WO2014117318A1

WO2014117318A1 - Novel triazole antifungal compounds, and pharmaceutical composition, preparation method, and application thereof

Info

Publication number: WO2014117318A1
Application number: PCT/CN2013/001661
Authority: WO
Inventors: 杨玉社; 曹旭峰; 李站; 李纬
Original assignee: 中国科学院上海药物研究所; 南京长澳医药科技有限公司
Priority date: 2013-01-29
Filing date: 2013-12-30
Publication date: 2014-08-07
Also published as: CN103965194B; CN103965194A

Abstract

The present invention provides triazole compounds expressed by a general formula (I), and optical isomers or pharmaceutically acceptable salts thereof; and application of the compounds, and the optical isomers or pharmaceutically acceptable salts thereof in preparing drugs against fungus, especially, candida albicans, candida parapsilosis, candida glabrata, cryptococcus neoformans, gypsum microspore bacteria, trichophyton rubrum, and/or aspergillus fumigatus. The present invention also provides a pharmaceutical composition, which comprises one or more of the compounds expressed by the general formula (I) and the optical isomers and pharmaceutically acceptable salts thereof, and pharmaceutical excipients in therapeutically effective amounts.

Description

Novel triazole antifungal compound, pharmaceutical composition thereof, preparation method and use thereof

The invention belongs to the field of pharmacy and relates to the fields of drug synthesis and pharmacology. More specifically, it relates to a triazole antifungal compound containing an azacyclic ring, a pharmaceutical composition thereof, a process for the preparation thereof, and its use in the preparation of an antifungal drug. Background technique

Deep fungal infections caused by Candida, Aspergillus, and Cryptococcus neoformans in the past decade due to the continued increase in the incidence of cancer, the widespread development of bone marrow and organ transplants, and the dramatic increase in the use of immunosuppressants and broad-spectrum antibiotics. It has become an increasingly common problem in the clinic. Systemic deep fungal infections seriously endanger the lives of patients, and the mortality rate is as high as 50% or more. However, existing antifungal drugs have shortcomings such as narrow antibacterial spectrum, high toxicity, poor water solubility, etc., and their drug resistance problems are becoming more and more serious, so look for new ones. The more ideal antifungal drugs have always been a hot and difficult topic for pharmaceutical chemists.

Currently used anti-deep fungal infection drugs include polyenes, triazoles, and newly developed echinocanins. The representative drug of polyenes is amphotericin B and its liposomes, and its serious side effects limit its clinical use. Azole antifungal drugs are the largest of all types of antifungal drugs. The original azole antifungal drugs can only be used for the treatment of superficial fungal infections due to their toxic side effects. Ketoconazole is the first azole antifungal drug that can be taken orally for the treatment of deep fungal infections, but it still has problems with large side effects. Until the 1970s, fluconazole and itraconazole emerged as the first oral antifungal drugs. However, the antibacterial spectrum of fluconazole is narrow and the drug resistance is becoming more and more serious. Itraconazole is poorly water-soluble and has low bioavailability. Another serious problem caused by poor water solubility is that these drugs must be made into special preparations. Oral effective, which greatly increases the cost of treatment for patients. Itraconazole is used to rescue critically ill patients. In order to increase water solubility, cyclodextrin must be added, and cyclodextrin will have additional side effects, especially for patients with renal insufficiency. The second-generation oral antifungal drug, posaconazole, was launched in 2006, which expands the antibacterial spectrum, but its metabolic properties and physicochemical properties are not ideal, especially its water solubility is extremely low, resulting in its oral bioavailability. Low, the effect is greatly affected by food, and the individual differences are very large, which greatly reduces the stability of the effect [Ex/^rt /m^t g.Drag 2009,18(9),1279-1295\. Therefore, there is an urgent need to find a new antifungal drug with a broad spectrum of antibacterial spectrum, high bioavailability and good water solubility, both orally and injectable [oorg. Med. Chem. Lett. 2009, 19, 3559- 3563].

Summary of the invention

In view of the above deficiencies of the prior art, it is an object of the present invention to provide a novel azole antifungal compound represented by the following formula (I), an optical isomer thereof, and a salt to be obtained.

General formula (I)

In general formula (I)

for:

(1) hydrogen, halogen, COOR ₃ , carboxyl, CONR4R5 or NR4R5;

Preferred is hydrogen, COOR ₃ or CONR4R ₅ ;

(2) unsubstituted or substituted with 1-5 halogen atoms substituted d_ ₆ linear alkyl, C ₃ _ ₆ branched alkyl or C ₃ _ ₆ cycloalkyl; preferably unsubstituted or substituted with 1-5 a halogen atom-substituted d- ₆ straight-chain alkyl group or a C ₃ _-6 branched-chain alkyl group;

More preferably, it is a d- ₆ straight-chain alkyl group or a C ₃ _-6 branched-chain alkyl group which is unsubstituted or substituted by 1 to 3 halogen atoms; most preferably a methyl group which is unsubstituted or substituted by 1 to 3 halogen atoms , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl;

(3) a substituent-substituted or unsubstituted phenyl group, wherein the substituent of the phenyl group is 1-3 substituents independently selected from the group consisting of halogen, N0 ₂ , cyano, hydroxy, R ₃ , OR ₃ , NHS0 ₂ R ₃ , N(; C _6·6 alkyl) S0 ₂ R ₃ , S0 ₂ R ₃ , S0 ₂ NR4R ₅ , NR4R ₅ , CONR4R ₅ COOH and B COOR ₃ ;

Preferred is a substituent-substituted or unsubstituted phenyl group, wherein the substituent of the phenyl group is 1-3 substituents independently selected from the group consisting of halogen, N0 ₂ , cyano, hydroxy, R ₃ and OR _{3 ;}

More preferably, it is a substituted or unsubstituted phenyl group, wherein the substituent of the phenyl group is one to three substituents independently selected from the group consisting of halogen, cyano, R ₃ and OR _{3 ;}

(4) a substituted or unsubstituted 5- or 6-membered heterocyclic group having 1 to 4 hetero atoms independently selected from N, S and 0, wherein the 5- or 6-membered heterocyclic ring The substituent of the group is independently selected from the group consisting of 1-3 substituents: halogen, N0 ₂ , cyano, hydroxy, R ₃ , OR ₃ , NHS0 ₂ R ₃ , N(Cw alkyl) S0 ₂ R ₃ , S0 ₂ R ₃ , S0 ₂ NR4R ₅ , NR4R ₅ , CONR4R ₅ COOH and COOR ₃ ;

Preferred is a substituent-substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group having 1 to 4 hetero atoms independently selected from N, S and 0, wherein the 5- or 6-membered aromatic hetero The substituent of the ring group is independently selected from the group consisting of 1-3 substituents of the following substituents: halogen, cyano, R ₃ and OR _{3 ;}

More preferably, the substituent is substituted or unsubstituted, and a 5- or 6-membered aromatic heterocyclic group having 1-2 hetero atoms independently selected from N, S and 0, wherein the 5- or 6-membered aromatic The substituent of the heterocyclic group is independently selected from the group consisting of 1-3 substituents of the following substituents: halogen, cyano, R ₃ and OR _{3 ;}

Most preferred is a substituted or unsubstituted pyridyl, pyrimidinyl or thienyl group, wherein the substituent of the pyridyl, pyrimidinyl or thienyl group is independently selected from the group consisting of 1-3 substituents of the following substituents : halogen, cyano, R ₃ and OR ₃ ;

R ₂ is:

(1) a substituted or unsubstituted phenyl group, wherein the substituent of the phenyl group is 1-3 substituents independently selected from the group consisting of halogen, N0 ₂ , cyano, hydroxy, R ₃ , OR ₃ , NHS0 ₂ R ₃ , NCd_ ₆ alkyl) S0 ₂ R ₃ , S0 ₂ R ₃ , S0 ₂ NR4R ₅ , NR4R ₅ , CONR4R ₅ COOH and B COOR ₃ ;

More preferably, it is a substituted or unsubstituted phenyl group, wherein the substituent of the phenyl group is one to three substituents independently selected from the group consisting of halogen, cyano, R ₃ and OR _{3 ;} or

(2) a substituted or unsubstituted 5- or 6-membered heterocyclic group having 1 to 4 hetero atoms independently selected from N, S and 0, wherein the 5- or 6-membered heterocyclic ring The substituent of the group is 1-3 substituents independently selected from the group consisting of: halogen, N0 ₂ , cyano, hydroxy, R ₃ , OR ₃ , NHS0 ₂ R ₃ , N(Cw alkyl) S0 ₂ R ₃ , S0 ₂ R ₃ , S0 ₂ NR4R ₅ , NR4R ₅ , CONR4R ₅ COOH and COOR ₃ ;

Preferred is a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group having 1 to 4 hetero atoms independently selected from N, S and 0, wherein the 5- or 6-membered heterocyclic ring The substituent of the group is independently selected from the group consisting of 1-3 substituents of the following substituents: halogen, cyano, R ₃ and OR _{3 ;}

More preferably, the substituent is substituted or unsubstituted and contains 1-2 heteroatoms independently selected from N, S and 0. a 5- or 6-membered aromatic heterocyclic group, wherein the substituent of the 5- or 6-membered heterocyclic group is independently selected from the group consisting of 1-3 substituents: halogen, cyano, R ₃ and OR _{3 ;}

Most preferred is a substituted or unsubstituted pyridyl or pyrimidinyl group, wherein the substituent of the pyridyl or pyrimidinyl group is independently selected from the group consisting of 1-3 substituents of the following substituents: halogen, cyano, R ₃ and OR _{3 ;}

R ₃ is a d- ₆ straight chain alkyl group, a C ₃ _-6 branched alkyl group or a cycloalkyl group which is unsubstituted or substituted by 1 to 3 halogen atoms;

Preferably, R ₃ is a d- ₆ straight-chain alkyl group or a C ₃ _-6 branched-chain alkyl group which is unsubstituted or substituted by 1 to 3 halogen atoms; more preferably, R ₃ is unsubstituted or is 1-2 a halogen atom substituted methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl;

R4 and R ₅ are each independently:

(1) hydrogen; or

(2) a d- ₆ straight-chain alkyl group, a C ₃ _-6 branched alkyl group or a C ₃ _-6 cycloalkyl group which is unsubstituted or substituted by 1 to 3 halogen atoms;

Preferred is a d- ₆ straight-chain alkyl group or a C ₃ _-6 branched-chain alkyl group which is unsubstituted or substituted by 1 to 3 halogen atoms; more preferably a methyl group which is unsubstituted or substituted by 1-2 halogen atoms , ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl;

Wherein the halogen atom is? , Cl, Br or I; preferably F, C1 or Br.

Preferably, the compound of the formula (I) of the present invention is one of the following compounds

The pharmaceutically acceptable salt of the compound of the formula ω of the present invention is a pharmaceutically acceptable inorganic or organic salt, and for example, may be a compound of the formula (I) with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, Fumar. a salt formed from acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, glutamic acid or aspartic acid, wherein Preferably, the optical isomer of the compound of the formula (I) of the present invention formed with hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, fumaric acid or maleic acid is the S-isomer and the R-isomer. Or a racemate. It is still another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of a compound of the above formula ω, various optical isomers thereof, and pharmaceutically acceptable salts thereof And pharmaceutically acceptable excipients.

A further object of the present invention is to provide a use of a compound of the formula (I), various optical isomers thereof or a pharmaceutically acceptable salt thereof for the preparation of an antifungal drug, in particular for the preparation of Candida albicans, Uses in drugs for near Candida glabrata, Candida glabrata, Cryptococcus neoformans, Microsporum gypsum, Trichophyton rubrum and/or Aspergillus fumigatus. It is a further object of the present invention to provide a method of treating a fungal infection comprising administering to a subject a therapeutically effective amount of a compound of formula (I), various optical isomers thereof, or a pharmaceutically acceptable salt thereof.

A further object of the present invention is to provide a compound of the formula (I), various optical isomers thereof or a pharmaceutically acceptable salt thereof for use as an antifungal agent; or a formula (I for providing a disease for the treatment of fungal infections) a compound, various optical isomers thereof, or a pharmaceutically acceptable salt thereof.

Besides, the compound of the formula (I) of the present invention can also be used as an antifungal drug in the form of a hydrate and a solvate.

When the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof is used for the preparation of an antifungal drug, it may be used alone or diluted with a pharmaceutically acceptable excipient. The agent or the like is mixed and prepared into a tablet, a capsule, a granule or a syrup for oral administration, or an elixirs or injections for parenteral administration.

A further object of the present invention is to provide a process for the preparation of the compound of the formula (I), but these specific methods do not limit the scope of the invention.

The compound of the present invention can be produced by the following method, however, the conditions of the method, such as the reactant, the solvent, the acid, the base, the amount of the compound used, the reaction temperature, the reaction time and the like are not limited to the following description. The compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known to those skilled in the art, and those skilled in the art can easily carry out the above combination.

In a preferred embodiment, the compound of the formula (I) of the present invention can be produced according to the method of the reaction formula (1). Reaction formula (1

Wherein, and R ₂ are as defined above. Under the catalysis of acid or base, in the solvent, compound 2A [Chem. Pharm. Bull. 1993, 41 (6), 1035-1042] is respectively subjected to epoxy ring-opening reaction with the compound of the formula 3a-3d to obtain a compound of the formula. La-ld. The equivalent ratio of each of the compounds of the formula 3a-3d to the compound 2A is preferably from 1 to 3. The base used in the reaction formula (1) is an inorganic base or an organic base, and the inorganic base is sodium hydride, potassium carbonate and/or sodium methoxide, and the organic base is triethylamine and/or 1,8-diaza Bicyclo [5.4.0] ^ - carbon-7-ene (DBU).

The acid used in the reaction formula (1) is a Lewis acid which is lithium perchlorate, sodium perchlorate, potassium perchlorate and/or cesium perchlorate.

The solvent used in the reaction formula (1) is a polar organic solvent, and the polar organic solvent is methanol, ethanol, acetonitrile, ethylene glycol dimethyl ether, N,N-dimethylformamide, dimethyl sulfoxide and / or tetrahydrofuran.

The reaction temperature of the reaction formula (1) is from 0 ° C to 200 ° C, preferably from 30 ° C to 200 ° C.

The reaction of the reaction formula (1) can be carried out by a conventional synthesis method or a microwave reaction synthesis method, and the reaction time is preferably from 2 minutes to 24 hours, preferably from 6 hours to 12 hours.

In a preferred embodiment, the above compounds 3a-1 to 3a-19 can be produced according to the method of the reaction formula (2) by referring to the synthesis method of the patent [WO2010125101].

Reaction formula (2): (corresponding to compound 1-19)

R

81 82 83a-l~a-19 3a-l~3a-19

Wherein, Ri is as defined above; (1) hydrogen, halogen, COOR ₃ , carboxyl, CONF Rs or NF R5;

(2) unsubstituted or substituted with 1-5 halogen atoms substituted d_ ₆ linear alkyl, C ₃ _ ₆ branched alkyl or C ₃ _ ₆ cycloalkyl

(3) a substituent-substituted or unsubstituted phenyl group, wherein the substituent of the phenyl group is 1-3 substituents independently selected from the group consisting of halogen, NO ₂ , hydroxyl group, R ₃ , OR ₃ , NHS0 ₂ R ₃ , N(C^alkyl) S0 ₂ R ₃ , S0 ₂ R ₃ , S0 ₂ NR4R ₅ , NR4R ₅ , CONR4R ₅ COOH and B COOR ₃ ;

R ₃ is a d- ₆ straight-chain alkyl group, a C ₃ _-6 branched-chain alkyl group or a cyclodecyl group which is unsubstituted or substituted by 1 to 3 halogen atoms;

R4 and R ₅ are each independently:

(1) hydrogen; or

Wherein the halogen atom is? , Cl, Br or I.

Compound 81 and compound 82 are cyclically reacted in ethanol under reflux to form the corresponding compound of formula 83a-l-83a-19; compound of formula 83a-l-83a-19 in methanol, Pd/C catalyzed Hydrogenation under reduced conditions gave compounds 3a-1 to 3a-19.

In a preferred embodiment, the above compounds 3a-20 to 3a-25 can be produced according to the method of the reaction formula (3).

Among them, are:

(3) a substituted phenyl group, wherein the substituent of the phenyl group is a cyano group;

R4 and R ₅ are each independently: (1) hydrogen; or

Wherein the halogen atom is? , Cl, Br or I.

The compound of the formula 91 is a substituted boronic acid ester, and the compound of the formula 92 is a substituted boronic acid.

Compound 84 [Preparation method see WO2009090055] Hydrolyzed under basic conditions in ethanol and water to give compound 85. Compound 85 undergoes a curtius rearrangement reaction with triethylamine, diphenylphosphoryl azide, and tert-butanol in toluene to form compound 86. Compound 86 is deprotected from tert-butoxycarbonyl in 4N HC1/1,4-dioxane solution

87. Compound 87 is brominated with sodium nitrite, cuprous bromide, hydrobromic acid in acetic acid and water to form a compound

88. Compound 88 is refluxed with lithium borohydride in ethanol to give a compound 89. Compound 89 is subjected to a tert-butoxycarbonyl protecting reaction of a N atom with a boc anhydride and triethylamine in dichloromethane to give a compound 90. The compound 90 is reacted with the compound of the formula 91 or the compound of the formula 92 in 1,4-dioxane and water to obtain the compound of the formula 93a-20-93a-25, and then the HC1/1,4- at 4N. The tert-butoxycarbonyl group is removed from the dioxane solution to form the compounds of the formula 3a-20 to 3a-25.

In a preferred embodiment, the above compounds 3b-1 to 3b-18 can be used according to the literature [S oorga 'c cfe Medicinal Chemistry Letters 17 (2007) 5934-5939] ^&\^ (corresponding to compound 26-43), Wherein the definition corresponding to the compound of formula I is:

(1) hydrogen, halogen, C0 ₂ R ₃ , carboxyl, CONR4R5 or NR ₄ R ₅ ;

(2) a d- ₆ straight-chain alkyl group, a C ₃ _-6 branched alkyl group or a C ₃ _-6 cycloalkyl group which is unsubstituted or substituted with 1 to 5 halogen atoms;

(3) a substituent-substituted or unsubstituted phenyl group, wherein the substituent of the phenyl group is 1-3 substituents independently selected from the group consisting of halogen, NO ₂ , hydroxyl group, R ₃ , OR ₃ , NHS0 ₂ R ₃ , N(C^alkyl) S0 ₂ R ₃ , SO2R3 , S0 ₂ NR4R ₅ , NR4R ₅ , CONR4R ₅ COOH and B COOR ₃ ;

R4 and R ₅ are each independently:

(1) hydrogen; or

Wherein the halogen atom is? , Cl, Br or I.

In a preferred embodiment, the above compounds 3b-19 to 3b-28 can be produced according to the method of the reaction formula (4).

98 b-19~b-28 where:

R4 and R ₅ are each independently: (1) hydrogen; or

Wherein the halogen atom is? , Cl, Br or I.

The compound of the formula 91 is a substituted boronic acid ester, and the compound of the formula 92 is a substituted boronic acid. Compound 94 [Preparation method see US2010099684] bromination reaction with sodium nitrite, cuprous bromide, hydrobromic acid in acetic acid and water to form compound 95. Compound 95 is refluxed with lithium borohydride in ethanol to cause a reduction reaction to give compound 96. The compound 96 is subjected to a tert-butoxycarbonyl protecting reaction of a N atom with a boc anhydride and triethylamine in dichloromethane to give a compound 97. The compound 97 is reacted with the compound of the formula 91 or the compound of the formula 92 in 1,4-dioxane and water to obtain the compound of the formula 98 b-19~98b-28, followed by HC1/1,4 at 4N. - The tert-butoxycarbonyl group is removed from the dioxane solution to form the compounds of the formula 3b-19 to 3b-28.

