KR20150136294A - New Compound Having Inhibition Activity to Factor XIa - Google Patents

Abstract

(1)
상기 화학식 1에서, A, L, X, Y, Z 및 n은 본 명세서에 정의된 바와 동일하다.The present invention relates to a novel compound represented by the following formula (1) having a pharmacologically effective inhibitory activity against the factor XIa (Factor XIa, FXIa), a process for producing the same, and a pharmaceutically acceptable salt, hydrate, solvate, And a pharmaceutical composition for preventing blood clotting and treating various types of thrombosis containing prodrug as an active ingredient.

(One)
In Formula 1, A, L, X, Y, Z and n are the same as defined herein.

Description

New Compound Having Inhibition Activity to Factor XIa < RTI ID = 0.0 >

The present invention relates to a novel compound having an inhibitory activity against factor XIa (Factor XIa, FXIa), a process for producing the same, and a pharmaceutical composition for preventing blood clotting and treating various thromboses containing the same as an active ingredient.

Normal blood should be in the blood vessel inside the blood vessel, and if blood vessels are injured, it should be rapidly coagulated to stop blood loss from damaged blood vessels to maintain homeostasis. When the balance between thrombogenesis and dissolution mechanism in blood is broken, the pathological phenomenon of the normal hemostatic mechanism appears, which is called thrombosis.

Such thrombosis causing thrombosis is a cause of cardiovascular diseases such as cerebral vascular diseases such as cerebral infarction and stroke, acute myocardial infarction and pulmonary embolism, and vascular diseases caused by thrombosis are very dangerous diseases which are the first in mortality and incidence of modern people to be.

The blood coagulation process involves many serine proteases and cofactors. Factor XIa (FXIa) is an enzyme that works early in the onset of the intrinsic pathway of blood coagulation. The endogenous pathway of blood coagulation is initiated through a process called contact activation. Whereby activated Factor XIIa activates Factor XI to Factor XIa from which it is activated by a cascade of Factor IXa, Factor Xa. Factor Xa crosses the extrinsic pathway of blood clotting, resulting in the production of thrombin (FIIa), which results in the formation of a final hemostatic clot. The endogenous pathway involved in factor XIa is responsible for the amplification phase of the blood clotting process and plays a role in strengthening this clot once the hemostatic clot is created by the exogenous pathway at the wounded site.

Inhibition of factor XIa has been reported to be very safe in the side effects of bleeding, which is the most serious side effect of antithrombotic agents, in preventing thrombogenesis compared to the thrombin inhibitor or factor Xa (FXa) inhibitors disclosed in many previous studies. In fact, in rabbits, the amount of thrombus significantly decreased when the antibody against factor XI was treated, but the bleeding time was not affected ( J Thromb Haemost 2006, 4, 1496). In addition, when carotid occlusion experiments using FeCl ₃ were performed on mice without factor XI enzyme, there was no change in bleeding time ( J Thromb Haemost 2005, 3, 695).

For this reason, there is a growing need for factor XIa inhibitors and development of factor XIa inhibitors is underway by global research organizations. However, no inhibitors of factor XIa have yet been reported for low molecular weight compounds in clinical trials.

In this regard, BMS262084 of the following structure being developed by Bristol Myers Squibb (BMS) shows a factor XIa inhibitory activity of Ki of 2.8 nM, but the indications are being studied in antiallergic field, and the beta- lactam ring of the molecule and the factor XIa form a covalent bond Lt; RTI ID = 0.0 > irreversible < / RTI >

Factor XIa inhibitors ( J. Med. Chem. , 2006, 49, 7781) of the following peptide structures reported by DAIAMED showed excellent in vitro potency (Ki 6 nM) and superior efficacy in animal rat thrombosis models gave. However, like BMS262084, it is an irreversible inhibitor that forms a covalent bond with factor XIa.

However, these irreversible inhibitors are likely to cause problems of side effects that are difficult to predict because there are many reactive nucleophiles in the body.

Therefore, there is an urgent need for a novel compound having an excellent inhibitory activity against factor XIa (Factor XIa, FXIa) and having reversible characteristics.

SUMMARY OF THE INVENTION Accordingly, the present invention has been made to solve the above-mentioned problems of the prior art and the technical problems required from the past.

The present inventors have continued intensive studies and various experiments. As will be described later, the novel compounds having the structure represented by the formula (I) have excellent inhibitory activity against the factor XIa (Factor XIa, FXIa) And the present invention has been completed.

Specifically, the first object of the present invention is to provide a compound represented by the formula (I) having a novel XIa-inhibiting structure having an antithrombotic effect.

A second object of the present invention is to provide a process for preparing the novel compounds represented by the formula (1).

A third object of the present invention is to provide an antithrombotic pharmaceutical composition comprising a novel pharmacologically effective amount of this novel compound as an active ingredient.

The present invention provides a compound represented by the following formula (1), a pharmaceutically acceptable salt, a hydrate, a solvate, an isomer or a prodrug thereof.

(1)

(One)

In this formula,

A is selected from the group consisting of phenyl, phenyl containing 1 to 3 independently selected substituents, and 6-membered heteroaryl containing 1 to 3 independently selected substituents and containing 1 to 2 nitrogen atoms And,

Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br _{, -CN, -OH, -CF 3,} -NO 2, -OR, and selected from the group consisting of -CO ₂ R, and -NHR (R = hydrogen, C ₁ -C ₄ alkyl),

L is phenyl, phenyl optionally substituted with one or two independently selected substituents, pyridine, pyrrole, pyrrole, triazole, furan, thiophene, oxazole, Diazines, pyrazines (= 1,2-diazines), pyrazines (= 1,4-diazines), naphthalenes, quinolines, isoquinolines, benzo Furan, benzothiophene, and indole,

Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br _{, -CN, -OH, -CF 3,} -NO 2, -OR, and selected from the group consisting of -CO ₂ R, and -NHR (R = hydrogen, C ₁ -C ₄ alkyl),

X is C or N,

Y is selected from the group consisting of hydrogen, C ₁ -C ₂₀ alkyl, arylalkyl, cyclohexyl, cyclopentyl, adamantanemethyl, phenyl, phenyl, benzyl, phenetyl, pyridine, and phenyl substituted with one or two independently selected substituents Naphthalene, < / RTI >

Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br _{, -CN, -OH, -CF 3,} -NO 2, -OR, and selected from the group consisting of -CO ₂ R, and -NHR (R = hydrogen, C ₁ -C ₄ alkyl),

Z is hydrogen, C ₁ -C ₂₀ alkyl, arylalkyl,

, ≪ / RTI >

Wherein R ¹ is selected from the group consisting of hydrogen, C ₁ -C ₂₀ alkyl, arylalkyl, cyclohexyl, cyclopentyl, adamantanemethyl, phenyl, phenyl containing 1 or 2 independently selected substituents, benzyl, Benzyl, phenethyl, pyridine, and naphthalene containing 1 or 2 carbon atoms,

Wherein the independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, -F, -Cl, -Br, -CN, -OH, -CF ₃ , -OR, -CO ₂ R and -NHR is selected from the group consisting of ₁ -C ₄ alkyl),

R ² and R ³ are Phenyl, benzyl, phenethyl containing 1 or 2 independently selected substituents, phenethyl having 1 or 2 independently selected substituents, phenyl optionally substituted with 1 or 2 substituents independently selected from hydrogen, C ₁ -C ₂₀ alkyl, arylalkyl, (= 1, 2-diazines), pyrimidines, pyrazines (= 1, 4-dioxolane), pyridine, pyrrole, furan, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole, - diazines), naphthalene, quinoline, isoquinoline, benzofuran, benzothiophene and indole,

Wherein said independently selected substituent is selected from the group consisting of C ₁ -C ₄ alkyl, -F, -Cl, -Br, -CN, -OH, -CF ₃ , -OR, -CO ₂ R, -CH ₂ CO ₂ R, _{CO 2 NH 2 -NHR, -NHCOR,} -NHCO 2 R, -NHSO 2 R, CO 2 R a substituted or unsubstituted phenylamide, and CO ₂ R a substituted or unsubstituted isoxazole-in to the (R = hydrogen, C ₁ -C ₄ alkyl), -NO ₂ , And pentacyclic heteroaryl optionally substituted with C ₁ -C ₄ alkyl and containing 1 to 4 heteroatoms selected from N, O and S;

n is 0, 1, 2 or 3;

Unless specifically stated otherwise, the term "alkyl" specifically includes acyclic saturated hydrocarbon residues of 1 to 6 carbon atoms, which may be linear or branched, (C ₂ -C ₆ ) -alkenyl and (C ₂ -C ₆ ) -alkynyl, and a cyclic alkyl group having 3 to 8 ring carbon atoms, which may be linear or branched, and the like.

In addition, regardless of the particular substituent (s) attached to the alkyl group described in the definition of formula (1), the alkyl group is generally unsubstituted or substituted by one or more, for example, from one to four, identical or different substituents. Certain substituents present in the substituted alkyl moiety may be present at any desired position, unless the substitution leads to an unstable molecule. Examples of certain types of substituents include halogen atoms, hydroxy, carboxy groups and the like.

Unless specifically stated otherwise, the term "arylalkyl" includes acyclic saturated hydrocarbon moieties of 1 to 6 carbon atoms which may be linear or branched containing a specific aryl group. Examples of particular aryl groups include phenyl, phenyl having 1 or 2 independently selected substituents, pyridine, pyrrole, furan, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole , Pyridazine (= 1,2-diazine), pyrimidine, pyrazine (= 1,4-diazine), naphthalene, quinoline, isoquinoline, benzofuran, benzothiophene, indole and the like.

Unless otherwise specified hereinafter, the compounds of formula (I) as active ingredients of the therapeutic agent include all pharmaceutically acceptable salts, hydrates, solvates, isomers and prodrugs thereof, all of which are in the scope of the present invention Should be interpreted to include. For convenience of explanation, the compound of formula (I) may be briefly referred to as the compound of the present invention.

The terms used herein are briefly described.

The term " pharmaceutically acceptable salt "means a formulation of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound. The terms "hydrate "," solvate ", "isomer ", and" prodrug " The pharmaceutical salts may be formed with acids which form non-toxic acid addition salts containing a pharmaceutically acceptable anion, for example inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like, tartaric acid, formic acid, Organic carboxylic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and salicinic acid, and organic carboxylic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- Sulfonic acid, sulfonic acid, sulfonic acid, sulfonic acid, sulfonic acid, For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed with lithium, sodium, potassium, calcium, magnesium and the like, amino acid salts such as lysine, arginine and guanidine, dicyclohexylamine, N Organic salts such as methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline and triethylamine, and the like. The compound of formula (I) according to the present invention may be converted into a salt thereof by a conventional method.

The term "hydrate" refers to a compound of the present invention which contains a stoichiometric or non-stoichiometric amount of water combined by non-covalent intermolecular forces Or a salt thereof.

The term "solvate" means a compound of the present invention or a salt thereof, comprising a stoichiometric or non-stoichiometric amount of a solvent bound by noncovalent intermolecular forces. Solvents for that are volatile, non-toxic and / or solvents suitable for administration to humans.

The term "isomer" means a compound of the present invention or a salt thereof, which has the same chemical or molecular formula but is structurally or sterically different. Such isomers include all stereoisomers such as tautomers, R or S isomers with asymmetric carbon centers, geometric isomers (trans, cis), and the like. All of these isomers and mixtures thereof are also included within the scope of the present invention.

The term " prodrug "refers to a substance that is transformed into a parent drug in vivo. Prodrugs are often used in some cases because they are easier to administer than parent drugs. For example, they may achieve viability by oral administration, whereas parent drugs may not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. For example, prodrugs can be prepared by esterification ("prodrug") which facilitates passage of the cell membrane, which is hydrolyzed to the active carboxylic acid by metabolism in cells whose water solubility is detrimental to mobility, ). ≪ / RTI > Another example of a prodrug may be a short peptide (polyamino acid) that is attached to an acid group that is converted by metabolism so that the peptide reveals the active site.

Other terms may be construed as meaning commonly understood in the field to which the present invention belongs.

