GLP-1 receptor agonist, pharmaceutical composition comprising same, and method for preparing same

Abstract

To solve the following problem that: there is a need for small molecule agonists of GLP-1 receptors with oral bioavailability, since GLP-1 and GLP-1 receptor agonists may lack sufficient oral bioavailability to be considered as peptide-based oral drugs.SOLUTION: The compound of the present invention is a novel compound having excellent GLP-1 agonist activity and an excellent DMPK profile, and is useful as an agent for treating or preventing various metabolic diseases such as obesity, diabetes, or hyperlipidemia, an isomer thereof, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the compound, and a method for preparing the compound.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to novel compounds, isomers or pharmaceutically acceptable salts thereof, which exhibit GLP-1 receptor agonist activity, pharmaceutical compositions containing said compounds, and methods for preparing said compounds. [Background technology]

[0002] Glucagon-like peptide-1 (GLP-1) is a polypeptide hormone secreted by intestinal L cells after a meal, which can stimulate insulin secretion from pancreatic islet β cells, thereby stabilizing postprandial blood glucose levels. GLP-1 binds to the GLP-1 receptor (GLP-1R). The GLP-1 receptor is a subclass of Class B receptors, a type of G protein-coupled receptor (GPCR), which regulates important physiological and pathophysiological processes. Because the tertiary structure of the protein remains unknown and the receptor has a unique binding mode in which the N-terminus of the receptor determines the affinity of the ligand, it is recognized as a very difficult drug target for the development of small molecule synthetic ligands.

[0003] Exogenous administration of GLP-1 normalizes blood glucose levels in patients with type 2 diabetes. The effect of GLP-1 on lowering blood glucose levels varies depending on the glucose concentration, thereby significantly reducing the risk of hypoglycemia while regulating blood glucose levels. Additionally, GLP-1-based drugs such as Byetta™ and Bydureon BCise™ (exenatide), Ozempic™ (semaglutide), Victoza™ (liraglutide), Adlyxin™ (lixisenatide), Tanzeum™ (albiglutide), and Trulicity™ (dulaglutide) have been successfully marketed as GLP-1 receptor agonists in recent years and have been shown to provide effective glycemic control for treating, for example, type 2 diabetes patients, as well as weight loss, preservation of beta-cell function, and reduction of hypertension, hypoglycemia, and / or hyperlipidemia.

[0004] However, the GLP-1 and GLP-1 receptor agonists mentioned above may lack sufficient oral bioavailability to be considered oral peptide-based drugs, and therefore there is a need for small molecule agonists of the GLP-1 receptor that have oral bioavailability. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention has been proposed to solve the above problems and provides novel compounds having activity as GLP-1 agonists.

[0006] The present invention also provides a pharmaceutical composition for preventing or treating metabolic diseases or degenerative neurological diseases, which comprises the novel compound as an active ingredient. [Means for solving the problem]

[0007] The definitions of each group used in this specification will be explained in detail below. Unless otherwise specified, each group has the following definition.

[0008] As used herein, examples of "halo" may be fluoro, chloro, bromo, or iodo.

[0009] In this specification, "alkyl" means a linear or branched aliphatic saturated hydrocarbon group, specifically having 1 to 6 carbon atoms, i.e., C 1-6 Alkyl, C 1-4 Alkyl, or C 1-3 Examples of such alkyls include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, or 2-ethylbutyl.

[0010] As used herein, "alkoxy" refers to an oxygen radical combined with a single bonded straight or branched chain saturated hydrocarbon, specifically C 1-6 Alkoxy, C 1-4 Alkoxy, or C 1-3 Examples of such alkoxy may be methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, or 1-methylpropoxy.

[0011] In this specification, "cycloalkyl" refers to a cyclic, single-bonded saturated hydrocarbon group, specifically, C 3-8 Cycloalkyl or C 3-6 It may also be cycloalkyl, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0012] In this specification, "cycloalkyl" may be two or more fused or bridged cycloalkyls, specifically, bridged bicycloalkyls and bridged tricycloalkyls, and may encompass prismanes and asteranes such as prismane, cubane, basketane, etc. Examples of such bridged cycloalkyls include bicyclo[1,1,0]butane, bicyclo[1,1,1]pentane, bicyclo[2,1,1]hexane, bicyclo[2,2,1]heptane, bicyclo[2,2,2]octane, etc.

[0013] In this specification, the term "heterocycloalkyl" refers to a cyclic, single-bonded, saturated hydrocarbon group containing, in addition to carbon atoms, one or more heteroatoms such as N, O, or S as ring-constituting atoms, and may be monocyclic or fused-ring polycyclic. Specifically, it may be a 4- to 10-membered heterocycloalkyl, a 4- to 7-membered heterocycloalkyl, or a 4- to 6-membered heterocycloalkyl containing one or more, preferably one to three, heteroatoms selected from the group consisting of N, O, and S. Examples of such heterocycloalkyl include oxetanyl, aziridine, pyrrolidine, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl.

[0014] As used herein, "aryl" refers to an aromatic substituent having at least one ring having a conjugated pi-electron system, which may be monocyclic or fused-ring polycyclic (i.e., rings having adjacent pairs of carbon atoms separated). Specifically, such aryls are classified according to the number of carbon atoms in the ring, as follows: C 4-10 Aryl, or C 6-10 It may be aryl, such as phenyl or naphthyl.

[0015] In this specification, the term "heteroaryl" refers to an aromatic ring compound containing one or more heteroatoms such as N, O, or S as ring-constituting atoms other than carbon atoms, and may be monocyclic or fused-ring polycyclic. Specifically, the heteroaryl may be a 4- to 10-membered heteroaryl, a 4- to 7-membered heteroaryl, or a 4- to 6-membered heteroaryl containing one or more, preferably one to three, heteroatoms selected from the group consisting of N, O, and S. Examples of the heteroaryl include, but are not limited to, furanyl, pyranyl, imidazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, triazinyl, and triazolyl.

[0016] Within this specification, "substituents" include halo, nitrile groups, and C 1-3 The alkyl groups may be one or more selected from the group consisting of the alkyl groups listed above.

[0017] The present invention will be described in detail below.

[0018] To achieve the above object, the present invention provides a compound of the following formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0019] [ka]

[0020] A is -(CH2) m -, -O-, or -N(R a )-, where m is an integer from 1 to 3, and R a is hydrogen or alkyl,

[0021] Z1, Z2, Z3, Z4, Z5, Z6, and Z7 each independently represent CH, CF, CCl, CBr, CI, or N;

[0022] Z8 or Z9 are each independently C or N substituted with an -O-CH2-R group, or when Z8 and Z9 are all C, the respective substituents can be fused with each other to form a dioxole structure;

[0023] R is cycloalkyl or [ka] and

[0024] R1 is (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, or (heteroaryl)alkyl;

[0025] R2, R3, or R4 are each independently hydrogen, deuterium, halo, alkyl, alkoxy, alkylamine, or nitrile groups;

[0026] n1 to n3 each independently represent an integer of 1 to 4, and when n1 to n3 represent an integer of 2 or greater, each R2, R3, or R4 may be the same or different from each other;

[0027] In this case, the alkyl, alkoxy, alkylamine, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be unsubstituted or substituted.

[0028] Specifically, the compound of Formula I may be a compound represented by the following Formula 1, Formula 1′, or Formula 1″, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0029] [ka]

[0030] [ka]

[0031] [ka]

[0032] A, Z1, Z2, Z3, Z4, Z5, Z6, Z7, R, R1, R2, R3, R4, and n1 to n3 are as defined in claim 1.

[0033] In a preferred embodiment, A is -CH2-, -O-, or -N(R a )-can be.

[0034] In a preferred embodiment, the R a is hydrogen or C 1-3 It can be alkyl.

[0035] In a preferred embodiment, R is C 3-8 cycloalkyl or [ka] C 3-8 The cycloalkyl can be a bridged or unbridged cycloalkyl and can include, but is not limited to, mono-, bi-, poly-, and bridged ring systems.

[0036] In a preferred embodiment, R1 is (C 3-8 Cycloalkyl)C 1-3 Alkyl, (4- to 10-membered heterocycloalkyl)C 1-3 Alkyl, (C 6-10 (aryl) alkyl, or (4- to 10-membered heteroaryl) C 1-3 alkyl, where the heterocycloalkyl or heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S.

[0037] In a preferred embodiment, R2, R3, or R4 are each independently hydrogen, deuterium, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Alkoxy, C1-3 It is an alkylamine or nitrile group.

[0038] In a preferred embodiment, n1 to n3 are each independently an integer of 1 to 3, and when n1 to n3 are an integer of 2 or greater, each R2, R3, or R4 may be the same or different from one another.

[0039] In a preferred embodiment, Z1, Z2, Z3, Z4, Z5, Z6, or Z7 may each independently be CH, CF, or CCl.

[0040] In a preferred embodiment, the alkyl, alkoxy, alkylamine, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is unsubstituted or halo or C 1-3 It may be alkyl substituted.

[0041] In a more preferred embodiment, A may be -CH2- or -O-.

[0042] In a more preferred embodiment, R is bicyclo[1,1,0]butane, bicyclo[1,1,1]pentane, bicyclo[2,1,1]hexane, bicyclo[2,2,1]heptane, bicyclo[2,2,2]octane, or [ka] It could be.

[0043] In more preferred forms, R1 can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, oxetanylmethyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, oxazolylmethyl, benzyl, unsubstituted or propyl-substituted triazolylmethyl, or unsubstituted or ethyl-substituted imidazolylmethyl.

[0044] In a more preferred form, R2, R3, or R4 are each independently hydrogen, deuterium, F, Cl, or a nitrile group.

[0045] In a more preferred embodiment, n1 to n3 are 2, and each R2, R3, or R4 may be the same or different from each other.

[0046] Representative compounds of Formula I according to the present invention may include, but are not limited to, the following compounds:

[0047] 1](S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-(oxytan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid,

[0048] 2] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(((S)-oxytan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0049] 3] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-(((S)-oxytan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0050] 4] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0051] 5] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0052] 6] 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid,

[0053] 7] 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0054] 8] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0055] 9] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0056] 10] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0057] 11] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0058] 12] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,

[0059] 13](S)-2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)benzyl)-1-(oxytan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0060] The compounds of the above-mentioned formula I can exhibit excellent GLP-1 receptor agonist activity, thereby exhibiting hypoglycemic effects and positive effects on pancreatic beta cells, and can therefore be effectively used to treat various metabolic diseases.

