇ Cl ₂ N ₃ O [M ⁺ ] 313.0749, found 313.0753

Example 41 Preparation of 2- (4- (3-aminophenyl) -1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol

In the same manner as in Example 34, using 3-ethynylaniline as a starting material instead of the propazyl alcohol of Example 34, the compound of Example 41 was obtained in a white solid at 81% yield.

Mp = 176.8-177.0 ° C .;

¹ HNMR (CDCl ₃ ) δ 3.75 (s, 2H), 4.40 (dd, J = 14.1, 8.1 Hz, 1H), 4.74 (dd, J = 14.4, 2.4 Hz, 1H), 5.54-5.57 (m, 1H) , 6.65-6.68 (m, 1H), 7.10 (d, J = 7.5 Hz, 1H), 7.17-7.19 (m, 2H), 7.30 (dd, J = 8.4, 1.8 Hz, 2H), 7.42 (d, J = 2.1 hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.75 (s, 1H);

HRMS (ESMS) calcd for C ₁₆ H ₁₄ Cl ₂ N ₄ O [M ⁺ ] 348.0545, found 348.0550.

Example 42 Preparation of 2- (4- (4-aminophenyl) -1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol

Example 42 compound was obtained in a 87% yield as a white solid in the same manner as in Example 34, using 4-ethynylaniline as a starting material instead of the propazyl alcohol of Example 34.

 Mp = 209.8-210.6 ° C .;

¹ HNMR (CDCl ₃ ) δ 3.59 (s, br, 1H), 3.77 (s, br, 1H), 4.40 (dd, J = 14.1, 7.8 Hz, 1H), 4.72 (dd, J = 14.1, 2.4 Hz, 1H), 5.52-5.54 (m, 1H), 6.76 (d, J = 8.1 Hz, 2H), 7.26-7.31 (m, 1H), 7.42 (s, 1H), 7.53 (d, J = 8.1 Hz, 1H ), 7.59 (d, J = 8.4 Hz, 1H), 7.66 (s, 1H);

HRMS (ESMS) calcd for C ₁₆ H ₁₄ Cl ₂ N ₄ O [M ⁺ ] 348.0545, found 348.0553.

Example 43 Preparation of 1- (2,4-dichlorophenyl) -2- (4- (pyridin-2-yl) -1H-1,2,3-triazol-1-yl) ethanol

Example 43 compound was obtained in 94% yield as a white solid in the same manner as in Example 34, using 2-ethynylpyridine as a starting material instead of the propazyl alcohol of Example 34.

Mp = 120.7-122.2 ° C .;

¹ HNMR (CDCl ₃ ) δ 4.49 (dd, J = 14.1, 7.8 Hz, 1H), 4.83 (d, J = 13.8 Hz, 1H), 5.60-5.62 (m, 1H), 7.15-7.27 (m, 2H) , 7.43 (s, 1H), 7.60 (d, J = 8.4Hz, 1H), 7.74-7.79 (m, 1H), 8.15 (d, J = 7.8Hz, 1H), 8.22 (d, J = 4.2Hz, 1H), 8.50 (s, 1 H);

HRMS (ESMS) calcd for C ₁₅ H ₁₂ Cl ₂ N ₄ O [M ⁺ ] 334.0388, found 334.0391.

The structural formulas of the compounds obtained in Examples 1 to 43 are shown in Table 1 below.

Example rescue Example rescue One

14

2

15

3

16

4

17

5

18

6

19

7

20

8

21

9

22

10

23

11

24

12

25

13

26

Example rescue Example rescue 27

37

28

38

29

39

30

40

31

41

32

42

33

43

34

35

36

<Test Example 1>

The efficacy of the compounds obtained in Examples 1 to 43 and the toxicity against Vero cells was confirmed as follows, and the results are shown in Table 2 below.

1) Efficacy on Mycobacterium tuberculosis

In order to evaluate the efficacy of the anti-tuberculosis of the compound of the present invention was tested using the Mycobacterium tuberculosis minimum inhibition concentration method (MIC) as follows.