The compounds of formula (1), in one specific example,

A is selected from the group consisting of phenyl, phenyl containing from 1 to 3 independently selected substituents, and pyridine containing from 1 to 3 independently selected substituents,

Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br _{, -CN, -OH, -CF 3,} OR, -CO 2 R, and is selected from the group consisting of -NHR (R = hydrogen, C ₁ -C ₄ alkyl),

L is phenyl, phenyl optionally substituted with one or two independently selected substituents, pyridine, pyrrole, pyrrole, triazole, furan, thiophene, oxazole, Pyrazoles, thiazoles, isothiazoles and indoles, wherein R < 1 >

Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br _{, -CN, -OH, -CF 3,} OR, -CO 2 R, and is selected from the group consisting of -NHR (R = hydrogen, C ₁ -C ₄ alkyl),

X is C or N,

Y is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, arylalkyl, cyclohexyl, phenyl, phenyl, benzyl, phenethyl, pyridine, naphthalene containing 1 or 2 independently selected substituents,

Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br _{, -CN, -OH, -CF 3,} OR, -CO 2 R, and is selected from the group consisting of -NHR (R = hydrogen, C ₁ -C ₄ alkyl),

Z is hydrogen, C ₁ -C ₄ alkyl, arylalkyl,

, ≪ / RTI >

Wherein R ¹ is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, arylalkyl, cyclohexyl, phenyl, phenyl, benzyl containing one or two independently selected substituents, one or two independently selected substituents Lt; / RTI > is selected from the group consisting of benzyl, phenethyl, pyridine and naphthalene,

Wherein the independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, -F, -Cl, -Br, -CN, -OH, -CF ₃ , -OR, -CO ₂ R and -NHR is selected from the group consisting of ₁ -C ₄ alkyl),

R ² and R ³ is Phenyl, benzyl, phenethyl, phenetyl containing one or two substituents independently selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, arylalkyl, phenyl, phenyl containing one or two independently selected substituents, (= 1, 2-diazines), pyrimidines, pyrazines (= 1, 4-dioxolane), pyridine, pyrrole, furan, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole, - diazines), naphthalene and indole,

Wherein said independently selected substituent is selected from the group consisting of C ₁ -C ₄ alkyl, -F, -Cl, -Br, -CN, -OH, -CF ₃ , -OR, -CO ₂ R, -CH ₂ CO ₂ R, _{CO 2 NH 2 -NHR, -NHCOR,} -NHCO 2 R, -NHSO 2 R, CO 2 R a substituted or unsubstituted phenylamide, and CO ₂ R a substituted or unsubstituted isoxazole-in to the (R = hydrogen, C ₁ -C ₄ alkyl), -NO ₂ , And pentacyclic heteroaryl optionally substituted with C ₁ -C ₄ alkyl and containing 1 to 4 heteroatoms selected from N, O and S;

n may be 0, 1 or 2;

More specifically,

A is selected from the group consisting of phenyl, phenyl containing 1 to 3 independently selected substituents,

Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br , -CN, -OH, -CF _3, is selected from the group consisting of -OMe,

L is phenyl, phenyl optionally substituted with one or two independently selected substituents, pyridine, pyrrole, pyrrole, triazole, thiophene, oxazole, isoxazole, , Imidazole, pyrazole, thiazole and isothiazole,

Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br _{, -CN, -OH, -CF 3,} -OMe, -CO 2 R is selected from the group consisting of (R = hydrogen, C ₁ -C ₄ alkyl),

X is C,

Y is selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, arylalkyl, phenyl, benzyl, phenethyl, phenyl containing one or two substituents independently selected, pyridine,

Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br , -CN, -OH, -CF _3, is selected from the group consisting of -OMe,

Z is hydrogen and

, ≪ / RTI >

Wherein R ¹ is selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, arylalkyl, phenyl, benzyl, phenethyl, phenyl, pyridine and naphthalene containing one or two substituents independently selected,

Wherein the independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, -F, -Cl, -Br, -CN, -OH, -CF ₃ , -OR, -CO ₂ R and -NHR is selected from the group consisting of ₁ -C ₄ alkyl),

R ² and R ³ is C ₁ -C ₄ alkyl, arylalkyl, phenyl, phenyl containing one or two independently selected substituents, benzyl, phenethyl, phenethyl containing one or two independently selected substituents, Is selected from the group consisting of pyridine, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole and indole,

Wherein the independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, -F, -Cl, -Br, -CN, -OH, -CF ₃ , -NO _{2 ,} -OR, -CO ₂ R and -NHR (R = is selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl);

n may be 0 or 1.

Representative compounds of the novel compounds of formula ( 1) according to the present invention include the following compounds, but the following compounds do not limit the present invention.

The present invention also provides a process for preparing a compound of formula (1)

(a) preparing a triazole skeleton compound including a click reaction of an alkyne compound and an azaide compound; or

(b) a step of preparing a compound of isoxazole skeleton including a cyclization reaction of an alkane compound and an oxime compound; or

및 TosMIC(톨루엔설포닐메틸아이소시아나이드)의 고리화 반응을 포함하여 피롤 골격의 화합물을 제조하는 과정 (여기서, A는 화학식 1에서 정의한 내용과 동일함);(c)

And a cyclization reaction of TosMIC (toluenesulfonylmethylisocyanide), wherein A is the same as defined in Chemical Formula 1;

As a process for preparing an intermediate compound.

That is, the compound of formula (1) defined above may be prepared by preparing an intermediate compound according to any one of the reaction schemes 1 to 3 according to its structure. Specifically, the intermediate compound In the manufacturing process,

In one example, a process for producing a triazole skeleton compound [1] through a click reaction of an alkyne compound [2] and an azaide compound [3] according to the following Reaction Scheme 1 . ≪ / RTI >

(1)

(One)

In another example, a process for preparing a compound of the isoxazole skeleton [4] through a cyclization reaction of an alkane compound [2] and an oxime compound [5] according to the following Reaction Scheme 2 may be included.

(2)

(2)

[7] 및 TosMIC(톨루엔설포닐메틸아이소시아나이드) [8]의 고리화 반응을 통해 화합물 [9]를 제조하고, 통상의 몇가지 반응을 거쳐 피롤 골격의 화합물 [6]을 제조하는 과정을 포함할 수 있다.In another example, according to Scheme 3 below,

(9) is prepared by cyclization of TosMIC (toluene sulfonylmethylisocyanide) [7] and TosMIC (toluenesulfonylmethylisocyanide) [8], and the compound of the pyrrole skeleton [6] can do.

(3)

(3)

Those skilled in the art ("a person skilled in the art") in the field of the present invention can prepare the compound according to the type of the substituent on the basis of the structure of the formula (1) by various methods as well as the above production method. Therefore, it is obvious that the compound of formula (1) can be easily modified by a person skilled in the art depending on the specific substituent. Thus, the production method does not limit the method for producing the compound of formula (1) according to the present invention.

The preparation of the final compound through an intermediate compound can also be carried out by a variety of conventional methods, and after completion of the reaction, the general mixture can be separated by conventional post-treatment methods such as tube chromatography, recrystallization, HPLC and the like Can be separated.

Further details, such as processes after the preparation of the intermediate compounds, are described in the following plurality of preparation examples and examples.

The present invention also relates to a pharmaceutical composition comprising (a) a pharmacologically effective amount of a compound of formula (I), a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof; And (b) a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof. The present invention also provides a pharmaceutical composition for the prevention of blood clotting and the treatment of thrombosis.

The term "pharmaceutical composition" means a mixture of compounds of the present invention and other chemical components such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound into the organism. Various techniques exist for administering the compounds, including, but not limited to, oral, injectable, aerosol, parenteral, and topical administration. The pharmaceutical composition may be obtained by reacting acid compounds such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

The term "therapeutically effective amount" means that the amount of the compound administered will alleviate or reduce to some extent one or more symptoms of the disorder being treated, delay the onset of clinical markers or symptoms of the disease in need of prevention, Quot; means the amount of active ingredient that is effective to effect. Thus, a pharmacologically effective amount can be any amount effective to (1) reverse the rate of progression of the disease, (2) to some extent inhibit further progression of the disease, and / or (3) (In detail, eliminating) the degree of the effect. A pharmacologically effective amount can be determined empirically by testing compounds in known in vivo and in vitro model systems for diseases in need of treatment.

The term "carrier" is defined as a compound that facilitates the addition of a compound into a cell or tissue. For example, dimethylsulfoxide (DMSO) is a commonly used carrier that facilitates the introduction of many organic compounds into cells or tissues of an organism.

The term "diluent" is defined as a compound that not only stabilizes the biologically active form of the compound of interest, but also dilutes in water to which the compound is dissolved. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, since it mimics the salt state of the human solution. Since buffer salts can control the pH of the solution at low concentrations, buffer diluents rarely modify the biological activity of the compounds.

The compounds used herein may be administered to a human patient either as such, or as a pharmaceutical composition mixed with other active ingredients, such as in a combination therapy, or with suitable carriers or excipients. A description of the formulation and administration of the compounds in this application can be found in "Remington ' s Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition,

The pharmaceutical compositions of the present invention can be prepared in a known manner, for example, by means of conventional mixing, dissolving, granulating, sugar-making, pulverizing, emulsifying, encapsulating, trapping or lyophilizing processes.

The pharmaceutical composition for use according to the present invention thus comprises one or more pharmacologically acceptable carriers comprising excipients or auxiliaries which facilitate the treatment of the active compound with pharmaceutically acceptable formulations May also be prepared by conventional methods. Suitable formulations depend on the route of administration chosen. The known techniques, both carrier and excipients, may be used as appropriate and as understood in the art, for example Remingston's Pharmaceutical Sciences, as described above. In the present invention, the compound of Chemical Formula 1 may be formulated into injectable preparations and oral preparations according to the purpose.

For injection, the components of the present invention may be formulated as a liquid solution, in particular a pharmacologically compatible buffer, such as a Hank solution, a Ringer solution, or a physiological saline solution. A non-penetrating agent suitable for the barrier to be passed for mucosal permeation administration is used in the formulation. Such impermeabilizers are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the pharmacologically acceptable carriers known in the art with the active compounds. Such carriers enable the compounds of the present invention to be formulated into tablets, pills, powders, granules, sugars, capsules, liquids, gels, syrups, slurries, suspensions and the like. Specifically, capsules, tablets, pills, powders and granules can be used, and particularly, capsules and tablets are useful. Tablets and pills are preferably prepared as preservative. Pharmaceutical preparations for oral use can be prepared by mixing one or two or more compounds of the present invention with one or more excipients, optionally milling such mixture, and if necessary passing the appropriate adjuvant, then treating the mixture of granules Tablets or sugar cores can be obtained. Suitable excipients include fillers such as lactose, sucrose, mannitol, or sorbitol; Corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone PVP), and the like. If necessary, a carrier such as a crosslinking polyvinylpyrrolidone, a starch or a disintegrating agent such as alginic acid or sodium alginate and a lubricant such as magnesium stearate, a binder and the like may be added.

Pharmaceutical preparations which can be used orally may include soft seal capsules made of gelatin and a plasticizer such as glycol or sorbitol, as well as push-fix capsules made of gelatin. Capsules for push-fixing may also contain active ingredients, such as a filler such as lactose, a binder such as starch, and / or a mixture with talc or a lubricant such as magnesium stearate. In soft capsules, the active compounds may be dissolved or dispersed in suitable solvents such as fatty acids, liquid paraffin, or liquid polyethylene glycols. A stabilizer may also be included. All formulations for oral administration should be in amounts suitable for such administration.

Compounds may be formulated for parenteral administration by injection, for example by parenteral injection or continuous infusion. The injectable formulation may be presented in unit dosage form, for example, as an ampoule or a multi-dose container with an added preservative. The compositions may take such forms as suspensions, solutions, emulsions on oily or liquid vehicles, and may also contain components for the formulation, such as suspending, stabilizing and / or dispersing agents.

The active ingredient may also be in the form of a powder for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

The compounds may also be formulated into rectal compositions such as suppositories or rectal enema containing, for example, conventional suppository bases such as cocoa butter or other glycerides.

Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount refers to an amount of a compound that is effective to prolong the survival of an object to be treated or to prevent, alleviate, or alleviate symptoms of the disease. The determination of a therapeutically effective amount is well within the ability of those skilled in the art, particularly in light of the detailed disclosure provided herein.

When formulated in unit dose form, the compound of formula (I) as an active ingredient is preferably contained in a unit dose of about 0.1 to 1,000 mg. The dosage of the compound of formula (1) depends on the physician's prescription depending on factors such as the patient's weight, age and the particular nature and severity of the disease. However, the dosage required for adult therapy is usually in the range of about 1 to 1000 mg per day depending on the frequency and intensity of administration. A total dosage of about 1 to 500 mg per day, separated by a single dose when administered intramuscularly or intravenously to an adult, may be sufficient, but in some patients a higher daily dose may be desirable.

The present invention also provides a method of treating or preventing a thrombosis-related disease using an effective amount of a compound of formula (I). A "thrombosis-related disease" is a pathological phenomenon of a normal hemostatic mechanism including, for example, cerebral infarction, stroke, deep vein thrombosis, pulmonary embolism, acute myocardial infarction, and the like. The term " treatment "as used herein refers to stopping or delaying the progression of a disease when used in an object exhibiting an onset symptom. The term " prevention" means stopping or delaying the onset symptom .

The activity of the preferred compounds of formula (I) of the present invention is less than or equal to 10 μM, particularly less than or equal to 1 μM Ki for inhibiting factor XIa as determined by assays known in the art.

In order to achieve the desired anticoagulant effect and thrombolytic effect by clinically administering the compound of the present invention, the active compound of formula (I) may be administered simultaneously with one or more components selected from a thrombolytic agent and a platelet activity inhibitor . Examples of thrombolytic agents that can be administered in admixture with the compound of the present invention in this manner include t-PA, urokinase, streptokinase, and the like. Examples of thrombocyte activity inhibitors include aspirin, Ticlopidine, clopidogrel, 7E3 monoclonal antibody, and the like.

However, the preparations containing the compounds according to the present invention for the purpose of treatment and prevention of thrombosis are not limited to those described above, and any agents useful for the treatment and prevention of thrombosis can be included.

The compounds of formula (I) according to the present invention are novel substances and can be easily prepared by a comparatively easy method and exhibit an excellent inhibitory activity effect on the factor XIa (Factor XIa, FXIa) It is possible to provide a pharmaceutical composition for preventing various blood coagulation and treating thrombosis Can be usefully used.

EXAMPLES The following Preparation Examples, Examples and Experimental Examples are provided to facilitate understanding of the present invention. However, these production examples, examples and experimental examples are intended to assist the understanding of the present invention, and the scope of the present invention is not limited thereto in any sense.