[0061] Meanwhile, the compound represented by Formula I may have an asymmetric carbon center, and when it has an asymmetric carbon center, it may exist as each optical isomer, partial optical isomer, or racemate, and all forms of isomers, including these, may be included in the category of a compound according to an embodiment of the invention. Of course, any form of isomer may also belong to the category of a compound according to an embodiment. As used below, the term "isomer" may refer collectively to different compounds having the same molecular formula, and "optical isomer" may refer collectively to any stereoisomers that may exist for a compound according to an embodiment, including the same geometric isomer.

[0062] In an embodiment of the compound of Formula I, it is understood that each substituent may be attached to a chiral carbon atom. Any asymmetric carbon atom in the compound of this embodiment may exist in any of the (R)-, (S)-, or (R,S)-configurations, suitably in the isolated (R)- or (S)-configurations. The compound of this embodiment may also exist in any of the possible isomers or mixtures thereof, such as pure geometric isomers, partial stereoisomers, optical isomers, racemates, or mixtures thereof. Additionally, when the compound of this embodiment contains a double bond, each substituent associated with the double bond may be in the E- or Z-configuration. When the compound of this embodiment contains a substituted cycloalkyl, each substituent on the cycloalkyl may be in the cis- or trans-configuration.

[0063] Meanwhile, the term "pharmaceutically acceptable salt" as used hereinafter may refer collectively to any salt that equally retains the biological effectiveness and properties of a compound of Formula I according to an embodiment and is preferable in terms of pharmaceutical, biological, or other properties. Non-limiting examples of such salts include salts in which an inorganic or organic base is added to a compound of Formula I, or acid addition salts. Examples of organic acids that can form such acid addition salts include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid, and examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0064] Pharmaceutically acceptable salts of the compounds of the above-described embodiments can be synthesized from the free base form of the compound or any basic or acidic residue derived therefrom by conventional chemical methods. Additionally, a second pharmaceutically acceptable salt can be synthesized from a first pharmaceutically acceptable salt. As a specific example, an acid addition salt of the compound of the present embodiment can be obtained by reacting the free base form of the compound with a stoichiometric amount of an appropriate acid. The reaction can be carried out in water, an organic solvent, or a mixture thereof, specifically in a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Alternatively, depending on the form of the pharmaceutically acceptable salt, each salt can be obtained by conventional reactions known to those skilled in the art.

[0065] Meanwhile, according to yet another embodiment of the present invention, there is provided a pharmaceutical composition for treating or preventing metabolic diseases, comprising as an active ingredient the compound represented by the above-mentioned Chemical Formula I, its isomer, or a pharmaceutically acceptable salt thereof. As described above, the compound represented by the above-mentioned Chemical Formula I according to the present invention exhibits GLP-1 receptor (GLP-1R) agonist activity, and a pharmaceutical composition comprising such a compound has an effective blood glucose lowering effect and a positive effect on pancreatic beta cells, while also exhibiting the effect of improving lipid metabolism, which is a chronic cardiovascular risk factor, and is therefore effective in treating and / or preventing diseases associated with GLP-1 receptor activity, such as metabolic diseases or degenerative neurological diseases. The metabolic disease may be selected from the group consisting of diabetes (preferably type 2 diabetes), hypertension, hypoglycemia, hyperlipidemia (dyslipidemia), atherosclerosis, coronary artery disease, cardiovascular disorder, blood coagulation disorder, obesity, diabetic complications, diabetic retinopathy, liver disease, hepatobiliary disease, fatty liver, alcoholic steatohepatitis, chronic kidney disease, insulin resistance, and impaired glucose tolerance. The degenerative neurological disease may be selected from the group consisting of Parkinson's disease and Alzheimer's disease.

[0066] Pharmaceutical compositions containing the compound represented by Formula I, its isomer, or a pharmaceutically acceptable salt thereof as an active ingredient can be used in the form of a conventional pharmaceutical formulation. That is, the pharmaceutical composition can be administered in various oral or parenteral dosage forms during clinical administration, and preferably in an oral dosage form. Furthermore, depending on the dosage form, the composition can be formulated by further including pharmaceutically acceptable diluents or excipients such as conventional fillers, extenders, binders, wetting agents, disintegrants, or surfactants.

[0067] Solid formulations for oral administration include tablets, pills, powders, granules, or capsules. These solid formulations may be prepared by mixing starch, calcium carbonate, sucrose, lactose, gelatin, or the like with the active ingredient. Lubricants such as magnesium stearate or talc may also be used in addition to excipients. Liquid formulations for oral administration include suspensions, anti-solvents, emulsions, or syrups. These liquid formulations may contain multiple excipients, such as wetting agents, sweeteners, flavoring agents, or preservatives, in addition to simple diluents such as water or liquid paraffin. In addition, formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, or suppositories. These parenteral formulations may contain non-aqueous solvents, such as propylene glycol, polyethylene glycol, vegetable oils such as olive oil, or injectable esters such as ethyl oleate. As a suppository base, witepsol, macrogol, Tween 61, cacao butter, laurin oil, glycerogelatin, or the like can be used.

[0068] Furthermore, the compound represented by formula I or its isomer composition of the pharmaceutical invention containing the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be administered in an effective amount in the range of about 0.1 to about 1,000 mg. The dosage or dose can be administered in various dosages and ways, such as once a day or several times a day, depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease.

[0069] The present invention also provides a method for preparing a compound of Formula 1, Formula 1', or Formula 1''.

[0070] To facilitate understanding of the present invention, a method for preparing a compound represented by Chemical Formula 1, Chemical Formula 1', or Chemical Formula 1" will be described below based on exemplary reaction schemes. However, a person skilled in the art to which the present invention pertains would be able to prepare a compound represented by Chemical Formula 1, Chemical Formula 1', or Chemical Formula 1" by various methods based on the structure of Chemical Formula 1, Chemical Formula 1', or Chemical Formula 1", and all such methods should be construed as being within the scope of the present invention. In other words, a compound represented by Chemical Formula 1, Chemical Formula 1', or Chemical Formula 1" can be prepared by any combination of multiple synthetic methods described herein or disclosed in the prior art, and this is understood to be within the scope of the present invention, and the method for preparing a compound represented by Chemical Formula 1, Chemical Formula 1', or Chemical Formula 1" is not limited to the methods described below.

[0071] In a specific embodiment, when A of the compound of Chemical Formula 1 according to the present invention is carbon, the compound of Chemical Formula 1 can be prepared by a preparation method including the following steps:

[0072] 1) reacting a compound of the following formula 2 with a compound of the following formula 3 under a palladium catalyst to obtain a compound of the following formula 4:

[0073] 2) reacting the compound of formula 4 obtained in step 1) with a compound of formula 5 in the presence of a palladium catalyst, followed by hydrolysis to obtain a compound of formula 6:

[0074] 3) A step of obtaining a compound of the following Chemical Formula 1 through a coupling reaction between the compound of the following Chemical Formula 6 obtained in step 2) and a compound of the following Chemical Formula 7, followed by a condensation reaction and a hydrolysis reaction:

[0075] The base used in steps 1) and 2) is C 1-4 The ligands used in steps 1) and 2) may be selected from the group consisting of triarylphosphine compounds, trialkylphosphine compounds, biaryl(dialkyl)phosphine compounds, diphosphine compounds, N-heterocyclic carbene compounds, diisopropylethyleneamine (DIPEA, Hunig's base), pyridine, K2CO3, KOH, NaOH, Na2CO3, NaOAc, Ca(OH)2, NaHCO3, Cs2CO3, and LiOH, and may be used alone or in combination. The compound may be, but is not limited to, carbenes, cyclopentadienides, acetylacetonates, diamines, bipyridines, pyridines, DIOP, DiPAMP, BINAP, chiraphos, etc.

[0076] The hydrolysis reaction of step 2) may be carried out using NaOH, KOH, LiOH, etc., and may be carried out at a temperature of, but not limited to, 0° C. to 80° C., 10° C. to 70° C., 20° C. to 60° C., room temperature, or 50° C. Furthermore, the reaction may be carried out with stirring for an appropriate time during the reaction, which may be appropriately controlled.

[0077] This can be represented by the following reaction scheme 1:

[0078] [ka]

[0079] In a specific embodiment, when A is carbon, the compound of Formula 1′ according to the present invention can be prepared by a preparation method including the following steps:

[0080] 1') reacting a compound of the following formula 3' with a compound of the following formula 5 in the presence of a palladium catalyst to obtain a compound of the following formula 8:

[0081] 2') reacting the compound of Formula 8 obtained in step 1') with a compound of Formula 2 to obtain a compound of Formula 6':

[0082] 3') A step of obtaining a compound of the following formula 1' through a coupling reaction between the compound of the following formula 6' obtained in step 2') and a compound of the following formula 7, followed by a condensation reaction and a hydrolysis reaction.

[0083] The base, ligand, hydrolysis reaction conditions, etc. used in the above production method can all be the same as those explained in the production method of Compound 1.

[0084] This can be represented by the following reaction scheme 2:

[0085] [ka]

[0086] In a specific embodiment, when A of the compound of Formula 1″ according to the present invention is carbon, the compound of Formula 1″ can be prepared by a preparation method including the following steps:

[0087] 1'') reacting a compound of the following formula 2' with a compound of the following formula 3'' to obtain a compound of the following formula 4';

[0088] 2'') reacting the compound of formula 4' obtained in step 1'' with a compound of formula 5 under a palladium catalyst, and then hydrolyzing the reactant to obtain a compound of formula 6'':

[0089] 3'') A step of obtaining a compound of the following formula 1'' through a coupling reaction between the compound of the following formula 6'' obtained in step 2'') and a compound of the following formula 7, followed by a condensation reaction and a hydrolysis reaction.

[0090] The base, ligand, hydrolysis reaction conditions, etc. used in the above production method can all be the same as those explained in the production method for Compound 1''.

[0091] This can be represented by the following reaction scheme 3:

[0092] [ka]

[0093] In the above reaction formulas 1 to 3, m, n1, n2, n3, R a , R, R1, R2, R3, R4, Z1, Z2, Z3, Z4, Z5, Z6, and Z7 are as defined in Chemical Formula 1 above;

[0094] R5 is alkyl;

[0095] X is halo, preferably Cl, Br, or I.

[0096] Compounds not specifically described in the preparation methods of the present specification are either known compounds or compounds that can be easily synthesized from known compounds by known synthesis methods or methods similar thereto.

[0097] The compound of Formula 1, Formula 1′, or Formula 1″ obtained through the above method can be separated or purified from the reaction product by a number of methods, such as recrystallization, iontophoresis, silica gel column chromatography, or ion exchange resin chromatography.