In a preferred embodiment, the above compounds 3c-1 to 3c-24 can be produced according to the method of the literature [O2iWS_3S] (corresponding to the compound 54-77), wherein, corresponding to the definition of R ₂ in the compound of the formula I, General formula (I).

Representative structural formulae of the compound of the formula 3d are shown below.

/^^S /=\

3d-2 In a preferred embodiment, the above compounds 3d-1 to 3d-3 can be produced according to the method of the reaction formula (5). <Reaction formula (5): (corresponding to compound 78-80)

99 102 d-1 -d-3

3d-l~3d-3 where R ₂ is:

a substituted or unsubstituted 5- or 6-membered heterocyclic group containing 1-4 hetero atoms independently selected from N, S and 0, wherein the 5- or 6-membered heterocyclic group is substituted The group is 1-3 substituents independently selected from the group consisting of: halogen, N0 ₂ , cyano, hydroxy, R ₃ , OR ₃ , NHS0 ₂ R ₃ , N(C _1-6 alkyl) S0 ₂ R ₃ , S0 ₂ R ₃ , S0 ₂ NR4R ₅ , NR4R ₅ , CONR4R ₅ COOH and COOR ₃ ;

R4 and R ₅ are each independently selected from:

(1) hydrogen;

Wherein the halogen atom is? , Cl, Br or I.

The compound of the formula 100 is an R ₂ -substituted boronic acid ester, and the compound of the formula 101 is an R ₂ -substituted boronic acid.

Compound 99 [Preparation method see US2005020645] with compound of formula 100 or compound of formula 101

The suzuki coupling reaction between 1,4-dioxane and water gives the compound 102 dl~102 d-3 of the formula, and then reacts in a 4N solution of HC1/1,4-dioxane to form the compound of formula 3d- l to 3d-3.

The pharmaceutically acceptable salt of the compound of the formula (I) is prepared by a conventional method in the art.

DRAWINGS

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the results of experiments on the antifungal activity of preferred compounds of the invention in vivo.

Specific form

The invention is more specifically explained in the following examples. However, it is to be understood that the examples are not intended to limit the scope of the invention in any way. In all the examples, ifi-NMR was recorded with a Varian Mercury-plus 300 NMR spectrometer (Varian, USA) and a Bruker Avance III 400 NMR spectrometer (Bruker, Germany), chemical shifts in ppm); silica gel for separation unless otherwise specified Both are 200-300 mesh (Qingdao Ocean Chemical Co., Ltd.), and the ratio of the eluent is a volume ratio.

Example 1 (2R,3R)-2-(2,4-difluorophenyl)-3-(5,6-dihydroimidazole [l,2-a] piperazine-7(8H)-yl)- Preparation of 1-(1Η-1,2,4-triazole-i-yl)butan-2-ol (Compound 1)

2A 3a-l Compound 2A (126.0 mg, 0.48 mmol) was dissolved in 10.0 mL of acetonitrile and ar. Compound 3a-1 (118.0 mg, 0.96 mmol) and lithium perchlorate (102.0 mg, 0.96 mmol) were added, and the reaction mixture was heated to 80 ° C. After 20 hours of reaction, it was cooled to room temperature. The reaction mixture was concentrated under reduced pressure to dryness, the residue was taken up with CH _₂ C1 _2, the organic phase was washed 3 times with saturated NaCl solution, dried over anhydrous Na ₂ S0 _4, filtered, evaporated to dryness and separated by column chromatography (dichloro residue Methane: methanol = 100:1 - 50:1) gave 80.8 mg of Compound 1 as a white solid, melting: 86-88 ° C, yield 45.0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.86 (s, 1H), 7.79 (s, 1H), 7.48 -7.36 (m, 1H), 7.15 (s, 1H), 6.90(s, 1H), 6.81 -6.76 (m, 2H), 5.01 (s, 1H), 4.96 -4.79 (m, 2H), 4.18 - 4.00 (m, 3H), 3.98-3.87 (m, 1H), 3.79-3.70 (m, 1H), 3.26 (q, J = 6.8 Hz, 1H), 2.92 -2.71 (m, 1H), 0.96 (d, J = 6.8 Hz, 3H). ESI-MS: 375.1 (M+1).

Example 2 (2R,3R)-2-(2,4-difluorophenyl)-1-(1Η-1,2,4-triazole small group)-3-(2-(trifluoromethyl) -5,6-dihydroimidazole [l,2-a] piperazine-7 (8H)-

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3a-2 (152.0 mg, 0.80 mmol) and lithium perchloric acid (85.1 mg, 0.80 mmol). Compound 2, melting point: 141-143 ° C, yield 50.6%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.83 (s, 1H), 7.77 (s, 1H), 7.48 -7.36 (m, 1H), 7.20 (s, 1H), 6.81 -6.66 (m, 2H), 5.01 (s, 1H), 4.96 -4.79 (m, 2H), 4.18 - 4.00 (m, 3H), 3.95-3.87 (m, 1H), 3.75-3.79 (m, 1H), 3.27 (q, J = 6.8 Hz , 1H), 2.92 -2.71 (m, 1H), 0.96 (d, J = 6.8 Hz, 3H). ESI-MS: 443.1 (M+1).

Example 3 (2R,3R)-3-(2-tert-butyl-5,6-dihydroimidazo[1,2-a]piperazine-7(8H)-yl)-2-(2,4- Preparation of difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Compound 3)

Compound 2A (126.0 mg, 0.48 mmol) was added to compound 3a-3 (172.0.0 mg, 0.96 mmol) and lithium perchlorate (102.0 mg, 0.96 mmol). Solid compound 3, melting point: 129-131 ° C, yield 45.6%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.84 (s, 1H), 7.75 (s, 1H), 7.39 (m, 1H), 6.79-6.67 (m, 2H), 6.62 (s, 1H), 5.02 (s , 1H), 4.97-4.80 (m, 2H), 4.28-4.21 (m, 2H), 4.12-3.94 (m, 3H), 3.29 (q, J = 6.8 Hz, 1H), 2.89-2.74 (m, 1H) ), 1.35 (s, 9H), 0.94 (d, J = 6.8 Hz, 3H). ESI-MS: 431.2 (M+1). Example 4 (2R,3R)-3-(2-carbamoyl- 5,6-dihydroimidazo[1,2-a]piperazine-7(8H)-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-tri Azole

Compound 2A (150.0 mg, 0.60 mmol) was added to compound 3a-4 (199.0 mg, 1.20 mmol) and lithium perchloric acid (127.7 mg, 1.20 mmol). Compound Compound 4, melting point: 126-127 ° C, yield 31.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.86 (s, 1H), 7.78 (s, 1H), 7.41 (m, 1H), 6.75-6.65 (m, 2H), 6.72 (s, 1H), 5.01 (s , 1H), 4.96-4.80 (m, 2H), 4.30-4.18 (m, 2H), 4.22-3.94 (m, 3H), 3.26 (q, J = 6.8 Hz, 1H), 2.80-2.75 (m, 1H) ), 0.96 (d, J = 6.8 Hz, 3H). ESI-MS: 418.2 (M+1).

Example 5 (2R,3R)-3-(2-ethoxyformyl-5,6-dihydroimidazole [l,2-a] piperazine-7(8H)-yl)-2-(2, 4-difluorophenyl)-1-(1H-1,2,4-three

Compound 2A (150.0 mg, 0.60 mmol) was added to compound 3a-5 (233.2 mg, 1.20 mmol) and lithium perchloric acid (127.7 mg, 1.20 mmol). Compound 5, melting point: 106-107 ° C, yield 35.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.82 (s, 1H), 7.75 (s, 1H), 7.50 (m, 1H), 7.39 (s, 1H), 7.37 (m, 1H), 6.76-6.69 (m , 2H), 5.00 (s, 1H), 4.98-4.86 (m, 2H), 4.37-4.33 (q, J = 5.4 Hz, 2H), 4.03-4.10 (m, 3H), 3.85-3.90 (m, 1H ), 3.73-3.76 (m, 1H), 3.32 -3.16 (q, J = 6.9 Hz, 1H), 2.89 -2.78 (m, 1H), 1.37 (t, J = 5.4 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H). ESI-MS: 447.2 (M+1).

Example 6 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-phenyl-5,6-dihydroimidazole [l,2-a] piperazine-7 (8H )- base) -1-(1H-1,2,4-three

Compound 2A (125.0 mg, 0.50 mmol) was added to compound 3a-6 (199.6 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.0 mmol). White solid compound 6, melting point: 107-108 ° C, yield 55.0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.83 (s, 1H), 7.76 (s, 1H), 7.78-7.72 (m, 2H), 7.45-7.41 (m, 1H), 7.38-7.35 (m, 2H) , 7.21-7.12 (m, 1H), 7.14 (s, 1H), 6.80 -6.67 (m, 2H), 5.00 (s, 1H), 4.93-4.86 (m, 2H), 4.15-4.10 (m, 3H) , 3.98-3.90 (m, 2H), 3.78-3.71 (m, 1H), 3.32 -3.16 (q, J = 6.9 Hz, 1H), 2.89 -2.78 (m, 1H), 0.98 (d, J = 6.9 Hz , 3H). ESI-MS: 451.0 (M+1).

Example 7 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-methoxyphenyl)-5,6-dihydroimidazole [l,2-a Piperazine-7(8H)-yl)-1-(1Η-1

Compound 2A (125.0 mg, 0.50 mmol) was added to compound 3a-7 (229.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.0 mmol). 0%。 The white solid compound 7, a melting point: 110-112 ° C, a yield of 46.0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.83 (s, 1H), 7.76 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.42 (m, 1H), 7.04 (s, 1H), 6.91 (d, J = 8.8 Hz, 2H), 6.82 -6.63 (m, 2H), 5.00 (s, 1H), 4.91-4.87 (m, 2H), 4.12-4.06(m, 3H), 3.87-3.98 ( m, 1H), 3.82 (s, 3H), 3.75-3.71 (m, 1H), 3.26 (q, J = 6.8 Hz, 1H), 2.94 - 2.69 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H). ESI-MS: 481.0 (M+1).

Example 8 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-fluorophenyl)-5,6-dihydroimidazole [ 1 ,2-a]piperidin Oxazide-7(8H)-yl)-1-(1H-1,2,4-three

The product was obtained in the same manner as in Example 1 to give 101. 1 mg of white. 0%。 The solid compound 8, a melting point: 185-187 ° C, a yield of 36.0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.83 (s, 1H), 7.76 (s, 1H), 7.69 ( m, 2H), 7.49 -7.36 (m, 1H), 7.12 -6.98 (m, 3H), 6.73 -6.60(m, 2H), 4.99 (s, 1H), 4.95-4.89 (m, 2H), 4.24 -4.01 (m, 3H), 3.95-3.87 (m, 1H), 3.75-3.68 (m, 1H) , 3.26 (q, J = 6.8 Hz, 1H), 2.91 -2.74 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H). ESI-MS: 469.2 (M+1).

Example 9 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-chlorophenyl)-5,6-dihydroimidazole [ 1 ,2-a]piperidin Oxazide-7(8H)-yl)-1-(1H-1,2,4-three

Compound 2A (150.0 mg, 0.60 mmol) was added to compound 3a-9 (279.6 mg, 1.20 mmol) and lithium perchloric acid (127.7 mg, 1.20 mmol). 0%。 Compound 9, melting point: 121-123 ° C, yield 38. 0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.84 (s, 1H), 7.78 (s, 1H), 7.72 (m, 2H), 7.45-7.38 (m, 1H), 7.16 -6.95 (m, 3H), 6.78 (m, 2H), 5.00(s, 1H), 4.95-4.88 (m, 2H), 4.25-4.01 (m, 3H), 3.97-3.91 (m, 1H), 3.75-3.68 (m, 1H), 3.25 (q, J = 6.8 Hz, 1H), 2.91-2.74 (m, 1H), 0.99 (d, J = 6.8 Hz, 3H). ESI-MS: 485.2 (M+1).

Example 10 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-bromophenyl)-5,6-dihydroimidazole [l,2-a]piperidin Oxazide-7(8H)-yl)-1-(1H-1,2,4-three

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3a-10 (221.6 mg, 0.80 mmol) and lithium perchlorate (84.8 mg, 0.80 mmol). 0%。 Compound 10, the melting point: 125-127 ° C, the yield of 32. 0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.80 (s, 1H), 7.75 (s, 1H), 7.70 (m, 2H), 7.40 -7.34 (m, 1H), 7.26 -6.90 (m, 3H), 6.73 (m, 2H), 5.01(s, 1H), 4.95-4.91 (m, 2H), 4.15 -4.01 (m, 3H), 3.85-3.79 (m, 1H), 3.73-3.66 (m, 1H), 3.29 (q, J = 6.8 Hz, 1H), 2.91 -2.74 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H). ESI-MS: 529.1 (M+1).

Example 11 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(2,4-difluorophenyl)-5,6-dihydroimidazole [1,2- a] piperazine -7(8H)-yl)-1-(1Η-1,2

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3a-ll (187.3 mg, 0.80 mmol) and lithium perchloric acid (84.8 mg, 0.80 mmol). 0%。 Compound 11, melting point: 83-85 ° C, yield 36. 0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.10-8.05 (m, 1H), 7.83 (s, 1H), 7.76 (s, 1H), 7.47 -7.38 (m, 1H), 7.27 (s, 1H), 6.96 -6.67 (m, 4H), 5.00 (s, 1H), 4.95-4.87 (m, 2H), 4.04-3.85 (m, 4H), 3.75-3.67 (m, 1H), 3.32 -3.18 (q, J = 6.9 Hz, 1H), 2.91 -2.78 (m, 1H), 0.98 (d, J = 6.9 Hz, 3H). ESI-MS: 487.1 (M+1).

Example 12 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-methylphenyl)-5,6-dihydroimidazole [l,2-a] Piperazine-7(8H)-yl)-1-(1H-1,2,4-tri

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3a-12 (169.8 mg, 0.80 mmol) and lithium perchlorate (84.8 mg, 0.80 mmol). 5%。 Compound 12, mp: 81-82 ° C, yield 41. 5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.83 (s, 1H), 7.76 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.47-7.37 (m, 1H), 7.17 (d, J = 8.0 Hz, 2H), 7.09 (s, 1H), 6.81-6.66 (m, 2H), 4.99 (s, 1H), 4.95-4.88 (m, 2H), 4.19-3.91 (m, 4H), 3.76- 3.63 (m, 1H), 3.26 (q, J = 6.9 Hz, 1H), 2.86-2.79 (m, 1H), 2.35 (s, 3H), 0.98 (d, J = 6.9 Hz, 3H). ESI-MS : 465.2(M+1).

Example 13 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-methylphenyl)-5,6-dihydroimidazole [l,2-a] Preparation of piperazine-7(8H)-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Compound 13)

Compound 2A (125.0 mg, 0.50 mmol) was added to compound 3a-13 (266.0 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). 8%。 White solid compound 13, melting point: 200-201 ° C, yield 31.8%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.86 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.77 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.48- 7.36(m, 1H), 7.23 (s, 1H), 6.86-6.66 (m, 2H), 5.01 (s, 1H), 4.95-4.90 (m, 2H), 4.19-3.81 (m, 4H), 3.76- 3.67 (m, 1H), 3.27 (q, J = 6.9 Hz, 1H), 2.83-2.79 (m, 1H), 0.98 (d, J = 6.9 Hz, 3H). ESI-MS: 519.1 (M+1) .

Example 14 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-methoxyphenyl)-5,6-dihydroimidazole [l,2-a Preparation of piperazine-7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol (Compound 14)

2A 3a-14 14

Compound 2A (125.0 mg, 0.50 mmol) was added to compound 3a-14 (229.1 mg, 1.0 mmol) and lithium perchlorate (106.4 mg, 1.0 mmol). 8%。 White solid compound 14, melting point: 82-84 ° C, yield 36.8%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.85 (s, 1H), 7.69 (s, 1H), 7.56-7.50 (m, 3H), 7.43-7. 38 (m, 1H), 7.10 (s, 1H), 6.98-6.89 (m, 1H), 6.80 -6.68 (m, 2H), 5.01 (s, 1H), 4.93 -4.90 (m, 2H), 4.1- 4.03 (m, 3H), 3.98-3.93 (m, 1H), 3.81 (s, 3H), 3.76-3.71(m, 1H), 3.27 (q, J= 6.8 Hz, 1H), 2.94 -2.69 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H). ESI-MS: 481.0 (M+1).

Example 15 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-fluorophenyl)-5,6-dihydroimidazole [l,2-a]piperidin Oxazine-7(8H)-yl)-1-(1H-1,2,4-

2A 3a-15 15

Compound 2A (150.0 mg, 0.60 mmol) was added to compound 3a-15 (260.5 mg, 1.20 mmol) and lithium perchloric acid C127.7 mg (1.20 mmol). 0%。 Compound 15, melting point: 80-81 ° C, yield 46.0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.85 (s, 1H), 7.81 (s, 1H), 7.56-7.49 (m, 3H), 7.45 -7.36 (m, 1H), 7.21 -6.98 (m, 2H) , 6.78-6.71 (m, 2H), 4.97 (s, 1H), 4.95-4.90 (m, 2H), 4.23 -4.01 (m, 3H), 3.97-3.91 (m, 1H), 3.76-3.71 (m, 1H), 3.26 (q, J = 6.8 Hz, 1H), 2.96 -2.77 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H). ESI-MS: 469.2 (M+1).

Example 16 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-chlorophenyl)-5,6-dihydroimidazole [l,2-a]piperidin Preparation of azine-7(8H)-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Compound 16)

2A 3a-16 16

Compound 2A (150.0 mg, 0.60 mmol) was added to compound 3a-16 (279.6 mg, 1.20 mmol) and lithium perchloric acid C127.7 mg (1.20 mmol). 6%。 Compound 16, melting point: 85-86 ° C, yield 41.6%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.85 (s, 1H), 7.80 (s, 1H), 7.70 -8.01 (m, 3H), 7.45 -7.38 (m, 1H), 7.06(s, 1H), 6.95 -6.76 (m, 3H), 5.00(s, 1H), 4.95-4.86(m, 2H), 4.25 -4.01 (m, 3H), 4.95-4.90 (m, 1H), 3.76-3.68 (m, 1H) , 3.26 (q, J = 6.8 Hz, 1H), 2.91 -2.74 (m, 1H), 1.01 (d, J = 6.8 Hz, 3H). ESI-MS: 485.2 (M+1).

Example 17 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-bromophenyl)-5,6-dihydroimidazole [l,2-a]piperidin Oxazide-7(8H)-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Compound 17)

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3a-17 (221.6 mg, 0.80 mmol) of lithium perchlorate (84.8 mg, 0.80 mmol). Melting point: 76-78 ° C, yield 42.8%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.82 (s, 1H), 7.78 (s, 1H), 7.70 -7.63 (m, 3H), 7.41 -7.35 (m, 1H), 7.09(s, 1H), 6.90 -6.75 (m, 3H), 4.98 (s, 1H), 4.97-4.87 (m, 2H), 4.15 -4.05 (m, 3H), 3.90-3.84 (m, 1H), 3.71-3.65 (m, 1H) , 3.26 (q, J = 6.8 Hz, 1H), 2.90 -2.74 (m, 1H), 0.99 (d, J = 6.8 Hz, 3H). ESI-MS: 529.1 (M+1).

