Benzimidazole compounds having GLP-1 receptor agonist activity, methods for preparing same, and medical uses thereof

Abstract

The present disclosure provides GLP-1 receptor agonist compounds, methods for preparing the same, and medical uses thereof. The compounds of the present disclosure have excellent pharmacological efficacy, relatively low side effects, and ensured safety, making them very useful as active ingredients. That is, the compounds of the present disclosure are effective in treating, improving, or preventing various GLP-1 receptor agonist-related diseases, particularly metabolic diseases including obesity, diabetes, and the like.

Description

BENZIMIDAZOLE COMPOUNDS HAVING GLP-1 RECEPTOR AGONIST ACTIVITY, METHODS FOR PREPARING SAME, AND MEDICAL USES THEREOF

[0001] This application claims priority based on Korean patent application No. 10-2024-0116246 filed on August 28, 2024, and all of the contents disclosed in the specification and drawings of that application are incorporated herein by reference.

[0002] The present disclosure relates to small molecule compounds exhibiting novel structural GLP-1 receptor (Glucagon-like peptide-1 receptor) agonist activity, methods for their preparation, and their medical uses. In particular, the present disclosure relates to a group of compounds exhibiting a strong pharmacological response to the GLP-1 receptor and having excellent properties as an active ingredient of a medical product, and their medical uses.

[0003]

[0004] GLP-1 is a hormone composed of 30-31 amino acids and is secreted from the beta cells of the pancreas or nerve cells. This hormone binds to the GLP-1 receptor, a type of GPCR (G protein coupled receptor), and regulates body metabolism. Metabolism is regulated by transmitting signals to the lower part through G-protein (guanine nucleotide-binding protein). The effects of GLP-1 through this are as follows. GLP-1 induces the promotion of insulin secretion from the pancreas in the body and suppresses the secretion of glucagon from the liver to lower blood sugar, and delays the fasting time in the stomach and maintains a feeling of fullness, thereby reducing appetite and showing an effect on weight loss. In 1992, a study confirmed the possibility of GLP-1 as a treatment for lowering blood sugar, and in 2002, a study reported that blood sugar levels dramatically decreased in a group of type 2 diabetes patients through 6 weeks of artificial GLP-1 subcutaneous injection. However, GLP-1 showed instability with a plasma half-life of only 2 minutes, making it difficult to use as a drug on its own. Therefore, the development of GLP-1 analogs that overcome this instability was necessary, and several pharmaceutical companies have conducted research on GLP-1 analogs to develop type 2 diabetes treatments, and currently 6 FDA-approved drugs (Exenatide, Lixisenatide, Liraglutide, Dulaglutide, Albiglutide, and Semaglutide) have been reported. However, since these are all peptide-based macromolecules, most of their formulations are limited to injections. Among these, Semaglutide (Rybelsus) is currently an FDA-approved drug that can be administered orally. However, since this drug is also a peptide-based macromolecule, it has disadvantages that are difficult to overcome. First, since it is a peptide-based macromolecule, the preparation cost is high. Second, it can affect the pharmacokinetics (PK) of other drugs due to changes in gastric pH caused by sodium N-(8-[2-hydroxybenzoyl]amino)caprylate (SNAC), an absorption enhancer used to increase oral absorption of high-molecular substances. Third, there is a difficult limitation that it must be taken on an empty stomach 30 minutes before eating water and food. Due to these shortcomings, oral Semaglutide (Rybelsus) still has a minimal prescription share in the market even after FDA approval in 2019. Therefore, the need for research to replace these peptide-based GLP-1 analog drugs with small-molecule new drugs has been greatly emphasized in order to overcome the shortcomings of these peptide-based GLP-1 analog drugs, such as manufacturing cost and ease of taking. There are currently three major leading substances undergoing clinical trials in this research field. There are Lilly's Orforglipron (LY-3502970) currently in phase 3 clinical trials, Pfizer's Danuglipron (PF-06882961) and Lotiglipron (PF-07081532). Among these, Pfizer's compounds Danuglipron and Lotiglipron showed good efficacy in clinical trials, but the clinical trials were discontinued due to side effects such as gastrointestinal side effects, vomiting, dizziness, and liver toxicity.

[0005]

[0006] Based on the above-mentioned background, the present invention aims to provide a GLP-1 receptor agonist compound having an excellent DMPK (drug metabolism and pharmacokinetics) profile and pharmacological properties that can be administered orally through the development of various forms of agonists.

[0007] The present invention also aims to provide a pharmaceutical composition useful for the treatment or prevention of metabolic diseases such as obesity and diabetes, comprising such a GLP-1 receptor agonist compound as an active ingredient, i.e., a medical use thereof.

[0008] The present invention also aims to provide a method of treating, preventing or improving obesity, diabetes, etc., characterized by administering such a GLP-1 receptor agonist compound to a patient in need of the treatment, improvement or prevention of a disease related to GLP-1 receptor efficacy.

[0009]

[0010] Compounds of the present invention

[0011] In order to address the above-mentioned problems, one embodiment of the present invention provides a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0012] [Chemical Formula 1]

[0013]

[0014] In the above chemical formula 1,

[0015] X is N, CH or C, is a single bond or a double bond, wherein, when X is N or CH, is a single bond, and when X is C, is a double bond;

[0016] m1, m2, m3, and m4 are each independently 0 or 1;

[0017] R1is -(CH2)qRa, q is 1 or 2, Rais C1-6alkyl, C3-6cycloalkyl, 3 to 12 membered heterocycloalkyl, or 5 to 12 membered heteroaryl, and Rais optionally substituted with 1 to 3 substituents selected from the group consisting of C1-6alkyl, halogen, cyano, C1-6cyanoalkyl, and C1-6alkoxy;

[0018] A is phenyl, 5 to 12 membered heterocycloalkyl, or 5 or 6 membered heteroaryl;

[0019] B is phenyl, 5 to 12 membered heteroaryl, or 5 to 12 membered heterocycloalkyl;

[0020] R2is each independently halogen or C1-6alkyl, and o is 0, 1, or 2;

[0021] L is a direct bond or -CH2O-;

[0022] R3is each independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkylthio, cyano, C1-6alkoxy, C1-6haloalkoxy, C3-6cycloalkyl, -O-C3-6cycloalkyl, -CO-C3-6cycloalkyl, and 5 or 6 membered heteroaryl, wherein said cycloalkyl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-6alkyl, and C1-6haloalkyl, and p is 0, 1, 2, or 3.