[0098] As described above, the compounds according to the present invention, starting materials or intermediates for the preparation thereof, etc. can be synthesized by various methods, and such methods should be construed as being included in the scope of the present invention in relation to the preparation of the compounds represented by Chemical Formula 1, Chemical Formula 1', or Chemical Formula 1''. [Effects of the Invention]

[0099] The novel compounds according to the present invention are useful as therapeutic or preventive agents for various metabolic diseases such as obesity, diabetes, and hyperlipidemia due to their excellent GLP-1 agonist activity and excellent DMPK profile. DETAILED DESCRIPTION OF THE INVENTION

[0100] The present invention will be described in more detail below with reference to the following examples and experimental examples, which are provided merely to illustrate the present invention and to facilitate understanding of the present invention, and are not intended to limit the scope of the present invention.

[0101] In the examples, the following abbreviations are defined to represent the following substances:

[0102] DMF Dimethylformamide

[0103] THF tetrahydrofuran

[0104] TEA Triethylamine

[0105] EtOAc ethyl acetate

[0106] MgSO4 Magnesium Sulfate

[0107] MPLC High-Speed ​​Automated Separation and Purification System

[0108] Pd / C Palladium / carbon

[0109] AcOH acetic acid

[0110] HCl Hydrochloric acid

[0111] CS2 Carbon disulfide

[0112] NaH sodium hydride

[0113] DCM dichloromethane

[0114] mCPBA 3-chloroperbenzoic acid

[0115] NaHCO3 Sodium bicarbonate

[0116] t-BuOK Potassium tert-butoxide

[0117] Cs2CO3 Cesium Carbonate

[0118] K2CO3 Potassium Carbonate

[0119] BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)

[0120] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium

[0121] Fe Iron

[0122] NH4Cl Ammonium chloride

[0123] CDI Carbonyldiimidazole

[0124] DCE 1,2-dichloroethane

[0125] POCl3 Phosphoryl chloride

[0126] NaOH Sodium hydroxide

[0127] H2O Water

[0128] MeOH Methanol

[0129] HOBt Hydroxybenzotriazole

[0130] EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0131] Dppf 1,1'-bis(diphenylphosphino)ferrocene

[0132] Na2SO4 Sodium Sulfate

[0133] NMR nuclear magnetic resonance

[0134] HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0135] [Production Example 1: Production of methyl (S)-4-nitro-3-((oxytan-2-ylmethyl)amino)benzoic acid]

[0136] [ka] methyl(S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate

[0137] (S)-Oxytan-2-ylmethylamine (539 mg, 6.19 mmol) was dissolved in DMF (7 mL) and THF (~10 mL). TEA (2.59 mL, 18.56 mmol) and methyl 3-fluoro-4-nitrobenzoate (1.23 g, 6.19 mmol) were added and the mixture was stirred at room temperature under nitrogen for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure. Purification by MPLC gave methyl (S)-4-nitro-3-((oxytan-2-ylmethyl)amino)benzoate (813 mg, 3.05 mmol, 49%).

[0138] 1 H NMR(500MHz,CDCl3)δ8.36(brs,1H), 8.24(d, J=8.5Hz,1H),7.63(d,J=1.5Hz,1H),7.28(d,J=1.5Hz,1H),5.16-5.20(m,1H),4.73 -4.76(m,1H),4.61-4.65(m,1H),3.94(s,3H),3.62-3.65(m,2H),2.76-2.80(m,1H),2.59-2.75(m,1H);LC-MS(ESI):267.26[M+H] +

[0139] [Production Example 2: Production of methyl(S)-4-amino-3-((oxytan-2-ylmethyl)amino)benzoic acid]

[0140] [ka] methyl(S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate

[0141] Methyl (S)-4-nitro-3-((oxytan-2-ylmethyl)amino)benzoate (813 mg, 3.05 mmol) obtained in Preparation 1 was dissolved in THF (13 mL), and then 10% Pd / C (325 mg) was added and stirred at room temperature under hydrogen for 4 hours. After the reaction was completed, the mixture was filtered through Celite with EtOAc and concentrated under reduced pressure to obtain methyl (S)-4-amino-3-((oxytan-2-ylmethyl)amino)benzoate (720 mg, 3.05 mmol, 100%).

[0142] 1 H NMR(500MHz,CDCl3)δ7.48(dd,J=8.0,1.5Hz,1H),7.38(d,J=1.5Hz,1H),6.68(d,J=8.0Hz,1H),5.12-5.10(m,1H),4.77-4.73(m,1H),4.64-4. 59(m,1H),3.86(s,5H),3.53(brs,1H),3.46-3.42(m,1H),3.37-3.34(m,1H),2.78-2.74(m,1H),2.61-2.57(m,1H);LC-MS(ESI):237.27[M+H] +

[0143] [Production Example 3: Production of methyl 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate]

[0144] [ka] methyl3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate

[0145] Methyl 3-fluoro-4-nitrobenzoate (700 mg, 3.52 mmol) was dissolved in THF (12 mL), followed by the addition of (1-ethyl-1H-imidazol-5-yl)methanamine dihydrochloride (696 mg, 3.52 mmol) and TEA (1.47 mL, 10.55 mmol). The mixture was stirred under nitrogen at 80°C for 24 hours. After the reaction was complete, the mixture was cooled to room temperature and the reaction solvent was concentrated under reduced pressure. Water was added, and the mixture was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure. MPLC afforded methyl 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate (442 mg, 1.452 mmol, 41%).

[0146] 1 H NMR(500MHz,CDCl3)δ8.25(d,J=9.0Hz,1H),7.94(brs,1H),7.69(d,J=1.5Hz,1H),7.57(s,1H),7.34(dd,J=9.0,1.5 Hz,1H),7.11(s,1H),4.54(d,J=5.0Hz,2H),3.99(m,5H),1.48(t,J=7.5Hz,3H);LC-MS(ESI):305.1[M+H] +

[0147] [Production Example 4: Production of methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate]

[0148] [ka] methyl4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate

[0149] Methyl 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate (440 mg, 1.446 mmol) obtained in Preparation 3 was dissolved in MeOH / HO (6 mL / 2 mL), and then Fe (242 mg, 4.34 mmol) and NHCl (1.55 g, 28.9 mmol) were added. The mixture was stirred under nitrogen at 80°C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, water was added, and the mixture was extracted with EtOAc, dried over MgSO, and concentrated under reduced pressure. MPLC yielded methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (254 mg, 0.925 mmol, 64%).

[0150] 1 H NMR(400MHz,CDCl3)δ7.53-7.50(m,2H),7.46(d,J=1.6Hz,1H),7.03(s,1H),6.70(d,J=8.4Hz,1H) ,4.27(s,2H),4.01(q,J=7.4Hz,2H),3.87(s,3H),1.45(t,J=7.2Hz,3H);LC-MS(ESI):275.1[M+H] +

[0151] [Production Example 5: Production of methyl 4-nitro-3-((oxazol-5-ylmethyl)amino)benzoate]

[0152] [ka] methyl4-nitro-3-((oxazol-5-ylmethyl)amino)benzoate

[0153] Methyl 3-fluoro-4-nitrobenzoate (904 mg, 4.54 mmol) was dissolved in THF (15 mL), followed by the addition of oxazol-5-ylmethanamine hydrochloride (600 mg, 4.33 mmol) and TEA (1.81 mL, 12.98 mmol). The mixture was stirred at room temperature under nitrogen for 16 hours. After completion of the reaction, the reaction solvent was concentrated under reduced pressure. Water was added, and the mixture was extracted with EtOAc. The extract was dried over MgSO4 and concentrated under reduced pressure. Purification by MPLC gave methyl 4-nitro-3-((oxazol-5-ylmethyl)amino)benzoate (682 mg, 2.46 mmol, 57%).

[0154] 1 H NMR(400MHz,CDCl3)δ8.25-8.23(m,2H),7.87(s,1H),7.64(d,J=1.2Hz,1H), 7.33(dd,J=2.0,1.2Hz,1H),7.09(s,1H),4.66(d,J=5.6Hz,2H),3.94(s,3H)

[0155] [Production Example 6: Production of methyl 4-amino-3-((oxazol-5-ylmethyl)amino)benzoate]

[0156] [ka] methyl4-amino-3-((oxazol-5-ylmethyl)amino)benzoate

[0157] Methyl 4-nitro-3-((oxazol-5-ylmethyl)amino)benzoate (682 mg, 2.46 mmol) obtained in Preparation 5 was dissolved in THF (12 mL), and then 10% Pd / C (262 mg) was added and stirred at room temperature under hydrogen for 24 hours. After the reaction was completed, the mixture was filtered through Celite with EtOAc and concentrated under reduced pressure to obtain methyl 4-amino-3-((oxazol-5-ylmethyl)amino)benzoate (600 mg, 2.43 mmol, 99%).

[0158] 1H NMR(500MHz,CDCl3)δ7.86(s,1H),7.52(dd,J=8.0,1.5Hz,1H),7.43(d,J=2.0Hz,1H),7.04(s,1H),6.72( d,J=8.0Hz,1H),4.41(d,J=5.5Hz,2H),3.86(s,3H),3.83(s,2H),3.46(s,1H);LC-MS(ESI):248.25[M+H] +

[0159] [Production Example 7: Production of methyl (S)-4-nitro-3(((tetrahydrofuran-2-yl)methyl)amino)benzoic acid]

[0160] [ka] methyl(S)-4-nitro-3-(((tetrahydrofuran-2-yl)methyl)amino)benzoate

[0161] Methyl 3-fluoro-4-nitrobenzoate (1.39 g, 7.0 mmol) was dissolved in DMF (2.5 mL), and then (S)-(tetrahydrofuran-2-yl)methanamine (0.868 mL) and K2CO3 (967 mg) were added at room temperature. The reaction mixture was stirred at 50 °C for 4 hours. Water was added and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to give methyl (S)-4-nitro-3(((tetrahydrofuran-2-yl)methyl)amino)benzoate (1.69 g, 6.86 mmol, 86%).