Reagents frequently used in the following preparation examples and examples are described by abbreviations as follows.

rt: room temperature

AcOH: acetic acid

DCM: dichloromethane

DMF: dimethylformamide

DMSO: dimethylsulfoxide

THF: tetrahydrofuran

TEA: Triethylamine

Me: methyl

Et: ethyl

Bu: butyl

TMOF: Trimethylol ols formate

TMS: trimethylsilyl

TBAF: tetrabutylammonium fluoride

Ph: phenyl

ACN: acetonitrile

BoC: t-Butoxy

MS ₂ O: Methanesulfonic anhydride

DIPEA: diisopropylethylamine

PyBOP: Benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate

TBSCl: t-butyl dimethylsilyl chloride

TBSO: t-butyldimethylsilyloxy

PMB: 4-methoxybenzyl

TosMIC: Toluenesulfonylmethylisocyanide

CDI: Carbonyldiimidazole

LAH: Lithium aluminum hydride

Pyr: Pyridine

NCS: N-Chloroacridiniumide

TFA: Trifluoroacetic acid

DBU: 1,8-Diazabicyclo [5.4.0] undec-7-ene

PREPARATION EXAMPLE 1 Preparation of 1- (4-chloro-2-ethynylphenyl) -1 H - Preparation of tetrazole

Production Example 1-1) 1- (4-Chloro-2-iodophenyl) -1 H - Preparation of tetrazole

4-chloro-2-iodo-aniline (30 g, 118.4 mmol) acetic acid sodium azide (23 g, 355.1 mmol) at 0 ^o C was dissolved in (300 mL), trimethyl olsso formate (38.85 mL, 355.1 mmol ), And the mixture was stirred under a nitrogen atmosphere for 4 hours. The reaction solution was concentrated under reduced pressure, added to distilled water (30 mL), and extracted with ethyl acetate (50 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized in diethyl ether (30 mL) to give the title compound (31.1 g, 85%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 8.92 (s, 1 H), 8.05 (d, J = 2 Hz, 1 H), 7.56 (dd, J = 2.4, 8.4 Hz, 1 H), 7.38 ( d, J = 8.4 Hz, 1H).

Preparation 1-2) 1- (4-Chloro-2 - ((trimethylsilyl) ethynyl) phenyl) -1 H - Preparation of tetrazole

1- (4-Chloro-2-iodo-phenyl) -1 H - tetrazole (10 g, 32.6 mmol) in acetonitrile-trimethyl-silane ethynyl dissolved in (180 mL) (4.5 mL, 32.6 mmol) and After adding triethylamine (13.6 mL, 97.9 mmol), bis (triphenylphosphine) palladium (II) dichloride (230 mg, 0.326 mmol) and copper iodide, the mixture was stirred under a nitrogen atmosphere for 3 hours. The reaction solution was concentrated under reduced pressure, and the reaction solution was filtered using Celite. The collected filtrate was concentrated under reduced pressure. The title compound (3.8 g, 42%) was obtained by column chromatography.

¹ H-NMR (600 MHz, CDCl ₃ ) ? 9.33 (s, 1H) 7.69-7.67 (m, 2H), 7.53-7-51 (m, 1H), 0.22 (s, 9H).

Production Example 1-3) 1- (4-Chloro-2-ethynylphenyl) -1 H - Preparation of tetrazole

1- (4-Chloro-2 - ((trimethylsilyl) ethynyl) phenyl) -1 H-tetrazole (3.8 g, 13.7 mmol) of tetrabutyl at -78 ^o C was dissolved in tetrahydrofuran (50 mL) Ammonium fluoride (16.5 mL, 16.5 mmol) was added thereto, followed by stirring under a nitrogen atmosphere for 1 hour. Saturated ammonium chloride aqueous solution (20 mL) was added to the reaction solution, which was then extracted with distilled water (20 mL × 1) and ethyl acetate (20 mL × 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (2.1 g, 75%).

¹ H-NMR (600 MHz, CDCl ₃ ) ? 9.29 (s, 1H) 7.71 (d, J = 2.4 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.57 (dd, J = 2.4, 9.0 Hz, 1H), 3.41 (s, 1H).

≪ Preparation Example 2 & t -Butyl 1-azido-3-phenylpropan-2-ylcarbamate

t - butyl-1-hydroxy-3-phenyl propane-2-ylcarbamate (3 g, 11.9 mmol) triethylamine at 0 ^o C was dissolved in tetrahydrofuran (30 mL) (4.98 mL, 3.57 mmol) And methanesulfonic anhydride (2.5 g, 14.28 mmol) were added thereto, followed by stirring for 1 hour. Distilled water (20 mL) was added to the reaction solvent, followed by extraction with ethyl acetate (20 mL x 2) and concentration under reduced pressure. This compound was dissolved in dimethylformamide (30 mL), sodium azide (3.9 mL, 59.5 mmol) was added, and the mixture was stirred at 50 ^° C. A saturated aqueous sodium chloride solution (30 mL) and distilled water (30 mL) were added to the reaction solvent, which was then extracted with ethyl acetate (50 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized in diethyl ether (5 mL) to give the title compound (21 mg, 95%).

¹ H-NMR (600 MHz, DMSO-d ₆ ) ? 7.72 (d, J = 44.4 Hz, 5 H), 6.99 , 2.72-2.66 (m, 2H), 1.27 (s, 9H).

Preparation Example 3 1- (4- (5-Chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropane-2-amine hydrochloride

Production example 3-1) t -Butyl 1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropan-2-ylcarbamate

1- (4-ethynyl-2-chloro-phenyl) -1 H - tetrazole (500 mg, 2.44 mmol) dimethyl sulfoxide and distilled water (1: 1), sodium ascorbate at 0 ^o C was dissolved in (48 mg, 0.24 mmol) and Kappa (II) sulfate (30 mg, 0.12 mmol) were added thereto, followed by stirring under a nitrogen atmosphere for 2 hours. Distilled water (10 mL) was added to the reaction solution and extracted with ethyl acetate (10 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (10 mL) to give the title compound (1.1 g, 90%).

¹ H-NMR (600 MHz, DMSO- d ₆ ) ? 8.77 (s, 1H), 8.07 (s, 1H), 7.55 (s, 1H), 7.42-7.17 s, 1H), 4.66 (s, 1H), 4.43-4.15 (m, 2H), 2.76 (d, J = 7.8 Hz, 2H), 1.40 (s, 9H). LCMS (m / z): 481.2 (M + H ^& lt ^{; +} & gt ^; ).

Preparation 3-2) 1- (4- (5-Chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropane-2-amine hydrochloride

The compound (500 mg, 1.039 mmol) obtained in Preparative Example 3-1 was dissolved in dichloromethane (5 mL), hydrochloric acid (4M 1,4-dioxane solution, 5 mL) was added, and the mixture was stirred for 1 hour. The reaction solvent was concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (433 mg, 96%).

¹ H-NMR (600 MHz, DMSO-d ₆ ) ? 9.73 (s, 1H), 8.38 (br s, 1H), 8.11 , 2.89-2.94 (m, 1H), 2.83-2.78 (m, 1H), 7.37-7.26 (m, 5H) ).

Preparation Example 4 Synthesis of 4-amino- N - (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropan-2-yl) benzamide hydrochloride

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (150 mg, 0.36 mmol) was dissolved in dimethylformamide (3 mL) and diisopropylethylamine (188 uL, 1.08 mmol) and 4- ( t- butoxycarbonylamino) benzoic acid mg, 0.40 mmol) and benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (281 mg, 0.54 mmol) were added thereto and stirred for 6 hours. Saturated ammonium chloride aqueous solution (20 mL) and distilled water (20 mL) were added to the reaction solvent, followed by extraction with ethyl acetate (20 mL x 2). Over dried over anhydrous sodium sulfate and after filtration concentrated under reduced pressure and column separation t - butyl-4- (1- (4- (5-chloro -2- (1 H - tetrazol-1-yl) phenyl) -1 H -1 , 2,3-triazol-1-yl) -3-phenylpropan-2-ylcarbamoyl) phenylcarbamate (170 mg, 78%). This compound was dissolved in dichloromethane (5 mL), hydrochloric acid (4M 1,4-dioxane solution, 5 mL) was added, and the mixture was stirred for 1 hour. The reaction solvent was concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (124 mg, 86%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.63 (s, 1 H), 7.99-7.95 (m, 3 H), 7.71 (s, 2 H), 7.46 (d, J = 8.4 Hz, 2 H), 7.27-7.16 (m, 5H), 6.50 (d, J = 8.4 Hz, 2H), 4.54-4.45 (m, 3H), 2.84-2.80 (m, 2H). LCMS (m / z): 481.2 (M + H < ⁺ & gt ^; ) .; LCMS (m / z): 499.95 (M + H ^& lt ^{; +} & gt ^; ).

PREPARATION EXAMPLE 5 Preparation of methyl 4- (3-azido-2-benzylpropaneamido) benzoate

Preparation 5-1) 2-Benzyl-3- ( t -Butyldimethylsilyloxy) propanoic acid < / RTI >

(5 g, 27.70 mmol) was dissolved in dichloromethane (200 mL) at 0 ^° C. Imidazole (8.5 g, 124.70 mmol) and t -butyldimethylsilyl Chloride (9.2 g, 61.0 mmol) was added thereto, followed by stirring for 5 hours. A saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solvent and extracted with dichloromethane (50 mL x 2). Dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. This compound was dissolved in tetrahydrofuran, methanol and distilled water, and lithium hydroxide (554 mg, 13.2 mmol) was added thereto, followed by stirring for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (8.7 g, 99%).

¹ H-NMR (600 MHz, DMSO-d ₆ ) ? 7.32-7.29 (m, 2 H), 7.23-7.21 (m, 3 H), 3.74-3.69 1 H), 2.77 - 2.72 (m, 2 H), 0.88 (s, 15 H).

Preparation Example 5-2) Preparation of methyl 4- (2-benzyl-3- (t-butyldimethylsilyloxy) propanamide) benzoate

2-benzyl -3- (t - butyl-dimethyl-silyloxy) propanoyl ripening Acid (1 g, 3.39 mmol) to dichloromethane (20 mL) at 0 ^o C-methyl-4-amino-benzoate was dissolved in (565 mg , Benzyltriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (2.3 g, 4.40 mmol) was added to the solution, and the mixture was stirred for 6 hours Lt; / RTI > Saturated ammonium chloride aqueous solution (20 mL) and distilled water (20 mL) were added to the reaction solvent, followed by extraction with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the title compound (206 mg, 15%) was obtained by column separation.

Preparation Example 5-3) Preparation of methyl 4- (2-benzyl-3-hydroxypropaneamido) benzoate

Benzoate (206 mg, 0.48 mmol) was dissolved in tetrahydrofuran (5 mL) and at 0 ^° C, tetrabutylammonium (2-benzyloxyphenyl) Fluoride (1M tetrahydrofuran solution, 0.5 mL, 0.48 mmol) was added thereto, followed by stirring for 1 hour. Saturated ammonium chloride aqueous solution (20 mL) and distilled water (20 mL) were added to the reaction solvent, followed by extraction with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the title compound (94 mg, 63%) was obtained by column separation.

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 7.96 (s, 2 H), 7.69 (s, 1 H), 7.44 (s, 2 H), 7.30-7.14 (m, 5 H), 3.89 ( s, 3H), 3.10-3.07 (m, 1H), 2.91-2.88 (m, 1H), 2.75 (s, 1H), 2.47 (s, 1H).

Preparation Example 5-4) Preparation of methyl 4- (3-azido-2-benzylpropaneamido) benzoate

(94 mg, 0.30 mmol) was dissolved in tetrahydrofuran (5 mL), and triethylamine (0.13 mL, 0.89 mmol) and methanesulfonic acid Anhydride (63 mg, 0.36 mmol) was added thereto, followed by stirring for 1 hour. Distilled water (10 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. This compound was dissolved in dimethylformamide (5 mL) and sodium azide was added thereto, followed by stirring for 3 hours. A saturated aqueous sodium chloride solution (10 mL) and distilled water (10 mL) were added to the reaction solvent, followed by extraction with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Column separation afforded the title compound (82 mg, 81%).

Preparation Example 6 Preparation of 4-methoxybenzyl 3- (3-azido-2-benzylpropaneamido) benzoate

4-methoxybenzyl 3- (3-azido-2-benzylpropaneamido) benzoate was synthesized by a method similar to that of Preparation Example 5 above.

¹ H-NMR (600 MHz, DMSO-d ₆ ) ? 7.80-7.79 (m, 2H), 7.72 (s, 1H), 7.39-7.34 (m, 3H), 7.31-7.23 ), 7.21-7.17 (m, 2H), 7.07 (s, 1H), 6.92-6.89 (m, 2H), 5.30-5.25 3.48 (m, 1H), 2.99-2.96 (m, 1H), 2.90-2.86 (m, 1H), 2.68-2.66 (m, 1H).

PREPARATION EXAMPLE 7 Preparation of 4-methoxybenzyl 3- (2-benzyl-3- (4- (5-chloro-2- H- Yl) phenyl) -1 H -1,2,3-triazol-1-yl) propenamido) benzoate

1- (4-ethynyl-2-chloro-phenyl) -1 H - tetrazole (128 mg, 0.63 mmol) of dimethyl-sulfonic side and distilled water (1: 1) is dissolved in from 0 ^o C 4-methoxybenzyl 3 Benzoate (279 mg, 0.63 mmol), sodium ascorbate (12 mg, 0.06 mmol) and cupper (II) sulfate (8 mg, 0.03 mmol) And the mixture was stirred under a nitrogen atmosphere for 2 hours. Distilled water (20 mL) was added to the reaction solution and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (10 mL) to give the title compound (267 mg, 66%).

¹ H-NMR (600 MHz, DMSO-d ₆ ) ? 10.07 (s, 1H), 9.63 (s, 1H), 7.99 m, 3 H), 7.61 ( s, 1 H), 7.40-7.38 (m, 3 H), 7.26-7.16 (m, 5 H), 6.95 (d, J = 7.8 Hz, 2 H), 5.24 (s (M, 1H), 2.78-2.74 (m, 1H), 4.64-4.61 H) .; LCMS (m / z): 649.09 (M + H ^& lt ^{; +} & gt ^; ).

PREPARATION EXAMPLE 8 Preparation of 4-methoxybenzyl 4- (1- (4- (5-chloro-2- (1 H- Yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropane-2-ylcarbamoyl) benzoate

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL) and diisopropylethylamine (42 uL, 0.24 mmol) and 4- (4-methoxybenzyloxy) benzoic acid , 0.13 mmol) and benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (94 mg, 0.18 mmol) were added and stirred for 6 hours. 20 mL x 2) and extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (68 mg, 87% .