Example 18 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-methylphenyl)-5,6-dihydroimidazole [l,2-a] Piperazine-7(8H)-yl)-1-(1H-1,2,4-triazol-1-yl)

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3a-18 (169.8 mg, 0.80 mmol) and lithium perchlorate (84.8 mg, 0.80 mmol). 5%。 Compound 18, the melting point: 83-85 ° C, yield 38. 5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.83 (s, 1H), 7.76 (s, 1H), 7.68-7.60 (m, 3H), 7.41-7.37 (m, 1H), 7.13 (s, 1H), 6.80 -6.65 (m, 3H), 5.03 (s, 1H), 4.91-4.86 (m, 2H), 4.29-3.91 (m, 4H), 3.75-3.63 (m, 1H), 3.27 (q, J = 6.9 Hz , 1H), 2.86-2.79 (m, 1H), 2.36 (s, 3H), 0.99 (d, J = 6.9 Hz, 3H). ESI-MS: 465.2 (M+1).

Example 19 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-trifluoromethylphenyl)-5,6-dihydroimidazole [l,2- a] piperazine-7(8H)-yl)-1-(1Η-1,2,4-three

2A 3a-19 19

Compound 2A (125.0 mg, 0.50 mmol) was added to compound 3a-19 (266.0 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). The white solid compound 19, m.p.: 107-109 ° C, yield 41. 0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.86 (s, 1H), 7.83-7.79 (m, 2H), 7.76 (s, 1H), 7.48-7.34 (m, 1H), 7.21 (s, 1H), 6.86 -6.65 (m,3H), 5.00(s, 1H), 4.95-4.90 (m, 2H), 4.16-3.85 (m, 4H), 3.73-3.65 (m, 1H), 3.26 (q, J = 6.9 Hz , 1H), 2.86-2.79 (m, 1H), 0.96 (d, J = 6.9 Hz, 3H). ESI-MS: 519.1 (M+1). Example 20 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(pyridin-3-yl)-5,6-yl

First step: Lithium chloride monohydrate (6.50 g, 0.156 mol) was added to a solution of compound 84 (9.73 g, 0.05 mol) at room temperature (preparation method WO2009090055) in ethanol/water solution (400 ml/100 ml), stirred at room temperature. After 8 hours, the solvent was evaporated under reduced pressure. The pH was adjusted to 3-4 with 1N aqueous hydrochloric acid, and the precipitated solid was filtered, washed with dichloromethane and acetone, and dried at 50 ° C under reduced pressure. Pink solid powder compound 85, a total of 7.69 g (9.4 mmol), yield 93.7%.

1H NMR (300 MHz, DMSO) δ 13.15 (s, 1 Η), 9.15 (s, 1H), 8.70 - 8.42 (m, 2H), 7.96 (d, J = 4.5 Hz, 1H). ESI-MS: 164.0 ( M+1).

Step 2: Under the protection of Ar gas, triethylamine (13.1 g, 0.12 mol) was slowly added dropwise to the toluene solution of compound 85 at 0-5 ° C. After stirring for 30 minutes, the azide diphenyl phosphate was slowly added. The ester (23.61 g, 85.79 mmol) was stirred slowly to room temperature and stirred for 3 hours, then t-butanol (50.0 ml) was slowly added, the mixture was heated to 80 ° C, stirred overnight, cooled to room temperature, and the reaction mixture was evaporated. Concentrated to dryness, the residue was crystallised eluted with ethyl acetate. The organic phase was washed three times with saturated NaCI solution, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to dryness. 1 : 4-1 : 2), Compound 86 was obtained as a white solid, 5.54 g (23.58 mmol), yield 55.0%.

1H NMR (400 MHz, CDC1 ₃ ) δ 8.94 (s, 1H), 8.48 (s, 1H), 8.00 (dd, J = 4.5, 1.4 Hz, 1H), 7.96 (s, 1H), 7.88 (d, J = 4.5 Hz, 1H), 1.57 (s, 9H). ESI-MS: 235.1 (M+1).

The third step: Compound 86 (3.20 g, 13.61 mmol) was dissolved in 4N hydrogen chloride in 1,4-dioxane solution (20 mL), stirred at room temperature overnight, and the mixture was concentrated to dryness. The methane was dissolved, and the mixture was neutralized with a saturated sodium hydrogen carbonate solution. The organic phase was washed three times with a saturated NaCI solution, dried over anhydrous Na ₂ SO ₄ , and evaporated to dryness to give a pale yellow solid powder compound 87, 1.84 g (13.61 mmol). The yield was 71.0%.

1H NMR (300 MHz, DMSO-de) δ 8.51 (s, 1H), 8.31 (d, J = 4.3 Hz, 1H), 7.68 (d, J = 4.3 Hz, 1H), 7.17 (s, 1H), 5.55 (s, 2H). ESI-MS: 135.1 (M+1).

The fourth step: compound 87 (0.78g, 5.79mmol) was dissolved in acetic acid (10.Oml) and water C5.0ml), protected by Ar gas, slowly hydrobromide (5.0ml) at 0-5 °C Then, an aqueous solution of sodium nitrite (0.45 g, 6.38 mmol) was slowly added, stirred for 30 minutes, and copper bromide powder (0.21 g, 1.45 mmol) was gradually added, and the mixture was slowly heated to 80 ° C. Was stirred overnight, cooled to room temperature, the reaction mixture to dryness, the residue was dissolved with ethyl acetate and concentrated under reduced pressure, the organic phase was washed with a saturated NaCl solution three times, dried over anhydrous Na ₂ S0 _4, filtered, evaporated to dryness and the residue was column Chromatography (ethyl acetate: petroleum ether = 1 : 10-1 : 6) gave Compound 88 as a white solid (yield: 0.40 g (2.04 mmol).

1H NMR (400 MHz, CDC1 ₃ ) δ 9.04 (d, J = 1.5 Hz, 1H), 8.03 (dd, J = 4.6, 1.5 Hz, 1H), 7.94 (d, J = 4.6 Hz, 1H), 7.69 ( s, 1H). ESI-MS: 198.0 (M+1).

Step 5: Add lithium borohydride (1.00 g, 45.50 mmol) to a solution of compound 88 (2.25 g, 11.30 mmol) in ethanol at 0-5 ° C, slowly warm to 50 ° C, stir for 12 hours, cool To the room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The mixture was adjusted to pH 2-3 with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The pH of the aqueous layer was adjusted to 9-10 with sodium carbonate. The methyl chloride was extracted several times, and the saturated NaCl solution was washed three times, dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated to dryness to give a pale yellow solid powder compound 89, 1.35 g (6.68 mmol), yield 60.0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.16 (s, 1H), 4.16-3.81 (m, 4H), 3.16 (t, J = 5.5 Hz, 2H). ESI-MS: 202.0 (M+1).

The sixth step: Compound 89 G.30 g, 6.43 mmol) was dissolved in dichloromethane (20.0 ml), and triethylamine (0.78 g, 7.73 mmol) and di-tert-butyl dicarbonate were slowly added at 0-5 ° C. (1.55 g, 7.08 m mol), after completion of the dropwise addition, the temperature was raised to room temperature, and the reaction was stirred overnight. After adding 3⁄40, the organic phase was washed three times with a saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated to dryness. The white solid 90 was obtained in a total of 1.60 g (5.30 mmol), yield 83.0%.

1H NMR (400 MHz, CDC1 ₃ ) δ 7.21 (s, 1H), 4.76 (s, 2H), 4.15 (t, J = 5.3 Hz, 2H), 3.91 (t, J = 5.3 Hz, 2H), 1.51 ( s, 9H). ESI-MS: 302.2 (M+1).

Step 7: Compound 90 (0.30 g, 1.0 mmol), compound 103 (0.27 g, 1.30 mmol), tetrakis(triphenylphosphine)palladium (0.12 g, 0.10 mmol), cesium carbonate (0.65 g, 2.0 mmol The solution was dissolved in dioxane in an aqueous solution (20 mL, 4:1) and reacted at 80 ° C for 12 h under argon atmosphere. Concentrated to dryness, ethyl acetate and EtOAc (EtOAc)EtOAc.EtOAc. : 10-1 : 6) gave white solid compound 93a-20, 0.21 g (0.70 mmol), yield 70.0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 9.30 (d, J = 1.1 Hz, 1H), 8.65 (dd, J = 4.9, 1.1 Hz, 1H), 8.36-8.25 (m, 1H), 7.44-7.40 (m , 1H), 7.15 (s, 1H), 4.71 (s, 2H), 4.16 (t, J = 5.1 Hz, 2H), 3.93 (t, J = 5.2 Hz, 2H), 1.50 (s, 9H). ESI -MS: 301.2 (M+1).

The eighth step: a solution of the compound 93a-20C (0.21 g, 0.70 mmol) in THF (4 mL) The mixture was dissolved in dichloromethane, and the mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate. The organic phase was washed three times with a saturated NaCI solution, dried over anhydrous Na ₂ SO ₄ , and evaporated to dryness to give a white powder compound 3a-20 (0.11 g, 0.53 mmol) , yield 76.0%.

1H NMR (300 MHz, DMSO-de) δ 9.21 (d, J = 1.2 Hz, 1H), 8.68 (dd, J = 4.8, 1.2 Hz, 1H), 8.31-8.25 (m, 1H), 7.41-7.35 ( m, 1H), 7.16 (s, 1H), 4.70 (s, 2H), 4.15 (t, J = 5.1 Hz, 2H), 3.91 (t, J = 5.2 Hz, 2H). ESI-MS: 201.1 (M +1).

The ninth step: Compound 2A (125.0 mg, 0.50 mmol) was added to compound 3a-20 (200.1 mg, 1.0 mmol) and lithium perchlorate (106.4 mg, 1.0 mmol). 5%。 The yield of 70.8mg of a white solid compound 20, the melting point: 110-112 ° C, the yield of 31. 5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 9.31 (d, J = 1.3 Hz, 1H), 8.63 (dd, J = 4.9, 1.3 Hz, 1H), 8.34-8.28 (m, 1H), 7.82 (s, 1H ), 7.77 (s, 1H), 7.446-7.40 (m, 1H), 7.39-7.35 (m, 1H), 7.11 (s, 1H), 6.81-6.68 (m, 2H), 4.91 (s, lH), 4.98-4.86 (m, 2H), 4.32-4.28 (m, 3H), 4.01-3.96 (m, 1H), 3.87-3.79 (m, 1H), 3.35 (q, J = 6.9 Hz, 1H), 3.01- 2.95 (m, 1H), 1.00 (d, J = 6.9 Hz, 3H). ESI-MS: 452.2 (M+1).

Example 21 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(pyridin-4-yl)-5,6-dihydroimidazole [l,2-a]piperidin Preparation of azine-7(8H)-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Compound 21)

Compound 90 (0.30 g, 1.00 mmol), compound 104 (0.27 g, 1.30 mmol), tetrakis(triphenylphosphine)palladium (0.12 g, 0.10 mmol), cesium carbonate (0.65 g, 2.0 mmol) according to Example 20 A similar preparation method in the seventh step gave white solid compound 93a-21, a total of 0.22 g (0.75 mmol), yield 75.0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.65 (d, J = 6.2 Hz, 2H), 7.95 (d, J = 6.2 Hz, 2H), 7.15 (s, 1H), 4.75 (s, 2H), 4.23 ( t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz, 2H), 1.49 (s, 9H). ESI-MS: 301.2 (M+1).

The compound 93a-21 (0.22 g, 0.75 mmol) was obtained m. m.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.51 (d, J = 6.2 Hz, 2H), 7.86 (d, J = 6.2 Hz, 2H), 7.21 (s, 1H), 4.68 (s, 2H), 4.21 (t, J = 5.2 Hz, 2H), 3.95 (t,J = 5.2 Hz, 2H). ESI-MS: 201.2 (M+1). Compound 2A (125.0mg, 0.50mmol) was added to compound 3a-21 (200.1 mg, 1.0 mmol) and lithium perchlorate (106.4 mg, 1.0 mmol) were obtained in a similar manner as in Example 1 to give 80.1 mg of Compound Compound 21 as a white solid, melting point: 120-123 ° C, yield 35. 5%.

NMR NMR (400 MHz, CDC1 ₃ ) δ 8.69 (d, J = 6.1 Hz, 2H), 7.93 (d, J = 6.1 Hz, 2H), 7.82 (s, 1H) 7.77 (s, 1H), 7.45-7.39 (m, 1H), 7.16 (s, 1H), 6.79-6.70 (m, 2H), 5.07 (s, 1H), 4.96-3.89 (m, 2H), 4.33 -4.28 (m, 3H), 4.03-3.97 (m 1H), 3.88-3.81 (m, 1H), 3.35 (q, J = 6.8 Hz, 1H), 3.02 - 2.95 (m, lH), 1.00 (d, J = 6.8 Hz, 3H). ESI-MS : 452.2 (M+1).

Example 22 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-cyanophenyl)-5,6-dihydroimidazole [l,2-a] Piperazine-7(8H)-yl)-1-(1)

Compound 90 (0.30 g, 1.00 mmol), compound 105 (0.30 g, 1.30 mmol), tetrakis(triphenylphosphine)palladium (0.12 g, 0.10 mmol), cesium carbonate (0.65 g, 2.0 mmol) according to Example 20 A similar preparation method in the seventh step gave white solid compound 93a-22, a total of 0.20 g (0.69 mmol), yield 68.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.15 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.21 (s, 1H), 4.58 (s, 2H), 4.21 ( t, J = 5.1 Hz, 2H), 3.93 (t, J = 5.1 Hz, 2H), 1.48 (s, 9H). ESI-MS: 325.2 (M+1).

Compound 93a-22 (0.20 g, 0.69 mmol) was obtained as white in the same manner as in the eighth step of Example 20 Solid compound a-22, a total of 0.12 g (0.53 mmol), yield 77.5%.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.21 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 7.16 (s, 1H), 4.65 (s, 2H), 4.22 (t, J = 5.1 Hz, 2H), 3.93 (t,J = 5.1 Hz, 2H). ESI-MS: 225.2 (M+1). Compound 2A (100.0mg, 0.40mmol) was added to compound 3a-22 (178.6 mg, 0.80 mmol) and lithium perchlorate (85.1 mg, 0.80 mmol) were obtained in the same manner as in Example 1 to give 57.7 mg of Compound Compound 22 as a white solid, melting point: 139-140 ° C, yield 30. 5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.18 (d, J = 8.3 Hz, 2H), 7.82 (s, 1H), 7.77 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.45- 7.40 (m, 1H), 7.22 (s, 1Η), 6.82-6.66 (m, 2H), 5.06 (s, 1H), 4.98-4.79 (m, 2H), 4.35 -4.28 (m, 3H), 4.02- 3.96 (m, 1H), 3.85-3.81 (m, 1H), 3.35 (q, J = 6.8 Hz, 1H), 3.02 - 2.95 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H). ESI -MS: 476.2 (M+1).

Example 23 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-cyanophenyl)-5,6-dihydroimidazole [l,2-a] Piperazine-7(8H)-yl)-1-(1)

Compound 90 (0.30 g, 1.00 mmol), compound 106 (0.30 g, 1.30 mmol), tetrakis(triphenylphosphine)palladium (0.12 g, 0.10 mmol), cesium carbonate (0.65 g, 2.0 mmol) according to Example 20 A similar preparation method in the seventh step gave white solid compound 93a-23, a total of 0.23 g (0.72 mmol), yield 71.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.16-7.86 (m, 3H), 7.71-7.65 (s, 1H), 7.20 (s, 1H), 4.61 (s, 2H), 4.23 (t, J = 5.1 Hz , 2H), 3.95 (t,J = 5.1 Hz, 2H), 1.49 (s, 9H). ESI-MS: 325.2 (M+1). Compound 93a-23 (0.23 g, 0.72 mmol) A similar preparation method in the eighth step gave a white solid compound a-23, a total of 0.13 g (0.56 mmol), yield 78.5%.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.21-7.90 (m, 3H), 7.76-7.65 (s, 1H), 7.20 (s, 1H), 4.66 (s, 2H), 4.22 (t, J = 5.1 Hz, 2H), 3.95 (t, J = 5.1 Hz, 2H). ESI-MS: 225.2 (M+1).

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3a-23 (178.6 mg, 0.80 mmol) and lithium perchlorate (85.1 mg, 0.80 mmol). 8%。 Compound 23, mp 129-130 ° C, yield 35.8%.

1H NMR (300 MHz, CDC1 ₃ ) 58.16-7.90 (m, 3H), 7.81 (s, 1H), 7.75 (s, 1H), 7.71-7.65 (m, 2H), 7.41-7.46 (m, 1H), 7.21 (s, 1H), 6.81-6.68 (m, 2H), 5.01 (s, 1H), 4.95-4.89 (m, 2H), 4.30-4.26 (m, 3H), 4.12-3.96 (m, 1H), 3.85-3.81 (m, 1H), 3.36 (q, J = 6.8 Hz, 1H), 3.01 - 2.97 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H). ESI-MS : 476.2 (M+ 1).

Example 24 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(2-cyanopyridine-5-yl)-5,6-dihydroimidazole [l, 2 -a]Preparation of piperazine-7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol (Compound 24)

Compound 90 (0.30 g, 1.00 mmol), compound 107 (0.30 g, 1.30 mmol), tetrakis(triphenylphosphine)palladium (0.12 g, 0.10 mmol), cesium carbonate (0.65 g, 2.0 mmol) according to Example 20 A similar preparation method in the seventh step gave white solid compound 93a-24, a total of 0.20 g (0.61 mmol), yield 61.0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 9.40 (d, J = 2.1 Hz, 1H), 8.51 (dd, J = 8.1, 2.1 Hz, 1H), 7.76-7.66 (m, 1H), 7.18 (s, 1H ), 4.65 (s, 2H), 4.21 (t, J = 5.1 Hz, 2H), 3.93 (t, J = 5.1 Hz, 2H), 1.51 (s, 9H). ESI-MS: 326.1 (M+1) .

The compound 93a-24 (0.20 g, 0.61 mmol) was obtained m. m.

1H NMR (300 MHz, DMSO-de) δ 9.31 (d, J = 2.2 Hz, 1H), 8.28 (dd, J = 8.2, 2.1 Hz, 1H), 7.73-7.68 (m, 1H), 7.15 (s, 1H), 4.63 (s, 2H), 4.21 (t, J = 5.2 Hz, 2H), 3.93 (t, J = 5.1 Hz, 2H). ESI-MS: 226.1 (M+1).

Compound 2A (125.0 mg, 0.50 mmol) was added to compound 3a-24 (225.3 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.0 mmol). White solid compound 24, melting point: 165-167 ° C, yield 30.6%.

1H NMR (300 MHz, CDC1 ₃ ) δ 9.40 (d, J = 2.1 Hz, 1H), 8.46 (dd, J = 8.1, 2.1 Hz, 1H), 7.78-7.74 (m, 3H), 7.53-7.31 (m , 1H), 7.13 (s, 1H), 6.84-6.64 (m, 2H), 5.07(s, 1H), 4.97-4.84 (m, 2H), 4.34-4.25 (m, 3H), 4.10-4.03 (m , 1H), 3.91-3.84(m, 1H), 3.36 (q, J = 6.8 Hz, 2H), 3.07-2.85 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H). ESI-MS: 477.1 (M+1).