[0162] 1H NMR(400MHz,CDCl3)δ8.26-8.12(m,2H),7.59(d,J=1.8Hz,1H),7.24(dd,J=9.1,1.8Hz,1H),4.22(qd,J=6.9,4.1Hz,1H),4.02-3.91(m,4H),3.87 -3.77(m,1H),3.53(td,J=8.7,4.3Hz,1H),3.46-3.34(m,1H),2.18-2.04 (m,1H),2.05-1.90(m,2H),1.82-1.61(m,1H);LC-MS(ESI):281.28[M+H] +

[0163] Preparation Example 8: Preparation of methyl(S)-4-amino-3-(((tetrahydrofuran-2-yl)methyl)amino)benzoic acid

[0164] [ka] methyl(S)-4-amino-3-(((tetrahydrofuran-2-yl)methyl)amino)benzoate

[0165] Methyl (S)-4-nitro-3-(((tetrahydrofuran-2-yl)methyl)amino)benzoate (1.69 g, 6.86 mmol) obtained in Preparation Example 7 was dissolved in THF (50 mL), and 10% Pd / C (169 mg) was added. The mixture was stirred at room temperature under hydrogen for 17.5 hours. After the reaction was completed, the Pd / C was filtered through Celite, and the mixture was concentrated under reduced pressure to obtain methyl (S)-4-amino-3-(((tetrahydrofuran-2-yl)methyl)amino)benzoate (1.68 g, 6.72 mmol, 98%).

[0166] 1H NMR(500MHz,CDCl3)δ7.46(dd,J=8.1,1.7Hz,1H),7.34(d,J=1.5Hz,1H),6.67(d,J=7.9Hz,1H),4.20(qd,J=7.3,3.2Hz,1H),3.96-3.76(m,5H),3. 53(brs,1H),3.26(dd,J=11.9,3.1Hz,1H),3.15-3.03(m,1H),2.14-2.04 (m,1H),2.00-1.90(m,2H),1.77-1.63(m,1H);LC-MS(ESI):251.29[M+H] +

[0167] [Production Example 9: Production of 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole]

[0168] [ka] 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole

[0169] 3-Bromobenzene-1,2-diol (20 g, 105.814 mmol) was dissolved in toluene (211 mL), followed by the addition of 1-(4-chloro-2-fluorophenyl)ethan-1-one (19.08 g, 110.576 mmol) and PTSA-HO (402 mg, 2.116 mmol). The mixture was refluxed under a Dean-Stark trap for 96 hours. The toluene was removed by concentration under reduced pressure, and the mixture was purified by MPLC to give 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole (9.163 g, 26.7 mmol, 25.2%).

[0170] 1 H NMR(500MHz,CDCl3)δ7.54(t,J=8.1Hz,1H),7.12-7.17(m,2H),6.95(d,J=7.9Hz,1H),6.75(d,J=7.6Hz,1H),6.70(t,J=7.9Hz,1H),2.11(s,3H).

[0171] [Production Example 10: Production of methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)phenyl)acetate]

[0172] [ka] methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)phenyl)acetate

[0173] 4-Bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole (1.32 g, 3.85 mmol) from Preparation 9, Pd(dppf)Cl-DCM (315 mg, 0.385 mmol), CsCO (3.14 g, 9.63 mmol), and methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.08 g, 3.89 mmol) were dissolved in 17 mL of THF / HO (9 / 1) and purged with nitrogen. The reaction mixture was stirred at 85 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through Celite with EtOAc, and concentrated under reduced pressure. MPLC gave methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)phenyl)acetate (1.2 g, 2.91 mmol, 75%).

[0174] 1 H NMR(500MHz,CDCl3)δ7.74(d,J=8.2Hz,2H),7.55(t,J=8.2Hz,1H),7.40(d,J=8.2Hz,2H),7.15(dd,J=23.3,10.5H z,2H),7.07(d,J=7.9Hz,1H),6.92(t,J=7.8Hz,1H),6.83(d,J=7.6Hz,1H),3.75(s,3H),3.70(s,2H),2.12(s,3H).

[0175] Preparation Example 11: Preparation of 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)phenyl)acetic acid

[0176] [ka] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)phenyl)acetic acid

[0177] Methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)phenyl)acetate (1.17 g, 2.83 mmol) obtained in Preparation 10 was dissolved in 10 mL of THF / HO (1 / 1), and NaOH (340 mg, 8.49 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed, the pH was adjusted to 2 using 1N HCl and extracted with EtOAc. The organic layer was dried over NaSO, concentrated under reduced pressure, and purified by MPLC to give 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)phenyl)acetic acid (1.10 g, 2.76 mmol, 97%).

[0178] 1 H NMR(500MHz,MeOD)δ7.73-7.75(m,2H),7.59(t,J=8.2Hz,1H),7.39(d,J=7.9Hz,2H),7.31(dd,J=10.8,2.0Hz,1H),7.2 2(d,J=8.5Hz,1H),7.11(d,J=7.9Hz,1H),6.94(t,J=7.8Hz,1H),6.84(d,J=7.9Hz,1H),3.66-3.70(m,2H),2.10(s,3H).

[0179] [Production Example 12: Production of methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorophenyl)acetate]

[0180] [ka] methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorophenyl)acetate

[0181] 4-Bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole (1.17 g, 3.40 mmol) from Preparation 9, Pd(dppf)Cl-DCM (278 mg, 0.340 mmol), CsCO (2.77 g, 8.50 mmol), and methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.00 g, 3.40 mmol) were dissolved in 17 mL of THF / HO (9 / 1) and purged with nitrogen. The reaction mixture was stirred at 85 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through Celite with EtOAc, and concentrated under reduced pressure. MPLC gave methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorophenyl)acetate (920 mg, 2.14 mmol, 63%).

[0182] 1 H NMR(500MHz,MeOD)δ7.74(d,J=8.2Hz,2H),7.55(t,J=8.2Hz,1H),7.40(d,J=8.2Hz,2H),7.15(dd,J=23.3,10.5Hz ,2H),7.07(d,J=7.9Hz,1H),6.92(t,J=7.8Hz,1H),6.83(d,J=7.6Hz,1H),3.75(s,3H),3.70(s,2H),2.12(s,3H).

[0183] Preparation Example 13: Preparation of 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorophenyl)acetic acid

[0184] [ka] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorophenyl)acetic acid

[0185] Methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorophenyl)acetate (920 mg, 2.135 mmol) obtained in Preparation 12 was dissolved in 14 mL of THF / HO (1 / 1), and NaOH (214 mg, 5.34 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed, the pH was adjusted to 2 using 1N HCl and extracted with EtOAc. The organic layer was dried over NaSO, concentrated under reduced pressure, and purified by MPLC to give 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorophenyl)acetic acid (880 mg, 2.111 mmol, 99%).

[0186] 1 H NMR(500MHz,MeOD)δ7.63(t,J=8.4Hz,1H),7.42-7.48(m,1H),7.30(dd,J=10.7,1.8Hz,1H),7.15- 7.24(m,3H),6.93-6.95(m,2H),6.87-6.91(m,1H),3.68(d,J=8.8Hz,2H),2.04(d,J=10.1Hz,3H).

[0187] [Production Example 14: Production of methyl 2-(4-(2-fluoropyridin-3-yl)phenyl)acetate]

[0188] [ka] methyl2-(4-(2-fluoropyridin-3-yl)phenyl)acetate

[0189] 3-Bromo-2-fluoropyridine (2.00 g, 11.36 mmol), Pd(dppf)Cl-DCM (928 mg, 1.136 mmol), CsCO (9.26 g, 28.4 mmol), and methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (3.45 g, 12.50 mmol) were dissolved in 34 mL of THF / HO (9 / 1) and purged with nitrogen. The reaction mixture was stirred at 85 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure with EtOAc. MPLC yielded methyl 2-(4-(2-fluoropyridin-3-yl)phenyl)acetate (2.70 g, 11.01 mmol, 97%).

[0190] 1 H NMR(500MHz,MeOD)δ8.19(t,J=4.6Hz,1H),8.04-8.08(m,1H),7.57(d,J=8.2Hz,2H),7.42(d,J=7.9Hz,3H),3.74(s,2H),3.72(s,3H).

[0191] Preparation Example 15: Preparation of 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)phenyl)acetic acid

[0192] [ka] 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)phenyl)acetic acid

[0193] (4-Chloro-2-fluorophenyl)methanol (655 mg, 4.08 mmol) was dissolved in 30 mL of DMF, and NaH (60% dispersion in mineral oil, 489 mg, 12.23 mmol) was added at 0°C. After stirring for 10 minutes at the same temperature, methyl 2-(4-(2-fluoropyridin-3-yl)phenyl)acetate (1.00 g, 4.08 mmol) obtained from Preparation 14 was added, and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, water was added at 0°C, and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to give methyl 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)phenyl)acetate (890 mg, 2.307 mmol). Without further purification, the residue was dissolved in THF / HO (5 mL / 5 mL) and stirred at room temperature for 24 hours with NaOH (277 mg, 6.92 mmol). After completion of the reaction, water was added and the mixture was acidified to pH 2 with 1N HCl. The mixture was extracted with EtOAc, dried over MgSO, and concentrated under reduced pressure. MPLC afforded 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)phenyl)acetic acid (450 mg, 1.210 mmol, 53%).

[0194] 1 H NMR(400MHz,CDCl3)δ8.14(q,J=2.2Hz,1H),7.63(dd,J=7.3,1.8Hz,1H),7.56-7.49(m,2H), 7.37-7.30(m,3H),7.13-7.02(m,2H),6.99(dd,J=7.3,5.0Hz,1H),5.46(s,2H),3.70(s,2H).

[0195] Preparation Example 16: Preparation of methyl 4-nitro-3-(((4-propyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate

[0196] [ka] methyl4-nitro-3-(((4-propyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate

[0197] Methyl 3-fluoro-4-nitrobenzoate (934 mg, 4.69 mmol) was dissolved in THF (10 mL) / MeOH (6.67 mL), followed by the addition of (4-propyl-4H-1,2,4-triazol-3-yl)methanamine dihydrochloride (696 mg, 4.69 mmol) and TEA (3.27 mL, 23.46 mmol). The mixture was stirred under nitrogen at room temperature for 24 hours. After the reaction was complete, the mixture was cooled to room temperature and the reaction solvent was concentrated under reduced pressure. Water was added, and the mixture was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure. MPLC afforded methyl 4-nitro-3-(((4-propyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate (918 mg, 2.87 mmol, 61%).

[0198] 1 H NMR(500MHz,MeOD)δ8.54(s,1H),8.27(d,J=8.8Hz,1H),7.76(d,J=1.5Hz,1H),7.34(dd,J=8.5,1.5Hz,1 H),4.91(d,J=3.4Hz,2H),4.15(t,J=7.5Hz,2H),3.93(s,3H),1.81-1.91(m,2H),0.98(t,J=7.3Hz,3H).