¹ H-NMR (600 MHz, DMSO-d ₆ ) ? 9.63 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.00-7.94 (m, 4H), 7.73-7.68 , 4 H), 7.41 (d , J = 9.0 Hz, 2 H), 7.27-7.15 (m, 5 H), 6.95 (d, J = 8.4 Hz, 2 H), 5.29 (s, 1 H), 4.62 -4.46 (m, 4 H), 3.76 (s, 3 H); LCMS (m / z): 649.19 (M + H ^& lt ^{; +} & gt ^; ).

≪ Production Example 9 & t - Preparation of butyl 2- (hydroxyimino) ethyl (phenethyl) carbamate

Production Example 9-1) Preparation of phenethylamino-acetic acid ethyl ester

(1.30 g, 8.11 mmol) and diisopropylethylamine (2.83 mL, 16.2 mmol) were dissolved in acetonitrile (20 mL), and the mixture was stirred at room temperature for 2 hours. And stirred at room temperature under a nitrogen atmosphere for 48 hours. The reaction solution was concentrated under reduced pressure, and the mixture was added to a saturated aqueous solution of sodium hydrogencarbonate (30 mL), followed by extraction with ethyl acetate (30 mL x 2), drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure. g, 37%) as a yellow solid.

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.30-7.19 (m, 5 H), 4.16 (q, J = 7.2 Hz, 2 H), 3.39 (s, 2 H), 2.89 (t, J = 2.7 Hz, 2 H), 2.81 (t, J = 12.4 Hz, 2 H), 1.25 (t, J = 7.2 Hz, 3 H).

Production Example 9-2) ( t -Butoxycarbonyl-phenethyl-amino) -acetic < / RTI > acid ethyl ester

After loading was dissolved the compound (1.41 g, 6.80 mmol) obtained in Preparation Example 9-1 in 1,4-dioxane (20 mL) and distilled water (20 mL) sodium carbonate (1.08 g, 10.2 mmol) dimethyl - t - Butoxydicarbonate (1.78 g, 8.16 mmol) was added thereto, followed by stirring at room temperature for 5 hours under a nitrogen atmosphere. The reaction solution was extracted with a saturated aqueous ammonium chloride solution (100 mL) and ethyl acetate (100 mL), and the organic layer was washed with an aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a compound.

¹ H-NMR (600 MHz, CDCl ₃ ) ? 7.29-7.15 (m, 5 H), 4.16 (q, J = 14.4 Hz, 2 H), 3.70 , 1.47 (s, 9 H), 1.25 (t, J = 18 Hz, 3 H).

Preparation 9-3) (2-Hydroxy-ethyl) -phenethyl-carbamic acid t - Preparation of butyl ester

The compound obtained in Preparation 9-2 was dissolved in dry tetrahydrofuran (30 mL), the temperature was lowered to -20 ^° C, and lithium aluminum hydride (1 M tetrahydrofuran solution, 8.84 mL, 8.84 mmol) was slowly added The mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. After stirring for 30 minutes, distilled water (0.33 mL), 15% aqueous sodium hydroxide solution (0.33 mL) and distilled water (0.99 mL) were separated by column chromatography to give the title compound (2.43 g, 99%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.30-7.17 (m, 5 H), 3.70 (s, 2 H), 3.49 (s, 2 H), 3.44 (s, 2 H), 2.87 (s, 2 H), 1.29 (s, 9 H).

Preparation 9-4) (2-Oxo-ethyl) -phenethyl-carbamic acid t - Preparation of butyl ester

The compound obtained in Preparative Example 9-3 (2.43 g, 9.16 mmol) was dissolved in dry dichloromethane (20 mL) and dimethylsulfoxide (20 mL), and the temperature was lowered to 0 ^° C. Triethylamine 5.15 mL, 36.6 mmol) and sulfur trioxide pyridine complex (2.94 g, 18.3 mmol) were added thereto, followed by stirring for 3 hours. The mixture was extracted with 1 N aqueous hydrochloric acid solution (30 mL) and ethyl acetate (50 mL x 2), washed with 30 mL of distilled water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a compound.

¹ H-NMR (600 MHz, CDCl ₃ ) ? 9.47 (S, 1H), 7.30-7.14 (m, 5H), 4.12 (s, 1H), 3.82 m, 2 H), 2.87-2.80 (m, 2 H), 1.26 (s, 9 H).

Production example 9-5) t - Preparation of butyl 2- (hydroxyimino) ethyl (phenethyl) carbamate

The compound obtained in Preparation Example 9-4 was dissolved in ethanol (30 mL), sodium carbonate (3.88 g, 36.6 mmol) and hydroxylamine hydrochloride (1.27 g, 18.3 mmol) were added thereto and stirred at room temperature under a nitrogen atmosphere for 8 hours . The reaction solution was concentrated to 90%, extracted with ethyl acetate (50 mL) and distilled water (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (2.17 g, 76%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 8.47 (s, 1 H), 7.43-7.15 (m, 5 H), 3.91 (m, 2 H), 3.44 (m, 2 H), 2.82 (m, 2 H), 1.26 (s, 9 H).

PREPARATION EXAMPLE 10 Preparation of [5- (5-chloro-2-tetrazol-1-yl-phenyl) -isoxazole-3-yl-methyl] -phenethylamine hydrochloride

Preparation 10-1) Preparation of [5- (5-chloro-2-tetrazol-1-yl-phenyl) -isoxazole-3-yl- methyl] -phenethyl-carbamic acid t-

t - butyl-2- (hydroxyimino) ethyl (phenethyl) carbamate (2.17 g, 6.93 mmol), the N-dimethylformamide at 0 ^o C was dissolved in 10 mL amide - chloro seed rot you polyimide (1 g, 7.70 after mmol) maintaining the temperature with stirring for 2 hours, then put the 1- (4-ethynyl-2-chloro-phenyl) -1 H - tetrazol-a (1.1 g, 5.38 mmol) was dissolved in dimethylformamide (5 mL) A solution of triethylamine (1.5 mL, 10.75 mmol) was added to the reaction solution, the temperature was gradually raised from room temperature to 0 ^° C, and the mixture was stirred for 5 hours. The mixture was diluted with an aqueous solution of sodium chloride (100 mL), extracted with ethyl acetate (60 mL x 2) and washed with distilled water (60 mL). Dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.86 g, 46%).

¹ H-NMR (600 MHz, CDCl ₃ ) ? 8.68 (s, 1H), 7.96 (s, 1H), 7.64 5 H), 5.741 (s, 1H), 4.31 (s, 2H), 3.37 (m, 2H), 2.80 (m, 2H), 1.40 (s, 9H).

Preparation 10-2) Preparation of [5- (5-chloro-2-tetrazol-l-yl-phenyl) -isoxazole-3- yl-methyl] -phenethylamine hydrochloride

The compound (860 mg, 1.79 mmol) obtained in Preparative Example 10-1 was dissolved in dry dichloromethane (10 mL), the temperature was lowered to 0 ^° C and HCl (4 M 1,4-dioxane solution, 10 mL ) Was added slowly, and the temperature was gradually raised to room temperature and stirred for 4 hours. The reaction solution was concentrated under reduced pressure and recrystallized in diethyl ether (50 mL) to give the title compound (690 mg, 84%) as a solid.

¹ H-NMR (400 MHz, DMSO- d ₆ ) ? 8.18 (s, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 7.54-7.51 7.43 (m, 3H), 6.67 (s, 1H), 4.28 (m, 2H), 3.56 (m, 2H), 2.74 (m, 2H).

Preparation 11 Synthesis of (4- {3- [5- (5-chloro-2-tetrazol-1-yl-phenyl) -isoxazole-3- ylmethyl] -3-phenethyl- urea iodo] -Phenyl) -acetic acid < / RTI > Preparation of 4-methoxybenzyl diether

(123 mg, 0.479 mmol) was dissolved in tetrahydrofuran (5 mL), the temperature was lowered to 0 ^° C., and then carbonyldiimidazole (81.6 g, mg, 0.503 mmol) and the mixture was stirred at room temperature for 2 hours. Then, a solution of [5- (5-chloro-2-tetrazol-1-yl-phenyl) -isoxazol- Ethyl-amine hydrochloride (100 mg, 0.239 mmol) and diisopropylethylamine (0.086 mL, 0.479 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and then subjected to column chromatography to obtain the title compound (128 mg, 80%) as a white solid.

^{1 H-NMR (600 MHz,} CDCl 3) δ 8.72 (s, 1 H), 7.92 (s, 1 H), 7.65 (dd, J = 1.8, 8.4 Hz, 1 H), 7.47 (d, J = 8.4 (D, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 1H), 7.40-7.23 3H), 3.55 (t, J ), 4.50 (s, 2H), 6.81 (s, 1H) = 6.3 Hz, 2 H), 2.91 (t, J = 6.3 Hz, 2H).

Preparation Example 12 Synthesis of 1-carboxymethyl-4- (5-chloro-2-tetrazol-1 -yl-phenyl) H -Pyrrole-3-carboxy &lt; / RTI &gt; acid methyl ester

Production Example 12-1) 4- (5-Chloro-2-tetrazol-1 -yl-phenyl) H -Pyro-3-carboxal &lt; / RTI &gt; acid methyl ester

(2 g, 7.56 mmol, see US 2010-0173899) and 4-toluenesulfonylmethylisocyanide (1.55 g, 7.93 mmol) were added to a solution of 3- (5-chloro-2-tetrazol- mmol) was dissolved in dry tetrahydrofuran (30 mL), and the temperature was lowered to 78 ^° C. Sodium hydride (0.317 g, 7.93 mmol) was slowly added thereto, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was diluted with an aqueous ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL x 2), dried over anhydrous sodium sulfate and concentrated to give 1.51 g (66%) of the title compound as a white solid.

Production Example 12-2) 1- (2- t - butoxy-2-oxoethyl) -4- (5-chloro-2-tetrazol- H -Pyrrole-3-carboxy &lt; / RTI &gt; acid methyl ester

The compound (0.30 g, 0.99 mmol) obtained in Preparative Example 12-1 was dissolved in dimethylformamide (5 mL), and t -butyl bromoacetate (0.36 mL, 2.37 mmol) and 1,8-diazabicyclo [ , 4,0] undet-7-yne (0.36 mL, 2.37 mmol) were added thereto, and the mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The reaction mixture was diluted with an aqueous ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL x 2), and washed with a saturated aqueous sodium chloride solution (30 mL). After drying with anhydrous sodium sulfate and concentration, the title compound (0.363 g, 88%) was obtained as a white solid by column chromatography.

^{1 H-NMR (600 MHz,} CDCl 3) δ 8.47 (s, 1H), 7.55-7.48 (m, 3H), 7.25 (d, J = 2.4 Hz, 1 H), 6.54 (d, J = 2.4 Hz, 1 H), 4.48 (s, 2 H), 1.47 (s, 9 H).

Preparation 12-3) 1-Carboxymethyl-4- (5-chloro-2-tetrazol-1-yl-phenyl) H -Pyrrole-3-carboxy &lt; / RTI &gt; acid methyl ester

The compound obtained in Preparation Example 12-2 (0.36 g, 0.87 mmol) was dissolved in dry dichloromethane (10 mL), and phenol (1.64 g, 17.4 mmol) and trifluoroacetic acid (0.67 mL, 8.69 mmol) And the mixture was stirred at room temperature for 24 hours. The reaction solution was extracted with ethyl acetate (30 mL x 2) and distilled water (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (0.205 g, 65%) by column chromatography.

Example 1 Methyl 1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropan-2-ylcarbamate

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL), diisopropylethylamine (0.042 mL, 0.24 mmol) and methyl chloroformate (0.010 mL, 0.13 mmol) Lt; / RTI &gt; Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (55 mg, 83%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) ? 9.66 (s, 1H), 8.06 (s, 1H), 7.94 H), 3.40 (s, 3H), 2.75 (m, 2H), 7.29-7.26 (m, 2H), 7.21-7.18 -2.61 (m, 2 H); LCMS (m / z): 438.92 (M + H ^& lt ^{; +} & gt ^; ).

&Lt; Example 2 > N - (1- (4- (5-chloro-2- (1 H- Yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropan-2-yl) acetamide

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL), diisopropylethylamine (42 uL, 0.24 mmol) and acetic anhydride (12 uL, 0.13 mmol) Lt; / RTI &gt; Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized in diethyl ether (5 mL) to give the title compound (42 mg, 83%).

^{1 H-NMR (400 MHz,} DMSO-d 6) δ 9.66 (s, 1 H), 8.07 (s, 1 H), 7.89 (s, 1 H), 7.83 (d, J = 7.8 Hz, 1 H) , 7.75-7.21 (m, 2H), 7.29-7.26 (m, 2H), 7.25-7.19 , 2.64-2.60 (m, 1H), 1.68 (s, 3H); LCMS (m / z): 422.92 (M + H ^& lt ^{; +} & gt ^; ).

&Lt; Example 3 > N - (1- (4- (5-chloro-2- (1 H- Yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropan-2-yl) methanesulfonamide Produce

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL), diisopropylethylamine (0.042 mL, 0.24 mmol) and methanesulfanic anhydride (23 mg, 0.13 mmol) And stirred for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized in diethyl ether (5 mL) to give the title compound (25 mg, 45%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.65 (s, 1 H), 8.04 (d, J = 2.0 Hz, 1 H), 7.76-7.72 (m, 2 H), 7.46 (d, J = 9 Hz, 1H), 7.33-7.22 (m, 5H), 4.47 (dd, J = 14.4,4.8 Hz, 1H), 4.34 (dd, J = 14.4,7.8 Hz, 1H), 3.86 m, 1H), 2.78-2.58 (m, 2H), 2.16 (s, 3H); LCMS (m / z): 458.87 (M + H ^& lt ^{; +} & gt ^; ).