Example 25 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(pyrimidin-5-yl)-5,6-dihydroimidazole [l,2-a]piperidin Oxazine-7(8H)-yl)-1-(1H-

Compound 90 (0.30 g, 1.00 mmol), compound 108 (0.27 g, 1.30 mmol), tetrakis(triphenylphosphine)palladium (0.12 g, 0.10 mmol), cesium carbonate (0.65 g, 2.0 mmol) according to Example 20 A similar preparation method in the seventh step gave white solid compound 93a-25, a total of 0.22 g (0.75 mmol), yield 75.0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 9.31 (s, 2H), 9.21 (s, 1H), 7.21 (s, 1H), 4.61 (s, 2H), 4.25 (t, J = 5.1 Hz, 2H), 3.91 (t, J = 5.1 Hz, 2H), 1.52 (s, 9H). ESI-MS: 302.1 (M+1).

The compound 93a-25 (0.22 g, 0.75 mmol) was obtained as a white solid compound a-25 (yield: 0.12 g (0.57 mmol). NMR NMR (300 MHz, DMSO-de) δ 9.36 (s, 2H), 9.20 (s, 1H), 7.17 (s, 1H), 4.58 (s, 2H), 4.23 (t, J = 5.1 Hz, 2H) , 3.92 (t, J = 5.2 Hz, 2H). ESI-MS: 202.1 (M+1).

Compound 2A (125.0 mg, 0.50 mmol) was added to compound 3a-25 (201.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.0 mmol). White solid compound 25, melting point: 105-107 ° C, yield 28.8%.

1H NMR (300 MHz, CDC1 ₃ ) δ 9.37 (s, 2H), 9.24 (s, 1H), 7.82 (s, 1H), 7.77 (s, 1H), 7.48 -7.37 (m, 1H), 7.13 (s , 1H), 6.81 -6.67 (m, 2H), 5.07 (s, 1H), 4.99 -4.83 (m, 2H), 4.37 -4.24 (m, 3H), 4.06-4.0 l(m, 1H), 3.91- 3.85 (m, 1H), 3.36 (q, J = 6.9 Hz, 1H), 3.01-2.96 (m, 1H), 1.00 (d, J = 6.9 Hz, 3H). ESI-MS: 453.1 (M+1) .

Hereinafter, in Examples 26-43, the compounds 3b-1 to 3b-18 can be produced by the method described in the paper Bioorganic & Medicinal Chemistry Letters 17 (2007) 5934-5939.

Example 26 (2R,3R)-2-(2,4-difluorophenyl)-1-(1Η-1,2,4-triazole small)-3-(2-(trifluoromethyl) -5,6-dihydro-[1,2,4]triazole [l,5

Compound 2A (125.0 mg, 0.50 mmol) was added to compound 3b-1 (192.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.0 mmol). White solid compound 26, melting point: 178-180 ° C, yield 31.8%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.81 (s, 1H), 7.77 (s, 1H), 7.45 -7.38 (m, 1H), 6.85-6.57 (m, 2H), 5.09 (s, 1H), 4.98 -4.78 (m, 2H), 4.37-4.20 (m, 3H), 4.05-4.00 (m, 1H), 3.90-3.85 (m, 1H), 3.42-3.25 (q, J = 6.9 Hz, 1H), 3.02 -2.86 (m, 1H), 0.98 (d, J = 6.9 Hz, 3H). ESI-MS: 444.1 (M+1).

Example 27 (2R,3R)-2-(2,4-difluorophenyl)-3-(5,6-dihydro-[1,2,4]triazolo[1,5-a]piperazine -7(8H)-yl)-1-(1H-1,2,4-

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3b-2 (99.2 mg, 0.80 mmol) and lithium perchlorate (85.1 mg, 0.80 mmol). Compound 27, melting point: 88-90 ° C, yield 43.5%.

1H NMR (400 MHz, CDC1 ₃ ) δ 7.88 (s, 1H), 7.82 (s, 1H), 7.77 (s, 1H), 7.45-7.39 (m, 1H), 6.81-6.76 (m, 2H), 5.04 (s, 1H), 4.94 -4.85 (m, 2H), 4.37-4.20 (m, 3H), 3.99-3.87 (m, 1H), 3.85-3.81 (m, 1H), 3.36 -3.24 (q, J = 6.8 Hz, 1H), 2.97 -2.83 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H). ESI-MS: 376.1 (M+1).

Example 28 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-tert-butyl-5,6-dihydro-[ 1,2,4]triazole [ 1, Preparation of 5-a] piperazine-7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol (Compound 28)

3b-3 2A 28

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3b-3 (144.1 mg, 0.80 mmol) and lithium perchlorate (85.1 mg, 0.80 mmol). Compound 28, m.p.: 139-141 ° C, yield 43.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.86 (s, 1H), 7.78 (s, 1H), 7.41-7.36 (m, 1H), 6.76-6.67 (m, 2H), 5.01 (s, 1H), 4.96 -4.80 (m, 2H), 4.31-4.20 (m, 3H), 4.12-3.94 (m, 1H), 3.85-3.80 (m, 1H), 3.28 (q, J = 6.8 Hz, 1H), 2.89-2.76 (m, 1H), 1.36 (s, 9H), 0.98 (d, J = 6.8 Hz, 3H). ESI-MS: 432.2 (M+1).

Example 29 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-ethyl-5,6-dihydro-[1,2,4]triazole [l,5 -a] piperazine-7(8H)-yl)-1-(1H-1,2 compound 29)

3b-4 2Α 29

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3b-4 (121.7 mg, 0.80 mmol) and lithium perchlorate (85.1 mg, 0.80 mmol). Compound 29, melting point: 125-126 ° C, yield 33.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.87 (s, 1H), 7.75 (s, 1H), 7.30 (m, 1H), 6.78-6.67 (m, 2H), 4.98 (s, 1H), 4.90-4.80 (m, 2H), 4.25-4.20 (m, 3H), 4.12-3.94 (m, 1H), 3.85-3.80 (m, 1H), 3.28 (q, J = 6.8 Hz, 1H), 2.89-2.86 (m , 1H), 2.76 (q, J = 8.0Hz, 2H), 1.25 (t, J = 8.0Hz, 3H), 0.96 (d, J = 6.8Hz, 3H). ESI-MS: 376.1(M+1) .

Example 30 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-phenyl-5,6-dihydro-[1,2,4]triazole [l,5 -a]Preparation of piperazine-7(8H)-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Compound 30)

3b- 5 2A 30

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3b-5 (160.1 mg, 0.80 mmol) and lithium perchloric acid (85.1 mg, 0.80 mmol). Compound 30, melting point: 190-192 ° C, yield 36.5%.

1H NMR (300MHz, CDC1 ₃ ) δ 8.09-8.05 (m, 2H), 7.82 (s, 1H), 7.76 (s, 1H), 7.52-7.33 (m, 4H), 6.80-6.69 (m, 2H), 5.05 (s, 1H), 4.97-4.85 (m, 2H), 4.32-4.21 (m, 3H), 4.11-4.01 (m, 1H), 3.87-3.82 (m, 1H), 3.33 (q, J = 7.0 Hz, 1H), 2.98-2.95 (m, 1H), 0.99 (d, J = 6.8 Hz, 3H). ESI-MS: 452.2 (M+1).

Example 31 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-fluorophenyl)-5,6-dihydro-[1,2,4] Preparation of azole [l,5-a] piperazine-7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol (Compound 31)

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3b-6 (174.5 mg, 0.80 mmol) and lithium perchlorate (85.1 mg, 0.80 mmol). Compound 31, melting point: 121-123 ° C, yield 36.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.05 (d, J = 8.7 Hz, 2H), 7.82 (s, 1H), 7.76 (s,lH), 7.45-7.43 (m, 1H), 7.11 (d, J = 8.7 Hz, 2H), 6.81-6.67 (m, 2H), 5.05 (s, 1H), 5.00-4.71 (m, 2H), 4.33-4.22 (m, 3H), 4.00 (m, 1H), 3.87- 3.82 (m, 1H), 3.39-3.28 (q, J = 6.8Hz, 1H), 3.02-2.85 (m, 1H), 0.99 (d, J = 6.8 Hz, 3H). ESI-MS: 470.2 (M+ 1).

Example 32 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-fluorophenyl)-5,6-dihydro-[1,2,4] Preparation of azole [l,5-a] piperazine-7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol

3b-7 2A 32

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3b-7 (174.5 mg, 0.80 mmol) and lithium perchlorate (85.1 mg, 0.80 mmol). Compound 32, melting point: 171-173 ° C, yield 39.5%.

1H NMR (400 MHz, CDC1 ₃ ) δ 7.88-7.84 (m, 1H), 7.83 (s, 1H), 7.79-7.75 (m, 2H), 7.47-7.35 (m, 2H), 7.13-7.05 (m, 1H), 6.80-6.69 (m, 2H), 5.06 (s, 1H), 4.98-4.85 (m, 2H), 4.32-4.26 (m, 3H), 4.02 (m, 1H), 3.84 (m, 1H) , 3.39-3.29 (q, J = 6.8 Hz, 1H), 3.00-2.92 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H). ESI-MS: 470.2 (M+1).

Example 33 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-bromophenyl)-5,6-dihydro-[1,2,4] Preparation of azole [l,5-a] piperazine-7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol

3b- 8 2A 33

The product was obtained in the same manner as in Example 1 to give 75. 1 mg of white. Solid compound 33, melting point: 165-170 ° C, yield 35.5%.

1H NMR (400 MHz, CDC1 ₃ ) δ 7.94 (d, J = 8.7 Hz, 2H), 7.82 (s, 1H), 7.77 (s, 1H), 7.56 (d, J = 8.7 Hz, 2H), 7.45- 7.39 (m, 1H), 6.78-6.71 (m, 2H), 4.96 -4.85 (m, 2H), 4.30 -4.23 (m, 3H), 4.05-3.96 (m, 1H), 3.85-3.80 (m, 1H ), 3.33 (q, J = 6.8 Hz, 1H), 3.03 - 2.87 (m, 1H), 0.99 (d, J = 6.8 Hz, 3H). ESI-MS: 530.1 (M+1).

Example 34 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-bromophenyl)-5,6-dihydro-[1,2,4] Azole [l,5-a] piperazine Preparation of -7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3b-9 (222.4 mg, 0.80 mmol) and lithium perchloric acid (85.1 mg, 0.80 mmol). Compound 34, melting point: 136-138 ° C, yield 28.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.13-8.06 (m, 1H), 7.98-7.91 (m, 1H), 7.85 (s, 1H), 7.78 (s, 1H), 7.71-7.60 (m, 1Η) , 7.53-7.44 (m, 1H), 7.40-7.31 (m, 1H), 6.75 (m, 2H), 5.01 (s, 1H), 4.95-4.85 (m, 3H), 4.33-4.26 (m, 4H) , 4.00-3.98 (m, 1H), 3.85-3.81 (m, 1H), 3.36 (q, J = 6.9 Hz, 1H), 3.06- 2.93 (m, 1H), 1.00 (d, J = 6.87Hz, 3H ). ESI-MS: 530.1 (M+1).

Example 35 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-chlorophenyl)-5,6-dihydro-[1,2,4]3 Azole [l,5-a]piperazine-7(8H)-yl

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3b-10 (234.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol) in the same manner as in Example 1 to give 76.4 mg white. Solid compound 35, melting point: 120-123 ° C, yield 31.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.01 (d, J = 8.6 Hz, 2H), 7.82 (s, 1H), 7.77 (s, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.45- 7.40 (m, 1H), 6.81-6.68 (m, 2H), 5.05 (s, 1H), 4.97-4.84 (m, 2H), 4.33 - 4.24 (m, 3H), 4.01-3.95 (m, 1H), 3.85-3.80 (m,lH), 3.34 (q, J = 6.8 Hz, 1H), 2.98-2.95(m, 1H), 0.99 (d, J = 6.8 Hz, 3H). ESI-MS: 486.2 (M+ 1).

Example 36 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-chlorophenyl)-5,6-dihydro-[1,2,4] Azole [l,5-a] piperazine-7(8H)-yl)

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3b-ll (234.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 36, melting point: 120-122 ° C, yield 36.6%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.11-8.08 (m, 1H), 7.98-7.95 (m, 1H), 7.83 (s, 1H), 7.77 (s, 1H), 7.73-7.62 (m, 1Η) , 7.50-7.44 (m, 1H), 7.41-7.34 (m, 1H), 6.76 (m, 2H), 5.06 (s, 1H), 4.98-4.85 (m, 3H), 4.35-4.21 (m, 4H) , 4.01-3.99 (m, 1H), 3.84-3.81 (m, 1H), 3.34 (q, J = 6.9 Hz, 1H), 3.06- 2.91 (m, 1H), 1.00 (d, J = 6.87Hz, 3H ). ESI-MS: 486.2 (M+1).

Example 37 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(2,4-difluorophenyl)-5,6-dihydro-[1,2, 4] Triazole [l,5-a] piperidine Preparation of azine-7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol (

3b-12 2A 37

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3b-12 (236.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.0 mmol). White solid compound 37, melting point: 127-129 ° C, yield 31.9%.

1H NMR (400 MHz, CDC1 ₃ ) δ 8.03 (m, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 7.43-7.39 (m, 1H), 6.99 -6.88 (m, 2H), 6.75 -6.70 (m, 2H), 5.05 (s, 1H), 4.915-4.90 (m, 2H), 4.31-4.35 (m, 3H), 4.05-4.01 (m, 1H), 3.85-3.79 (m, 1H) , 3.39 -3.26 (q, J = 6.8 Hz, 1H), 2.98-2.96 (m, 1H), 0.99 (d, J = 6.8 Hz, 3H). ESI-MS: 488.2 (M+1).

Example 38 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-trifluoromethylphenyl)-5,6-dihydro-[1,2, 4] Preparation of triazole [l,5-a] piperazine-7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol (compound 38 )

3b-13 2A 38

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3b-13 (268.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.0 mmol). White solid compound 38, melting point: 127-130 ° C, yield 41.6%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.19 (d, J = 8.4 Hz, 2H), 7.82 (s, 1H), 7.77 (s, lH), 7.69 (d, J = 8.4 Hz, 2H), 7.45- 7.40(m, 1H), 6.81 -6.65 (m, 2H), 5.06 (s, 1H), 4.99 -4.82 (m, 2H), 4.33 - 4.26 (m, 3H), 4.02 (m, 1H), 3.87- 3.81 (m, 1H), 3.40 -3.30 (q, J = 6.8 Hz, 1H), 3.03 - 2.92 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H). ESI-MS: 520.2 (M+ 1).

Example 39 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-trifluoromethylphenyl)-5,6-dihydro-[1,2, 4] Preparation of triazole [l,5-a] piperazine-7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol

3b-14 2A 39

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3b-14 (268.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 39, melting point: 117-118 ° C, yield 35.6%.

1H NMR (300 MHz, CDC13) δ 8.36-8.34 (m, 1H), 8.26-8.19 (m, 1H), 7.83 (s, 1H), 7.77 (s, 1H), 7.65-7.61 (m, 1H), 7.56-7.53 (m, 1H), 7.49-7.37 (m, 1H), 6.81-6.66 (m, 2H), 5.07 (s, 1H), 5.02-4.85 (m, 2H), 4.38-4.25 (m, 3H ), 4.03 (m, 1H), 3.86-3.81 (m, 1H), 3.35 (q, J = 6.9 Hz, 1H), 2.98-2.86 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H) ESI-MS: 520.2 (M+1). Example 40 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-methylphenyl)-5,6--7(8H)-yl)-1 Preparation of (1Η-1,2,4-triazol-1-yl)butan-2-ol

3b- 15 2A 40

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3b-15 (214.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 40, melting point: 106-108 ° C, yield 31.6%.

1H NMR (400 MHz, CDC1 ₃ ) δ 7.95 (d, J = 8.1 Hz, 2H), 7.82 (s, 1H), 7.76 (s, 1H), 7.41-7.38 (m, 1H), 7.24 (d, J = 8.1 Hz, 2H), 6.82 -6.67 (m, 2H), 5.05-5.01 (m, 1H), 4.96 -4.84 (m, 2H), 4.32 -4.16 (m, 3H), 4.05-3.96 (m, 1H ), 3.81 (s, 1H), 3.36 -3.25 (q, J= 6.8 Hz, 1H), 3.00 -2.87 (m, 1H), 2.38 (s, 3H), 0.99 (d, J= 6.8 Hz, 3H) . ESI-MS 466.2 (M+1).

Example 41 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-methylphenyl)-5,6-dihydro-[1,2,4] Preparation of triazole [l,5-a] piperazine-7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol

3b- 16

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3b-16 (171.2 mg, 0.80 mmol) and lithium perchlorate (85.1 mg, 0.80 mmol). Compound 41, melting point: 104-105 ° C, yield 43.0%.

1H NMR (400 MHz, CDC1 ₃ ) δ 7.90 (s, 1H), 7.87 (m, 1H), 7.83 (m, 1H), 7.76 (s, 1H), 7.46-7.38 (m, 1H), 7.33 (m , 1H), 7.21 (m, 1H), 6.81-6.68 (m, 2H), 5.05 (s, 1H), 4.99-4.83 (m, 2H), 4.32-4.23 (m, 3H), 4.02 (m, 1H) ), 3.83 (m, 1H), 3.37-3.29 (q, J= 6.9 Hz, 1H), 3.02-2.89 (m, 1H), 2.41 (s, 3H), 0.99 (d, J= 6.9 Hz, 3H) . ESI-MS 466.2 (M+1).

Example 42 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-methoxyphenyl)-5,6-dihydro-[1,2,4 Preparation of triazole [l,5-a] piperazine-7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol (Compound 42)

3b- 17 2A 42

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3b-17 (184.1 mg, 0.80 mmol) and lithium perchlorate (85.1 mg, 0.80 mmol). Compound 42, melting point: 102-104 ° C, yield 33.5%.

1H NMR (400 MHz, CDC1 ₃ ) δ 7.99 (d, J = 8.9 Hz, 2H), 7.82 (s, 1H), 7.76 (s, 1H), 7.49-7.37 (m, 1H), 6.95 (d, J =8.9 Hz, 2H), 6.80-6.63 (m, 2H), 5.04 (s, 1H), 4.95 -4.84 (m, 2H), 4.32-4.16 (m, 3H), 3.99-3.96 (m, 1H), 3.88-3.85 (m, 3H), 3.80 (s, 3H), 3.32 (q, J = 6.9 Hz, 1H), 2.98-2.95 (m, 1H), 0.99 (d, J= 6.9 Hz, 3H). ESI -MS 482.2 (M+1). Example 43 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-methoxyphenyl)-5,6-azine-7(8H)-yl) Preparation of -1-(1Η-1,2,4-triazol-1-yl)butan-2-ol (

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3b-18 (184.1 mg, 0.80 mmol) and lithium perchlorate (85.1 mg, 0.80 mmol). Compound 43, melting point: 110-112 ° C, yield 31.8%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.83 (s, 1H), 7.77 (s, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.62 (s, 1H), 7.44-7.40 (m, 1H) ), 7.35-7.31 (m, 1H), 6.96-6.90 (m, 1H), 6.81 -6.68 (m, 2H), 5.05 (s, 1H), 5.01 -4.79 (m, 2H), 4.33 -4.25 (m , 3H), 4.05-4.01 (m, 1H), 3.89 (s, 3H), 3.85-3.76 (m, 1H), 3.34 (q, J = 6.8 Hz, 1H), 3.02 - 2.90 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H). ESI-MS 482.2 (M+1).