[0199] Preparation Example 17: Preparation of methyl 4-amino-3-(((4-propyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate

[0200] [ka] methyl4-amino-3-(((4-propyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate

[0201] Methyl 4-nitro-3-(((4-propyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate (918 mg, 2.87 mmol) obtained in Preparation 16 was dissolved in THF (10 mL), and then 10% Pd / C (922 mg) was added and stirred at room temperature under hydrogen for 24 hours. After the reaction was complete, the mixture was filtered through Celite with EtOAc and concentrated under reduced pressure. MPLC afforded methyl 4-amino-3-(((4-propyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate (500 mg, 1.73 mmol, 60%).

[0202] 1 H NMR(500MHz,MeOD)δ8.55(d,J=25.0Hz,1H),7.39(dd,J=8.1,1.7Hz,1H),7.32-7.35(m,1H),6.70(d,J=8.2Hz ,1H),4.62(d,J=18.3Hz,2H),4.12(t,J=7.5Hz,2H),3.80-3.88(m,3H),1.82-1.91(m,2H),0.92-1.02(m,3H).

[0203] [Production Example 18: Production of bicyclo[2.2.2]octan-1-ylmethanol]

[0204] [ka] bicyclo[2.2.2]octan-1-ylmethanol

[0205] Bicyclo[2.2.2]octane-1-carboxylic acid (1110 mg, 7.198 mmol) was dissolved in EtO and LiAlH (409 mg, 10.797 mmol) was added slowly at 0°C. After stirring at room temperature for 1 hour, the temperature was lowered to 0°C again and 0.41 mL of water was added slowly. 0.41 mL of 15% NaOH (aq) was added, followed by an additional 1.23 mL of water, and the mixture was stirred at room temperature for 15 minutes. The aluminum complex was filtered through filter paper and concentrated under reduced pressure to yield bicyclo[2.2.2]octan-1-ylmethanol (972.8 mg, 6.937 mmol, 96%).

[0206] 1 H NMR(500MHz, CDCl3)δ3.21(d,J=5.8Hz,2H),1.34-1.61(m,13H).

[0207] [Production Example 19: Production of 2-(bicyclo[2.2.2]octan-1-ylmethoxy)-6-chloropyridine]

[0208] [ka] 2-(bicyclo[2.2.2]octan-1-ylmethoxy)-6-chloropyridine

[0209] Bicyclo[2.2.2]octan-1-ylmethanol (537 mg, 3.63 mmol) obtained in Preparation 18 was dissolved in 10 mL of THF and t-BuOK (733 mg, 6.534 mmol) was added at 0°C. After stirring for 10 minutes at the same temperature, 2,6-dichloropyridine was added and stirred at room temperature for 1 hour. After the reaction was completed, water was added and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to obtain 2-(bicyclo[2.2.2]octan-1-ylmethoxy)-6-chloropyridine (886 mg, 3.521 mmol, 97%).

[0210] 1H NMR(500MHz,CDCl3)δ7.48(t,J=7.9Hz,1H),6.85(d,J=7.6Hz,1H),6.62(d,J=8.2Hz,1H),3.88(s,2H),1.47-1.60(m,13H).

[0211] Preparation Example 20: Preparation of methyl 2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)phenyl)acetate

[0212] [ka] methyl2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)phenyl)acetate

[0213] 2-(bicyclo[2.2.2]octan-1-ylmethoxy)-6-chloropyridine (541 mg, 2.149 mmol) obtained from Preparation 19 was dissolved in THF / HO (20 mL / 2 mL). Methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (2967 mg, 10.74 mmol) and CsCO (1960 mg, 6.02 mmol) were added, and the mixture was purged with nitrogen three times. Pd(dppf)Cl-DCM (87.7 mg, 0.107 mmol) was added, and the atmosphere was purged with nitrogen again. The mixture was stirred at 85 °C for 21 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered through Celite with EtOAc, and concentrated under reduced pressure. MPLC yielded methyl 2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)phenyl)acetate (415.9 mg, 1.138 mmol, 53%).

[0214] 1H NMR(500MHz,CDCl3)δ7.97(d,J=8.2Hz,2H),7.59(t,J=7.8Hz,1H),7.37(d,J=7.9Hz,2H),7.27(d ,J=7.6Hz,1H),6.66(d,J=8.2Hz,1H),4.03(s,2H),3.71(s,3H),3.68(s,2H),1.52-1.62(m,13H).

[0215] Preparation Example 21: Preparation of 2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)phenyl)acetic acid

[0216] [ka] 2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)phenyl)acetic acid

[0217] Methyl 2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)phenyl)acetate (415 mg, 1.138 mmol) obtained from Preparation 20 was dissolved in 6 mL of THF and 2.85 mL of 1N NaOH was added. The reaction mixture was stirred at room temperature for 19 hours. After the reaction was completed, the pH was adjusted to 4 using 1N HCl and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to give 2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)phenyl)acetic acid (376 mg, 1.070 mmol, 94%).

[0218] 1 H NMR(500MHz,CDCl3)δ7.98(d,J=8.2Hz,2H),7.59(t,J=7.8Hz,1H),7.37(d,J=8.2Hz,2H),7 .27(d,J=3.2Hz,1H),6.67(d,J=8.2Hz,1H),4.03(s,2H),3.69(s,2H),1.52-1.63(m,13H).

[0219] [Preparation Example 22: Preparation of methyl (S)-2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)benzyl)-1-(oxytan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate]

[0220] [ka] methyl(S)-2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0221] Methyl (S)-4-amino-3-((oxytan-2-ylmethyl)amino)benzoate (83 mg, 0.35 mmol) obtained from Preparation 2 and 2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)phenyl)acetic acid (147 mg, 0.42 mmol) obtained from Preparation 21 were dissolved in 5 mL of DMF, and then EDC (135 mg, 0.703 mmol) and HOBt (108 mg, 0.703 mmol) were added and stirred at room temperature for 15 hours. After completion of the reaction, water was added and the mixture was extracted with EtOAc. The organic layer was dried over NaSO, concentrated under reduced pressure, and purified by MPLC to give the intermediate methyl (S)-4-(2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)phenyl)acetamido)-3-((oxytan-2-ylmethyl)amino)benzoic acid. Without further purification, the resulting solution was dissolved in 5 mL of acetic acid and stirred at 120 °C for 2 h. Water was added, and the mixture was extracted with EtOAc. The organic layer was dried over NaSO, concentrated under reduced pressure, and purified by MPLC to give methyl (S)-2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)benzyl)-1-(oxytan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (110 mg, 0.199 mmol, 57%).

[0222] 1 H NMR(500MHz,CDCl3)δ8.07(s,1H),7.95-7.99(m,3H),7.79(d,J=8.5Hz,1H),7.58(t,J= 7.8Hz,1H),7.32(d,J=8.2Hz,2H),7.25(d,J=7.3Hz,1H),6.65(d,J=8.2Hz,1H),5.07(q d,J=6.8,2.7Hz,1H),4.49-4.63(m,3H),4.31-4.39(m,2H),4.24(dd,J=15.6,3.1Hz,1H ),4.00(s,2H),3.94(s,3H),2.61-2.68(m,1H),2.29-2.36(m,1H),1.49-1.64(m,13H).

[0223] Example 1: Preparation of (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-(oxytan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0224] [ka] (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0225] 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)phenyl)acetic acid (150 mg, 0.403 mmol) from Preparation 15 is dissolved in DMF (2 mL) followed by the addition of methyl (S)-4-amino-3-((oxytan-2-ylmethyl)amino)benzoate (95 mg, 0.403 mmol) from Preparation 2, EDC (155 mg, 0.807 mmol), and HOBt (124 mg, 0.807 mmol). The reaction is stirred at ambient temperature under nitrogen for 24 hours. After the reaction was completed, water was added and the mixture was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure to give the intermediate methyl (S)-4-(2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)phenyl)acetamido)-3-((oxytan-2-ylmethyl)amino)benzoic acid (210 mg, 0.356 mmol). Without further purification, the mixture was dissolved in AcOH (2.04 mL, 35.6 mmol) and stirred at 120 °C for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. After adding water and extracting with EtOAc, the mixture was dried over MgSO4 and concentrated under reduced pressure to give the intermediate methyl (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-(oxytan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (131 mg, 0.229 mmol). Without further purification, the mixture was dissolved in THF / HO (1 mL / 1 mL) and NaOH (28 mg, 0.687 mmol) was added and stirred at room temperature for 24 hours. After the reaction was complete, water was added and the mixture was acidified to pH 2 with 1N HCl. The mixture was extracted with EtOAc, dried over MgSO4 and concentrated under reduced pressure. MPLC afforded (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-(oxytan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (50 mg, 0.090 mmol, 39%).

[0226] 1H NMR(500MHz,MeOD)δ8.30(s,1H),8.15(dd,J=4.9,1.5Hz,1H),7.99(d,J=8.5Hz,1H),7.74(dd,J=7.3,1.8Hz ,1H),7.70(d,J=8.5Hz,1H),7.55(d,J=8.2Hz,2H),7.41(t,J=8.1Hz,1H),7.33(d,J=8.2Hz,2H),7.21(dd,J= 10.1,1.8Hz,1H),7.13(d,J=8.2Hz,1H),7.08(dd,J=7.3,4.9Hz,1H),5.45(s,2H),4.96-5.00(m,1H),4.53- 4.62(m,2H),4.51(s,2H),4.45(dd,J=15.6,2.4Hz,1H),4.37-4.41(m,1H),2.59-2.63(m,1H),2.32-2.36(m, 1H).

[0227] Example 2: Preparation of 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(((S)-oxytan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0228] [ka] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl]benzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0229] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)phenyl)acetic acid (150 mg, 0.376 mmol) from Preparation 11 was dissolved in DMF (3 mL) followed by the addition of methyl (S)-4-amino-3-((oxytan-2-ylmethyl)amino)benzoate (107 mg, 0.451 mmol) from Preparation 2, EDC (144 mg, 0.752 mmol), and HOBt (115 mg, 0.752 mmol). The reaction was stirred at ambient temperature under nitrogen for 24 hours. After the reaction was completed, water was added and the mixture was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure to give the intermediate methyl 4-(2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)phenyl)acetamido)-3-((((S)-oxytan-2-yl)methyl)amino)benzoate (170 mg, 0.275 mmol). Without further purification, the mixture was dissolved in AcOH (1.58 mL, 27.5 mmol) and stirred at 120 °C for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure. Water was added, and the mixture was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure to give the intermediate methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(((S)-oxytan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (130 mg, 0.217 mmol). Without further purification, the mixture was dissolved in THF / HO (1 mL / 1 mL) and NaOH (26 mg, 0.651 mmol) was added and stirred at room temperature for 24 hours. After completion of the reaction, water was added and the mixture was acidified to pH ∼2 with 1N HCl. The mixture was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure. MPLC afforded 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(((S)-oxytan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (80 mg, 0.137 mmol, 63%).