Example 4 Methyl 4- (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) l- H -1,2,3-triazol-1-yl) -3-phenylpropene-2-ylcarbamoyl) benzoate

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (100 mg, 0.24 mmol) was dissolved in dimethylformamide (3 mL) and diisopropylethylamine (0.084 mL, 0.48 mmol) and 4- (methoxycarbonyl) benzoic acid mmol) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (187 mg, 0.36 mmol) were added thereto, followed by stirring for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized in diethyl ether (5 mL) to give the title compound (98 mg, 75%).

¹ H-NMR (600 MHz, DMSO- d ₆ ) ? 9.64 (s, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.01-7.97 (m, 3H), 7.74-7.71 3H), 3.87 (s, 3H), 3.01 (m, 1H), 2.94-2.84 (m, 2H), 7.28-7.17 ; LCMS (m / z): 542.93 (M + H ^& lt ^{; +} & gt ^; ).

Example 5 Preparation of ethyl 4- (3- (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1- H -1,2,3-triazol-1-yl) -3-phenylpropen-2-yl ureido) benzoate

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (100 mg, 0.24 mmol) was dissolved in dimethylformamide (3 mL), diisopropylethylamine (0.084 mL, 0.48 mmol) and ethyl 4-isocyanatobenzoate were added and stirred for 2 hours Respectively. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized in diethyl ether (5 mL) to give the title compound (121 mg, 88%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.66 (s, 1 H), 8.84 (s, 1 H), 7.99 (s, 1 H), 7.90 (d, J = 9.0 Hz, 1 H) , 7.79 (d, J = 9.0 Hz, 2 H), 7.73-7.70 (m, 2 H), 7.62 (d, J = 8.4 Hz, 1 H), 7.41 (d, J = 8.4 Hz, 2 H), 7.31-7.29 (m, 2 H), 7.24-7.19 (m, 3 H), 6.35 (d, J = 8.4 Hz, 1 H), 4.55 (dd, J = 14.0, 4.8 Hz, 1 H), 4.45 ( dd, J = 14.0, 7.8 Hz , 1 H), 4.30-4.23 (m, 2 H), 2.82 (dd, J = 13.8, 5.4 Hz, 1 H), 2.65 (dd, J = 13.8, 9.6 Hz, 1 H), 1.31 (m, 3 H).

Example 6: Synthesis of N- (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropen-2-yl) benzamide

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- (0.063 mL, 0.36 mmol) and benzoyl chloride (0.017 mL, 0.14 mmol) were added to the solution, and the mixture was stirred for 2 hours. Respectively. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized in diethyl ether (5 mL) to give the title compound (19 mg, 32%).

^{1 H NMR (600 MHz, DMSO} -d 6) δ 9.64 (s, 1 H), 8.35 (d, J = 7.8 Hz, 1 H), 7.99 (s, 1 H), 7.96 (s, 1 H), (M, 2H), 7.49-7.70 (m, 2H), 7.63-7.61 (m, 2H) 4.46 (m, 3 H), 2.89 - 2.85 (m, 2 H); LCMS (m / z): 484.94 (M + H ^& lt ^{; +} & gt ^; ).

Example 7: Synthesis of N- (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropen-2-yl) benzamide

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL), diisopropylethylamine (0.063 mL, 0.36 mmol) and 2-methylbenzoyl chloride (0.019 mL, 0.14 mmol) Lt; / RTI &gt; Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (18 mg, 30%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.69 (s, 1 H), 8.19 (d, J = 8.4 Hz, 1 H), 8.06 (s, 1 H), 8.02 (s, 1 H) , 7.74-7.71 (m, 2H), 7.31-7.19 (m, 6H), 7.15 (t, J = 7.2 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H) , J = 7.8 Hz, 1H), 4.62-4.59 (m, 2H), 4.44 (m, 1H), 2.94-2.72 (m, 2H), 1.87 (s, 3H); LCMS (m / z): 498.96 (M + H ^& lt ^{; +} & gt ^; ).

Example 8: Preparation of N- (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropen-2-yl) -3-methylbenzamide

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL), diisopropylethylamine (0.063 mL, 0.36 mmol) and 3-methylbenzoyl chloride (0.019 mL, 0.14 mmol) Lt; / RTI &gt; Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (27 mg, 45%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.63 (s, 1 H), 8.30 (d, J = 7.8 Hz, 1 H), 7.99 (s, 1 H), 7.96 (s, 1 H) , 7.71 (s, 2H), 7.43-7.41 (m, 2H), 7.31-7.17 (m, 7H), 4.60-4.47 , 3 H); LCMS (m / z): 498.92 (M + H ^& lt ^{; +} & gt ^; ).

Example 9: Preparation of N- (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropen-2-yl) -4-methylbenzamide

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL), diisopropylethylamine (0.063 mL, 0.36 mmol) and 4-methylbenzoyl chloride (0.019 mL, 0.14 mmol) Lt; / RTI &gt; Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized in diethyl ether (5 mL) to give the title compound (28 mg, 46%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.64 (s, 1 H), 8.28 (d, J = 8.4 Hz, 1 H), 7.98 (s, 1 H), 7.95 (s, 1 H) , 7.73-7.65 (m, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.27-7.17 2 H), 2.32 (s, 2 H); LCMS (m / z): 498.93 (M + H ^& lt ^{; +} & gt ^; ).

Example 10: Preparation of 3-chloro-N- (1- (4- (5-chloro-2- H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropen-2-yl) benzamide

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL) and diisopropylethylamine (0.063 mL, 0.36 mmol) and 3- chlorobenzoic acid (21 mg, L-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (94 mg, 0.18 mmol) was added thereto, followed by stirring for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized in diethyl ether (5 mL) to give the title compound (24 mg, 38%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.63 (s, 1 H), 8.48 (d, J = 8.4 Hz, 1 H), 8.01 (s, 1 H), 7.97 (s, 1 H) , 7.73-7.71 (m, 2H), 7.65 (s, 1H), 7.59-7.57 (m, 2H), 7.47 (t, J = 7.8 Hz, 1H), 7.28-7.17 ), 4.62-4.46 (m, 3 H), 2.91-2.82 (m, 2 H); LCMS (m / z): 518.89, 520.86 (MH & lt ^; + ^& gt ^; , M + H ^& lt ^{; +} & gt ^; ).

Example 11: Preparation of 4-chloro-N- (1- (4- (5-chloro-2- H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropen-2-yl) benzamide

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL) and diisopropylethylamine (0.063 mL, 0.36 mmol) and 4-chlorobenzoic acid (21 mg, 1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (281 mg, 0.54 mmol) was added thereto, followed by stirring for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (39 mg, 62%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.64 (s, 1 H), 8.44 (d, J = 8.4 Hz, 1 H), 7.98 (s, 1 H), 7.96 (s, 1 H) , 7.71-7.65 (m, 2H), 7.64 (d, J = 7.2 Hz, 2H), 7.50 (d, J = 7.2 Hz, 2H), 7.27-7.17 (m, 3 H), 2.89-2.82 (m, 2 H) .; LCMS (m / z): 518.90, 520.80 (MH & lt ^; + ^& gt ^; , M + H ^& lt ^{; +} & gt ^; ).

Example 12: Synthesis of N- (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropen-2-yl) -3-methoxybenzamide

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL), diisopropylethylamine (0.063 mL, 0.36 mmol) and 3-methoxybenzoyl chloride (0.020 mL, 0.14 mmol) And stirred for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized in diethyl ether (5 mL) to give the title compound (28 mg, 45%).

^{1 H NMR (600 MHz, DMSO} -d 6) δ 9.63 (s, 1 H), 8.33 (d, J = 8.4 Hz, 1 H), 8.01 (s, 1 H), 7.96 (s, 1 H), J = 7.8 Hz, 1H), 7.28-7.15 (m, 7H), 7.06 (dd, J = 8.4, 2.4 Hz, 1H), 4.61-7.71 (m, 2H) 4.47 (m, 3 H), 3.76 (s, 3 H), 2.87 - 2.84 (m, 2 H) .; LCMS (m / z): 514.93 (M + H ^& lt ^{; +} & gt ^; ).

Example 13 Synthesis of N- (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropen-2-yl) -4-methoxybenzamide

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL), diisopropylethylamine (0.063 mL, 0.36 mmol) and 4-methoxybenzoyl chloride (0.020 mL, 0.14 mmol) And stirred for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized in diethyl ether (5 mL) to give the title compound (19 mg, 30%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.64 (s, 1 H), 8.21 (d, J = 8.4 Hz, 1 H), 7.98 (s, 1 H), 7.94 (s, 1 H) , 7.73-7.69 (m, 2 H) , 7.63 (d, J = 7.2 Hz, 2 H), 7.27-7.14 (m, 5 H), 6.95 (d, J = 9.0 Hz, 2 H), 4.59-4.46 (m, 3 H), 3.79 (s, 3 H), 2.86 (d, J = 7.2 Hz, 2 H); LCMS (m / z): 514.94 (M + H ^& lt ^{; +} & gt ^; ).

Example 14 Synthesis of N- (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropen-2-yl) -3-nitrobenzamide

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL), diisopropylethylamine (0.063 mL, 0.36 mmol) and 3-nitrobenzoyl chloride (27 mg, 0.14 mmol) And stirred for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized in diethyl ether (5 mL) to give the title compound (24 mg, 37%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.61 (s, 1 H), 8.74 (d, J = 7.8 Hz, 1 H), 8.47 (s, 1 H), 8.37 (d, J = 7.8 Hz, 1 H), 8.08 ( d, J = 7.8 Hz, 1 H), 7.98 (s, 1 H), 7.97 (s, 1 H), 7.75 (t, J = 7.8 Hz, 1 H), 7.71 ( s, 2 H), 7.27-7.17 (m, 5 H), 4.65-4.48 (m, 3 H), 2.95-2.85 (m, 2 H). LCMS (m / z): 529.92 (M + H ^& lt ^{; +} & gt ^; ).

&Lt; Example 15 > N - (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropen-2-yl) -4-nitrobenzamide

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL), diisopropylethylamine (0.063 mL, 0.36 mmol) and 4-nitrobenzoyl chloride (27 mg, 0.14 mmol) And stirred for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (39 mg, 61%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.64 (s, 1 H), 8.69 (d, J = 8.4 Hz, 1 H), 8.29 (d, J = 9.0 Hz, 2 H), 7.97 ( (m, 3 H), 2.95-2.84 (m, 2H), 7.84 (d, J = 7.2 Hz, 2H), 7.71 (s, 2H), 7.28-7.18 (m, 2H); LCMS (m / z): 529.90 (M + H ^& lt ^{; +} & gt ^; ).

Example 16: Synthesis of 4- (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropen-2-ylcarbamoyl) benzoic acid

4-methoxybenzyl 4- (1- (4- (5-chloro -2- (1 H- tetrazol-1-yl) phenyl) -1 H -1,2,3- triazol-1-yl) Benzoate (50 mg, 0.07 mmol) was dissolved in methylene chloride (3 mL). Trifluoroacetic acid (0.059 mL, 0.77 mmol) and phenol (145 mg, 1.54 mmol ) Was added thereto, followed by stirring for 1 hour. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the title compound (19 mg, 79%) was obtained by column separation.

¹ H-NMR (600 MHz, DMSO-d ₆ ) ? 9.65 (s, 1H), 8.52 (d, J = 8.4 Hz, 1H), 7.99-7.96 (m, 4H), 7.73-7.69 , 4 H), 7.28-7.16 (m, 5 H), 4.62-4.47 (m, 3 H), 2.90-2.86 (m, 2 H); LCMS (m / z): 528.93 (M + H ^& lt ^{; +} & gt ^; ).

Example 17: Preparation of 4- (N- (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropan-2-yl) sulfamoyl) benzoic acid

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (100 mg, 0.24 mmol) was dissolved in dimethylformamide (3 mL) and diisopropylethylamine (0.083 mL, 0.48 mmol) and 4- (chlorosulfonyl) benzoic acid (58 mg, 0.26 mmol ) Was added thereto, followed by stirring for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized in diethyl ether (5 mL) to give the title compound (14 mg, 35%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.66 (s, 1 H), 8.38 (d, J = 9.0 Hz, 1 H), 8.01 (s, 1 H), 7.98 (s, 1 H) , 7.72-7.69 (m, 2H), 7.62-7.58 (m, 3H), 7.29-7.15 .

Example 18: Synthesis of N- (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropan-2-yl) -4-cyanobenzamide

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL), diisopropylethylamine (0.063 mL, 0.36 mmol) and 4-cyanobenzoic acid (19 mg, 0.13 mmol) And then stirred for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized in diethyl ether (5 mL) to give the title compound (35 mg, 56%).

¹ H-NMR (600 MHz, DMSO- d ₆ ) ? 9.63 (s, 1H), 8.61 (d, J = 9.0 Hz, 1H), 7.98-7.92 (m, 4H), 7.76-7.71 , 4 H), 7.29-7.18 (m, 5 H), 4.64-4.46 (m, 3 H), 2.92-2.73 (m, 2 H); LCMS (m / z): 509.95 (M + H ^& lt ^{; +} & gt ^; ).

Example 19: Synthesis of N- (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropan-2-yl) -4- (1- H -Tetrazol-5-yl) benzamide &lt; / RTI &gt;

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -amine hydrochloride (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL) diisopropylethylamine (0.063 mL, 0.36 mmol), 4- (1- methyl -1 H-tetrazol-5-yl ) Benzoic acid (27 mg, 0.13 mmol) was added thereto, followed by stirring for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized in diethyl ether (5 mL) to give the title compound (47 mg, 75%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.65 (s, 1 H), 8.52 (d, J = 7.8 Hz, 1 H), 8.12 (d, J = 7.2 Hz, 2 H), 7.99 ( (d, J = 10.2 Hz, 2H), 7.81 (d, J = 6.6 Hz, 2H), 7.72 (m, 2H), 7.27-7.18 ), 4.44 (s, 3 H), 2.89-2.85 (m, 2 H); LCMS (m / z): 568.94 (M + H ^& lt ^{; +} & gt ^; ).