Example 44 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-cyanophenyl)-5,6-dihydro-[ 1,2,4] Preparation of triazole [1,5-a] piperazine-7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol (Compound 44)

94 95 96

First step: Compound 94 (3.38g, 25. Ommol) was dissolved in acetic acid (30.0ml) and water (30.0ml), protected by Ar gas, slowly hydrobromide (20.0ml) at 0-5 °C Then, an aqueous solution of sodium nitrite (1.89 g, 27.5 mmol) was slowly added, stirred for 30 minutes, and copper bromide powder (1.80 g, 12.5 mmol) was gradually added, and the mixture was slowly heated to 80 ° C, stirred overnight, and cooled. to rt, the reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved with ethyl acetate, the organic phase was washed with a saturated NaCl solution three times, dried over anhydrous Na ₂ S0 _4, filtered, evaporated to dryness and the residue was purified by column chromatography ( Ethyl acetate: petroleum ether = 1 : 10-1 : 6) gave Compound 95 as a white solid, 2.80 g ( 14.1 mmol), yield 56.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 9.24 (s, 1 Η), 8.51 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.5 Hz, 1H).

ESI-MS 199.0 (M+1).

The second step: lithium borohydride (2.86 g, 131.3 mmol) was added to a solution of compound 95 (2.25 g, 32.8 mmol) in ethanol at 0-5 ° C, slowly rising to 50 ° C, stirring for 12 hours, cooling To the room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The mixture was adjusted to pH 2-3 with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The pH of the aqueous layer was adjusted to 9-10 with sodium carbonate under ice bath. Methyl chloride extraction multiple times, washing with saturated NaCl solution 3 times, drying with anhydrous Na ₂ S0 ₄ Filtration and evaporation of the solvent gave a pale-yellow solid powder compound 96, 4.97 g (24.6 mmol).

1H NMR (300 MHz, CDC1 ₃ ) δ 4.15 - 4.10 (m, 4H), 3.32 (t, J = 5.5 Hz, 2H). ESI-MS 203.0 (M+1).

The third step: Compound 96 (2.50 g, 12.4 mmol) was dissolved in dichloromethane (50.0 ml), and triethylamine (1.51 g, 14.90 mmol) and di-tert-butyl dicarbonate were slowly added at 0-5 ° C. (2.96 g, 13.6 m mol), after completion of the dropwise addition, the temperature was raised to room temperature, and the reaction was stirred overnight. After adding 3⁄40, the liquid phase was separated, and the organic phase was washed three times with a saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated to dryness and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 1 : 18-1 : 6 The white solid 97 was obtained in a total of 3.20 g (10.60 mmol), yield 85.6%.

1H NMR (400 MHz, CDC1 ₃ ) δ 4.71 (s, 2H), 4.17 (t, J = 5.4 Hz, 2H), 3.92 (t, J = 5.4 Hz, 2H), 1.49 (s, 9H). ESI- MS 303.0 (M+1).

Fourth step: Compound 97 (0.52 g, 1.72 mmol), compound 105 (0.50 g, 2.00 mmol), tetrakis(triphenylphosphine)palladium (0.20 g, 0.172 mmol), cesium carbonate (1.12 g, 3.50 mmol) The solution was dissolved in dioxane (50.0 mL, 4:1) and reacted at 80 ° C for 12 h under argon atmosphere. Concentrated to dryness, ethyl acetate and EtOAc (EtOAc)EtOAc.EtOAc. : 10-1 : 6) gave white solid compound 98b-19, 0.40 g (1.23 mmol), yield 71.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.16 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H), 4.81 (s, 2H), 4.27 (t, J = 5.4 Hz, 2H), 3.98 (t, J = 5.4 Hz, 2H), 1.51 (s, 9H). ESI-MS 325.1 (M+1). Step 5: Compound 98b-19C 0.50g, 1.54 mmol) dissolved in 4N A solution of hydrogen chloride in 1,4-dioxane (20 mL) was stirred at room temperature overnight. The mixture was evaporated to dryness. The solution was washed 3 times, dried over anhydrous Na ₂ SO ₄ , and evaporated to dryness to give the white powder compound 3b-19, 0.29 g (1.29 mmol) in a yield of 83.6%.

1H NMR (400 MHz, CDC1 ₃ ) δ 8.17 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 4.23 (m, 4H), 3.38 (q, J = 5.4 Hz, 2H). ESI-MS 225.1 (M+1).

The sixth step: Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3b-19 (179.2 mg, 0.80 mmol) and lithium perchlorate (85.1 mg, 0.80 mmol). 69.9 mg of a white solid compound 44, melting point: 239-242 ° C, yield 36.8%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.18 (d, J = 8.3 Hz, 2H), 7.82 (s, 1H), 7.77 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.45- 7.40 (m, 2H), 6.82-6.66 (m, 1H), 5.06 (s, 1H), 4.98-4.79 (m, 2H), 4.35-4.26 (m, 3H), 4.025-4.01 (m, 1H), 3.88-3.79 (m, 1H), 3.35 (q, J = 6.8 Hz, 3H), 2.99-2.95 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H). ESI-MS 477.2 (M+1) ).

Example 45 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-cyanophenyl)-5,6-dihydro-[1,2,4] Preparation of triazole [l,5-a]piperazine-7(8H)-)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol (Compound 45)

Compounds 97 (0.26 g, 0.86 mmol), Compound 106 (0.25 g, 1.03 mmol), tetrakis(triphenylphosphine)palladium (0.10 g, 0.09 mmol), cesium carbonate CO. 56 g, 1.72 mmol) A similar preparation method in the fourth step gave a white solid compound 98b-20, a total of 0.21 g (0.66 mmol), yield 76.8%.

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Compound 97 (0.30 g, 1.00 mmol), compound 104 (0.15 g, 1.20 mmol), tetrakis(triphenylphosphine)palladium (0.1 g, 0.10 mmol), cesium carbonate CO. 65 g, 2.00 mmol) A similar preparation of the fourth step of Example 44 gave white solid compound 98b-22 (0.22 g, 0.71 mmol), yield 71.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.69 (d, J = 6.1, 2Η), 7.93 (d, J = 6.1, 2H), 4.82 (s, 2H), 4.28 (t, J = 5.4 Hz, 2H) , 3.99 (t, J = 5.3 Hz, 2H), 1.51 (s, 9H). ESI-MS 302.1 (M+1).

Compound 98b-22 (0.20 g, 0.66 mmol) was obtained as a white solid compound 3b-22 (0.11 g (0.56 mmol).

1H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.65-8.58 (m, 2H), 8.02-7.98 (m, 2H), 4.24 (t, J = 5.6 Hz, 2H), 4.13 (s, 2H) , 3.37-3.32 (m, 2H). ESI-MS 202.1 (M+1).

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3b-22 (201.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.0 mmol). White solid compound 47, melting point: 150-154 ° C, yield 28.5%.

1H NMR (400 MHz, CDC1 ₃ ) δ 8.69 (d, J = 6.1 Hz, 2H), 7.93 (d, J = 6.1 Hz, 2H), 7.82 (s, 1H), 7.77 (s, 1H), 7.45- 7.41(m, 1H), 6.78-6.75 (m, 2H), 5.07 (s, 1H), 4.95-4.90 (m, 2H), 4.33 - 4.28 (m, 3H), 4.05-4.01 (m, 1H), 3.86-3.80(m, 1H), 3.35 (q, J = 6.8 Hz, 1H), 3.02 - 2.95 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H). ESI-MS 453.1 (M+1 ).

Example 48 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(2-cyanopyridine-5-yl)-5,6-dihydro-[1,2 , 4] Preparation of triazole [l,5-a] piperazine-7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol (compound 48)

Compound 97 (0.35 g, 1.16 mmol) Compound 107 (0.32 g, 1.39 mmol), tetrakis(triphenylphosphine)palladium (0.13 g, 0.12 mmol) cesium carbonate C 0.76 g, 2.32 mmol) A four-step similar preparation gave white solid compound 98b-23, a total of 0.28 g (0.86 mmol), yield 74.3%.

1H NMR (400 MHz, CDC1 ₃ ) δ 9.39 (dd, J = 2.1, 0.8 Hz, 1H), 8.45 (dd, J = 8.1, 2.1 Hz, 1H), 7.76 (dd, J = 8.1, 0.8 Hz, 1H ), 4.83 (s, 2H), 4.29 (t, J = 5.3 Hz, 2H), 4.00 (t, J = 5.2 Hz, 2H), 1.51 (s, 9H). ESI-MS 326.1 (M+1).

The compound 98b-23 (0.35 g, 1.08 mmol) was obtained from the white solid solid compound 3b-23 (yield: 0.19 g (0.83 mmol), yield 76.8%.

1H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 9.39-9.28 (m, 1H), 8.51-8.46 (m, 1H), 7.81-7.73 (m, 1H), 4.31 (t, J = 5.6 Hz, 2H), 4.16 (s, 2H), 3.38-3.32 (m, 2H). ESI-MS 226.1 (M+1).

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3b-23 (225.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.0 mmol). White solid compound 48, melting point: 199-201 ° C, yield 33.5%.

1H NMR (300 MHz, CDC1 ₃ ) 59.40 (d, J = 2.1 Hz, 1H), 8.46 (dd, J = 8.1, 2.1 Hz, 1H), 7.78-7.74 (m, 3H), 7.53-7.31 (m, 1H), 6.84-6.64 (m, 2H), 5.07 (s, 1Η), 4.97-4.84 (m, 2H), 4.34-4.25 (m, 3H), 4.06-4.01 (m, 2H), 3.91-3.85 ( m, 1H), 3.36 (q, J = 6.8 Hz, 2H), 3.07-2.85 (m, 2H), 1.00 (d, J = 6.8 Hz, 4H). ESI-MS 477.1 (M+1).

Example 49 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(pyrimidin-5-yl)-5,6-dihydro-[1,2,4] Preparation of azole [l,5-a] piperazine-7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol (Compound 49)

Compound 97 (0.35 g, 1.16 mmol), compound 108 (0.28 g, 1.39 mmol), tetrakis(triphenylphosphine)palladium (0.13 g, 0.12 mmol) cesium carbonate C 0.76 g, 2.32 mmol) A similar preparation method of the fourth step gave a white solid compound 98b-24, 0.25 g (0.83 mmol), yield 71.1%.

1H NMR (400 MHz, CDC1 ₃ ) δ 9.36 (d, J = 2.1 Hz, 1H), 8.41 (dd, J = 8.1, 2.1 Hz, 1H), 7.78 -7.75 (m, 1H), 4.81 (s, 2H ), 4.31 (t, J = 5.1 Hz, 2H), 4.01 (t, J = 5.3 Hz, 2H), 1.51 (s, 9H). ESI-MS 303.1 (M+1).

Compound 98b-24 (0.25 g, 0.83 mmol) was obtained as a white solid compound 3b-24 (yield: 0.12 g (0.58 mmol).

1H NMR (400 MHz, CD3OD-CI4) δ 9.31 (d, J = 2.1 Hz, 1H), 8.31 (dd, J = 8.1, 2.1 Hz, 1H), 7.78-7.75 (m, 1H), 4.32 (t, J = 5.6 Hz, 2H), 4.26 (s, 2H), 3.36-3.32 (m, 2H). ESI-MS 203.1 (M+1).

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3b-24 (202.1 mg, 1.00 mmol) and lithium perchlorate (85.1 mg, 0.80 mmol). Solid compound 49, melting point: 115-117 ° C, yield 23.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 9.40 (d, J = 2.1 Hz, 1H), 8.46 (dd, J = 8.1, 2.1 Hz, 1H), 7.78 -7.74 (m, 3H), 7.53 -7.31 (m , 1H), 6.84 -6.64 (m, 2H), 5.07(s, 1H), 4.97 -4.84 (m, 2H), 4.34 -4.25 (m, 3H), 4.05-4.01(m, 1H), 3.91-3.85 (m, 1H), 3.36 (q, J = 6.8 Hz, 1H), 3.07 - 2.85 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H). ESI-MS 454.1 (M+1).

Example 50 (2R,3R)-2-(2,4-difluorophenyl) 3-(2-(thiophen-2-yl)-5,6-dihydro-[1,2,4]triazole Preparation of [l,5-a]piperazine-7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol (Compound 50)

2A

Compound 97 (0.35 g, 1.16 mmol), compound 109 (0.18 g, 1.39 mmol), tetrakis(triphenylphosphine)palladium (0.13 g, 0.12 mmol) cesium carbonate C 0.76 g, 2.32 mmol) A similar preparation method of the fourth step gave a white solid compound 98b-25, a total of 0.24 g (0.79 mmol), yield 68.1%.

1H NMR (400 MHz, CDC1 ₃ ) δ 7.71 (dd, J = 3.6, 1.1 Hz, 1H), 7.46-7.43 (m, 1H), 7.36 (dd, J = 5.0, 1.1 Hz, 1H), 7.16 (dd , J= 5.0, 3.7 Hz, 1H), 4.83 (s, 2H), 4.36 (t, J = 5.1 Hz, 2H), 4.11 (t, J= 5.3 Hz, 2H), 1.50 (s, 9H). ESI -MS 307.1 (M+1).

Compound 98b-25 (0.24 g, 0.79 mmol) was obtained as a white solid compound 3b-25 (yield: 0.10 g (0.53 mmol), yield 65.5%.

1H NMR (400 MHz, CD3OD-CI4) 57.76 (dd, J = 3.6, 1.1 Hz, 1H), 7.49-7.42 (m, 1H), 7.35 (dd, J= 5.0, 1.1 Hz, 1H), 7.16 (dd , J = 5.0, 3.7 Hz, 1H), 4.35 (t, J = 5.6 Hz, 2H), 4.23 (s, 2H), 3.38-3.32 (m, 2H). ESI-MS 207.1 (M+1).

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3b-25 (188.1 mg, 1.00 mmol) and lithium perchlorate (85.1 mg, 0.80 mmol). Solid compound 50, melting point: 105-107 ° C, yield 25.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.82 (s, 1H), 7.77 (s, 1H), 7.66 (dd, J = 3.6, 1.1 Hz, 1H), 7.45-7.41 (m, 1H), 7.34 (dd , J = 5.0, 1.1 Hz, 1H), 7.10 (dd, J = 5.0, 3.7 Hz, 1H), 6.80 -6.68 (m, 2H), 5.05 (s, 1H), 4.98-4.81 (m, 2H), 4.27 (m, 3H), 4.00 (d, J = 15.7 Hz, 1H), 3.84 (m, 1H), 3.33 (q, J= 6.9 Hz, 1H), 2.95 (m, 1H), 0.99 (d, J ESI-MS 458.2 (M+1). Example 51 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-fluoropyridine)- 5-yl)-5,6-dihydro-[1,2,4]triazole [l,5-a]piperazine-7(8H)-yl)-1-(1Η-1,2,4- Preparation of triazol-1-yl)butan-2-ol (Compound 51)

Compound 97 (0.35 g, 1.16 mmol), compound 110 (0.31 g, 1.39 mmol), tetrakis(triphenylphosphine)palladium (0.13 g, 0.12 mmol) cesium carbonate C 0.76 g, 2.32 mmol) A similar preparation of the fourth step gave a white solid compound 98b-26, a total of 0.22 g (0.70 mmol), yield 60.5%.

1H NMR (400 MHz, CDC1 ₃ ) δ 9.16 (s, 1 Η), 8.45 (d, J = 2.5 Hz, 1H), 8.11 (d, J = 9.1 Hz, 1H), 4.81 (s, 2H), 4.33 ( t, J= 5.1 Hz, 2H), 4.12 (t, J= 5.3 Hz, 2H), 1.51 (s, 9H). ESI-MS 320.1 (M + 1). Compound 98b-26 (0.22 g, 0.70 mmol). %.

1H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 9.11 (s, 1H), 8.45 (d, J = 2.7 Hz, 1H), 8.15 (d, J = 9.1 Hz, 1H) „ 4.31(t, J = 5.6 Hz, 2H), 4.31 (s, 2H), 3.35-3.31 (m, 2H). ESI-MS 220.1 (M+1).

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3b-26 (219.1 mg, 1.00 mmol) and lithium perchlorate (85.1 mg, 0.80 mmol). Solid compound 51, melting point: 110-112 ° C, yield 31.5%.

1H NMR (400 MHz, CDC1 ₃ ) δ 9.12 (s, 1H), 8.48 (d, J = 2.7 Hz, 1H), 8.05 (d, J = 9.3 Hz, 1H), 7.82 (s, 1H), 7.77 ( s, 1H), 7.45-7.42 (m, 1H), 6.80-6.66 (m, 2H), 5.06 (s, 1H), 4.98-4.85 (m, 2H), 4.30 (t, J = 5.2 Hz, 3H) , 4.02 (d, J= 15.7 Hz, 1H), 3.85 (m, 1H), 3.39 (q, J= 6.9 Hz, 1H), 3.02-2.93 (m, 1H), 1.00 (d, J= 6.9 Hz, 3H). ESI-MS 471.2 (M+1).

Example 52 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(2-fluoropyridin-5-yl)-5,6-dihydro-[1,2, 4] Preparation of triazole [l,5-a] piperazine-7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol (Compound 52 )

Compound 97 (0.35 g, 1.16 mmol), compound 111 (0.31 g, 1.39 mmol), tetrakis(triphenylphosphine)palladium (0.13 g, 0.12 mmol) cesium carbonate C 0.76 g, 2.32 mmol) A similar preparation method of the fourth step gave a white solid compound 98b-27, a total of 0.18 g (0.56 mmol), yield 48.9%.

1H NMR (400 MHz, CDC1 ₃ ) δ 8.91 (d, J = 2.5 Hz, 1H), 8.45 (dd, J = 8.3, 7.8 Hz, 1H), 7.11 (dd, J = 8.5, 2.6 Hz, 1H), 4.83 (s, 2H), 4.35 (t, J = 5.1 Hz, 2H), 4.11 (t, J = 5.3 Hz, 2H), 1.50 (s, 9H). ESI-MS 320.1 (M+1).

The compound 98b-27 (0.18 g, 0.56 mmol) was obtained from white solid compound 3b-27 (yield: 65.2%).

1H NMR (400 MHz, CD3OD-CI4) δ 8.87 (d, J = 2.5 Hz, 1H), 8.41 (dd, J = 8.3, 7.6 Hz, 1H), 7.06 (dd, J = 8.6, 2.6 Hz, 1H) „ 4.31 (t, J = 5.5 Hz, 2H), 4.35 (s, 2H), 3.35-3.31 (m, 2H). ESI-MS 220.1 (M+1).

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3b-27 (219.1 mg, 1.00 mmol) and lithium perchloric acid (85.1 mg, 0.80 mmol). Solid compound 52, melting point: 106-108 ° C, yield 35.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.92 (d, J = 2.4 Hz, 1H), 8.43 (dd, J = 8.4, 7.8 Hz, 1H), 7.82 (s, 1H), 7.77 (s, 1H), 7.43 (m, 1H), 7.00 (dd, J= 8.5, 2.9 Hz, 1H), 6.81-6.67 (m, 2H), 5.06 (s, 1H), 4.97-4.85 (m, 2H), 4.39-4.20 ( m, 3H), 4.02 (m, 1H), 3.84 (s, 1H), 3.35 (q, J = 6.8 Hz, 1H), 2.98 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H). ESI-MS 471.2 (M+1).