[0023] In one embodiment of the present invention, when L is -CH2O-, the carbon of CH2is connected to B and O is connected to A.

[0024]

[0025] The compounds according to the present invention are GLP-1 agonists and exhibit excellent activities on various metabolic diseases. Specifically, as a result of performing a competitive immunoassay between intrinsic cAMP produced in cells and exogenous cAMP labeled with a dye, it was confirmed that the compounds of the present disclosure exhibit excellent activities with an EC50of 50 nM or less, thereby having excellent effects as GLP-1 agonists.

[0026]

[0027] As used herein, the terms "substituent", "radical", "group", "moiety", and "fragment" may be used interchangeably.

[0028] As used herein, the term "halogen" means fluorine, bromine, chlorine, or iodine.

[0029] As used herein, the term 'alkyl' means an aliphatic hydrocarbon radical, including both straight-chain and branched hydrocarbon radicals. For example, C1-6alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms, including methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and the like.

[0030] As used herein, the term 'haloalkyl' means an alkyl substituted with one or more halogens. For example, C1-6haloalkyl includes fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and the like.

[0031] As used herein, the term 'alkylthio' is defined as -SR (wherein R is alkyl).

[0032] As used herein, the term 'cyano' is defined as -CN, and the term 'cyanoalkyl' means an alkyl substituted with one or more cyanos. For example, C1-6cyanoalkyl includes -CH2CN, -(CH2)2CN, etc.

[0033] As used herein, the term 'alkoxy' means a radical in which the hydrogen atom of the hydroxy group is replaced with alkyl, unless otherwise defined. For example, C1-6alkoxy includes methoxy, ethoxy, propoxy, n-butoxy, n-pentyloxy, isopropoxy, sec-butoxy, tert-butoxy, neopentyloxy, isopentyloxy, etc.

[0034] As used herein, the term 'haloalkoxy' means -O-haloalkyl. For example, C1-6haloalkoxy includes trifluoromethoxy, etc.

[0035] As used herein, the term 'cycloalkyl', unless otherwise defined, means a saturated aliphatic 3 to 10 membered ring, preferably a 3 to 7 membered ring. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0036] As used herein, the term 'heterocycloalkyl' means a 3 to 12 membered mono-, bi-, or poly-cyclic non-aromatic ring containing at least one heteroatom, preferably 1 to 4 heteroatoms, selected from the group consisting of N, O and S atoms, and is a saturated or partially unsaturated ring. Non-limiting examples of heterocycloalkyl rings include, but are not limited to, oxetane, tetrahydrofuran, tetrahydrothiophene, imidazolidine, pyrazolidine, pyrrolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, thiadiazole, dithiolan, piperidine, tetrahydropyran, thiirane, thietane, piperazine, morpholine, dioxane, indoline, benzodioxole, dihydrobenzodioxin, dihydrobenzofuran, benzo[d][1,3]dioxazole, 2,3-dihydrobenzo[b][1,4]dioxine, and the like.

[0037] As used herein, the term 'heteroaryl' means a 5 to 12 membered aromatic radical containing 1 to 3 heteroatoms selected from the group consisting of N, O and S atoms. The heteroaryl may be a 5 to 6 membered monocyclic heteroaryl radical, or a bicyclic heteroaryl radical formed by fusion with a benzene ring or a pyridine ring. Non-limiting examples of heteroaryl rings include, but are not limited to, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, tetrazole, oxatetrazole, thiatetrazole, pyridine, pyrimidine, pyran, indole, indazole, quinoline, isoquinoline, purine, furopyridine, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzothiadiazole, benzotriazole, mono- or di-azabicycle, pyrrolopyrrole, pyrrolopyridine, imidazopyridazine, and the like.

[0038] If a substituent is described as "optionally substituted", it means that the substituent may be unsubstituted or substituted with one or more of the defined substituents. If the substitutable position is unsubstituted, the default substituent is hydrogen.

[0039] As used herein, if the term "C1-6", "C1-6", or "C1-C6" is used, it means the number of carbon atoms is from 1 to 6. For example, C1-6alkyl means an alkyl which carbon number is any integer of from 1 to 6.

[0040] In this specification, * or means connected to another moiety.

[0041]

[0042] A preferred embodiment of the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein in the chemical formula 1, is , and R4and R5are each independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkylthio, cyano, C1-6alkoxy, C1-6haloalkoxy, C3-6cycloalkyl, -O-C3-6cycloalkyl, -CO-C3-6cycloalkyl, and 5- or 6-membered heteroaryl, wherein the cycloalkyl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-6alkyl, and C1-6haloalkyl. That is, an embodiment of the present invention provides a compound represented by the following chemical formula 2, or a pharmaceutically acceptable salt thereof.

[0043] [Chemical Formula 2]

[0044]

[0045] In the above chemical formula 2, X, m1, m2, m3, m4, R1, A, R2, o, and L are the same as described in chemical formula 1, and R4and R5are each independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkylthio, cyano, C1-6alkoxy, C1-6haloalkoxy, C3-6cycloalkyl, -O-C3-6cycloalkyl, -CO-C3-6cycloalkyl, and 5- or 6-membered heteroaryl, wherein the cycloalkyl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-6alkyl, and C1-6haloalkyl.

[0046]

[0047] A preferred embodiment of the present invention provides a compound of the above chemical formula 1, wherein R1is , or a pharmaceutically acceptable salt thereof.

[0048]

[0049] More preferably for the purpose of the present invention, another embodiment of the present invention provides a compound of the chemical formula 1 or a pharmaceutically acceptable salt thereof, wherein is , R1is , and R4and R5are each independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkylthio, cyano, C1-6alkoxy, C1-6haloalkoxy, C3-6cycloalkyl, -O-C3-6cycloalkyl, -CO-C3-6cycloalkyl, and 5- or 6-membered heteroaryl, wherein the cycloalkyl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-6alkyl, and C1-6haloalkyl. That is, one embodiment of the present invention provides a compound represented by the following chemical formula 3 or a pharmaceutically acceptable salt thereof.