Example 20: Synthesis of N- (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropan-2-yl) -4- H -Tetrazol-5-yl) benzamide &lt; / RTI &gt;

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL) and diisopropylethylamine (0.063 mL, 0.36 mmol) and 4- ( 1H -tetrazol-5-yl) benzoic acid (25 mg, 0.13 mmol) was added thereto, followed by stirring for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (25 mg, 40%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.65 (s, 1 H), 8.51 (d, J = 7.8 Hz, 1 H), 8.07 (d, J = 7.2 Hz, 2 H), 8.04 ( (m, 2H), 7.96 (s, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.72-7.68 (m, 3 H), 3.13-3.09 (m, 2 H); LCMS (m / z): 552.97 (M + H ^& lt ^{; +} & gt ^; ).

Example 21 Methyl 4- (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropan-2-ylcarbamoyl) phenylcarbamate

4-amino - N - (1- (4- ( 5- chloro -2- (1 H-tetrazol-1-yl) phenyl) -1 H -1,2,3- triazol-1-yl) - (30 mg, 0.06 mmol) was dissolved in dimethylformamide (3 mL), diisopropylethylamine (0.020 mL, 0.12 mmol), methyl chloroformate 0.005 mL, 0.07 mmol) was added thereto, followed by stirring for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (14 mg, 44%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.64 (s, 1 H), 8.23 (d, J = 8.4 Hz, 1 H), 7.97 (s, 1 H), 7.92 (s, 1 H) , 7.71-7.65 (m, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.32-7.17 (m, 3 H), 3.00 - 2.90 (m, 2 H).

Example 22: Preparation of 4-acetamido-N- (1- (4- (5-chloro-2- H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropan-2-yl) benzamide

4-amino - N - (1- (4- ( 5- chloro -2- (1 H-tetrazol-1-yl) phenyl) -1 H -1,2,3- triazol-1-yl) - (30 mg, 0.06 mmol) was dissolved in dimethylformamide (3 mL), diisopropylethylamine (0.020 mL, 0.12 mmol), acetic anhydride (0.006 mL, 0.07 mmol) was added thereto, followed by stirring for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (27 mg, 89%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 10.13 (s, 1 H), 9.63 (s, 1 H), 8.24 (d, J = 7.8 Hz, 1 H), 7.97 (s, 1 H) , 7.95 (s, 1H), 7.71 (s, 2H), 7.60 (s, 4H), 7.28-7.17 (m, 5H), 4.59-4.46 (m, 3H), 2.81-2.62 , 2 H); LCMS (m / z): 541.95 (M + H ^& lt ^{; +} & gt ^; ).

&Lt; Example 23 > N - (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropan-2-yl) -4- (methylsulfonamido) benzamide

4-amino - N - (1- (4- ( 5- chloro -2- (1 H-tetrazol-1-yl) phenyl) -1 H -1,2,3- triazol-1-yl) - (30 mg, 0.06 mmol) was dissolved in dimethylformamide (3 mL), diisopropylethylamine (0.020 mL, 0.12 mmol), methanesulfonyl chloride ( 12 mg, 0.07 mmol) was added thereto, followed by stirring for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (23 mg, 71%).

¹ H-NMR (600 MHz, DMSO-d ₆ ) ? 9.62 (s, 1H), 7.96 (d, J = 10.2 Hz, 2H), 7.89 , 7.41 (d, J = 7.2 Hz, 2H), 7.26-7.17 (m, 5H), 6.51 (d, J = 7.2 Hz, 1H), 5.58 (s, 1H), 4.59-4.42 , 3 H), 3.26 (s, 3 H), 2.83 - 2.71 (m, 2 H).

Example 24 Methyl 3- (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropan-2-ylcarbamoyl) benzoate

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL) and diisopropylethylamine (0.063 mL, 0.36 mmol) and 3- (methoxycarbonyl) benzoic acid 1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (281 mg, 0.54 mmol) was added to the solution, and the mixture was stirred for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (65 mg, 98%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.62 (s, 1 H), 8.59 (d, J = 8.4 Hz, 1 H), 8.22 (s, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 8.01 ( s, 1 H), 7.94 (s, 1 H), 7.89 (d, J = 7.8 Hz, 1 H), 7.71 (s, 2 H), 8.59 (t, J = 8.4 Hz, 1H), 7.27-7.18 (m, 5H), 4.62-4.48 (m, 3H), 3.87 (s, 3H), 2.90-2.87 (m, 2H); LCMS (m / z): 542.95 (M + H ^& lt ^{; +} & gt ^; ).

&Lt; Example 25 > N - (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropan-2-yl) thiophene-2-carboxamide

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL) and diisopropylethylamine (0.063 mL, 0.36 mmol), thiophene-2-carboxy acid (0.023 mL, 1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (281 mg, 0.54 mmol) was added thereto, followed by stirring for 2 hours. Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (41 mg, 69%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.62 (s, 1 H), 8.38 (d, J = 7.2 Hz, 1 H), 8.00 (s, 1 H), 7.94 (s, 1 H) , 7.71 (s, 2H), 7.64 (s, 1H), 7.26-7.11 (m, 6H), 4.59-4.45 (m, 3H), 2.85-2.81 (m, 2H); LCMS (m / z): 490.88 (M + H ^& lt ^{; +} & gt ^; ).

Example 26 Synthesis of phenyl 1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropan-2-ylcarbamate

1 - (4- (5-chloro-2- (1 H -tetrazol-1-yl) phenyl) -1 H- 1,2,3- triazol- 1 -yl) -3-phenylpropane- -Amine hydrochloride (50 mg, 0.12 mmol) was dissolved in dimethylformamide (3 mL), diisopropylethylamine (0.063 mL, 0.36 mmol) and phenyl chloroformate (0.018 mL, 0.14 mmol) Lt; / RTI &gt; Distilled water (20 mL) was added to the reaction solvent and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (31 mg, 51%).

^{1 H-NMR (600MHz, DMSO} ) δ 9.63 (s, 1 H), 8.06 (s, 1 H), 8.02 (s, 1 H), 7.83 (d, J = 9.0 Hz, 1 H), 7.74 (s (M, 2H), 7.34-7.23 (m, 10H), 7.14 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 4.59-4.41 , 4.11-4.09 (m, 1H), 2.87-2.72 (m, 2H); LCMS (m / z): 500.92 (M + H ^& lt ^{; +} & gt ^; ).

Example 27 Methyl 4- (2-benzyl-3- (4- (5-chloro-2- ( H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) propanamido) benzoate

Methyl 4- (3-at 0 ^o C was dissolved in: - 1- (4-ethynyl-2-chloro-phenyl) -1 H-tetrazole (50 mg, 0.24 mmol) dimethyl sulfoxide and distilled water (1: 1) (5 mg, 0.02 mmol) and copper sulfate (3 mg, 0.01 mmol) were added to the mixture, and the mixture was added with a nitrogen atmosphere &Lt; / RTI &gt; for 2 hours. Distilled water (20 mL) was added to the reaction solution and extracted with ethyl acetate (20 mL x 2). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized in diethyl ether (10 mL) to give the title compound (82 mg, 63%).

¹ H-NMR (600 MHz, DMSO-d ₆ ) ? 10.20 (s, 1H), 9.64 (s, 1H), 7.97 J = 8.4 Hz, 2 H) , 7.70 (s, 2 H), 7.56 (d, J = 8.4 Hz, 2 H), 7.28-7.18 (m, 5 H), 4.65 (dd, J = 9.0, 13.8 Hz , 1H), 4.47 (dd, J = 5.4,13.8 Hz, 1H), 3.81 (s, 3H), 3.01-2.73 (m, 2H); LCMS (m / z): 542.96 (M + H ^& lt ^{; +} & gt ^; ).

Example 28: 3- (2-Benzyl-3- (4- (5-chloro-2- H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) propanamido) benzoic acid

4-methoxybenzyl 3- (2-benzyl-3- (4- (5-chloro -2- (1 H- tetrazol-1-yl) phenyl) -1 H -1,2,3- triazol- 1-yl) propenamido) benzoate (50 mg, 0.07 mmol) was dissolved in dichloromethane, phenol (145 mg, 1.54 mmol) and trifluoroacetic acid (0.059 mL, 0.72 mmol) &Lt; / RTI &gt; for 2 hours. The reaction solution was concentrated under reduced pressure and recrystallized in diethyl ether (10 mL) to give the title compound (34 mg, 85%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 12.92 (br s, 1 H), 10.05 (s, 1 H), 9.65 (s, 1 H), 8.04 (t, J = 1.8 Hz, 1 H ), 8.01 (s, 1 H ), 7.94 (m, 1 H), 7.72-7.68 (m, 2 H), 7.65-7.58 (m, 2 H), 7.37 (t, J = 7.8 Hz, 1 H) , 7.28-7.17 (m, 5H), 4.64 (dd, J = 9.0,13.8 Hz, 1H), 4.45 (dd, J = 4.8,13.8 Hz, 1H) (dd, J = 9.0, 13.2 Hz, 1H), 2.77 (dd, J = 6.0, 13.2 Hz, 1H); LCMS (m / z): 528.92 (M + H ^& lt ^{; +} & gt ^; ).

Example 29: Synthesis of 3- (1- (4- (5-chloro-2- (1 H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) -3-phenylpropan-2-ylcarbamoyl) benzoic acid

Methyl 3- (1- (4- (5-chloro -2- (1 H - tetrazol-1-yl) phenyl) -1 H -1,2,3- triazol-1-yl) -3-phenyl Benzoate (30 mg, 0.05 mmol) was dissolved in dichloroethane, and trimethyltin chloride (30 mg, 0.05 mmol) was added thereto. The mixture was stirred at 50 ^° C under a nitrogen atmosphere for 2 hours. The reaction solution was concentrated under reduced pressure and recrystallized in diethyl ether (10 mL) to give the title compound (3 mg).

^{1 H-NMR (600 MHz,} CD 3 OD) δ 9.34 (s, 1 H), 8.19 (s, 1 H), 8.07 (d, J = 7.8 Hz, 1 H), 7.89 (d, J = 2.4 Hz , 7.71 (s, 1H), 7.63-7.57 (m, 3H), 7.40 (t, J = 7.2 Hz, 1H), 7.31-7.17 (m, 5H), 4.72-4.64 m, 2 H), 4.53 (dd, J = 8.4, 13.8 Hz, 1H), 3.01-2.93 (m, 2H).

Example 30: 4- (2-Benzyl-3- (4- (5-chloro-2- H -Tetrazol-1-yl) phenyl) -1 H -1,2,3-triazol-1-yl) propanamido) benzoic acid

Methyl 4- (2-benzyl-3- (4- (5-chloro -2- (1 H - tetrazol-1-yl) phenyl) -1 H -1,2,3- triazol-1-yl) (30 mg, 0.05 mmol) was dissolved in dichloroethane. Trimethyltin chloride (30 mg, 0.65 mmol) was added thereto, followed by stirring at 50 ^° C under a nitrogen atmosphere for 2 hours. The reaction solution was concentrated under reduced pressure and recrystallized in diethyl ether (10 mL) to give the title compound (3 mg).

¹ H-NMR (600 MHz, CD ₃ OD) ? 9.27 (s, 1H), 8.26 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.86-7.82 ), 7.61 (s, 1 H ), 7.39 (d, J = 7.2 Hz, 2 H), 7.31-7.17 (m, 5 H), 5.46 (m, 1 H), 4.67 (dd, J = 9.6, 13.8 J = 9.0, 13.8 Hz, 1H), 2.86 (dd, J = 6.0,13.8 Hz, 1H), 4.54 (dd, J = 4.8,13.8 Hz, 1H), 3.02 .

Example 31 Synthesis of (4- {3- [5- (5-chloro-2-tetrazol-l-yl-phenyl) -isoxazole-3- yl- methyl] -3-phenethyl- } -Phenyl) -acetic acid < / RTI >

Phenol (366 mg, 3.89 mmol) and trifluoroacetic acid (0.144 mL, 1.95 mmol) were added to a solution of the compound (132 mg, 0.194 mmol) obtained in Preparation Example 11 in 3 mL of dry dichloromethane Stir for 24 hours. The reaction solution was concentrated under reduced pressure and recrystallized in diethyl ether (10 mL) to give the title compound (36 mg, 33%) as a white solid.

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.81 (s, 1 H), 8.39 (s, 1 H), 8.23 (d, J = 2.4 Hz, 1 H), 7.88 (dd, J = 2.4, 8.4 Hz, 1 H ), 7.83 (d, J = 8.4 Hz, 1 H), 7.37 (d, J = 8.4 Hz, 2 H), 7.29-7.19 (m, 5 H), 7.13 (d, J = 8.4 Hz, 2H), 6.49 (s, 1H), 4.52 (s, 2H), 3.56 (m, 2H), 3.48 (m, 2H), 2.80 (m, 2H); LCMS (m / z): 527.90 (M + H ^& lt ^{; +} & gt ^; ).

The following compounds were synthesized by a method similar to that of Example 31.

EXAMPLE 32 Preparation of 3- {3-benzyl-3- [5- (5-chloro-2-tetrazol-l-yl-phenyl) -isoxazole-3- ylmethyl] -urea iodo} Manufacture of Waste Acid

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.81 (s, 1 H), 9.00 (s, 1 H), 8.20 (s, 1 H), 8.10 (m, 1H), 7.88 (dd, J = 2.4, 8.4 Hz, 2H), 7.84-7.80 (m, 2H), 7.56 (d, J = 7.8 Hz, 1H), 7.39-7.24 ), 4.61 (s, 2H), 4.54 (s, 2H); LCMS (m / z): 529.92 (M + H ^& lt ^{; +} & gt ^; ).