Example 53 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-cyanopyridine-5-yl)-5,6-dihydro-[1,2 , 4] Preparation of triazole [l,5-a] piperazine-7(8H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol (compound 53)

Compound 97 (0.35 g, 1.16 mmol), compound 112 (0.32 g, 1.39 mmol), tetrakis(triphenylphosphine)palladium (0.13 g, 0.12 mmol) cesium carbonate C 0.76 g, 2.32 mmol) A similar preparation method of the fourth step gave a white solid compound 98b-28, a total of 0.19 g (0.59 mmol), yield 50.6%.

1H NMR (400 MHz, CDC1 ₃ ) δ 9.51 (d, J = 2.1 Hz, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.56 (t, J = 2.1 Hz, 1H), 4.81 (s, 2H), 4.31 (t, J = 5.3 Hz, 2H), 4.10 (t, J = 5.2 Hz, 2H), 1.51 (s, 9H). ESI-MS 327.1 (M+1).

The compound 98b-28 (0.19 g, 0.59 mmol) was obtained from white solid compound 3b-28 (yield: 68.2%).

1H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 9.46 (d, J = 2.0 Hz, 1H), 8.78 (d, J = 2.1 Hz, 1H), 8.65 (t, J = 2.1 Hz, 1H), 4.33 (t, J = 5.6 Hz, 2H), 4.21 (s, 2H), 3.38-3.32 (m, 2H). ESI-MS 227.1 (M+1).

Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3b-28 (226.1 mg, 1.00 mmol) and lithium perchlorate (85.1 mg, 0.80 mmol). White solid compound 53, melting point: 150-151 ° C, yield 33.6%.

1H NMR (400 MHz, CDC1 ₃ ) δ 9.48 (d, J = 2.0 Hz, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.61 (t, J = 2.1 Hz, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.43-7.39 (m, 1H), 6.80-6.70 (m, 2H), 5.07 (s, 1H), 4.97-4.87 (m, 2H), 4.35-4.27 (m, 3H), 4.03 (d, J = 15.7 Hz, 1H), 3.87 (m, 1H), 3.36 (q, J = 7.1 Hz, 1H), 3.04-2.95 (m, 1H), 1.00 (d, J= 6.9 Hz, 4H). ESI-MS 477.2 (M+1).

Example 54 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-phenyl-6,7-dihydrothiazole [5,4-c]piperidin-5 (4H )- base)- 1-(1H-1 ,2

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-1 (216.0 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.0 mmol). White solid compound 54, melting point: 72-73 ° C, yield: 28.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.92 (s, 1H), 7.91-7.86 (m, 2H), 7.78 (s, 1H), 7.57-7.36 (m, 4H), 6.84-6.68 (m, 2H) , 5.12 (s, 1H), 4.98-4.82 (m, 2H), 4.11 (d, J = 14.8 Hz, 1H), 3.81 (d, J = 14.8 Hz, 1H), 3.35-3.28 (m, 1H), 3.24 (q, J= 6.8 Hz, 1H), 2.98-2.93 (m, 2H), 2.82- 2.69 (m, 1H), 1.03 (d, J= 6.8 Hz, 3H). ESI-MS 468.1 (M+1) ).

Example 55 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-chlorophenyl)-6,7-dihydrothiazole [5,4-c]piperidin Pyridin-5(4H)- Preparation of 1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Compound 55)

3c-2 2A 55

Compound 2AC 126.0 mg, 0.50 mmol) was added to compound 3c-2C (250.0 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). Compound 55, melting point: 74-75 ° C, yield 26.8%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.91 (s, 1H), 7.82 (d, J = 8.5 Hz, 2H), 7.78 (s, 1H), 7.49-7.41 (m, 1H), 7.39 (d, J = 8.5 Hz, 2H), 6.76 (m, 2H), 5.11 (s, 1H), 4.98- 4.80 (m, 2H), 4.12 (d, J = 14.9 Hz, 1H), 3.81 (d, J = 14.9 Hz , 1H), 3.37-3.28 (m, 1H), 3.25 (q, J = 6.8 Hz, 1H), 2.94 (m, 2H), 2.81-2.76 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H). ESI-MS 502.1 (M+1).

Example 56 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-trifluoromethylphenyl)-6,7-dihydrothiazole [5,4- Preparation of c]piperidin-5(4H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol

3c-3 2A 56

Compound 2AC 126.0 mg, 0.50 mmol) was added to compound 3c-3C 284.0 mg, 1.00 mmol, and lithium perchlorate (106.4 mg, 1.00 mmol). Compound 56, melting point: 81-82 ° C, yield 23.6%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.93 (s, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.76 (s, 1H), 7.45-7.41 (m, 1H), 7.36 (d, J = 8.5 Hz, 2H), 6.78-6.71 (m, 2H), 5.10 (s, 1H), 4.96- 4.80 (m, 2H), 4.11 (d, J = 14.9 Hz, 1H), 3.83 (d, J = 14.9 Hz, 1H), 3.36-3.28 (m, 1H), 3.26 (q, J = 6.8 Hz, 1H), 2.98-2.95 (m, 2H), 2.83-2.76 (m, 1H), 1.01 (d, J = 6.8 Hz, 3H). ESI-MS 536.1 (M+1).

Example 57 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-methoxyphenyl)-6,7-dihydrothiazole [5,4-c Preparation of piperidine-5(4H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol (Compound 57)

3c-4 2A 57

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-4 (246.0 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 57, melting point: 93-95 ° C, yield 33.6%.

1H NMR (300 MHz, CDC13) δ 7.92 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.78 (s, 1H), 7.50-7.45 (m, 1H), 6.93 (d, J= 8.5 Hz, 2H), 6.76-6.68 (m, 2H), 4.97- 4.84 (m, 2H), 4.07 (d, J = 14.8Hz, 1H), 3.85 (s, 3H), 3.78 (d, J= 14.8 Hz, 1H), 3.35-3.28 (m, 1H), 3.27 (q, J= 6.8 Hz, 1H), 2.92-2.71 (m, 2H), 2.81-2.73 (m, 1H), 1.03 (d, J = 6.8 Hz, 3H). ESI-MS 498.1 (M+1). Example 58 (2R, 3R )-2-(2,4-difluorophenyl)-3-(2-(4-methylphenyl)-6,7-dihydrothiazole [5,4-c]piperidin-5(4H) -base) Preparation of 1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Compound 58)

3c- 5 2A 58

Compound 2AC 126.0 mg, 0.50 mmol) was added to compound 3c-5C (230.0 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). Compound 58, melting point: 86-87 ° C, yield 25.6%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.92 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.76 (s, 1H), 7.50-7.45 (m, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.81-6.76 (m, 2H), 4.98 -4.82 (m, 2H), 4.09 (d, J = 14.8 Hz, 1H), 3.79 (d, J = 14.8 Hz, 1H), 3.35 -3.28 (m, 1H), 3.27 (q, J = 6.8 Hz, 1H), 2.93 (m, 2H), 2.95-2.71 (m, 2H), 2.38 (s, 3H), 1.03 (d, J= 6.8 Hz, 3H). ESI-MS 482.1 (M+1).

Example 59 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-fluorophenyl)-6,7-dihydrothiazole [5,4-c]piperidin Pyridin-5(4H)-yl)-1-(1H-

3c- 6 2A 59

Compound 2AC 126.0 mg, 0.50 mmol) was added to compound 3c-6 C 234.0 mg, 1.00 mmol, and lithium perchlorate (106.4 mg, 1.00 mmol) in the same manner as in Example 1 to give 52.4 mg white. Solid compound 59, melting point: 94-95 ° C, yield 21.6%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.91 (s, 1H), 7.87 (d, J = 8.6, 2H), 7.78 (s, 1H), 7.55- 7.43 (m, lH), 7.10 (d, J= 8.6 Hz, 2H), 6.83- 6.65 (m, 2H), 4.98- 4.83 (m, 2H), 4.11 (d, J= 14.8 Hz, 1H), 3.80 (d, J= 14.8 Hz, 1H), 3.36- 3.28 (m, 1H), 3.26 (q, J = 6.8 Hz, 1H), 2.93 (m, 2H), 2,91-2.77 (m, 1H), 1.03 (d, J=6.8 Hz, 3H). ESI -MS 486.1 (M+1).

Example 60 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-bromophenyl)-6,7-dihydrothiazole [5,4-c]piperidin Pyridin-5(4H)-yl)-1-(1

3c-7 2A 60

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-7 (294.0 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 60, melting point: 82-83 ° C, yield 31.0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.90 (s, 1H), 7.78 (s, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.55 (d, J = 8.9 Hz, 2H), 7.49- 7.46 (m, 1H), 6.86-6.75 (m, 2H), 4.97-4.84 (m, 2H), 4.11 (d, J = 15.1 Hz, 1H), 3.81 (d, J= 15.1 Hz, 1H), 3.37-3.25 (m, 1H), 3.26 (q, J= 6.8 Hz, 1H), 2.98-2.91 (m, 2H), 2.81-2.76 (m , 1H), 1.02 (d, J = 6.8 Hz, 3H). ESI-MS 546.0 (M+1).

Example 61 (2R,3R)-2-(2,4-Difluorophenyl)-3-(2-(4-isopropylphenyl)-6,7-dihydrothiazole [5,4-c Preparation of piperidine-5(4H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol

3c-8 2A 61

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-8 (258.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 61, melting point: 76-77 ° C, yield 21.6%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.92 (s, 1H), 7.82 (s, 1H), 7.78 (d, J = 7.6 Hz, 2H), 7.51-7.49 (m, 1H), 7.27 (d, J = 7.6 Hz, 2H), 6.78-6.76 (m, 2H), 5.13 (s, 1H), 4.97-4.84 (m, 2H), 4.09 (d, J = 14.9 Hz, 1H), 3.79 (d, J = 14.9 Hz, 1H), 3.37-3.25 (m, 1H), 3.26 (q, J = 6.8 Hz, 1H), 2.98-2.91 (m, 3H), 2.83-2.76 (m, 1H), 1.26 (d, J = 6.9 Hz, 6H), 1.03 (d, J = 6.8 Hz, 3H). ESI-MS 510.0 (M+1).

Example 62 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(4-cyanophenyl)-6,7-dihydrothiazole [5,4-c] Preparation of piperidine-5(4H)-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Compound 62)

3c-9 2A 62

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-9 (241.0 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 62, melting point: 97-98 ° C, yield 31.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.99 (d, J = 8.5 Hz, 2H), 7.90 (s, 1H), 7.78 (s, 1H), 7.70 (d, J = 8.5 Hz, 2H), 7.52- 7.40 (m, 1H), 6.76-6.75 (m, 2H), 4.97-4.83 (m, 2H), 4.17 (d, J= 15.3 Hz, 1H), 3.85 (d, J= 15.3 Hz, 1H), 3.37 -3.25 (m, 1H), 3.26 (q, J = 6.8 Hz, 1H), 2.98-2.95 (m, 2H), 2.86-2.78 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H). ESI-MS 493.0 (M+1).

Example 63 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-chlorophenyl)-6,7-dihydrothiazole [5,4-c]piperidin Preparation of pyridine-5(4H)-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Compound 63)

2A 63

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-10 (250.0 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 63, melting point: 84-85 ° C, yield 35.6%.

1H NMR (400 MHz, CDC1 ₃ ) δ 7.91 (s, 2H), 7.76 (s, 1H), 7.74-7.72 (m, 1 Η), 7.54-7.44 (m, 1H), 7.39-7.31 (m, 2H) , 6.84-6.68 (m, 2H), 4.96-4.85 (m, 2H), 4.13 (d, J= 15.7 Hz, 1H), 3.82 (d, J= 14.6Hz, 1H), 3.36-3.25 (m, 1H) ), 3.27 (q, J = 6.8 Hz, 1H), 2.95-2.93 (m, 2H), 2.86-2.77 (m, 1H), 1.02 (d, J = 6.0 Hz, 3H). ESI-MS 501.0 (M +1).

Example 64 (2R,3R)-2-(2,4-Difluorophenyl)-3-(2-(3-fluorophenyl)-6,7-dihydrothiazole [5,4-c]piperidin Pyridin-5(4H)-yl)-1-(1H-

3c-ll 2A 64

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-ll (234.0 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 64, melting point: 85-87 ° C, yield 33.2%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.91 (s, 1H), 7.91-7.87 (dd, J = 8.6, 5.3 Hz, 2H), 7.78 (s, 1H). 7.55- 7.43 (m,lH), 7.10 (d, J = 8.6 Hz, 2H), 6.83- 6.65 (m, 2H), 4.98- 4.83 (m, 2H), 4.11 (d, J = 14.8 Hz, 1H), 3.80 (d, J = 14.8 Hz, 1H), 3.36-3.25 (m, 1H), 3.27 (q, J = 6.8 Hz, 1H), 2.96-2.93 (m, 2H), 2.83-2.77 (m, 1H), 1.03 (d, J = 6.8 Hz , 3H). ESI-MS 486.1 (M+1).

Example 65 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-methylphenyl)-6,7-dihydrothiazole [5,4-c] Piperidine-5(4H)-yl)-1-(

3c-12 2A

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-12 (230.0 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 65, melting point: 88-89 ° C, yield 25.6%.

1H NMR (400 MHz, CDC1 ₃ ) δ 7.92 (s, 1H), 7.78 (s, 1H), 7.75-7.71 (m, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.53-7.44 (m , 1H), 7.32-7.30 (m, 1H), 7.21 (d, J = 8.3 Hz, 1H), 6.82- 6.70 (m, 2H), 5.13 (s, 1H), 4.98-4.82 (m, 2H), 4.10 (d, J = 15.2 Hz, 1H), 3.81 (d, J = 15.2 Hz, 1H), 3.32-3.28 (m, 1H), 3.23 (q, J = 6.8 Hz, 1H), 2.97-2.93 (m , 2H), 2.83-2.77 (m, 1H), 1.01 (d, J = 6.8 Hz, 3H). ESI-MS 482.1 (M+1).

Example 66 (2R,3R)-2-(2,4-Difluorophenyl)-3-(2-(2,4-difluorophenyl)-6,7-dihydrothiazole [5,4- c] piperidine-5(4H)-yl)-

3c-13 2A Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-13 (252.0 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 66, melting point: 86-88 ° C, yield 35.6%.

1H NMR (400 MHz, CDC13) δ 8.01 (m, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.41-7.35 (m, 1H), 6.95-6.86 (m, 2H), 6.73- 6.70(m, 2H), 5.01 (s, 1H), 4.93-4.90(m, 2H), 4.12 (d, J = 15.2 Hz, 1H), 3.85 (d, J = 15.2 Hz, 1H), 3.31-3.28 (m, 1H), 3.26 (q, J = 6.8 Hz, 1H), 2.98-2.91 (m, 2H), 2.81-2.77 (m, 1H), 1.03 (d, J = 6.8 Hz, 3H). ESI- MS: 504.1 (M + 1).

Example 67 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-bromophenyl)-6,7-dihydrothiazole [5,4-c]piperidin Pyridin-5(4H)-yl)-1-(1H-

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-14 (294.0 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 67, melting point: 92-93 ° C, yield 21.0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.91 (s, 1H), 7.86 (m, 1H), 7.76 (s, 1H), 7.58-7.56 (m, 1H), 7.46-7.40 (m, 3H), 6.83 -6.78 (m, 2H), 4.95-4.84 (m, 2H), 4.12 (d, J = 15.1 Hz, 1H), 3.83 (d, J = 15.1 Hz, 1H), 3.36-3.31 (m, 1H), 3.25 (q, J = 6.8 Hz, 1H), 2.96-2.91 (m, 2H), 2.83-2.76 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H). ESI-MS 546.0 (M+1) ).

Example 68 (2R,3R)-2-(2,4-Difluorophenyl)-3-(2-(3-methoxyphenyl)-6,7-dihydrothiazole [5,4-c Piperidine-5 (4

3c-15 2A 68

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-15 (246.0 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.0 mmol). White solid compound 68, melting point: 96-98 ° C, yield 31.6%.

1H NMR (300 MHz, CDC13) δ 7.91 (s, 1H), 7.81 (m, 1H), 7.76 (s, 1H), 7.51-7.45 (m, 1H), 7.41-7.36 (m, 2H), 6.96 ( m, 1H), 6.76-6.68 (m, 2H), 4.95- 4.86 (m, 2H), 4.05 (d, J = 14.8Hz, 1H), 3.83 (s, 3H), 3.76 (d, J = 14.8 Hz , 1H), 3.31-3.28 (m, 1H), 3.26 (q, J = 6.8 Hz, 1H), 2.96-2.71 (m, 2H), 2.87-2.75 (m, 1H), 1.01 (d, J = 6.8 Hz, 3H). ESI-MS 498.1 (M+1).

Example 69 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-trifluoromethylphenyl)-6,7-dihydrothiazole [5,4- Preparation of piperidine-5(4H)-yl)-1-(1Η-1,2,4-triazol-1-yl)butan-2-ol (Compound 69)

2A 69

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-16 (284.0 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 69, melting point: 91-92 ° C, yield 30.6%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.03 (m, 1H), 7.91 (s, 1H), 7.85-7.80 (m, 1H), 7.75 (s, 1H), 7.45_7.40 (m, 2H), 7.36-7.21 (m, 1H), 6.76-6.75 (m, 2H), 5.08 (s, 1H), 4.95-4.83 (m, 2H), 4.12 (d, J = 14.9 Hz, 1H), 3.81 (d, J = 14.9 Hz, 1H), 3.37-3.31 (m, 1H), 3.27 (q, J = 6.8 Hz, 1H), 2.98-2.95 (m, 2H), 2.83-2.76 (m, 1H), 1.03 (d , J = 6.8 Hz, 3H). ESI-MS 536.1 (M+1).

Example 70 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-cyanophenyl)-6,7-dihydrothiazole [5,4-c] Preparation of piperidine-5(4H)-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Compound 70)

3c-17 2A 70

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3d-17 (241.0 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). Omg white solid compound 70, melting point: 67-68 ° C, yield 25.5%.

1H NMR (300 MHz, CDC13) δ 8.20-8.18 (m, 1H), 8.12-8.07 (m, 1H), 7.90 (s, 1H), 7.78 (s, 1H), 7.62-7.56 (m, 1H), 7.52-7.42(m, 2H), 6.85-6.70 (m, 2H), 5.09 (s, 1H), 4.99-4.84 (m, 2H), 4.17 (d, J = 15.2 Hz, 1H), 3.85 (d, J = 15.2Hz, 1H), 3.40-3.34 (m, 1H), 3.27 (q, J = 6.8 Hz, 1H), 3.03-2.91 (m, 2H), 2.89-2.74 (m, 1H), 1.03 (d , J = 6.8 Hz, 3H). ESI-MS 493.0 (M+1). Example 71 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(3-) Propylphenyl)-6,7-dihydrothiazole [5,4-c]piperidin-5(4H)-yl)-1-(1Η-1,2,4-triazol-1-yl) Preparation of -2-ol (combination

3c-18 2A 71

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-18 (258.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 71, melting point: 78-79 ° C, yield 31.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 7.91 (s, 1H), 7.88-7.86 (m, 1H), 7.81 (s, 1H), 7.71-7.68 (m, 1H), 7.41-7.36 (m, 2H) , 7.26-7.21 (m, 1H), 6.76-6.78 (m, 2H), 5.11 (s, 1H), 4.96-4.85 (m, 2H) 4.12 (d, J = 14.9 Hz, 1H), 3.78 (d, J = 14.9 Hz, 1H), 3.36-3.21 (m, 1H), 3.27 (q, J = 6.8 Hz, 1H), 2.96-2.91 (m, 3H), 2.85-2.71 (m, 1H), 1.25 (d , J = 6.9 Hz, 6H), 1.01 (d, J = 6.8 Hz, 3H). ESI-MS 510.0 (M+1). Example 72 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(pyridin-3-yl)-6,7-dihydrothiazole [5,4-c]piperidin Pyridin-5(4H)-yl)-1-(1H-1

3c-19 2A 72

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-19 (217.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 72, melting point: 62-63 ° C, yield 25.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 9.11 (d, J = 1.6 Hz, 1H), 8.63 (dd, J = 4.8, 1.6 Hz, 1H), 8.21-8.16 (m, 1H), 7.91 (s, 1H ), 7.78 (s, 1H), 7.53-7.43 (m, 1H), 7.37 (m, 1H), 6.84-6.66 (m„ 2H), 5.10 (s, 1H), 4.99-4.83 (m, 2H), 4.16 (d, J = 15.1 Hz, 1H), 3.85 (d, J = 15.1 Hz, 1H), 3.44-3.32 (m, 1H), 3.26 (q, J = 6.8 Hz, 1H), 3.02-2.94 (m , 2H), 2.84-2.75 (m, 1H), 1.03 (d, J = 6.8 Hz, 3H). ESI-MS 469.1 (M+1).