[0230] 1H NMR(500MHz,MeOD)δ8.30(s,1H),8.00(dd,J=8.5,1.5Hz,1H),7.76(d,J=8.2Hz,2H),7.71(d,J=8.5Hz ,1H),7.57-7.63(m,1H),7.40(dd,J=23.7,8.1Hz,2H),7.30(d,J=10.7Hz,1H),7.22(d,J=8.5Hz,1H), 7.10(d,J=7.3Hz,1H),6.93(t,J=7.9Hz,1H),6.85(d,J=6.7Hz,1H),5.05(t,J=7.2Hz,1H),4.58-4.65 (m,2H),4.54(s,2H),4.42-4.50(m,2H),2.66-2.74(m,1H),2.39-2.46(m,1H),2.06(d,J=26.2Hz,3H).

[0231] Example 3: Preparation of 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-(((S)-oxytan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0232] [ka] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0233] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorophenyl)acetic acid (160 mg, 0.384 mmol) from Preparation 13 was dissolved in DMF (2 mL) followed by the addition of methyl (S)-4-amino-3-((oxytan-2-ylmethyl)amino)benzoate (91 mg, 0.384 mmol) from Preparation 2, EDC (147 mg, 0.768 mmol), and HOBt (118 mg, 0.768 mmol). The reaction was stirred at ambient temperature under nitrogen for 24 hours. After the reaction was completed, water was added and the mixture was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure to give the intermediate methyl 4-(2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorophenyl)acetamido)-3-((((S)-oxytan-2-yl)methyl)amino)benzoate (180 mg, 0.283 mmol). Without further purification, the mixture was dissolved in AcOH (1.62 mL, 28.3 mmol) and stirred at 120 °C for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure. After adding water and extracting with EtOAc, the mixture was dried over MgSO4 and concentrated under reduced pressure to give the intermediate methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-(((S)-oxytan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (135 mg, 0.219 mmol). Without further purification, the mixture was dissolved in THF / HO (1 mL / 1 mL) and NaOH (26 mg, 0.656 mmol) was added and stirred at room temperature for 24 hours. After completion of the reaction, water was added and the mixture was acidified to pH ∼2 with 1N HCl. The mixture was extracted with EtOAc, dried over MgSO4 and concentrated under reduced pressure. MPLC afforded 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-(((S)-oxytan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (56 mg, 0.093 mmol, 42%).

[0234] 1H NMR(500MHz,MeOD)δ8.30(s,1H),8.00(d,J=8.5Hz,1H),7.70(d,J=8.5Hz,1H), 7.61(t,J=8.2Hz,1H),7.48(dq,J=28.0,7.6Hz,1H),7.29(dd,J=11.0,1.8Hz,1H ),7.15-7.23(m,3H),6.87-6.93(m,3H),5.10(q,J=6.4Hz,1H),4.60-4.69(m,2 H),4.50-4.56(m,3H),4.42-4.46(m,1H),2.71-2.77(m,1H),2.42-2.49(m,1H).

[0235] Example 4: Preparation of 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0236] [ka] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0237] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)phenyl)acetic acid (150 mg, 0.376 mmol) from Preparation 11 is dissolved in DMF (2 mL) followed by the addition of methyl 4-amino-3-((oxazol-5-ylmethyl)amino)benzoate (102 mg, 0.414 mmol) from Preparation 6, EDC (144 mg, 0.752 mmol), and HOBt (115 mg, 0.752 mmol). The reaction is stirred at ambient temperature under nitrogen for 24 hours. After the reaction was completed, water was added and the mixture was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure to give the intermediate methyl 4-(2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)phenyl)acetamido)-3-((oxazol-5-ylmethyl)amino)benzoate (139 mg, 0.221 mmol). Without further purification, the mixture was dissolved in AcOH (1.27 mL, 22.13 mmol) and stirred at 120 °C for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure. After adding water and extracting with EtOAc, the mixture was dried over MgSO4 and concentrated under reduced pressure to give the intermediate methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.164 mmol). Without further purification, the mixture was dissolved in THF / HO (1 mL / 1 mL) and NaOH (20 mg, 0.492 mmol) was added and stirred at room temperature for 24 hours. After completion of the reaction, water was added and the mixture was acidified to pH ∼2 with 1N HCl. The mixture was extracted with EtOAc, dried over MgSO4 and concentrated under reduced pressure. MPLC afforded 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (20 mg, 0.034 mmol, 21%).

[0238] 1H NMR(500MHz,MeOD)δ8.31(s,1H),8.01-8.05(m,2H),7.71-7.74(m,3H),7.59(t,J=8.2Hz,1H),7.36(d,J=8.2Hz,2H),7.30(dd,J=11.0,1.8Hz,1H), 7.23(d,J=8.2Hz,1H),7.10(d,J=7.9Hz,1H),6.93(t,J=7.9Hz,2H),6.85 (d,J=7.6Hz,1H),5.63(s,2H),4.57(d,J=13.4Hz,2H),2.03-2.14(m,3H).

[0239] Example 5: Preparation of 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0240] [ka] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0241] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorophenyl)acetic acid (160 mg, 0.384 mmol) from Preparation 13 is dissolved in DMF (2 mL) followed by the addition of methyl 4-amino-3-((oxazol-5-ylmethyl)amino)benzoate (95 mg, 0.384 mmol) from Preparation 6, EDC (147 mg, 0.768 mmol), and HOBt (118 mg, 0.768 mmol). The reaction is stirred at ambient temperature under nitrogen for 24 hours. After the reaction was completed, water was added and the mixture was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure to give the intermediate methyl 4-(2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorophenyl)acetamido)-3-((oxazol-5-ylmethyl)amino)benzoate (148 mg, 0.229 mmol). Without further purification, the mixture was dissolved in AcOH (1.31 mL, 22.9 mmol) and stirred at 120 °C for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure. After adding water and extracting with EtOAc, the mixture was dried over MgSO4 and concentrated under reduced pressure to give the intermediate methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.159 mmol). Without further purification, the mixture was dissolved in THF / HO (1 mL / 1 mL) and NaOH (19 mg, 0.478 mmol) was added and stirred at room temperature for 24 hours. After completion of the reaction, water was added and the mixture was acidified to pH ∼2 with 1N HCl. The mixture was extracted with EtOAc, dried over MgSO4 and concentrated under reduced pressure. MPLC afforded 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (27 mg, 0.044 mmol, 28%).

[0242] 1H NMR(500MHz,MeOD)δ8.32(s,1H),8.05(s,1H),8.02(d,J=8.5Hz,1H),7.72( d,J=8.5Hz,1H),7.60-7.65(m,1H),7.47(t,J=7.9Hz,1H),7.28-7.31(m,1H ),7.23(d,J=8.2Hz,1H),7.14-7.17(m,2H),7.05(d,J=9.2Hz,1H),6.93(d, J=4.9Hz,2H),6.89(q,J=4.4Hz,1H),5.68(s,2H),4.57(s,2H),2.05(s,3H).

[0243] Example 6: Preparation of 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0244] [ka] 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0245] 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)phenyl)acetic acid (110 mg, 0.296 mmol) from Preparation 15 is dissolved in DMF (1.5 mL) followed by the addition of methyl 4-amino-3-((oxazol-5-ylmethyl)amino)benzoate (73 mg, 0.296 mmol) from Preparation 6, EDC (113 mg, 0.592 mmol), and HOBt (91 mg, 0.592 mmol). The reaction is stirred at ambient temperature under nitrogen for 24 hours. After the reaction was completed, water was added, extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure to give the intermediate methyl 4-(2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)phenyl)acetamido)-3-((oxazol-5-ylmethyl)amino)benzoate (134 mg, 0.223 mmol). Without further purification, the mixture was dissolved in AcOH (2.55 mL, 44.6 mmol) and stirred at 120 °C for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. Water was added, extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure to give the intermediate methyl 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (80 mg, 0.137 mmol). Without further purification, the residue was dissolved in THF / HO (1 mL / 1 mL) and stirred at room temperature for 24 hours with NaOH (16 mg, 0.412 mmol). After completion of the reaction, water was added and the mixture was acidified to pH 2 with 1N HCl. The mixture was extracted with EtOAc, dried over MgSO, and concentrated under reduced pressure. MPLC yielded 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (20 mg, 0.035 mmol, 26%).

[0246] 1H NMR(500MHz,MeOD)δ8.32(s,1H),8.15(d,J=3.1Hz,1H),8.00-8.03(m,2H),7.73(t,J=8.8Hz,2H),7.53(d,J=8.2Hz,2H),7.41(t,J=8.2 Hz,1H),7.31(d,J=8.2Hz,2H),7.21(d,J=10.1Hz,1H),7.07-7.12(m,2H),6.86(s,1H),5.62(s,2H),5.45(d,J=6.4Hz,2H),4.54(s,2H).

[0247] Example 7: Preparation of 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0248] [ka] 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0249] 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)phenyl)acetic acid (150 mg, 0.403 mmol) from Preparation 15 is dissolved in DMF (2 mL) followed by the addition of methyl 4-amino-3-(((4-propyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate (117 mg, 0.403 mmol) from Preparation 17, EDC (155 mg, 0.807 mmol), and HOBt (124 mg, 0.807 mmol). The reaction is stirred at ambient temperature under nitrogen for 24 hours. After the reaction was completed, water was added and the mixture was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure to give the intermediate methyl 4-(2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)phenyl)acetamido)-3-(((4-propyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate (161 mg, 0.250 mmol). Without further purification, the mixture was dissolved in AcOH (1.43 mL, 44.6 mmol) and stirred at 120 °C for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. After adding water and extracting with EtOAc, the mixture was dried over MgSO4 and concentrated under reduced pressure to give the intermediate methyl 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (86 mg, 0.138 mmol). Without further purification, the mixture was dissolved in THF / HO (1 mL / 1 mL) and NaOH (17 mg, 0.413 mmol) was added and stirred at room temperature for 24 hours. After completion of the reaction, water was added and the mixture was acidified to pH ∼2 with 1N HCl. The mixture was extracted with EtOAc, dried over MgSO4 and concentrated under reduced pressure. MPLC afforded 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (30 mg, 0.049 mmol, 36%).