The test subjects obtained in Examples 1 to 43 were subjected to 2x serial dilution using Middlebrook 7H9 liquid medium (Difco, USA) and then 50ul each in 96-well microplate. Busy. After freezing the stock solution of Mycobacterium tuberculosis H37Rv, Mycobacterium tuberculosis H.Rv. 50 ul each was inoculated on the drug dilution plate to 2 ~ 5 X 10 ⁵ colony / ml. After incubation of the test plate for 7 days at 37 ° C, 10 ul of AlamarBlue indicator was added to each well. After 24 hours, the color change of each well was observed to determine the lowest concentration remaining as blue as the minimum inhibitory concentration, and the results are shown in Table 2 below.

2) Toxicity Test on Vero Cells

In order to evaluate the toxicity of Vero cells of the compounds of the present invention, the following experiments were carried out.

Vero cell lines (obtained from the Korean Cell Line Bank, College of Medicine, Seoul National University) were cultured in DMEM medium until the logarithmic growth phase. After counting and diluting the cells to ⁵ × 10 ⁵ cells / ml, 90 ul were dispensed into each well. Incubated for 24 hours in a carbon dioxide incubator at 37 ℃. After the test material was diluted twice in DMEM medium, 10 μl of each concentration was dispensed. After incubation for 3 days, the medium was removed, MTT solution was added and incubated for 4 hours. The supernatant was removed, and DMSO was added to dissolve the precipitate, and the absorbance was measured at 570 nm. IC ₅₀ was calculated using GraphPad software using the measured values and the results are shown in Table 2.

Example MIC (ug / mL) IC50 (ug / mL) Example MIC (ug / mL) IC50 (ug / mL) One 128 10.61 23 > 256 > 6.25 2 256 24.34 24 > 256 > 12.5 3 > 256 63.38 25 16 > 12.5 4 > 64 Unmeasured 26 > 256 > 12.5 5 > 256 21.02 27 32 10.29 6 128 33.68 28 > 256 > 6.25 7 256 > 200 29 > 256 > 6.25 8 128 194.7 30 32 13.16 9 64 > 12.5 31 > 256 > 6.25 10 64 24.3 32 32 > 12.5 11 > 256 > 100 33 64 25.42 12 32 > 100 34 > 256 > 100 13 128 > 12.5 35 > 256 58.04 14 > 256 12.32 36 > 256 34.16 15 > 256 19.79 37 8 23.28 16 32 > 12.5 38 256 274.1 17 64 > 25 39 16 31.94 18 > 256 > 12.5 40 32 33.94 19 > 256 > 25 41 32 26.8 20 > 256 > 50 42 32 33.94 21 256 > 50 43 32 Unmeasured 22 256 > 50

As shown in Table 2, triazoles exhibited anti-tuberculosis effects similar to those of iconazole and were also safe in terms of Vero cell toxicity. Thus, the triazoles developed in the present invention can be developed for use as anti-tuberculosis therapeutics.

Claims (12)

A triazole compound represented by the following formula (1) or (2) or a pharmaceutically acceptable salt thereof: [Formula 1]

[Formula 2]