[0050] [Chemical Formula 3]

[0051]

[0052] In the above chemical formula 3, X, m1, m2, m3, m4, A, R2, o, and L are the same as described in chemical formula 1, and R4and R5are each independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkylthio, cyano, C1-6alkoxy, C1-6haloalkoxy, C3-6cycloalkyl, -O-C3-6cycloalkyl, -CO-C3-6cycloalkyl, and 5- or 6-membered heteroaryl, wherein the cycloalkyl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-6alkyl, and C1-6haloalkyl.

[0053]

[0054] For the purpose of the present invention, another embodiment of the present invention also provides a compound of the chemical formula 1 or a pharmaceutically acceptable salt thereof, wherein,

[0055] R1is -(CH2)qRa, q is 1 or 2, Rais C3-6cycloalkyl, and Rais substituted with C1-6cyanoalkyl;

[0056] A is pyridine;

[0057] B is phenyl;

[0058] R2is each independently F, and o is 0, 1 or 2;

[0059] L is -CH2O-; and

[0060] R3is each independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkylthio, cyano, C1-6alkoxy, C1-6haloalkoxy, C3-6cycloalkyl, -O-C3-6cycloalkyl, -CO-C3-6cycloalkyl, and 5 or 6 membered heteroaryl, and p is 2.

[0061]

[0062] Non-limiting examples of compounds of chemical formula 1 according to the present disclosure are compounds prepared in the Examples described below, and that is, are the compounds disclosed in Table 1. Each Example number corresponds to a compound number. For example, the number of the final compound prepared in Example 10 is Compound 10.

[0063]

[0064] As used herein, the term "pharmaceutically acceptable salt(s)" refers to a salt prepared from active compounds according to the present disclosure with relatively non-toxic acids or bases, depending on the particular substituents of those compounds. When the compounds of the present invention have a relatively acidic group, base-added salts can be obtained by contacting the neutral compounds with a sufficient amount of the desired base and a pure or inert solvent. Suitable pharmaceutically acceptable base addition salts include, but are not limited to sodium, potassium, calcium, aluminum, organic amino, magnesium salts and the like. When the compounds of the present invention have a relatively basic group, acid-added salts can be obtained by contacting the neutral compounds with a sufficient amount of the desired acid and a pure or inert solvent. Suitable pharmaceutically acceptable acid addition salts include salts derived from relatively non-toxic organic acids including, but are not limited to, acetic acid, propionic acid, isobutyl acid, oxalic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like, and hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydrogen iodide, phosphorous acid and the like. Also, it includes a salt of amino acid such as arginate or its analogues, and it also includes analogues of organic acid such as glucuronic or galacturonic acid or analogues thereof. Some specific compounds of this disclosure have both basic and acidic functionality for the conversion of compounds with a basic or acidic portion (addition) salts. Other examples of salts are well known through literature known in the art to which the present invention pertains.

[0065] As used herein, the term "compound of the present invention" is meant to include not only each compound of chemical formula 1, but also isotopic variants, clathrates, hydrates, solvates, or polymorphs thereof. And, even if the term "compound(s) of the invention" does not mention its pharmaceutically acceptable sat, the term includes salts thereof. In one embodiment, the compounds of this invention include stereo-chemically pure compounds, e.g., those substantially free (e.g., greater than 85% ee, greater than 90% ee, greater than 95% ee, greater than 97% ee, or greater than 99% ee) of other stereoisomers. That is, if the compounds of chemical formula 1 according to the present invention or salts thereof are tautomeric isomers and / or stereoisomers (e.g., geometrical isomers and conformational isomers), such isolated isomers and their mixtures also are included in the scope of this invention. If the compounds of the present invention or salts thereof have an asymmetric carbon in their structures, their active optical isomers and their racemic mixtures also are included in the scope of this invention.

[0066] As used herein, the term "isotopic variant" means a compound that contains an unusual ratio of isotopes at one or more of the atoms constituting the compound. For example, an isotopic variant of a compound may be radiolabeled, for example, the hydrogen atoms may be selected from hydrogen, deuterium, and tritium, and may contain carbon-13 (13C), nitrogen-15 (15N), etc.

[0067] As used herein, the term "solvate" means a compound or its pharmaceutically acceptable salt according to this disclosure that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and acceptable for administration to humans in trace amounts.

[0068] As used herein, the term "hydrate" means a compound or its pharmaceutically acceptable salt according to this disclosure that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0069] As used herein, the term "clathrate" means a compound of the present invention or a salt thereof in the form of a crystal lattice including spaces (e.g., channels) that confine guest molecules (e.g., a solvent or water).

[0070] As used herein, the term "purified" means that when isolated, the isolate is greater than 90% pure, in one embodiment greater than 95% pure, in another embodiment greater than 99% pure and in another embodiment greater than 99.9% pure.

[0071]

[0072] Method for preparing the compound of the present invention

[0073] One embodiment of the present invention provides a method for preparing a compound of the above chemical formula 1 according to the present disclosure.

[0074] That is, one embodiment of the present invention provides a method for preparing a compound according to the present disclosure as shown in the following scheme 1.

[0075] [Scheme 1]

[0076]

[0077] In the above scheme 1, the remaining definitions except for X' are the same as the definition of the above chemical formula 1, m is independently 0 or 1, and X' is halogen and preferably chloro or bromo.

[0078] The above step 1-1 is a step of preparing a compound represented by the above chemical formula C by reacting a compound represented by the above chemical formula A with a compound represented by the above chemical formula B through a Burchwald-Hartwick amination reaction. The above reaction is preferably performed in the presence of a palladium catalyst and a base, and the reaction conditions for the Burchwald-Hartwick amination reaction can be changed as known in the art.