[0250] 1H NMR(500MHz,MeOD)δ8.37(s,1H),8.20(s,1H),8.14(dd,J=4.9,1.8Hz,1H),8.03(d,J=8.2Hz,1H),7.73-7. 76(m,1H),7.71(dd,J=7.3,1.8Hz,1H),7.48(d,J=8.2Hz,2H),7.44(t,J=7.9Hz,1H),7.26(d,J=8.2Hz,2H) ,7.23(dd,J=10.1,1.8Hz,1H),7.16(d,J=8.2Hz,1H),7.08(dd,J=7.3,4.9Hz,1H),5.74-5.79(m,2H),5.44 (d,J=18.6Hz,2H),4.46(d,J=10.4Hz,2H),3.78(t,J=7.5Hz,2H),1.47(q,J=7.4Hz,2H),0.67-0.72(m,3H).

[0251] Example 8: Preparation of 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0252] [ka] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0253] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)phenyl)acetic acid (100 mg, 0.251 mmol) from Preparation 11 is dissolved in DMF (2 mL) followed by the addition of methyl 4-amino-3-(((4-propyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate (73 mg, 0.251 mmol) from Preparation 17, EDC (96 mg, 0.501 mmol), and HOBt (77 mg, 0.501 mmol). The reaction is stirred at ambient temperature under nitrogen for 24 hours. After the reaction was completed, water was added and the mixture was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure to give the intermediate methyl 4-(2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)phenyl)acetamido)-3-(((4-propyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate (103 mg, 0.154 mmol). Without further purification, the mixture was dissolved in AcOH (0.9 mL, 15.37 mmol) and stirred at 120 °C for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure. After adding water and extracting with EtOAc, the mixture was dried over MgSO4 and concentrated under reduced pressure to give the intermediate methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (60 mg, 0.092 mmol). Without further purification, the mixture was dissolved in THF / HO (1 mL / 1 mL) and NaOH (11 mg, 0.276 mmol) was added and stirred at room temperature for 24 hours. After completion of the reaction, water was added and the mixture was acidified to pH ∼2 with 1N HCl. The mixture was extracted with EtOAc, dried over MgSO4 and concentrated under reduced pressure. MPLC afforded 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (26 mg, 0.041 mmol, 44%).

[0254] 1 H NMR(500MHz,MeOD)δ8.40(s,1H),8.20(s,1H),8.03(d,J=8.5Hz,1H),7.76(d,J=7.9Hz,1 H),7.67(d,J=8.2Hz,2H),7.60(t,J=8.2Hz,1H),7.30-7.33(m,3H),7.24(d,J=8.2Hz,1H ),7.07(d,J=8.2Hz,1H),6.93(t,J=7.8Hz,1H),6.85(d,J=7.6Hz,1H),5.77(s,2H),4.49 (s,2H),3.83(t,J=7.5Hz,2H),2.09(s,3H),1.51(d,J=7.6Hz,2H),0.75(t,J=6.6Hz,3H).

[0255] Example 9: Preparation of 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0256] [ka] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-Carboxylic acid

[0257] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorophenyl)acetic acid (100 mg, 0.240 mmol) from Preparation 13 was dissolved in DMF (2 mL) followed by the addition of methyl 4-amino-3-(((4-propyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate (69 mg, 0.240 mmol) from Preparation 17, EDC (92 mg, 0.480 mmol), and HOBt (74 mg, 0.480 mmol). The reaction was stirred at ambient temperature under nitrogen for 24 hours. After the reaction was completed, water was added and the mixture was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure to give the intermediate methyl 4-(2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorophenyl)acetamido)-3-(((4-propyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate (118 mg, 0.171 mmol). Without further purification, the mixture was dissolved in AcOH (0.98 mL, 17.15 mmol) and stirred at 120 °C for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure. After adding water and extracting with EtOAc, the mixture was dried over MgSO4 and concentrated under reduced pressure to give the intermediate methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (70 mg, 0.104 mmol). Without further purification, the mixture was dissolved in THF / HO (1 mL / 1 mL) and NaOH (13 mg, 0.313 mmol) was added and stirred at ambient temperature for 24 hours. After completion of the reaction, water was added and the mixture was acidified to pH ∼2 with 1N HCl. The mixture was extracted with EtOAc, dried over MgSO4 and concentrated under reduced pressure. MPLC afforded 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (27 mg, 0.041 mmol, 39%).

[0258] 1 H NMR(500MHz,MeOD)δ8.43(s,1H),8.24(s,1H),8.04(d,J=8.2Hz,1H),7.88(d,J=8.5Hz ,1H),7.77(t,J=9.5Hz,2H),7.64(d,J=8.2Hz,1H),7.40(s,1H),7.31(d,J=11.0Hz,1H) ,7.24(d,J=8.5Hz,1H),7.11(d,J=9.5Hz,1H),6.90-6.93(m,2H),5.83(s,2H),4.51(s ,2H),3.90(t,J=7.3Hz,2H),2.05(s,3H),1.55(d,J=7.9Hz,2H),0.78(t,J=7.3Hz,3H).

[0259] Example 10: Preparation of 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0260] [ka] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0261] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)phenyl)acetic acid (155 mg, 0.389 mmol) from Preparation 11 is dissolved in DMF (2 mL) followed by the addition of methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (107 mg, 0.389 mmol) from Preparation 4, EDC (149 mg, 0.777 mmol), and HOBt (119 mg, 0.777 mmol). The reaction is stirred at ambient temperature under nitrogen for 24 hours. After the reaction was completed, water was added and the mixture was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure to give the intermediate methyl 4-(2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)phenyl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (129 mg, 0.197 mmol). Without further purification, the mixture was dissolved in AcOH (1.1 mL, 15.37 mmol) and stirred at 120 °C for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure. After adding water and extracting with EtOAc, the mixture was dried over MgSO4 and concentrated under reduced pressure to give the intermediate methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (116 mg, 0.182 mmol). Without further purification, the mixture was dissolved in THF / HO (1 mL / 1 mL) and NaOH (22 mg, 0.546 mmol) was added and stirred at room temperature for 24 hours. After completion of the reaction, water was added and the mixture was acidified to pH ∼2 with 1N HCl. The mixture was extracted with EtOAc, dried over MgSO4 and concentrated under reduced pressure. MPLC afforded 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (13 mg, 0.021 mmol, 11%).

[0262] 1H NMR(500MHz,MeOD)δ8.11(d,J=9.8Hz,1H),7.98-8.02(m,1H),7.75(d,J=8.5Hz,1H),7.6 8(t,J=8.2Hz,3H),7.58(t,J=8.2Hz,1H),7.29-7.34(m,3H),7.21(dd,J=8.4,1.7Hz,1H) ,7.06(d,J=7.9Hz,1H),6.91(t,J=7.9Hz,1H),6.84(d,J=7.9Hz,1H),6.51(s,1H),5.58( s,2H),4.44-4.53(m,2H),3.81-3.89(m,2H),2.06(d,J=12.8Hz,3H),1.15-1.22(m,3H).

[0263] Example 11: Preparation of 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0264] [ka] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0265] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorophenyl)acetic acid (103 mg, 0.247 mmol) from Preparation 13 is dissolved in DMF (1 mL) followed by the addition of methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (68 mg, 0.247 mmol) from Preparation 4, EDC (95 mg, 0.494 mmol), and HOBt (76 mg, 0.494 mmol). The reaction is stirred at ambient temperature under nitrogen for 24 hours. After the reaction was completed, water was added and the mixture was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure to give the intermediate methyl 4-(2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorophenyl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (109 mg, 0.162 mmol). Without further purification, the mixture was dissolved in AcOH (0.93 mL, 16.19 mmol) and stirred at 120 °C for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure. After adding water and extracting with EtOAc, the mixture was dried over MgSO4 and concentrated under reduced pressure to give the intermediate methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (90 mg, 0.137 mmol). Without further purification, the mixture was dissolved in THF / HO (1 mL / 1 mL) and NaOH (16 mg, 0.412 mmol) was added and stirred at ambient temperature for 24 hours. After completion of the reaction, water was added and the mixture was acidified to pH ∼2 with 1N HCl. The mixture was extracted with EtOAc, dried over MgSO4 and concentrated under reduced pressure. MPLC afforded 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (19 mg, 0.030 mmol, 22%).

[0266] 1 H NMR(500MHz,MeOD)δ8.15(s,1H),8.03(d,J=8.2Hz,1H),7.76(d,J=8.5Hz,1H), 7.60-7.64(m,2H),7.41(t,J=7.8Hz,1H),7.30(dd,J=11.0,2.1Hz,1H),7.23(d, J=8.2Hz,1H),7.06-7.10(m,2H),6.87-6.93(m,3H),6.51(s,1H),5.63(s,2H),4 .49(s,2H),3.90(q,J=7.2Hz,2H),2.04(d,J=7.0Hz,3H),1.21(t,J=7.3Hz,3H).

[0267] Example 12: Preparation of 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0268] [ka] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0269] Methyl (S)-4-amino-3-(((tetrahydrofuran-2-yl)methyl)amino)benzoate (50.5 mg, 0.202 mmol) obtained from Preparation Example 8 and 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)phenyl)acetic acid (89 mg, 0.222 mmol) obtained from Preparation Example 11 were dissolved in 5 mL of DMF, and then EDC (77 mg, 0.404 mmol) and HOBt (61.8 mg, 0.404 mmol) were added and the mixture was stirred at room temperature for 15 hours. After the reaction was completed, water was added and the mixture was extracted with EtOAc. The organic layer was dried over NaSO, concentrated under reduced pressure, and purified by MPLC to give the intermediate methyl 4-(2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)phenyl)acetamido)-3-((((S)-tetrahydrofuran-2-yl)methyl)amino)benzoic acid. Without further purification, the residue was dissolved in 10 mL of acetic acid and stirred at 120 °C for 2 h. The acetic acid was concentrated under reduced pressure and purified by MPLC to give the intermediate methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate. The intermediate was dissolved in 5 mL of THF, and 0.5 mL of 1 N NaOH was added to the reaction mixture, followed by stirring at 50 °C for 15 hours. 1 N HCl was added to adjust the pH to 4, and the mixture was extracted with EtOAc. The organic layer was dried over Na SO , concentrated under reduced pressure, and purified by MPLC to give 2-(4-(2-(4-chloro-2-propylphenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (35 mg, 0.058 mmol, 28.7%).