In the above equations, R ₁ is aryl or heteroaryl; R ₂ is hydroxy; Keto; Amino; Azido; C _1-6 alkylamino; C _1-6 acylamino group, C _1-3 arylalkyl or C _1-3 heteroarylalkyl unsubstituted or substituted with halogen, trifluoromethoxy; R ₃ is C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl or hydroxyC _1-4 alkyl. The method of claim 1, R ₁ is phenyl, biphenyl, monohalophenyl or dihalophenyl; R ₂ is hydroxy, keto, amino, azido, C _1-6 alkylamino, acylamino, benzyl, monohalbenzyl, dihalbenzyl or trifluoromethoxy; A triazole compound or a pharmaceutically acceptable salt thereof, wherein R ₃ is monohalo, dihalo, carboxyl, alkyl, hydroxyl, amino or alkylamino. The method of claim 1, A triazole compound or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of: 1) 4-butyl-1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole; 2) 2- (1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) ethanol; 3) 4-butyl-1- (2- (2,4-dichlorophenyl) -2- (4- (trifluoromethoxy) benzyloxy) ethyl) -1H-1,2,3-triazole; 4) 2- (1- (2- (2,4-dichlorophenyl) -2- (4- (trifluoromethoxy) benzyloxy) ethyl) -1H-1,2,3-triazol-4-yl )ethanol; 5) 4-butyl-1- (2- (2,4-dichlorophenyl) -2- (2,4-difluorobenzyloxy) ethyl) -1H-1,2,3-triazole; 6) 2- (1- (2- (2,4-dichlorophenyl) -2- (2,4-difluorobenzyloxy) ethyl) -1H-1,2,3-triazol-4-yl) ethanol; 7) 1- (2,4-dichlorophenyl) -2- (1H-1,2,3-triazol-1-yl) ethanol; 8) 1- (2,4-dichlorophenyl) -2- (2H-1,2,3-triazol-2-yl) ethanol; 9) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole; 10) 2- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -2H-1,2,3-triazole; 11) 2- (2H-benzo [d] [1,2,3] triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol; 12) 2- (2H-benzo [d] [1,2,3] triazol-2-yl) -1- (2,4-dichlorophenyl) ethanol; 13) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-benzo [d] [1,2,3] triazole; 14) 2- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -2H-benzo [d] [1,2,3] triazole; 15) (1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) methanol; 16) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4-cyclopropyl-1H-1,2,3-triazole; 17) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4-cyclopentyl-1H-1,2,3-triazole; 18) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4-cyclohexyl-1H-1,2,3-triazole; 19) 4-tert-butyl-1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole; 20) 3- (1- (2- (4-chlorobenzyloxy) -2- (2,4-2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) Benzineamine; 21) 4- (1- (2- (4-chlorobenzyloxy) -2- (2,4-2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) Benzineamine; 22) 2- (1- (2- (4-chlorobenzyloxy) -2- (2,4-2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) Pyridine; 23) 3- (1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) phenol; 24) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4- (4-methoxyphenyl) -1H-1,2,3-triazole; 25) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4-propyl-1H-1,2,3-triazole; 26) ethyl 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole-4-carboxylate; 27) methyl 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole-4-carboxylate; 28) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4- (2,5-dimethylphenyl) -1H-1,2,3-triazole; 29) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -4-m-tolyl-1H-1,2,3-triazole; 30) 1- (1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) ethanol; 31) 1- {1- [2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl] -1H- [1,2,3] triazol-4-yl} -hexane- 1-ol; 32) 2- (1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazol-4-yl) propane-2- Come; 33) 1- (2- (4-chlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl) -1H-1,2,3-triazole-4-carboxylic acid; 34) 1- (2,4-dichlorophenyl) -2- (4- (hydroxymethyl) -1H-1,2,3-triazol-1-yl) ethanol; 35) 2- (4-cyclopropyl-1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol; 36) 2- (4-cyclopentyl-1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol; 37) 2- (4-butyl-1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol; 38) 1- (2,4-dichlorophenyl) -2- (4- (2-hydroxyethyl) -1H-1,2,3-triazol-1-yl) ethanol; 39) 2- (4-cyclohexyl- [1,2,3] triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol; 40) 2- (4-tertiary-butyl-1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol; 41) 2- (4- (3-aminophenyl) -1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol; 42) 2- (4- (4-aminophenyl) -1H-1,2,3-triazol-1-yl) -1- (2,4-dichlorophenyl) ethanol; And 43) 1- (2,4-dichlorophenyl) -2- (4- (pyridin-2-yl) -1H-1,2,3-triazol-1-yl) ethanol. A pharmaceutical composition for treating tuberculosis, comprising the triazole compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. A triazole compound of formula 1a [Formula 1a]

Where R ₁ is C _1-6 alkyl, monohalo, dihalo, aryl or heteroaryl; R ₃ is as defined in claim 1. Triazole Compound of Formula 1b [Chemical Formula 1b]

Where R ₁ and R ₂ are each independently C _1-6 alkyl, monohalo, dihalo, aryl or heteroaryl; R ₃ is as defined in claim 1. A triazole compound of formula 1c [Formula 1c]

Where R ₁ is C _1-6 alkyl, monohalo, dihalo, aryl or heteroaryl. Triazole compound of formula 1d: &Lt; RTI ID = 0.0 &

Where R ₁ is C _1-6 alkyl, monohalo, dihalo, aryl or heteroaryl. A triazole compound of formula 1e [Formula 1e]

Triazole Compound of Formula 1f [Formula 1f]

A triazole compound of formula 1 g: [Formula 1g]

Triazole compound of formula 1h [Formula 1h]