[0079] The compound represented by the above D can be prepared by deprotecting the compound represented by the above C through a deprotection reaction, the above step 1-2. The above reaction is preferably performed in the presence of an acid in an organic solvent, and the acid is preferably a trifluoroacetic acid or hydrochloric acid solution.

[0080] The above step 1-3 is a step for preparing a compound represented by the above chemical formula F by reacting a compound represented by the above chemical formula E with a compound represented by the above chemical formula D through a nucleophilic aromatic substitution reaction. The above reaction is preferably performed in the presence of a base, and the reaction conditions for the nucleophilic aromatic substitution reaction can be changed according to what is known in the art.

[0081] The above step 1-4 is a hydrolysis reaction, which is a reaction for changing a methyl ester group into a carboxyl group. The above reaction is preferably performed in the presence of a base, and the reaction conditions for the hydrolysis reaction can be applied according to what is known in the art.

[0082] The preparation method of the above scheme 1 can be more specifically described in the examples described below.

[0083]

[0084] In addition, another embodiment of the present invention provides a method for preparing a compound according to the present disclosure as shown in the following reaction scheme 2.

[0085] [Scheme 2]

[0086]

[0087] In the above reaction formula 2, the remaining definitions except for X' are the same as those in the above chemical formula 1, m is independently 0 or 1, and X' is halogen and preferably chloro or bromo.

[0088] The above step 2-1 is a step of preparing a compound represented by the above chemical formula C' by reacting a compound represented by the above chemical formula A with a compound represented by the above chemical formula B' through a Suzuki coupling reaction. The above reaction is preferably performed in the presence of a palladium catalyst and a base, and the reaction conditions for the Suzuki coupling reaction can be changed as known in the art.

[0089] The compound represented by the above chemical formula D' can be prepared by deprotecting the compound represented by the above C' through a deprotection reaction, the above step 2-2. The above reaction is preferably performed in the presence of an acid in an organic solvent, and the acid is preferably a trifluoroacetic acid or hydrochloric acid solution.

[0090] The above step 2-3 is a step of preparing a compound represented by the above chemical formula F' by reacting a compound represented by the above chemical formula D' with a compound represented by the above chemical formula E' through a nucleophilic aromatic substitution reaction. The above reaction is preferably performed in the presence of a base, and the reaction conditions for the nucleophilic aromatic substitution reaction can be changed as known in the art.

[0091] The above step 2-4 is a hydrolysis reaction, which is a reaction for changing a methyl ester group into a carboxyl group. The above reaction is preferably performed in the presence of a base, and the reaction conditions for the hydrolysis reaction can be applied as known in the art.

[0092] The preparation method of the above reaction scheme 2 can be more specifically described in the examples described below.

[0093]

[0094] Medical uses and methods of treatment of the compounds according to the present invention

[0095] One embodiment of the present invention further provides methods for treating a disease or condition in a subject having or susceptible to having such a disease or condition, by administering to the subject a therapeutically-effective amount of one or more compounds as described above. In one embodiment, the treatment is preventative treatment. In another embodiment, the treatment is palliative treatment. In another embodiment, the treatment is restorative treatment.

[0096] 1. Disease or Condition

[0097] The compounds according to the present disclosure are excellent GLP-1 agonists with reduced side effects, and thus exhibit excellent effects on various metabolic diseases. Therefore, one embodiment of the present invention provides a pharmaceutical composition for treating, improving, or preventing metabolic diseases, which comprises a compound according to the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient.

[0098] Specifically, the compounds according to the present disclosure can act as a therapeutic agent for metabolic diseases through securing metabolic stability and an effect on pancreatic beta cells and thereby lowering blood sugar. The metabolic disease may be a disease selected from diseases consisting of, for example, hypertension, diabetes (particularly, type 2 diabetes), hyperlipidemia, hypoglycemia, cardiovascular disorder, coronary artery disease, fatty liver, alcoholic steatohepatitis, chronic kidney disease, insulin resistance, and impaired glucose tolerance, and means a disease related to metabolism, such as obesity. The compounds according to the present disclosure can be used for weight control in obese patients.

[0099] In this specification, the term 'obesity' can be defined as a state in which there is excessive fat tissue in the body, and a body mass index (BMI, weight (kg) divided by the square of height (m)) of 25 or more is obesity.

[0100] In another embodiment, the present invention provides a method for treating or preventing a GLP-1 receptor (Glucagon-like peptide-1 receptor)-related disease, preferably a metabolic disease, comprising administering to a subject a therapeutically effective amount of a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof. This method comprises administering to a subject in need of treatment a sufficient amount of a compound of the present invention to exhibit GLP-1 receptor agonist activity, i.e., a therapeutically effective amount. In this method, the compound of the present invention can be administered to the subject in the form of a pharmaceutical composition described herein. In this method, the metabolic disease is as mentioned above. That is, the method of the present disclosure can be used for weight control of obese patients, and in addition, it can be used for treating, improving, or preventing diseases consisting of hypertension, diabetes, hyperlipidemia, hypoglycemia, cardiovascular disorder, coronary artery disease, fatty liver, alcoholic steatohepatitis, chronic kidney disease, insulin resistance, and impaired glucose tolerance.

[0101] That is, one embodiment of the present invention provides medical uses of the compound of chemical formula 1 or a pharmaceutically acceptable salt thereof for treating or preventing the above diseases.

[0102] 2. Subjects

[0103] Suitable subjects to be treated according to the present invention include mammalian subjects. Mammals according to the present disclosure include, but are not limited to, human, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero.

[0104] In one embodiment, the suitable subject to be treated according to the present invention is a human.

[0105] 3. Administration and Dosing

[0106] The compounds of the present invention are generally administered in a therapeutically effective amount.

[0107] As used herein, an "effective amount" refers to an amount of a compound of the present invention sufficient to delay or minimize the progression of a GLP-1 receptor agonist-associated disease, preferably a metabolic disorder including obesity, or to provide a therapeutic benefit in the treatment or management of a metabolic disorder including obesity. An "effective amount" also refers to an amount sufficient to exhibit GLP-1 receptor agonist activity eitherin vitroorin vivo.