[0270] 1H NMR(400MHz,CDCl3)δ8.18(s,1H),8.08(dd,J=8.5,1.1Hz,1H),7.87(d,J=8.2Hz,1H),7.70(d,J=8.2Hz,2H),7.50(t,J=8.2Hz,1H),7.36(d,J=8.2Hz) ,2H),7.12(dd,J=10.5,1.8Hz,1H),7.07(d,J=8.2Hz,1H),7.01(d,J=7.8H z,1H),6.86(t,J=7.8Hz,1H),6.79(d,J=7.8Hz,1H),4.56(dd,J=42.8,15.8 Hz,2H),4.19-4.32(m,1H),4.10-4.17(m,2H),3.87(q,J=7.3Hz,1H),3.70-3.76(m,1H ),1.98-2.06(m,4H),1.82-1.89(m,2H),1.52-1.59(m,1H);LC-MS(ESI):599.33[M+H] +

[0271] Example 13: Preparation of (S)-2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)benzyl)-1-(oxytan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0272] [ka] (S)-2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0273] Methyl (S)-2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)benzyl)-1-(oxytan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (110 mg, 0.199 mmol) obtained from Preparation 22 was dissolved in 5 mL of THF, and 0.5 mL of 1N NaOH was added to the reaction mixture, which was then stirred at room temperature for 15 hours. After the reaction was complete, water was added, the pH was adjusted to 4 with 1N HCl, and the mixture was extracted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. MPLC afforded (S)-2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)benzyl)-1-(oxytan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (45 mg, 0.084 mmol, 42%).

[0274] 1 H NMR(500MHz,CDCl3)δ8.14(s,1H),8.07(d,J=8.5Hz,1H),7.96(d,J=8.2Hz,2H),7.86(d,J=8.5 Hz,1H),7.56(t,J=7.8Hz,1H),7.34(d,J=8.2Hz,2H),7.23(d,J=7.6Hz,1H),6.63(d,J=8.2Hz, 1H),5.05-5.08(m,1H),4.53-4.63(m,3H),4.32-4.40(m,2H),4.25(dd,J=15.6,2.7Hz,1H),3. 99(s,2H),2.61-2.68(m,1H),2.29-2.36(m,1H),1.49-1.60(m,13H);LC-MS(ESI):538.38[M+H] +

[0275] [Experimental Example 1: Activity measurement of GLP-1R agonists (Cell-based Luciferase assay)]

[0276] CHO-K1 / hGLP-1R / CRE-luciferase cell lines were seeded at 15,000 cells per well in a 96-well plate. Ham's F-12 Nutrient medium was used. After 18 hours of culture in a 5% CO2 incubator maintained at 37°C, drugs were treated. Each drug was divided into nine concentrations and dissolved in DMEM / F-12 + 1% FBS medium, and 100 μl of each was treated to the cell line. After 4 hours of culture, Bright-Glo TM Using the lucicerase assay system kit, 30 μL of assay reagent was added to each well. The plate was stored at room temperature for 15 minutes, and then luminescence was measured using a SpectraMax M5 instrument. The GLP-1R activity of the example compounds obtained through the above experiment was measured using EC 50 The values ​​are shown in Table 1 below in nM units.

[0277] [Table 1]

[0278] As can be seen from Table 1, the compounds represented by Chemical Formula 1, Chemical Formula 1', or Chemical Formula 1'' according to the present invention were confirmed to have excellent effects as excellent GLP-1 receptor agonists. Furthermore, through drug metabolism-related experiments and pharmacokinetics-related experiments such as cytochrome P (CYP) inhibition / induction experiments and metabolic stability (MS) experiments, it was confirmed that the compounds represented by Chemical Formula 1 have excellent DMPK profiles.

Claims

1. A compound of Formula I: 【Chemical 1】 A is -(CH ２ ) ｍ -, -O-, or -N(R ａ )-, where m is an integer from 1 to 3, and R ａ is hydrogen or alkyl, Z １ , Z ２ , Z ３ , Z ４ , Z ５ , Z ６ , or Z ７ each independently represents CH, CF, CCl, CBr, CI, or N; Z ８ or Z ９ are each independently —O—CH ２ C or N substituted with an —R group, or Z ８ and Z ９ When all of are C, the respective substituents can be fused together to form a dioxole structure, R is cycloalkyl or 【Chemistry 2】 and R １ is a (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, or (heteroaryl)alkyl; R ２ , R ３ , or R ４ are each independently hydrogen, deuterium, halo, alkyl, alkoxy, alkylamine, or nitrile groups; n １ or n ３ are each independently an integer of 1 to 4, １ or n ３ is an integer of 2 or more, each R ２ , R ３ , or R ４ may be the same or different from each other, In this case, the alkyl, alkoxy, alkylamine, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be unsubstituted or substituted.

2. The compound of formula I is represented by the following formula 1, formula 1', or formula 1'', or an isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1. 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 A, Z １ , Z ２ , Z ３ , Z ４ , Z ５ , Z ６ , Z ７ , R, R １ , R ２ , R ３ , R ４ , and n １ or n ３ is as defined in claim 1.

3. The A is —CH ２ -, -O-, or -N(R ａ )-, wherein R ａ is hydrogen or C １－３ 2. The compound of claim 1, its isomer, or its pharmaceutically acceptable salt, wherein R is alkyl.

4. The R is C ３－８ cycloalkyl or 【Chemistry 6】 and The R １ is (C ３－８ Cycloalkyl)C １－３ alkyl, (4- to 10-membered heterocycloalkyl)C １－３ Alkyl, (C ６－１０ (aryl) alkyl, or (4- to 10-membered heteroaryl) C １－３ alkyl, wherein the heterocycloalkyl or heteroaryl contains one to three heteroatoms selected from the group consisting of N, O, and S; The R ２ , R ３ , or R ４ are each independently hydrogen, deuterium, F, Cl, Br, I, C １－３ Alkyl, C １－３ Alkoxy, C １－３ alkylamine or nitrile group, n １ or n ３ are each independently an integer of 1 to 3, １ or n ３ is an integer of 2 or more, each R ２ , R ３ , or R ４ The compound according to claim 1, its isomer, or a pharmaceutically acceptable salt thereof, wherein may be the same or different from each other.

5. Z １ , Z ２ , Z ３ , Z ４ , Z ５ , Z ６ , or Z ７ are each independently CH, CF, or CCl, or an isomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 .

6. R is bicyclo[1,1,0]butane, bicyclo[1,1,1]pentane, bicyclo[2,1,1]hexane, bicyclo[2,2,1]heptane, bicyclo[2,2,2]octane, or 【Chemistry 7】 and The R １ is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, oxetanylmethyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, oxazolylmethyl, benzyl, unsubstituted or propyl-substituted triazolylmethyl, or unsubstituted or ethyl-substituted imidazolylmethyl, an isomer thereof, or a pharmaceutically acceptable salt thereof.

7. 2. The compound of claim 1, its isomer, or a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula I is selected from the group consisting of the following compounds: 1] (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-(oxytan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(((S)-oxytan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 3] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-(((S)-oxytan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 4] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 5] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 6] 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 7] 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)benzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 8] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 9] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 10] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 11] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 12] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 13] (S)-2-(4-(6-(bicyclo[2.2.2]octan-1-ylmethoxy)pyridin-2-yl)benzyl)-1-(oxytan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

8. A pharmaceutical composition for the prevention or treatment of a metabolic disease or a degenerative neurological disease, comprising a compound of any one of claims 1 to 7, its isomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent, or carrier.

9. 9. The pharmaceutical composition of claim 8, wherein the metabolic disease is selected from the group consisting of diabetes, hypertension, hypoglycemia, hyperlipidemia (dyslipidemia), atherosclerosis, coronary artery disease, cardiovascular disorder, blood coagulation disorder, obesity, diabetic complications, diabetic retinopathy, liver disease, hepatobiliary disease, fatty liver, alcoholic steatohepatitis, chronic kidney disease, insulin resistance, and impaired glucose tolerance.

10. 9. The pharmaceutical composition of claim 8, wherein the degenerative neurological disease is selected from the group consisting of Parkinson's disease and Alzheimer's disease.

11. 1) reacting a compound of the following formula 2 with a compound of the following formula 3 under a palladium catalyst to obtain a compound of the following formula 4: 2) reacting the compound of Formula 4 obtained in step 1) with a compound of Formula 5 in the presence of a palladium catalyst, followed by hydrolysis to obtain a compound of Formula 6: 3) obtaining a compound of Formula 1 through a coupling reaction between the compound of Formula 6 obtained in step 2) and a compound of Formula 7, followed by a condensation reaction and a hydrolysis reaction; A method for producing a compound of the following formula 1, comprising: 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 In the above formula, A is carbon; n １ , n ２ , n ３ , R, R １ , R ２ , R ３ , R ４ , Z １ , Z ２ , Z ３ , Z ４ , Z ５ , Z ６ , and Z ７ is as defined in claim 1, R ５ is alkyl, X is halo.

12. 1') reacting a compound of the following Formula 3' with a compound of the following Formula 5 in the presence of a palladium catalyst to obtain a compound of the following Formula 8: 2') reacting the compound of Formula 8 obtained in step 1') with a compound of Formula 2 to obtain a compound of Formula 6': 3') obtaining a compound of Formula 1' by coupling the compound of Formula 6' obtained in step 2') with a compound of Formula 7, followed by condensation and hydrolysis; A method for producing a compound of the following formula 1', comprising: 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemical 21】 In the above formula, A is carbon; n １ , n ２ , n ３ , R, R １ , R ２ , R ３ , R ４ , Z １ , Z ２ , Z ３ , Z ４ , Z ５ , Z ６ , and Z ７ is as defined in claim 1, R ５ is alkyl, X is halo.

13. 1″) reacting a compound of the following formula 2′ with a compound of the following formula 3″ to obtain a compound of the following formula 4′: 2″) reacting the compound of Formula 4′ obtained in step 1″) with a compound of Formula 5 under a palladium catalyst and then hydrolyzing the reacted compound to obtain a compound of Formula 6″: 3"); obtaining a compound of Formula 1" through a coupling reaction between the compound of Formula 6" obtained in step 2") and a compound of Formula 7, followed by condensation and hydrolysis; A method for producing a compound of the following formula 1″, comprising: 【Chemical 22】 【Chemical 23】 【Chemistry 24】 【Chemistry 25】 【Chemical 26】 【Chemical 27】 【Chemical Formula 28】 In the above formula, A is carbon; n １ , n ２ , n ３ , R, R １ , R ２ , R ３ , R ４ , Z １ , Z ２ , Z ３ , Z ４ , Z ５ , Z ６ , and Z ７ is as defined in claim 1, R ５ is alkyl, X is halo.

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