Example 33 Synthesis of 4- {3-benzyl-3- [5- (5-chloro-2-tetrazol-l-yl-phenyl) -isooxazole- 3- ylmethyl] -urea iodo} Manufacture of Waste Acid

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.81 (s, 1 H), 9.00 (s, 1 H), 8.20 (s, 1 H), 7.88 (dd, J = 2.4, 8.4 Hz, 2 H ), 7.84 (d, J = 9.0 Hz, 2 H) 7.63 (d, J = 9.0 Hz, 2 H), 7.36-7.33 (m, 5 H), 6.55 (s, 1 H), 4.60 (s, 2H), 4.54 (s, 2H); LCMS (m / z): 529.92 (M + H ^& lt ^{; +} & gt ^; ).

Example 34: 4- {3- [5- (5-Chloro-2-tetrazol-l-yl-phenyl) -isoxazole-3- ylmethyl] -3-phenethyl- ureaido} Preparation of benzoic acid

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.81 (s, 1 H), 9.31 (s, 1 H), 8.23 (s, 1 H), 7.88 (dd, J = 2.4, 8.4 Hz, 2 H), 7.84 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 5 H), 6.49 (s, 1H), 4.56 (s, 2H), 3.59 (t, J = 7.8 Hz, 2H), 2.80 (t, J = 7.8 Hz, 2H); LCMS (m / z): 543.97 (M + H ^& lt ^{; +} & gt ^; ).

Example 35 4- {3-Benzyl-3- [5- (5-chloro-2-tetrazol-l-yl-phenyl) -isoxazole-3- ylmethyl] -urea iodo} -phenyl ) -Acetic acid < / RTI >

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.82 (s, 1 H), 8.65 (s, 1 H), 8.20 (d, J = 2.4 Hz, 1 H), 7.90 (dd, J = 2.4, 8.4 Hz, 1 H ), 7.85 (d, J = 8.4 Hz, 1 H), 7.41-7.34 (m, 5 H), 7.27-7.24 (m, 3 H), 7.15 (d, J = 9.0 Hz, 2 H), 6.50 (s, 1H), 4.58 (s, 2H), 4.51 (s, 2H), 3.48 (s, 2H); LCMS (m / z): 543.85 (M + H ^& lt ^{; +} & gt ^; ).

Example 36: Preparation of benzyl- [5- (5-chloro-2-tetrazol-l-yl-phenyl) -isoxazole-3- ylmethyl]

Benzaldehyde (65.2 mg, 0.54 mmol) and diisopropylethylamine (0.095 ml, 0.54 mmol) were added to a solution of the compound (170 mg, 0.54 mmol) obtained in Preparation Example 10 in dichloroethane And the mixture was stirred at room temperature for 10 minutes. Then, sodium triacetoxyborohydride (172 mg, 0.81 mmol) was added thereto, followed by stirring for 6 hours. The reaction solution was extracted with ethyl acetate (20 mL) and distilled water (20 mL), dried over anhydrous sodium sulfate and purified by column chromatography to give the title compound (108 mg, 54%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 8.70 (s, 1 H), 7.99 (d, J = 2.4 Hz, 1 H), 7.65 (dd, J = 2.4, 8.4 Hz, 1H), 7.34-7.24 (m, 5H), 5.61 (s, 1H), 3.79 (s, 2H), 3.76 (s, 2H).

&Lt; Example 37 > N -benzyl- N - [5- (5-chloro-2-tetrazol-1-yl-phenyl) -isoxazole-3- ylmethyl] -tetrahphthalamic acid methyl ester

(100 mg, 0.27 mmol) and monomethylterephthalate (60 mg, 0.33 mmol) were dissolved in dimethylformamide (5 mL), diisopropylethylamine (0.10 mL, 0.54 mmol) placed next to the lower 0 ^o C-benzotriazol-1-yl-under phosphonium hexafluorophosphate (212 mg, 0.41 mmol), the last up to room temperature slowly and then air into nitrogen-oxy-tris- (dimethylamino) Stir for 12 hours. The reaction solution was added to a saturated aqueous ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL x 2), and the organic layer was washed with sodium chloride (30 mL). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (110 mg, 76%) as an amber solid.

^{1 H-NMR (600 MHz,} CDCl 3) δ 8.74 (s, 1 H), 8.10 (d, J = 6.6 Hz, 2 H), 7.97 (d, J = 2.4 Hz, 1 H), 7.67 (dd, J = 1.8 Hz, 8.4 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.48 (d, J (S, 2H), 4.63 (s, 2H), 4.63 (s, 2H) 3.93 (s, 3 H); LCMS (m / z): 528.92 (M + H ^& lt ^{; +} & gt ^; ).

&Lt; Example 38 > N -benzyl- N - [5- (5-chloro-2-tetrazol-1-yl-phenyl) -isoxazole-3- ylmethyl] -tetrahphthalamic acid

The compound (50 mg, 0.094 mmol) obtained in Example 37 was dissolved in dry dichloroethane (3 mL), trimethyltin chloride (51 mg, 0.28 mmol) was added and the mixture was stirred at 60 ^° C for 24 hours . The reaction solution was adjusted to pH 3 with a 2 N aqueous hydrochloric acid solution, extracted with ethyl acetate (10 mL) and distilled water (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. After separation by TLC, recrystallization from diethyl ether (10 mL) gave the title compound (1.4 mg, 3%) as a white solid.

LCMS (m / z): 515.00 (M + H ^& lt ^{; +} & gt ^; ) [

Example 39 Preparation of benzyl- (4-bromo-benzyl) - [5- (5-chloro-2-tetrazol- 1 -yl-phenyl) -isoxazole-3- ylmethyl]

(100 mg, 0.25 mmol) and 4-bromophenylacetic acid (69 mg, 0.32 mmol) were dissolved in dimethylformamide (5 mL), diisopropylethylamine (0.10 mL, 0.54 mmol ), And hydroxybenzotriazole (34 mg, 0.25 mmol) were added thereto. The mixture was cooled to 0 ^° C and 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (71 mg, 0.37 mmol) And the mixture was slowly warmed to room temperature and stirred under a nitrogen atmosphere for 12 hours. The reaction solution was added to a saturated aqueous solution of sodium hydrogencarbonate (30 mL), extracted with ethyl acetate (30 mL x 2), and washed with sodium chloride (30 mL). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (115 mg, 82%) as a pink solid.

¹ H-NMR (600 MHz, DMSO-d ₆ ) ? 9.83 (s, 1H), 8.17-8.15 (m, 1H), 7.92-7.84 (m, 2H), 7.49-7.47 ), 7.39-7.29 (m, 2H), 7.28-7.16 (s, 2H), 6.36 (s, 1H) 2 H); LCMS (m / z): 562.75 (MH & lt ^; + ^& gt ^; ), 564.77 (M + H ^& lt ^{; +} & gt ^; ).

&Lt; Example 40 > N Yl} - ethyl} -2- (4-fluoro-benzyl) -2,3- Methoxy-phenyl) -2-oxo-acetamide &lt; / RTI &gt;

(52 mg, 0.29 mmol) and 4-methoxyphenyl-oxo-acetic acid (100 mg, 0.24 mmol) obtained in Preparation Example 3-2 were dissolved in dimethylformamide (5 mL) and diisopropylethylamine 0.13 mL, 0.72 mmol) and hydroxybenzotriazole (49 mg, 0.36 mmol) were added to the reaction mixture and the mixture was cooled to 0 ^° C. Then, 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (69 mg, 0.36 mmol) was slowly added to the solution, and the mixture was stirred at room temperature for 12 hours under a nitrogen atmosphere. The reaction solution was added to a saturated aqueous solution of sodium hydrogencarbonate (30 mL), extracted with ethyl acetate (30 mL x 2), and washed with sodium chloride (30 mL). Dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. TLC afforded the title compound (6.7 mg, 5%) as a yellow solid.

¹ H-NMR (600 MHz, DMSO-d ₆ ) ? 9.65 (s, 1H), 8.81 (d, J = 9.0 Hz, 1H), 8.04 H), 7.73 (s, 2 H), 7.50 (d, J = 9.0 Hz, 2 H), 7.31-7.25 (m, 5 H), 6.90 (d, J = 8.4 Hz, 2 H), 4.66 (dd , J = 4.8, 13.8 Hz, 1H), 4.58-4.57 (m, 1H), 4.44 (dd, J = 9.0, 13.2 Hz, 1H), 3.83 (s, 3H), 2.95 (dd, J = 4.8, 14 Hz, 1H), 2.75 (dd, J = 9.0, 14 Hz, 1H); LCMS (m / z): 542.97 (M + H ^& lt ^{; +} & gt ^; ).

Example 41 Synthesis of 4- {3-benzyl-3- [5- (5-chloro-2-tetrazol-l-yl-phenyl) -isoxazole-3- ylmethyl] -urea iodo} Preparation of amide

(50 mg, 0.094 mmol) and ammonium chloride (25 mg, 0.47 mmol) were dissolved in dimethylformamide (5 mL), diisopropylethylamine (0.049 mL, 0.28 mmol) and hydroxy Benzotriazole (13 mg, 0.094 mmol) was added thereto, and the mixture was cooled to 0 ^° C. Finally, 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (27 mg, 0.14 mmol) &Lt; / RTI &gt; and stirred under a nitrogen atmosphere for 12 hours. The reaction solution was added to a saturated aqueous solution of sodium hydrogencarbonate (30 mL), extracted with ethyl acetate (30 mL x 2), and washed with sodium chloride (30 mL). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in diethyl ether (5 mL) to give the title compound (36 mg, 76%) as a white solid.

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.82 (s, 1 H), 8.89 (s, 1 H), 8.20 (d, J = 2.4 Hz, 1 H), 7.89 (dd, J = 2.4, 9.0 Hz, 1 H ), 7.84 (d, J = 8.4, Hz, 1 H), 7.79 (d, J = 9.0 Hz, 2 H), 7.57 (d, J = 9.0 Hz, 2 H), 7.38-7.20 (m, 5 H), 6.51 (s, 1H), 4.60 (s, 2H), 4.54 (s, 2H); LCMS (m / z): 528.85 (M + H ^& lt ^{; +} & gt ^; ).

Example 42 Synthesis of 1 - {[1- (4-carboxy-phenylcarbamoyl) -2-phenyl-ethylcarbamoyl] -methyl} -4- (5-chloro-2-tetrazol- )-One H -Pyro-3-carboxal &lt; / RTI &gt; acid methyl ester

Benzoic acid 4-methoxy-benzyl ester (134 mg, 0.30 mmol) was added to a solution of the compound obtained in Preparative Example 12-3 (100 mg, 0.28 mmol) Diisopropylethylamine (0.13 mL, 0.72 mmol) and hydroxybenzotriazole (42 mg, 0.28 mmol) were added to the solution, and the mixture was cooled to 0 ^° C. (3-dimethylaminopropyl) carbodiimide hydrochloride (80 mg, 0.41 mmol) was slowly added to the solution, and the mixture was stirred at room temperature for 12 hours under a nitrogen atmosphere. The reaction solution was added to a saturated aqueous ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL x 2), and the organic layer was washed with a saturated aqueous sodium chloride solution (30 mL). Dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the product (82 mg, 40%) was obtained by column chromatography.

¹ H-NMR (600 MHz, CDCl ₃ ) ? 8.54 (s, 1H), 8.28 (s, 1H), 7.98-7.91 (m, 2H), 7.54-7.46 7.44 (m, 1H), 7.44-7.39 (m, 2H), 7.38-7.34 (m, 2H), 7.26-7.18 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 7.8 Hz, 1H), 6.46-6.40 (m, 1H), 5.26 (s, 2H), 4.81-4.76 ), 4.51 (s, 2H), 3.81 (s, 3H), 3.58 (s, 3H), 3.19-3.08 (m, 2H).

The compound obtained above (82 mg, 0.11 mmol) was dissolved in dry dichloromethane (10 mL), phenol (0.206 g, 2.19 mmol) and trifluoroacetic acid (0.084 mL, 1.10 mmol) Lt; / RTI &gt; The reaction solution was concentrated under reduced pressure and recrystallized from diethyl ether (20 mL) to give the title compound (33 mg, 48%).

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 12.35 (br s, 1H), 10.52 (s, 1H), 9.11 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 7.89 ( d, J = 3.0 Hz, 2H ), 7.70-7.69 (m, 4H), 7.40 (d, J = 1.8 Hz, 1H), 7.31-7.26 (m, 4H), 7.23-7.17 (m, 1H), 6.65 (d, J = 2.4 Hz, 1H), 4.77-4.74 (m, 1H), 4.64 (d, J = 16.2 Hz, 1H), 3.42 (s, 3H), 3.10 (dd, J = 14, 5.4 Hz) , 2.92 (dd, J = 14, 9.6 Hz, 1 H); LCMS (m / z): 628.04 (M + H ^& lt ^{; +} & gt ^; ).

Example 43: 3- (l- {2- [3- (5-Chloro-2-tetrazol-l-yl-phenyl) -4- methoxycarbonyl- } -2-phenyl-ethyl) -isoxazole-5-carboxy < / RTI &

(200 mg, 0.55 mmol) and 3- (1-amino-2-phenyl-ethyl) -isoxazole-5-carboxy acid ethyl ester (164 mg, 0.55 mmol) (5 mL), diisopropylethylamine (0.24 mL, 1.38 mmol) and hydroxybenzotriazole (85 mg, 0.55 mmol) were added and the mixture was cooled to 0 ^° C. Dimethylaminopropyl) carbodiimide hydrochloride (159 mg, 0.83 mmol) was slowly added to the solution, and the solution was slowly warmed to room temperature and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was added to a saturated aqueous solution of sodium bicarbonate (30 mL), extracted with ethyl acetate (30 mL x 2), and the organic layer was washed with a saturated aqueous sodium chloride solution (30 mL). Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography to give the product (195 mg, 58%) as a colorless liquid.