[0108] The compounds of the present invention can be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. An effective dosage is typically in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 0.01 to about 50 mg / body weight kg / day, in single or divided doses. Depending on age, species and disease or condition being treated, dosage levels below the lower limit of this range may be suitable. In other cases, still larger doses may be used without harmful side effects. Larger doses may also be divided into several smaller doses, for administration throughout the day.

[0109]

[0110] Pharmaceutical composition of the compound of the present invention

[0111] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In one embodiment of the present invention, the use of the pharmaceutical composition is for the treatment or prevention of the aforementioned GLP-1 receptor agonist-related disease, preferably a metabolic disease.

[0112] The term "pharmaceutically acceptable" means suitable for use as a pharmaceutical preparation, and generally considered safe for such use. The term also means that it has been officially approved by the governing body of a country for this use, or is listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

[0113]

[0114] Pharmaceutical compositions, dosage forms and administration routes

[0115] For the treatment of the diseases or conditions referred to above, the compounds or pharmaceutically acceptable salts thereof described herein can be administered as follows:

[0116] 1. Oral administration

[0117] The compounds of the present invention may be administered orally, including by swallowing, so that the compound enters the gastrointestinal tract, or absorbed into the blood stream directly from the mouth (e.g., buccal or sublingual administration).

[0118] Suitable compositions for oral administration include solid, liquid, gel or powder formulations, and have a dosage form such as tablet, lozenge, capsule, granule or powder.

[0119] Compositions for oral administration may optionally be enteric coated and may exhibit delayed or sustained release through the enteric coating. That is, the composition for oral administration according to the present invention may be a formulation having an immediate or modified release pattern.

[0120] Liquid formulations can include solutions, syrups and suspensions, which can be used in soft or hard capsules. Such formulations may include a pharmaceutically acceptable carrier, for example, water, ethanol, polyethylene glycol, cellulose, or an oil. The formulation may also include one or more emulsifying agents and / or suspending agents.

[0121] Tablet dosage forms may contain a disintegrant. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.

[0122] Suitable lubricants, for use in a tablet, include, but are not limited to, talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate and the like.

[0123] Suitable binders, for use in a tablet, include, but are not limited to, gelatin, polyethylene glycol, sugars, gums, starch, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and the like. Suitable diluents, for use in a tablet, include, but are not limited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, microcrystalline cellulose and starch.

[0124] Suitable solubilizers, for use optionally in a tablet, include, but are not limited to, polysorbates, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethyleneglycol monoethyl ether, dimethyl isosorbide, polyethylene glycol (natural or hydrogenated) castor oil, HCORTM(Nikkol), oleyl ester, GelucireTM, caprylic / caprylic acid mono / diglyceride, sorbitan fatty acid esters, and Solutol HSTM.

[0125] Parenteral Administration

[0126] The compounds of the present invention may be administered directly into the blood stream, muscle, or internal organs. Suitable means for parenteral administration include intravenous, intra-muscular, subcutaneous intraarterial, intraperitoneal, intrathecal, intracranial, and the like. Suitable devices for parenteral administration include injectors (including needle and needle-free injectors) and infusion methods.

[0127] Compositions for parenteral administration may be formulations having an immediate or modified release pattern, wherein the modified release pattern may be a delayed or a sustained release pattern.

[0128] Most parenteral formulations are liquid compositions, and the liquid composition is an aqueous solution containing the active ingredient according to the present invention, a salt, a buffering agent, an isotonic agent, and the like.

[0129] Parenteral formulations may also be prepared in a dehydrated form (e.g., by lyophilization) or as sterile non-aqueous solutions. These formulations can be used with a suitable vehicle, such as sterile water. Solubility-enhancing agents may also be used in the preparation of parenteral solutions.

[0130] Topical Administration

[0131] The compounds of the present invention may be administered topically to the skin or transdermally. Formulations for this topical administration can include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches and the like. Pharmaceutically acceptable carriers for topical administration formulations can include water, alcohol, mineral oil, glycerin, polyethylene glycol and the like. Topical administration can also be performed by electroporation, iontophoresis, phonophoresis and the like.

[0132] Compositions for topical administration may be formulations having an immediate or modified release pattern, wherein the modified release pattern may be a delayed or a sustained release pattern.

[0133]

[0134] The present disclosure provides GLP-1 receptor agonist compounds, methods for preparing the same, and medical uses thereof. The compounds of the present disclosure have excellent pharmacological efficacy, relatively low side effects, and ensured safety, making them very useful as active ingredients. That is, the compounds of the present disclosure are effective in treating, improving, or preventing various GLP-1 receptor agonist-related diseases, particularly metabolic diseases including obesity, diabetes, and the like.

[0135]

[0136] Hereinafter, in order to help understand the present invention, examples and the like will be described in detail. However, the examples according to the present invention may be modified in various different forms, and the scope of the present invention should not be construed as being limited to the following examples. The examples of the present invention are provided to more completely explain the present invention to a person having average knowledge in the field to which the present invention belongs.

[0137] The analyses of the compounds prepared below were performed as follows. Nuclear magnetic resonance (NMR) spectral analysis was performed on a Bruker 400 MHz spectrometer, and chemical shifts were analyzed in ppm. HPLC was performed using Agilent's 1260 infinity HPLC system, Prep-HPLC was performed using Agilent's 1290 infinity II HPLC system, and the chiral column was Daicel's CHIRALPAK column. Column chromatography was performed on silica gel (Merck, 70-230 mesh). In addition, each starting material was a known compound, synthesized according to the literature, or purchased commercially.