Example 73 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(pyridin-4-yl)-6,7-dihydrothiazole [5,4-c]piperidin Pyridin-5(4H)-yl)-1-(1H-

3c-20 2A 73

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-20 (217.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol), which was obtained in the same manner as in Example 1 to give 55.2 mg. White solid compound 73, melting point: 133-134 ° C, yield 23.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.68 (d, J = 5.8 Hz, 2H), 7.90 (s, 1H), 7.78 (s, 1H), 7.75 (d, J = 5.8 Hz, 2H), 7.53- 7.43 (m, 1H), 6.85-6.67 (m, 2H), 5.08 (s, 1H), 4.98-4.84 (m, 2H), 4.18 (d, J = 15.3 Hz, 1H), 3.86 (d, J= (3, Hz, 1H) Hz, 3H). ESI-MS 469.1 (M+1).

Example 74 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(2-cyanopyridine-5-yl)-6,7-dihydrothiazole [5,4 -c] piperidine-5(4H)-yl)-1

3c-21 2A 74

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-21 (24. 1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). Mg white solid compound 74, melting point: 135-136 ° C, yield 15.5%. NMR NMR (300 MHz, CDC1 ₃ ) δ 9.20 (d, J = 2.1 Hz, 1H), 8.31 (dd, J = 8.1, 2.1 Hz, 1H), 7.89 (s, 1H), 7.78 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 5.06 (s, 1H), 4.91 (s, 2H), 4.22 (d, J = 15.3 Hz, 1H), 3.89 (d, J = 15.5 Hz, 1H), 3.43-3.40 (m, 1H), 3.29 (q, J = 6.5 Hz, 1H), 2.99 (t, J = 5.0 Hz, 5,4-c) piperidine

3c-22 2A 75

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-22 (235.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 75, melting point: 130-131 ° C, yield 13.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.90 (d, J = 1.6 Hz, 1H), 8.49 (d, J = 2.6 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.53-7.43 (m, 1H), 6.84-6.66 (m, 2H), 4.98-4.95 (m,

01-2.98 (m, [5,4-c] piperidine

3c- 23 2A 16

Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-23 (242.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 76, melting point: 125-126 ° C, yield 16.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 9.26 (s, 1H), 8.86 (s, 1H), 8.47 (d, J = 1.6 Hz, 1H), 7.89 (s, 1H), 7.78 (s, 1H), 7.55-7.39 (m, 1H), 6.85-6.67 (m, 2H), 4.96-4.93 (m, 2H), 4.23 (d, J = 12.4 Hz, 1H), 3.90 (d, J = 16.5 Hz, 1H) , 3.45-3.39 (m, 1H), 3.36-3.27 (m, 1H), 3.01-2.98 (m, 2H), 2.87-2.81 (m, 2H), 1.03 (d, J = 6.7 Hz, 3H). ESI -MS 494.2 (M+1).

Example 77 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(pyrimidin-5-yl)-6,7-dihydrothiazole [5,4-c]piperidin Pyridin-5(4H)-yl)-1-(1H-1,2

3c-24 2A 77 Compound 2A (126.0 mg, 0.50 mmol) was added to compound 3c-24 (218.1 mg, 1.00 mmol) and lithium perchlorate (106.4 mg, 1.00 mmol). White solid compound 77, melting point: 121-122 ° C, yield 18.5%.

1H NMR (300 MHz, CDC1 ₃ ) δ 9.23-9.19 (m, 3H), 7.89 (s, 1H), 7.78 (s, 1H), 7.51-7.42 (m, 1H), 6.82-6.70 (m, 2H) , 4.95-4.91 (m, 2H), 4.21 (d, J = 14.2 Hz, 1H), 3.88 (d, J = 15.3 Hz, 1H), 3.42-3.37 (m, 1H), 3.34-3.24 (m, 1H) ), 3.02-2.96 (m, 2H), 2.85-2.78 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H). ESI-MS 470.2 (M+1).

Example 78 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(pyridin-3-yl)-4H-pyrrole[3,4-d]thiazole-5 (6H Preparation of 1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Compound 78)

a ₂

-

99 103 102d-l

First step: Compound 99 (0.52 g, 1.71 mmol) Compound 103 (0.42 g, 2.05 mmol), tetrakis(triphenylphosphine)palladium (0.20 g, 0.172 mmol), cesium carbonate (1.12 g, 3.50 mmol) The reaction was carried out at 80 ° C for 16 h under argon atmosphere in an aqueous solution of dioxane (50.0 mL, 4:1). Concentrated to dryness, ethyl acetate and EtOAc (EtOAc)EtOAc.EtOAc. :10-1 :6) gave the compound as a white solid, 102d-1, 0.31 g (1.03 mmol), yield: 60.6%.

1H NMR (300 MHz, CDC1 ₃ ) δ 9.24 (d, J = 1.3 Hz, 1H), 8.70 (dd, J = 4.9, 1.2 Hz, 1H), 8.42 (dt, J = 7.9, 1.9 Hz, 1H), 7.46-7.41 (m, 1H), 4.87 (s, 2H), 4.23 (s, 2H), 1.51 (s, 9H). ESI-MS 304.1 (M+1).

The second step: Compound 102d-lC 0.50 g (1.64 mmol) was dissolved in 4N EtOAc EtOAc EtOAc EtOAc. Dichloromethane was dissolved, and the mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate. The organic phase was washed three times with a saturated NaCI solution, dried over anhydrous Na ₂ SO ₄ , and evaporated to dryness to give a white powder compound 3d-1, 0.29 g. , the yield was 86.6%.

1H NMR (300 MHz, CD3OD-CI4) δ 9.21 (d, J = 1.3 Hz, 1H), 8.66 (dd, J = 4.9, 1.2 Hz, 1H), 8.32 (dt, J = 7.9, 1.9 Hz, 1H) , 7.45-7.40 (m, 1H), 4.32 (s, 2H), 3.36-3.31 (m, 2H). ESI-MS 204.1 (M+1).

The third step: Compound 2A (100.0 mg, 0.40 mmol) was added to compound 3d-1 (162.6 mg, 0.80 mmol) and lithium perchlorate (85.1 mg, 0.80 mmol). 63.6 mg of a white solid compound 78, m.p.: 115-117 ° C, yield 35.0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 9.21 (d, J = 1.3 Hz, 1H), 8.65 (dd, J = 4.9, 1.3 Hz, 1H), 8.33 (dt, J = 7.9, 1.9 Hz, 1H), 7.88 (s, 1H), 7.76 (s, 1H), 7.51-7.43 (m, 1H), 6.78 (m, 2H), 4.98-4.96 (m, 2H), 4.43-4.16 (m, 4H), 3.51 ( q, 6.8 Hz, 1H), 0.99 (d, J = 6.8 Hz, 3H). ESI-MS 455.1 (M+1).

Example 79 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(pyridin-4-yl)-4H-pyrrole[3,4-d]thiazole-5 (6H Preparation of 1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Compound 79) Boc-N —Br Boc-N

HO

99 104

Compound 99 (0.30 g, 0.98 mmol), compound 104 (0.14 g, 1.17 mmol), tetrakis(triphenylphosphine)palladium (0.1 g, 0.10 mmol), cesium carbonate C 0.65 g, 2.0 mmol) A similar preparation in the first step of Example 78 gave white solid compound 102d-2, 3⁄4 0.2 lg (0.69 mmol), yield 70.0%.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.78 (d, J = 6.1 Hz, 2H), 7.81 (d, J = 6.0 Hz, 2H), 4.85 (s, 2H), 4.33 (s, 2H), 1.50 ( s, 9H). ESI-MS 304.1 (M+1).

Compound 102d-2 (0.21 g, 0.69 mmol) was obtained as a white solid compound 3d-2 (yield: 0.12 g (0.59 mmol).

1H NMR (300 MHz, CD ₃ OD-d ₄ ) δ 8.81 (d, J = 6.0 Hz, 2H), 7.89 (d, J = 6.1 Hz, 2H), 4.31 (s, 2H), 3.36-3.31 (m , 2H). ESI-MS 204.1 (M+1).

Compound 2A (125.0 mg, 0.50 mmol) was added to compound 3d-2 (202.5 mg, 1.00 mmol) of lithium perchlorate (106.4 mg, 1.00 mmol) according to the procedure of the third step of Example 78. , 71.6 mg of a white solid compound 79, m.p.: 121-123.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.68 (d, J = 6.0 Hz, 2H), 7.91 (d, J = 6.1 Hz, 2H), 7.86 (s, 1H), 7.78 (s, 1H), 7.53- 7.45 (m, 1H), 6.78 (m, 2H), 4.98-4.96 (m, 2H), 4.35-4.10 (m, 4H), 3.50 (q, 6.

EXAMPLES [3,4-d]thiazol-5(6H)-yl)-1-(1H

102d-3

Compound 99 (0.30 g, 0.98 mmol), compound 104 (0.14 g, 1.17 mmol), tetrakis(triphenylphosphine)palladium (0.1 g, 0.10 mmol), cesium carbonate C 0.65 g, 2.0 mmol) A similar preparation in the first step of Example 78 gave white solid compound 102d-3, 3⁄4 0.2 lg (0.70 mmol), yield 71.6%.

1H NMR (300 MHz, CDC1 ₃ ) δ 9.31 (s, 1H), 9.16 (s, 2H), 4.75 (s, 2H), 4.31 (s, 2H), 1.48 (s, 9H). ESI-MS 305.1 ( M+1).

The compound 102d-3 (0.21 g, 0.70 mmol) was obtained in a white solid solid compound 3d-3 (0.13 g, 0.62 mmol).

1H NMR (300 MHz, CD3OD-CI4) δ 9.23 (s, 1H), 9.11 (s, 2H), 4.35 (s, 2H), 3.41-3.36 (m, 2H). ESI-MS 205.1 (M+1) .

Compound 2A (125.0 mg, 0.50 mmol) was added to compound 3d-3 (202.5 mg, 1.00 mmol) of lithium perchlorate (106.4 mg, 1.00 mmol) according to the procedure of the third step of Example 78. , 83.1 mg of a white solid compound 80 was obtained, m.p.: 126. NMR NMR (300 MHz, CDC1 ₃ ) δ 9.24 (s, 1H), 9.22 (s, 2H), 7.87 (s, 1H), 7.79 (s, 1H) 7.50-7.41 (m, 1H), 6.76 (m, 2H), 4.98-4.96 (m, 2H), 4.44-4.14 (m, 4H), 3.52 (q, 6.8 Hz, 1H) 0.98 (d, J = 6.8 Hz, 3H). ESI-MS 456.1 (M+1) ).

Example 81 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(2-cyanopyridine-5-yl)-5,6-dihydro-[1,2 , 4] triazole [l,5-a: piperazine-7 (8H)-

The compound 48 (238.5 mg, 0.50 mmol) was dissolved in 5.0 ml of methanol, and a 2N solution of hydrogen chloride in methanol (0.28 ml, 0.55 mmol) was added dropwise thereto, and the mixture was stirred at room temperature for 1.0 hour to precipitate a white precipitate, suction filtration, methanol Washing, drying under reduced pressure to give a white solid compound 113, m.p.: 208 - 210 ° C, 205.5 mg, yield: 80.1%, ESI-MS 478.1 (M+l) o Elemental analysis C ₂₃ H ₂₂ C1F ₂ N ₉ 0 , calculated (%): C, 53.75; H, 4.31; Cl, 6.91; F, 7.39; N, 24.53; 0, 3.11, (%): C, 53.65; H, 4.48; Cl, 6.85; 7.35; N, 24.51; 0, 3.16

Example 82 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(2-cyanopyridine-5-yl)-5,6-dihydro-[1,2 , 4] triazole [l,5-a] piperazine-7 (8H)-

Compound 48 (238.5 mg, 0.50 mmol) was dissolved in 5.0 ml of methanol, and 2N dilute sulfuric acid (0.28 ml, 0.55 mmol) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1.0 hour to precipitate a white precipitate, suction filtered, and washed with methanol. Drying under reduced pressure gave a white solid compound 114, m.p.: 220-221 ° C, 218.0 mg, yield: 75.6%, ESI-MS 478.1 (M+l) o Elemental analysis C ₂₃ H ₂₃ F ₂ N ₉ 0 ₅ S , calculated value (%): C, 48.00; H, 4.03; F, 6.60; N, 21.90; 0, 13.90; S, 5.57; Found (%): C, 47.80; H, 4.55; F, 6.96; , 20.66; 0,14.30; S, 6.33

Example 83 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(2-cyanopyridine-5-yl)-5,6-dihydro-[1,2 , 4] triazole [l,5-a] piperazine-7(8H)-115)

Compound 48 (238.5 mg, 0.50 mmol) was dissolved in 5.0 ml of methanol, and p-toluenesulfonic acid (86.0 mg, 0.55 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1.0 hour, and a white precipitate was precipitated, filtered, and washed with methanol. Drying under reduced pressure gave a white solid compound 115, m.p.: 210-212 ° C, 232.3 mg, yield: 71.6%, ESI-MS 478.1 (M+l) o Elemental analysis C ₃₀ H ₂₉ F ₂ N ₉ O ₄ S Calculated (%): C, 55.46; H, 4.50; F, 5.85; N, 19.40; 0, 9.85; S, 4.94; Found (%): C, 55.48; H, 4.95; F, 5.98; , 18.86; 0,9.77; S, 4.96 Example (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(2-cyanopyridine-5-yl)-5,6-dihydro-[1,2, 4]

Piperazine-7(8H)-

The compound (238.5 mg, 0.50 mmol) was dissolved in 5.0 ml of methanol, and methanesulfonic acid (52.8 mg, 0.55 mmol) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1.0 hour, and a white precipitate was precipitated, suction filtered, and washed with methanol. pressure and dried to give a white solid compound, mp: 216_218 ° C, a total of 202.8 mg, yield: 70.8%, ESI-MS 478.1 + l Elementary analysis for _{_{_{_{C 24 H 25 F 2 N 9}}}} 0 4 S, Calcd. (%): C , 50.46; H, 4.39; F, 6.62; N, 21.98; 0,11.16; S, 5.59; Found: C, 50.41; H, 4.45; F, 6.53; N, 21.98; 0,11.36; S, 5.27

Example (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(pyrimidin-5-yl)-6,7-dihydrothiazole [5,4-c]piperidine -5(4H)-yl)-1-(1H-

The compound (200.0 mg, 0.42 mmol) was dissolved in 2.0 ml of ethyl acetate, and a solution of 3N hydrogen chloride in ethyl acetate (0.15 ml, 0.44 mmol) was added dropwise at room temperature, and stirred at room temperature for 1.0 hour to precipitate a precipitate, 0-5 The mixture was allowed to stand at rt overnight, EtOAc (EtOAc) EtOAc (EtOAc). . Elemental analysis for C ₂₂ H ₂₂ C1F ₂ N _{7 0 s} , calcd. (%): calc.: C.sup.sup.ssssssssssssssssssssssssssss , 51.98; H, 4.31; C1, 7.15, F, 7.46; N, 19.28; 0, 3.19; S, 6.63

Example (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(pyrimidin-5-yl)-6,7-dihydrothiazole [5,4-c]piperidine -5(4H)-yl) -1-(1H

The compound (200.0 mg, 0.42 mmol) was dissolved in 2.0 ml of ethyl acetate, and a solution of concentrated sulfuric acid in ethyl acetate (44.8 mg, 0.44 mmol) was added dropwise at room temperature, and stirred at room temperature for 1.0 hour to precipitate a precipitate, 0-5 After standing overnight at ° C, suction filtration, ethyl acetate washed and evaporated to drynessielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielieliel For C ₂₂ H ₂₃ F ₂ N ₇ 0 ₅ S ₂ , calcd for C, 46.55; H, 4.08; F, 6.69; N, 17.27; 0, 14.09; S, l 1.30; found C, 46.25; 4.16; F, 6.76; N, 17.18; 0, 14.29; S, 11.36

Example (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(pyrimidin-5-yl)-6,7-dihydrothiazole [5,4-c]piperidine -5(4H)-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol p-toluenesulfonate preparation (compound

The compound 77 (200.0 mg, 0.42 mmol) was dissolved in 2.0 ml of ethyl acetate, and ethyl acetate solution (85.0 mg, 0.44 mmol) of p-toluenesulfonic acid was added dropwise at room temperature, and the mixture was stirred at room temperature for 1.0 hour to precipitate a precipitate. The mixture was allowed to stand at 0 to 5 ° C, EtOAc (EtOAc) EtOAc (EtOAc) M+1). Elemental analysis for C ₂₉ H ₂₉ F ₂ N ₇ 0 ₄ S ₂ , calcd. (%): C,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, C, 54.15; H, 4.65; F, 5.98; N, 15.31; 0, 9.96; S, 9.95

Example 88 (2R,3R)-2-(2,4-difluorophenyl)-3-(2-(pyrimidin-5-yl)-6,7-dihydrothiazole [5,4-c]piperidin Preparation of pyridine-5(4H)-yl)-1-(1H-sulfonate)

The compound 77 (200.0 mg, 0.42 mmol) was dissolved in 2.0 ml of ethyl acetate, and a solution of methanesulfonic acid in ethyl acetate (43.0 mg, 0.44 mmol) was added dropwise at room temperature, and stirred at room temperature for 1.0 hour to precipitate a precipitate. The mixture was allowed to stand overnight at -5 ° C, filtered, washed with ethyl acetate and evaporated to drynessielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielieliel +l) o Elemental analysis C ₂₃ H ₂₅ F ₂ N ₇ 0 ₄ S ₂ , calculated (%): C, 48.84; H, 4.46; F, 6.72; N, 17.33; 0, 1 1.31 ; S, 1 1.34 ; measured value (%) C, 48.68; H, 4.56; F, 6.76; N, 17.18; 0, 1 1.36; S, 1 1.46

Example 89 In vitro antifungal activity of preferred compounds

I. Experimental materials

Strain

Table 1. Antifungal activity in vitro female test strain

(The test strain was provided by the fungal strain library of the New Drug Research Center of the Second Military Medical University School of Pharmacy)

Species name Species strain number Candida albicans Y0109

Candida albicans SC5314 Candida parapsilosis ATCC 22019 Candida glabrata 537

Cryptococcus neoformans cryptococcus neoformans 32609

Microsporum gypseum Cmccfinza Trichophyton rubrum Cmccftla Aspergillus fumigatus 07544

2. Fungal medium

(1) RPMI 1640 medium: RPMI1640 (Gibco BRL, Invitrogen, USA) 10g, NaHC0 ₃ 2.0g, morpholinepropanesulfonic acid (MOPS, Sigma, USA) 34.5 g (0.165 M), plus three steaming Dissolve 900 ml of water, adjust the pH to 7.0 (25 °C) with l M NaOH, dilute to l000 ml, filter and sterilize, and store at 4 °C. (2) YEPD culture solution: yeast extract 10g, peptone 20g, glucose 20g, add three distilled water 900ml dissolved, add 2ml / ml chloramphenicol aqueous solution 50ml, dilute to 1000ml, stored at 4 ° C after autoclaving.