¹ H-NMR (600 MHz, CDCl ₃ ) ? 8.56 (s, 1H), 7.55-7.48 (m, 2H), 7.46 (d, J = 2.4 Hz, 1H), 7.25-7.16 ), 7.12-7.10 (m, 3 H), 6.80 (s, 1H), 6.47 (d, J = 1.8 Hz, 1H), 7.46 6.43 (d, J = 8.4 Hz, 1H), 5.47 , J = 2.4 Hz, 1 H ), 4.54-4.45 (m, 2 H), 4.39 (q, J = 7.2 Hz, 2 H), 3.59 (s, 3 H), 3.24 (d, J = 7.2 Hz, 2 H), 1.38 (t, J = 7.2 Hz, 3 H).

The compound obtained above (95 mg, 0.16 mmol) tetrahydrofuran (3 mL), methanol (1 mL), 1 N sodium hydroxide aqueous solution at 0 ^o C was dissolved in distilled water (1 mL) (0.63 mL, 0.63 mmol ) Was added thereto, followed by stirring for 20 minutes. The mixture was adjusted to pH 3 with a 1 N aqueous hydrochloric acid solution, extracted with ethyl acetate (30 mL x 2) and distilled water (20 mL), dried and concentrated to give the title compound (70 mg, 77%) as a pink solid Respectively.

^{1 H-NMR (600 MHz,} DMSO-d 6) δ 9.11 (s, 1 H), 8.77 (d, J = 8.4 Hz, 1 H), 7.71-7.62 (m, 2 H), 7.48 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.26-7.18 (m, 4H), 7.17-7.13 , J = 2.4 Hz, 1 H ), 5.28-5.21 (m, 1 H), 4.66-4.55 (m, 2 H), 3.38 (s, 3 H), 3.22-3.14 (m, 1 H), 3.03- 3.02 (m, 1H); LCMS (m / z): 575.95 (M + H ^& lt ^{; +} & gt ^; ).

<Experimental Example 1> Analysis of inhibitory ability of factor XIa

One) Reagents and materials.

Factor XIa chromogenic substrate necessary for measuring the activity (chromogenic substrate) is S-2366 (PyroGlu-Pro- Arg-pNA. HCl) were purchased from chromotherapy Xenix (Chromogenics). Factor XIa was purchased and used from Enzyme Research Laboratories. All of the reagents used for activity measurement were reagent grade. 96-well microtiter plates were purchased from Costar.

2) Factor XIa inhibitory activity

The ability of the compounds according to the invention to inhibit factor XIa was determined as described below. To a 100 mM Tris buffer solution (pH 7.8) containing 150 mM NaCl, 0.1% PEG 8000 (polyethylene glycol, molecular weight about 8,000) was added to a 96-well plate with dimethylsulfoxide (DMSO ) And diluted with tertiary distilled water to make a 500 μM solution (final 10% DMSO solution) of pH 7.8. 10 μL of each solution was added to the solution, and S-2366 chromogenic substrate Were added in 20 μL portions. The reaction was started by adding 20 μL of 3.75 nM factor XIa solution dissolved in 100 mM Tris buffer solution (pH 7.8). The reaction was carried out at 37 ^° C for 30 minutes and the kinetic analysis of the reaction was carried out at 37 ^° C for 2 minutes using a kinetic plate reader (Molecular Devices, Spectramax 190) The amount of nitroanilide was monitored by the change in absorbance at 405 nm.

3) Analysis method of experimental results

In order to measure the inhibitory ability against the factor XIa of the compound of the formula (1), the concentration of the compound of the formula (1) which inhibits the enzyme activity by 50%, that is, the IC ₅₀ value (this is related to the inhibition constant Ki) . After plotting the log of the concentration of the compound of formula 1 relative to the relative rate of hydrolysis (as compared to the unconstrained control), the concentration of the inhibitor which reduces the rate of substrate hydrolysis by 50% was determined by linear regression analysis. When calculating the inhibition constant Ki, the IC ₅₀ value is calculated from the equation Ki = IC ₅₀ / {1+ (substrate concentration / Km)}, where Km is the Michaelis-Menten constant [ Chen and Prusoff, Biochem. Pharmacol., 1973, 22, 3099-3108; Which is hereby incorporated by reference) to compensate for competition with substrates.

As a result of the experiment, the inhibition constant Ki (FXIa) for the factor XIa was confirmed as follows.

The ability of the selected inhibitor to inhibit factor XIa Example # Ki (FXIa) ([mu] M) 4 1.0 13 5.7 18 6.0 30 0.9 32 6.7 33 2.2 34 10.0 35 7.9 41 2.3

It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (6)

Claims 1. A compound represented by the following formula (1), a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof:

(One)
In this formula,
A is selected from the group consisting of phenyl, phenyl containing 1 to 3 independently selected substituents, and 6-membered heteroaryl containing 1 to 3 independently selected substituents and containing 1 to 2 nitrogen atoms And,
Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br _{, -CN, -OH, -CF 3,} -NO 2, -OR, and selected from the group consisting of -CO ₂ R, and -NHR (R = hydrogen, C ₁ -C ₄ alkyl),
L is phenyl, phenyl optionally substituted with one or two independently selected substituents, pyridine, pyrrole, pyrrole, triazole, furan, thiophene, oxazole, Diazines, pyrazines (= 1,2-diazines), pyrazines (= 1,4-diazines), naphthalenes, quinolines, isoquinolines, benzo Furan, benzothiophene, and indole,
Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br _{, -CN, -OH, -CF 3,} -NO 2, -OR, and selected from the group consisting of -CO ₂ R, and -NHR (R = hydrogen, C ₁ -C ₄ alkyl),
X is C or N,
Y is selected from the group consisting of hydrogen, C ₁ -C ₂₀ alkyl, arylalkyl, cyclohexyl, cyclopentyl, adamantanemethyl, phenyl, phenyl, benzyl, phenetyl, pyridine, and phenyl substituted with one or two independently selected substituents Naphthalene, &lt; / RTI &gt;
Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br _{, -CN, -OH, -CF 3,} -NO 2, -OR, and selected from the group consisting of -CO ₂ R, and -NHR (R = hydrogen, C ₁ -C ₄ alkyl),
Z is hydrogen, C ₁ -C ₂₀ alkyl, arylalkyl,

, &Lt; / RTI &gt;
Wherein R ¹ is selected from the group consisting of hydrogen, C ₁ -C ₂₀ alkyl, arylalkyl, cyclohexyl, cyclopentyl, adamantanemethyl, phenyl, phenyl containing 1 or 2 independently selected substituents, benzyl, Benzyl, phenethyl, pyridine, and naphthalene containing 1 or 2 carbon atoms,
Wherein the independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, -F, -Cl, -Br, -CN, -OH, -CF ₃ , -OR, -CO ₂ R and -NHR is selected from the group consisting of ₁ -C ₄ alkyl),
R ² and R ³ are Phenyl, benzyl, phenethyl containing 1 or 2 independently selected substituents, phenethyl having 1 or 2 independently selected substituents, phenyl optionally substituted with 1 or 2 substituents independently selected from hydrogen, C ₁ -C ₂₀ alkyl, arylalkyl, (= 1, 2-diazines), pyrimidines, pyrazines (= 1, 4-dioxolane), pyridine, pyrrole, furan, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole, - diazines), naphthalene, quinoline, isoquinoline, benzofuran, benzothiophene and indole,
Wherein said independently selected substituent is selected from the group consisting of C ₁ -C ₄ alkyl, -F, -Cl, -Br, -CN, -OH, -CF ₃ , -OR, -CO ₂ R, -CH ₂ CO ₂ R, _{CO 2 NH 2 -NHR, -NHCOR,} -NHCO 2 R, -NHSO 2 R, CO 2 R a substituted or unsubstituted phenylamide, and CO ₂ R a substituted or unsubstituted isoxazole-in to the (R = hydrogen, C ₁ -C ₄ alkyl), -NO ₂ , And pentacyclic heteroaryl optionally substituted with C ₁ -C ₄ alkyl and containing 1 to 4 heteroatoms selected from N, O and S;
n is 0, 1, 2 or 3; The method according to claim 1,
A is selected from the group consisting of phenyl, phenyl containing from 1 to 3 independently selected substituents, and pyridine containing from 1 to 3 independently selected substituents,
Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br _{, -CN, -OH, -CF 3,} OR, -CO 2 R, and is selected from the group consisting of -NHR (R = hydrogen, C ₁ -C ₄ alkyl),
L is phenyl, phenyl optionally substituted with one or two independently selected substituents, pyridine, pyrrole, pyrrole, triazole, furan, thiophene, oxazole, Pyrazoles, thiazoles, isothiazoles and indoles, wherein R &lt; 1 &gt;
Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br _{, -CN, -OH, -CF 3,} OR, -CO 2 R, and is selected from the group consisting of -NHR (R = hydrogen, C ₁ -C ₄ alkyl),
X is C or N,
Y is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, arylalkyl, cyclohexyl, phenyl, phenyl, benzyl, phenethyl, pyridine, naphthalene containing 1 or 2 independently selected substituents,
Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br _{, -CN, -OH, -CF 3,} OR, -CO 2 R, and is selected from the group consisting of -NHR (R = hydrogen, C ₁ -C ₄ alkyl),
Z is hydrogen, C ₁ -C ₄ alkyl, arylalkyl,

, &Lt; / RTI &gt;
Wherein R ¹ is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, arylalkyl, cyclohexyl, phenyl, phenyl, benzyl containing one or two independently selected substituents, one or two independently selected substituents Lt; / RTI &gt; is selected from the group consisting of benzyl, phenethyl, pyridine and naphthalene,
Wherein the independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, -F, -Cl, -Br, -CN, -OH, -CF ₃ , -OR, -CO ₂ R and -NHR is selected from the group consisting of ₁ -C ₄ alkyl),
R ² and R ³ is Phenyl, benzyl, phenethyl, phenetyl containing one or two substituents independently selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, arylalkyl, phenyl, phenyl containing one or two independently selected substituents, (= 1, 2-diazines), pyrimidines, pyrazines (= 1, 4-dioxolane), pyridine, pyrrole, furan, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole, - diazines), naphthalene and indole,
Wherein said independently selected substituent is selected from the group consisting of C ₁ -C ₄ alkyl, -F, -Cl, -Br, -CN, -OH, -CF ₃ , -OR, -CO ₂ R, -CH ₂ CO ₂ R, _{CO 2 NH 2 -NHR, -NHCOR,} -NHCO 2 R, -NHSO 2 R, CO 2 R a substituted or unsubstituted phenylamide, and CO ₂ R a substituted or unsubstituted isoxazole-in to the (R = hydrogen, C ₁ -C ₄ alkyl), -NO ₂ , And pentacyclic heteroaryl optionally substituted with C ₁ -C ₄ alkyl and containing 1 to 4 heteroatoms selected from N, O and S;
and n is 0, 1 or 2, a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof. The method according to claim 1,
A is selected from the group consisting of phenyl, phenyl containing 1 to 3 independently selected substituents,
Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br , -CN, -OH, -CF _3, is selected from the group consisting of -OMe,
L is phenyl, phenyl optionally substituted with one or two independently selected substituents, pyridine, pyrrole, pyrrole, triazole, thiophene, oxazole, isoxazole, , Imidazole, pyrazole, thiazole and isothiazole,
Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br _{, -CN, -OH, -CF 3,} -OMe, -CO 2 R is selected from the group consisting of (R = hydrogen, C ₁ -C ₄ alkyl),
X is C,
Y is selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, arylalkyl, phenyl, benzyl, phenethyl, phenyl containing one or two substituents independently selected, pyridine,
Wherein said independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, pentachloroheteroyl containing 1 to 4 heteroatoms selected from N, O and S, phenoxy, -F, -Cl, -Br , -CN, -OH, -CF _3, is selected from the group consisting of -OMe,
Z is hydrogen and

, &Lt; / RTI &gt;
Wherein R ¹ is selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, arylalkyl, phenyl, benzyl, phenethyl, phenyl, pyridine and naphthalene containing one or two substituents independently selected,
Wherein the independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, -F, -Cl, -Br, -CN, -OH, -CF ₃ , -OR, -CO ₂ R and -NHR is selected from the group consisting of ₁ -C ₄ alkyl),
R ² And R ³ is C ₁ -C ₄ alkyl, arylalkyl, phenyl, phenyl containing one or two independently selected substituents, benzyl, phenethyl, phenethyl containing one or two independently selected substituents, Is selected from the group consisting of pyridine, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole and indole,
Wherein the independently selected substituents are selected from the group consisting of C ₁ -C ₄ alkyl, -F, -Cl, -Br, -CN, -OH, -CF ₃ , -NO _2, -OR, -CO ₂ R and -NHR (R = is selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl);
and n is 0 or 1, or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof. The compound of claim 1, wherein the compound of formula (I) is selected from the group consisting of compounds represented by the following structural formulas: embedded image or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof.

A process for preparing a compound of formula (1) according to claim 1,
(a) preparing a triazole skeleton compound including a click reaction of an alkyne compound and an azaide compound; or
(b) a step of preparing a compound of isoxazole skeleton including a cyclization reaction of an alkane compound and an oxime compound; or
(c)

And a cyclization reaction of TosMIC (toluenesulfonylmethylisocyanide), wherein A is the same as defined in Chemical Formula 1;
As a process for preparing an intermediate compound. (a) a pharmacologically effective amount of a compound of formula 1 according to claim 1, a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof; And
(b) a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof;
And a pharmaceutically acceptable carrier.