[0138]

[0139] Reference Example 1. Methyl 2-chloro-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0140] [Step 1] Methyl 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate

[0141] Methyl 3,4-diaminobenzoate (5 g, 30.09 mmol) was added to dimethylformamide (16.72 ml), and 1,1-carbonyldiimidazole (7.32 g, 45.12 mmol) was added, and stirred at 100 ℃ for 90 minutes. When the reaction was complete, water was added, and stirred for 30 minutes. The formed solid was filtered, and then dried under reduced pressure to prepare 5.5 g of the title compound. (Yield: 95.12%)

[0142] 1H NMR (400MHz, DMSO-d6) δ 11.04 (br s, 1H), 10.88 (br s, 1H), 7.64 (d, 1H), 7.47 (s, 1H), 7.02 (d, 1H), 3.82 (s, 3H)

[0143] [Step 2] Methyl 2-chloro-1H-benzo[d]imidazole-6-carboxylate

[0144] Methyl 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (1 g, 5.20 mmol) was added to phosphoryl chloride (9.7 ml) and stirred at 100 ℃ for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and ice water was added to stop the reaction. After neutralizing with potassium carbonate aqueous solution, it was extracted with ethyl acetate. The extracted organic layer was dried with anhydrous magnesium sulfate and filtered. The obtained filtrate was concentrated under reduced pressure. The obtained solid was filtered and dried under reduced pressure to prepare 1.05 g of the title compound. (Yield: 95.8%)

[0145] 1H NMR (400MHz, CDCl3) δ 8.92-9.17 (m, 1H), 7.84-8.02 (m, 1H), 7.80 (s, 1H), 7.11-7.18 (m, 1H), 4.42 (m, 2H), 3.99 (s, 2H), 2.56 (s, 2H), 1.44 (m, 3H), 1.28 (br s, 1H), 0.89-1.07 (m, 2H), 0.68-0.89 (m, 2H)

[0146] [Step 3] Methyl 2-chloro-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0147] Methyl 2-chloro-1H-benzo[d]imidazole-6-carboxylate (300 mg, 2.85 mmol) was added to dimethylformamide (5 ml), potassium carbonate (393.69 mg) and 2-[1-(bromomethyl)cyclopropyl]acetonitrile (297.48 mg, 1.71 mmol) were added, and the mixture was stirred at 100 ℃ for 12 hours. After the reaction was completed, water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained material was purified as one of the two isomers using a chiral column (CHIRALPAK ID column) of Agilent Prep-HPLC to prepare 102 mg of the title compound. (Yield: 23.58%)

[0148] 1H NMR (400MHz, CDCl3) δ 8.14 (s, 1H), 8.01 (d, 1H), 7.72 (d, 1H), 4.36 (s, 2H), 3.96 (s, 3H), 2.39 (d, 2H), 0.94-0.91 (m, 2H), 0.83-0.80 (m, 2H)

[0149]

[0150] Example 1. 2-(7-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0151] [Step 1] 2-Bromo-6-((4-chloro-2-methoxybenzyl)oxy)pyridine

[0152] 4-Chloro-2-methoxybenzyl alcohol (5.11 g, 29.6 mmol) was added to toluene (96.56 ml), and 2-bromo-6-fluoropyridine (5.21 g, 29.6 mmol), 18-crown-6-ether (391.25 mg, 1.48 mmol), and potassium hydroxide (2.49 g, 44.41 mmol) were added and stirred at room temperature for 24 hours. When the reaction was completed, water was added to stop the reaction, and then extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography to prepare 4.45 g of the title compound. (Yield: 45.7%)

[0153] 1H NMR (400MHz, CDCl3) δ 7.42 (t, 1H), 7.38 (d, 1H), 7.07 (d, 1H), 6.95 (d, 1H), 6.89 (s, 1H), 6.73 (d, 1H), 5.34 (s, 2H), 3.85 (s, 3H)

[0154] [Step 2] tert-Butyl 7-(6-(4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0155] 2-Bromo-6-((4-chloro-2-methoxybenzyl)oxy)pyridine (500 mg, 1.52 mmol) was added to toluene (5 ml), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (378.82 mg, 1.67 mmol), tris(dibenzylideneacetone)dipalladium(0) (139.34 mg, 0.15 mmol), rac-BINAP2 (189.50 mg, 0.30 mmol), and cesium carbonate (1.48 g, 4.56 mmol) were added and stirred at 100°C for 24 hours. When the reaction was complete, the reaction mixture was diluted with ethyl acetate and filtered, and the resulting filtrate was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography to prepare 410 mg of the title compound. (Yield: 56.85%)

[0156] 1H NMR (400MHz, CDCl3) δ 7.41 (t, 1H), 7.35 (d, 1H), 6.94 (d, 1H), 6.90 (s, 1H), 6.20 (d, 1H), 6.14 (d, 1H), 5.32 (s, 2H), 3.87 (s, 3H), 3.70 (s, 4H), 3.50-3.47 (m, 4H), 1.80-1.78 (m, 4H), 1.58 (s, 9H)

[0157] [Step 3] 7-(6-(4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,7-diazaspiro[3.5]nonane

[0158] tert-Butyl 7-(6-(4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (410 mg, 0.86 mmol) was added to dichloromethane (3 ml) and stirred at 0°C for 10 minutes. Then, 2,6-lutidine (556.15 mg, 5.19 mmol) and trimethylsilyl trifluoro-methanesulfonate (192.25 mg, 0.86 mmol) were added dropwise and stirred at room temperature for 90 minutes. When the reaction was completed, water was added to stop the reaction, and then extracted with dichloromethane. The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was concentrated under reduced pressure, and the obtained material was purified using KP-amino D column chromatography from Biotage to prepare 270 mg of the title compound. (Yield: 83.49%)

[0159] 1H NMR (400MHz, CDCl3) δ 7.38 (t, 1H), 7.33 (d, 1H), 6.91 (d, 1H), 6.87 (s, 1H), 6.17 (d, 1H), 6.09 (d, 1H), 5.31 (s, 2H), 3.85 (s, 3H), 3.45-3.44 (m, 4H), 1.82-1.80 (m, 4H), 1.59 (s, 4H)

[0160] [Step 4] Methyl 2-(7-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl]-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0161] Methyl 2-chloro-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Reference Example 1, 30 mg, 0.10 mmol) was added to tetrahydrofuran (1 ml), and 7-(6-(4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,7-diazaspiro[3.5]nonane (36.93 mg, 0.1 mmol), potassium carbonate (40.95 mg, 0.30 mmol), and cesium fluoride (15 mg, 0.10 mmol) were added and stirred at 100°C for 6 hours. After the reaction was completed, water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The resulting filtrate was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography to prepare 35 mg of the title compound. (Yield: 55.27%)