(3) Sabouraud dextrose agar (SDA): 10 g of peptone, 40 g of glucose, 18 g of agar, dissolved in 900 ml of distilled water, 50 ml of 2 mg/ml chloramphenicol solution, adjusted to pH 7.0 , to a volume of 1000 ml, 115 ° C, autoclaved, stored at 4 ° C.

(4) Potato dextrose agar medium (PDA medium): 200 g of peeled potatoes, 20 g of glucose, and 20 g of agar. Add 3 ml of distilled water to dissolve in 900 ml, dilute to 1 000 ml, autoclave, and store at 4 °C.

3. Control drug: fluconazole (FCZ, purchased from Pfizer Pharmaceuticals, Inc.), voriconazole (VCZ, purchased from Sigma, USA).

2. Experimental methods

This experiment used the Bruth Microdilution method recommended by the Clinical and Laboratory Standards Institute (CLSI) CLSI-M27A3 and B M38A2 documents to detect the compounds to be screened for 8 common pathogenic fungi. The minimum inhibitory concentration (MIC), the experimental data are shown in Table 2.

Table 2 Results of in vitro antifungal activity of some preferred compounds MIC ( μ _§ /ιη1)

77 0.031 0.031 0.062 0.031 0.06 1

0.25 0.5 25 25 5 25 25

80 0.03125 0.03125 0.0625 0.0625 0. 125 1 0.25 0.5 vcz 0.0625 0.0125 0.25 0.0625 0.125 8 0.125 0.5

FCZ 0.5 0.5 2 0.25 0.25 >64 4 16 The experimental results show that most of the compounds of the present invention have excellent in vitro antifungal activity and are superior to the positive control drug fluconazole (FCZ). In particular, the inhibitory activities of the example compounds 48, 72, 77 and 80 against Candida, Cryptococcus neoformans, Aspergillus fumigatus, T. rubrum and gypsum-like microspores have also exceeded the positive control drug voriconazole (VCZ).

The inhibitory activity of the compound of Example 48 against Candida albicans was 32 times that of fluconazole and 4 times that of voriconazole; its inhibitory activity against Candida parapsilosis was 8 times that of fluconazole and twice that of voriconazole; The inhibitory activity of Cryptococcus neoformans is 32 times that of fluconazole and 8 times that of voriconazole. Its inhibitory activity against Candida glabrata is 32 times that of fluconazole and 16 times that of voriconazole. Its inhibitory activity against Aspergillus fumigatus is 16 times of fluconazole, twice as much as voriconazole; its inhibitory activity against Rhodobacter sphaeroides is 64 times that of fluconazole and twice that of voriconazole; its inhibitory activity against gypsum-like microsporum is fluconazole 32 times, comparable to voriconazole.

The inhibitory activity of the compound of Example C against Candida albicans was 16 times that of fluconazole and twice that of voriconazole; its inhibitory activity against Candida parapsilosis was 8 times that of fluconazole and twice that of voriconazole; The inhibitory activity of Cryptococcus neoformans is 4 times that of fluconazole, which is equivalent to voriconazole. Its inhibitory activity against Candida glabrata is 2 times that of fluconazole, which is equivalent to voriconazole. Its inhibitory activity against Aspergillus fumigatus is fluconazole. 16 times, twice as much as voriconazole: its inhibitory activity against Trichophyton is 16 times that of fluconazole, comparable to voriconazole; its inhibitory activity against gypsum-like microsporum is 32 times that of fluconazole, Voriconazole is equivalent.

The inhibitory activity of the compound of Example 77 against Candida albicans was 16 times that of fluconazole and twice that of voriconazole; its inhibitory activity against Candida parapsilosis was 32 times that of fluconazole and 4 times that of voriconazole; The inhibitory activity of Cryptococcus neoformans is 8 times that of fluconazole and twice that of voriconazole. Its inhibitory activity against Candida glabrata is 4 times that of fluconazole and twice that of voriconazole. Its inhibitory activity against Aspergillus fumigatus It is 64 times that of fluconazole and 8 times that of voriconazole: its inhibitory activity against Trichophyton is 16 times that of fluconazole, and its inhibitory activity against gypsum-like microspores is 32 times that of fluconazole. Voriconazole is equivalent.

The inhibitory activity of the compound of Example 80 against Candida albicans was 16 times that of fluconazole and twice that of voriconazole; its inhibitory activity against Candida parapsilosis was 32 times that of fluconazole and 4 times that of voriconazole; The inhibitory activity of Cryptococcus neoformans is 4 times that of fluconazole, which is equivalent to voriconazole; its inhibitory activity against Candida glabrata is twice that of fluconazole, comparable to voriconazole; its inhibitory activity against Aspergillus fumigatus is fluconazole 64 times, it is 8 times that of voriconazole: its inhibitory activity against Trichophyton is 16 times that of fluconazole, and its inhibitory activity against gypsum-like microsporum is 32 times that of fluconazole, which is equivalent to voriconazole.

EXAMPLE 90 Preferred Water Soluble Tests for Compounds 46, 72, 48, 77, 114, 118

1. Water solubility test brigade

1. PH=1.2 (aqueous hydrochloric acid) solubility test

Preparation of the reference solution: accurately weigh the sample in a 25mL volumetric flask, add a small amount of methanol to dissolve, dilute with hydrochloric acid aqueous solution of pH = 1.2 and dilute to the mark, shake well, that is;

Preparation of sample solution: Precision transfer of saturated solution lmL in a 5mL volumetric flask, dilute with hydrochloric acid water solution of pH = 1.2 and dilute to the mark, shake well, that is.

The sample solution and the reference solution were each injected 20 μl, and the HPLC chromatographic conditions were as follows:

Flow rate: l.OmL/min; Detection wavelength: 210 nm; Column: Dikma C18 5μηι 4.6*250mm; Column temperature: 30.0 ° C; Injection volume: 20 μl; Mobile phase 25/75 (acetonitrile: water).

2. 溶解 = 7.4 (pure water) solubility test Preparation of the reference solution: accurately weigh the sample in 25mL capacity: bottle, add a small amount of methanol to dissolve, dilute with purified water with pH = 7.4 and dilute to the mark, shake well, that is;

Preparation of sample solution: Precision transfer of saturated solution lmL in 5mL capacity 9f watts, dilute with pure water of pH = 7.4 and dilute to the mark, shake well, that is.

Calculation formula: C saturation = dilution factor xC vs X Α /A pair

(Note: C _ffiW is the concentration of the sample saturated solution, C ^ is the concentration of the reference solution, A _{f ¥} is the peak area of the sample solution after dilution of the saturated solution, which is the peak area of the reference solution)

2. Partial compound water solubility test results

Table 3 Test results for solubility of compound 46, 48, 72 at pH = 1.2 and pH = 7.4 (mg/ml)

a. Voriconazole was purchased from Sigma, USA. b. Refconazole was purchased from Basileia, Switzerland < Table 4 Solubility (; mg/ml) of compound 77, 114, 118 at pH=7.4

The experimental results show that the water solubility of the compound 46, 72 of the present invention under gastric acid conditions (pH = 1.2) and neutral conditions (pH = 7.4) is much higher than that of voriconazole and refconazole; wherein compound 48 and compound Sulfate of 77, hydrazine: Compound 114 and Compound 118 have a solubility of 12.0 mg/mL and 67.4 mg/mL, which can be conveniently prepared into a preparation for treating antifungal infection, especially for making it more convenient for use. Injection for critically ill patients.

Example 91 Pharmacokinetic Experiment of Preferred Compound 48

(1) Experimental method

After the rats were intragastrically administered with the test compound, whole blood samples were collected at different time points, plasma was separated, and the concentration of the drug in the plasma was determined by liquid chromatography-tandem mass spectrometry.

Healthy SD rats, male, weighing 200-220 g, were randomly divided into two groups. The test compounds were administered by intragastric or intravenous injection. The specific arrangements are shown in Table 5 below:

The compound was formulated in 5% DMSO/5% Tween 80/90% physiological saline.

Fasting for 12 h before the test, free drinking water. Eat regularly 2 hours after administration. Blood collection time and sample treatment: intragastric administration: 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 卩 24 h after administration;

Intravenous administration: 5 min after administration, 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 24 h; at the above set time points, 0.3 ml of venous blood was taken from the posterior venous plexus of the rat eye. In heparinized tubes, the plasma was separated by centrifugation at llOOO rpm, and frozen in a refrigerator at -20 °C.

(2) Test results The pharmacokinetic parameters of rats after intragastric administration and intravenous administration of compound 48 are shown in Tables 6 and 7.

Table 6 Pharmacokinetic parameters of rats given 10 mg/kg compound 48 by intragastric administration

c AUC AUCo MRT tl F animal number

(h) (ng/ml) (ng-h/ml) (ng-h/ml) (h) (h) (%)

1 2.0 1432 8519 8550 4.57 2.99

2 2.0 1563 8148 8173 4.11 2.79

3 2.0 1339 8079 8497 6.49 5.52

4 1.0 1346 6396 6430 3.96 3.23

Average 1.75 1420 7785 7913 4.78 3.63 105.4 Standard deviation 0.50 104 946 1002 1.17 1.27

CV% 28.6 7.3 12.2 12.7 24.4 34.9

Table 7 Pharmacokinetic parameters of rats after intravenous injection of 3 mg/kg compound 48

AUC ₀ — _t AUC ₀ . _∞ MRT tl CLz Vss Animal Number

(ng-h/ml) (ng-h/ml) (h) (h) (L/h/kg) (L/kg)

5 2142 2162 1.77 1.18 1.39 2.46

6 2597 2645 2.12 1.37 1.13 2.40

7 1918 1929 1.69 1.05 1.56 2.63 Average 2219 2245 1.86 1.20 1.36 2.50 Standard deviation 346 365 0.23 0.16 0.21 0.12

CV% 15.6 16.3 12.2 13.7 15.6 4.8

(Note: (^^ Plasma peak concentration, _Tmax peak time, AUC. _{→ t} drug area under the curve, t _1/2 half-life, F absolute bioavailability after intragastric administration.)

After intragastric administration of 10 mg/kg compound 48, the plasma concentration in the body was 1.75 h, the peak concentration C _max was 1420 ± 104 ng/ml, and the area under the plasma concentration-time curve was 7785 946 946. Ng-h/ml, elimination half-life t _1/2 is 3.63 ± 1.27 h.

After intravenous administration of 3 mg/kg of compound 48, AUC0-t was 2219 ± 346 ng-h/ml, t _1/2 was 1.20 ± 0.16 h, and plasma clearance CLz was 1.36 ± 0.21 L/h/kg.

After dose standardization, the absolute bioavailability of rats administered with 10 mg/kg of Compound 48 was 105.4%. The above experimental results show that the compound 48 of the present invention has good pharmacokinetic properties.

Example 92 In vivo antifungal experiment of preferred compound 48 and compound 118

Preparation of pathogenic bacteria suspension

Experimental pathogenic strains (Candida albicans) After activation with modified SDA flat medium, the cells were expanded and adjusted to a lethal concentration (lx l0 ^1Q CFU/mL) using Sabour's liquid medium (SDB) to infect the guinea pigs. Lethal, after dissection, isolate strains that restore virulence and vitality. The isolated strain was cultured in SDB medium at 37 ° C, 250 r / min for 18 hours, and diluted with sterile physiological saline to lx 10 ⁸ CFU / mL for use.

1. Establish an immunosuppressive guinea pig model

On the fourth day before Candida albicans infection, each guinea pig was intraperitoneally injected with cyclophosphamide (300 mg/kg) once. At the same time, each guinea pig was injected subcutaneously with triamcinolone acetonide acetate (20 mg/kg) twice a day for 4 consecutive days to induce immunosuppression. Twelve hours after stopping the drug, blood was drawn from the small saphenous vein of the hind legs of the guinea pig, and the white blood cell count was <1000/mm ³ , which was considered to be successful in induction of immunosuppression.

2. Establish a deep guinea pig model of Candida albicans infection

Freshly prepared 0.5 mL of pathogenic bacterial suspension of lxl0 ⁸ CFU/mL was injected into the guinea pig through the small saphenous vein of the hind limb to infect the animals.

Forty animals were randomly divided into 4 groups. After 1 hour of infection, the test compounds (Examples Compound 48 and Compound 118) and fluconazole were administered orally, respectively, at a dose of 0.5 mg/Kg. The remaining group was used as a comfort. Agent control group. The experimental results are shown in Figure 1.

The results of the in vivo test showed that the compound synthesized by the present invention can significantly increase the survival number of guinea pigs, has a good in vivo anti-Candida infection activity, and its therapeutic effect is superior to that of fluconazole.

In summary, the in vitro antifungal activity, pharmacokinetic properties, in vivo antifungal activity, and water solubility of the compound of Formula I of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof are superior to the existing drugs. . Therefore, the compounds of the present invention can be used for the preparation of a medicament for the treatment of fungal infectious diseases, particularly fungal infections caused by deep fungal diseases.

Claims

The triazole-based compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, according to Claim 1 is: (1) hydrogen, halogen, COOR3, carboxyl group, CONR4R5 or NR4R5; (2) a d_6 linear alkyl group substituted with 1-5 halogen atoms, a C3_6 branched alkyl group or a C3_6 cycloalkyl group; (3) a substituted or unsubstituted phenyl group, wherein the phenyl group The substituent is 1-3 substituents independently selected from the group consisting of halogen, N02, cyano, hydroxy, R3, OR3, NHS02R3, N(;Cl.6 alkyl)S02R3, S02R3, S02NR4R5, NR4R5 And a substituted 5- or 6-membered heterocyclic group having 1 to 4 hetero atoms independently selected from N, S and 0, wherein the substituent is substituted or unsubstituted, wherein The substituent of the 5- or 6-membered heterocyclic group is independently selected from the group consisting of 1-3 substituents: halogen, N02, cyano, hydroxy, R3, OR3, NHS02R3, N(Cw alkyl) S02R3, S02R3, S02NR4R5, NR4R5, CONR4R5 COOH and COOR3; R2 is: (1) a substituted or unsubstituted phenyl group, wherein the substituent of the phenyl group is independently selected from the group consisting of 1-3 substituents of the following substituents: halogen, N02, cyano, hydroxy, R3, OR3, NHS02R3, NCd_6 alkyl) S02R3, S02R3, S02NR4R5, NR4R5, CONR4R5 COOH and B COOR3; (2) Substituents a substituted or unsubstituted 5- or 6-membered heterocyclic group having 1 to 4 hetero atoms independently selected from N, S and 0, wherein the substituent of the 5- or 6-membered heterocyclic group is 1-3 substituents independently selected from the group consisting of: halogen, N02, cyano, hydroxy, R3, OR3, NHS02R3, N(Cw alkyl) S02R3, S02R3, S02NR4R5, NR4R5, CONR4R5 COOH and COOR3 ; R 3 is unsubstituted or substituted by 1 to 3 halogen atoms, d 6 linear alkyl, C 3-6 branched alkyl or cycloalkane R 4 and R 5 are each independently: (1) hydrogen; or (2) unsubstituted Or a d_6 linear alkyl group, a C3_6 branched alkyl group or a C3_6 cycloalkane substituted by 1 to 3 halogen atoms, wherein the halogen atom is ? , Cl, Br or I. 2. The triazole compound according to claim 1, an optical isomer thereof, or a pharmaceutically acceptable substance thereof: (1) hydrogen, COOR3 or CONR4R5; (2) unsubstituted or 1-3 a halogen atom-substituted d-6 straight chain alkyl group or a C3_6 branched alkyl group; (3) a substituent-substituted or unsubstituted phenyl group, wherein the substituent of the phenyl group is independently selected from the following substituents 1-3 substituents: halogen, N02, cyano, hydroxy, R3 and OR3; (4) Substituted substituted or unsubstituted containing 1-2 heteroatoms independently selected from N, S and 0 a 5- or 6-membered aromatic heterocyclic group, wherein the substituent of the 5- or 6-membered aromatic heterocyclic group is independently selected from the group consisting of 1-3 substituents of the following substituents: halogen, cyano, R3 and OR3 R2 is: (1) a substituted or unsubstituted phenyl group, wherein the substituent of the phenyl group is 1-3 substituents independently selected from the group consisting of halogen, N02, cyano , a hydroxyl group, R3 and OR3; (2) a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group containing 1-2 hetero atoms independently selected from N, S and 0, Wherein the substituent of the 5- or 6-membered heterocyclic group is independently selected from the group consisting of 1-3 substituents: halogen, cyano, R3 and OR3; R3 is unsubstituted or is 1-3 a halogen atom-substituted d-6 straight chain alkyl group or a C3_6 branched alkyl group; R4 and R5 are each independently: (1) hydrogen; or (2) unsubstituted or d_6 straight chain substituted by 1-3 halogen atoms An alkyl group or a C3_6 branched alkyl group; wherein the halogen atom is ? , C1 or Br. The triazole compound according to claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

(1) Hydrogen, COOR ₃ or CONR4R ₅ ;

(2) methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl groups which are unsubstituted or substituted by 1 to 3 halogen atoms;

(3) a substituent-substituted or unsubstituted phenyl group, wherein the substituent of the phenyl group is 1-3 substituents independently selected from the group consisting of halogen, cyano, R ₃ and OR _{3 ;}

(4) a substituted or unsubstituted pyridyl group, pyrimidinyl group or thienyl group, wherein the substituent of the pyridyl group, pyrimidinyl group or thienyl group is independently selected from the group consisting of 1-3 substituents of the following substituents : halogen, cyano, R ₃ and OR _{3 ;}

R ₂ is:

(1) a substituent-substituted or unsubstituted phenyl group, wherein the substituent of the phenyl group is one to three substituents independently selected from the group consisting of halogen, cyano, R ₃ and OR _{3 ;}

(2) a substituted or unsubstituted pyridyl or pyrimidinyl group, wherein the substituent of the pyridyl or pyrimidinyl group is independently selected from the group consisting of 1-3 substituents of the following substituents: halogen, cyano group, R ₃ and OR _{3 ;}

R ₃ is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl which is unsubstituted or substituted by 1-2 halogen atoms ;

R4 and R ₅ are each independently:

(1) hydrogen; or

(2) methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl groups which are unsubstituted or substituted by 1-2 halogen atoms ;

Wherein the halogen atom is? , C1 or Br.

The triazole compound according to claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which is a compound having the following structure

61

62

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A pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of the compound represented by the formula (I) according to claim 1, an optical isomer thereof and a pharmaceutically acceptable salt thereof And pharmaceutically acceptable excipients.

The use of the compound represented by the formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof according to Claim 1 for the preparation of an antifungal drug.

7. A compound represented by the formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, in the preparation of Candida albicans, Candida parapsilosis, Candida glabrata Use in bacteria, Cryptococcus neoformans, gypsum-like microspores, Trichophyton rubrum and/or Aspergillus fumigatus.