[0162] 1H NMR (400MHz, CDCl3) δ 7.88 (d, 1H), 7.84 (s, 1H), 7.47 (d, 1H), 7.39 (t, 1H), 7.32 (d, 1H), 6.90 (d, 1H), 6.86 (s, 1H), 6.19 (d, 1H), 6.11 (d, 1H), 5.30 (s, 2H), 4.12 (s, 6H), 3.91 (s, 3H), 3.83 (s, 3H), 3.52 (s, 4H), 2.28 (s, 2H), 1.91 (s, 4H), 0.85 (s, 2H), 0.67 (s, 2H)

[0163] [Step 5] 2-(7-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0164] Methyl 2-(7-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl]-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (33 mg, 0.06 mmol) was added to a mixed solution of tetrahydrofuran (1 ml) and methanol (0.5 ml), 2M sodium hydroxide aqueous solution (0.26 mL, 0.52 mmol) was added dropwise and stirred at 50°C for 4 hours. When the reaction was completed, the reaction was concentrated under reduced pressure and water was added to terminate the reaction. 1N hydrogen chloride aqueous solution was added to neutralize the pH to 6-7 and extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The resulting filtrate was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography to prepare 6.4 mg of the title compound in a liquid phase. (Yield: 19.86%)

[0165]

[0166] Example 2. 2-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0167] The title compound was obtained in the same manner as in Example 1, except that (4-chloro-2-fluorophenyl)methanol was used instead of 4-chloro-2-methoxybenzyl alcohol. (Yield: 68.53%)

[0168]

[0169] Example 3. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0170] The title compound was obtained in the same manner as in Example 1, except that (2,4-dichlorophenyl)methanol was used instead of 4-chloro-2-methoxybenzyl alcohol. (Yield: 42.58%)

[0171]

[0172] Example 4. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0173] The title compound was obtained in the same manner as in Example 1, except that (2-methoxy-4-(trifluoromethyl)phenyl)methanol was used instead of 4-chloro-2-methoxybenzyl alcohol. (Yield: 36.05%)

[0174]

[0175] Example 5. 2-(7-(6-((4-chloro-2-methylbenzyl)oxy)pyridin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0176] The title compound was obtained in the same manner as in Example 1, except that (4-chloro-2-methylphenyl)methanol was used instead of 4-chloro-2-methoxybenzyl alcohol. (Yield: 14.46%)

[0177]

[0178] Example 6. 2-(6-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0179] [Step 1] tert-butyl 6-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0180] 2-Bromo-6-((4-chloro-2-methoxybenzyl)oxy)pyridine (1.5 g, 4.60 mmol) was added to toluene (15 ml), and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (1.01 g, 5.00 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.42 g, 0.40 mmol), Xantphos (0.53 g, 0.90 mmol), and cesium carbonate (3.00 g, 9.20 mmol) were added and stirred at 80°C for 12 hours under a nitrogen atmosphere. When the reaction was completed, the reaction mixture was diluted with ethyl acetate and filtered, and the resulting filtrate was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography to prepare 1.2 g of the title compound. (Yield: 56.01%)

[0181] 1H-NMR (400MHz, DMSO-d6) δ 7.48-7.38 (m, 2H), 6.89-6.74 (m, 2H), 6.03 (d, 1H), 5.88 (d, 1H), 5.21 (s, 2H), 4.04 (s, 8H), 3.77 (s, 3H), 1.37 (s, 9H).

[0182] [Step 2] 2-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane

[0183] tert-Butyl 6-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.2 g, 2.70 mmol) was added to dichloromethane (12 ml) and stirred at 0℃ or 10 minutes. Then, 2,6-lutidine (1.74 g, 16.0 mmol) and trimethylsilyltrifluoro-methanesulfonate (1.8 g, 8.10 mmol) were added dropwise and stirred at room temperature for 2 hours. After the reaction was completed, water was added to stop the reaction and the mixture was extracted with dichloromethane. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered. The obtained filtrate was concentrated under reduced pressure. The obtained material was purified by KP-amino D column chromatography of Biotage to prepare 510 mg of the title compound. (Yield: 48.11%)

[0184] 1H-NMR (400MHz, DMSO-d6) δ 7.48 (d, 1H), 7.41 (t, 1H), 7.07 (d, 1H), 6.93 (dd, 1H), 6.04 (d, 1H), 5.89 (d, 1H), 5.27 (s, 2H), 3.96 (s, 4H), 3.78 (s, 3H), 3.61 (s, 4H).

[0185] [Step 3] Methyl 2-(6-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0186] Methyl 2-chloro-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Reference Example 1, 30 mg, 0.1 mmol) was added to tetrahydrofuran (1 ml), and 2-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane (40.99 mg, 0.12 mmol), potassium carbonate (40.95 mg, 0.30 mmol), and cesium fluoride (15 mg, 0.10 mmol) were added and stirred at 100°C for 24 hours. After the reaction was completed, water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The resulting filtrate was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography to prepare 24 mg of the title compound. (Yield: 39.63%)

[0187] 1H NMR (400MHz, CDCl3) δ 7.90 (d, 1H), 7.86 (s, 1H), 7.51 (d, 1H), 7.40-7.35 (m, 2H), 6.92 (d, 1H), 6.86 (s, 1H), 6.14 (d, 1H), 5.88-5.83 (m, 1H), 5.30 (s, 2H), 4.51 (s, 4H), 4.19 (s, 4H), 4.11 (s, 2H), 3.92 (s, 3H), 3.84 (s, 3H), 2.29 (s, 2H), 0.88-0.85 (m, 2H), 0.70-0.67 (m, 2H)

[0188] [Step 4] 2-(6-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0189] Methyl 2-(6-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (24 mg, 0.04 mmol) was added to a mixed solution of tetrahydrofuran (1 ml) and methanol (0.5 ml), 2M sodium hydroxide aqueous solution (0.20 mL, 0.39 mmol) was added dropwise, and stirred at 40°C for 3 hours. When the reaction was completed, the reaction was concentrated under reduced pressure, and water was added to terminate the reaction. 1 N hydrogen chloride aqueous solution was added to neutralize the pH to 6-7, and then extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography to prepare 5.3 mg of the title compound. (Yield: 22.61%)

[0190]

[0191] Example 7. 2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0192] The title compound was obtained in the same manner as in Example 6, except that (4-chloro-2-fluorophenyl)methanol was used instead of 4-chloro-2-methoxybenzyl alcohol. (Yield: 58.94%)

[0193]

[0194] Example 8. 2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0195] The title compound was obtained in the same manner as in Example 6, except that 3-fluoro-4-(hydroxymethyl)benzonitrile was used instead of 4-chloro-2-methoxybenzyl alcohol. (Yield: 46.55%)

[0196]

[0197] Example 9. 2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0198] The title compound was obtained in the same manner as in Example 8, except that 2,6-dichloro-3-fluoropyridine was used instead of 2-bromo-6-fluoropyridine. (Yield: 46.74%)

[0199]

[0200] Example 10. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0201] The title compound was obtained in the same manner as in Example 6, except that (2,4-dichlorophenyl)methanol was used instead of 4-chloro-2-methoxybenzyl alcohol. (Yield: 9.40%)

[0202]

[0203] Example 11. 2-(6-(6-((2-chloro-4-fluorobenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0204] The title compound was obtained in the same manner as in Example 6, except that (2-chloro-4-fluorophenyl)methanol was used instead of 4-chloro-2-methoxybenzyl alcohol. (Yield: 14.85%)

[0205]

[0206] Example 12. 2-(6-(6-((2-chloro-4-methoxybenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0207] The title compound was obtained in the same manner as in Example 6, except that (2-chloro-4-methoxyphenyl)methanol was used instead of 4-chloro-2-methoxybenzyl alcohol. (Yield: 18.89%)

[0208]

[0209] Example 13. 2-(6-(6-((2-chloro-4-methylbenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0210] The title compound was obtained in the same manner as in Example 6, except that (2-chloro-4-methylphenyl)methanol was used instead of 4-chloro-2-methoxybenzyl alcohol. (Yield: 6.75%)

[0211]

[0212] Example 14. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0213] The title compound was obtained in the same manner as in Example 6, except that (2-methoxy-4-(trifluoromethyl)phenyl)methanol was used instead of 4-chloro-2-methoxybenzyl alcohol. (Yield: 22.60%)

[0214]

[0215] Example 15. 2-(6-(6-((4-chloro-2-methylbenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0216] The title compound was obtained in the same manner as in Example 6, except that (4-chloro-2-methylphenyl)methanol was used instead of 4-chloro-2-methoxybenzyl alcohol. (Yield: 24.75%)

[0217]

[0218] Example 16. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0219] [Step 1] 2-Bromo-6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine

[0220] 2-Methoxy-4-(trifluoromethyl)benzyl alcohol (500 mg, 2.43 mmol) was added to tetrahydrofuran (10 ml), and 2-bromo-6-fluoropyridine (426 mg, 2.43 mmol) and potassium tert-butoxide (544 mg, 4.85 mmol) were added and stirred at room temperature for 1 hour. When the reaction was completed, water was added to stop the reaction, and then extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography to prepare 776 mg of the title compound. (Yield: 88.35%)

[0221] 1H-NMR (600 MHz, CDCl3) δ 7.57 (d, 1H), 7.44 (t, 1H), 7.24 (d, 1H), 7.12-7.06 (m, 2H), 6.76 (d, 1H), 5.43 (s, 2H), 3.91 (s, 3H)

[0222] [Step 2] tert-Butyl 7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-ene-2-carboxylate

[0223] 2-Bromo-6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine (362 mg, 1.00 mmol) was added to a mixed solution of dioxane (6 ml) and distilled water (3 ml), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane (81 mg, 0.10 mmol), potassium carbonate (414.45 mg, 3.00 mmol), and tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.5]non-6-ene-2-carboxylate (349.13 mg, 1.00 mmol) were added and stirred at 90°C for one hour. After the reaction was completed, water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography to prepare 378 mg of the title compound. (Yield: 74.95%)

[0224] 1H-NMR (600 MHz, CDCl3) δ 7.56-7.51 (m, 2H), 7.21 (d, 1H), 7.09 (s, 1H), 6.94 (d, 1H), 6.72-6.69 (m, 1H), 6.67 (d, 1H), 5.48 (s, 2H), 3.92 (s, 3H), 3.75-3.70 (m, 2H), 3.66-3.62 (m, 2H), 2.58-2.52 (m, 2H), 2.50-2.45 (m, 2H), 1.95-1.90 (m, 2H), 1.45 (s, 9H)

[0225] [Step 3] 7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-ene

[0226] tert-Butyl 7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-ene-2-carboxylate (50 mg, 3.00 mmol) was added to dichloromethane (0.6 ml), and trifluoroacetic acid (4.45 g, 39.04 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, water was added to stop the reaction, and the mixture was neutralized with a saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate, and the extracted organic layer was dried over anhydrous magnesium sulfate and then filtered. The obtained filtrate was concentrated under reduced pressure to prepare 36 mg of the title compound as a brown liquid without purification.

[0227] 1H-NMR (600 MHz, CDCl3) δ 7.58-7.49 (m, 2H), 7.21 (d, 1H), 7.09 (s, 1H), 6.94 (d, 1H), 6.75-6.72 (m, 1H), 6.66 (d, 1H), 5.48 (s, 2H), 3.92 (s, 3H), 3.50-3.38 (m, 4H), 2.56-2.47 (m, 4H), 2.10 (s, 1H), 2.01-1.93 (m, 2H)

[0228] [Step 4] Methyl 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylate

[0229] Methyl 2-chloro-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Reference Example 1, 48.82 mg, 0.16 mmol) was added to a mixed solution of dimethylacetamide (0.7 ml) and dimethylformaldehyde (0.7 ml), 7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-ene (65 mg, 0.16 mmol), potassium carbonate (44.42, 0.32 mmol), and cesium fluoride (24.41 mg, 0.16 mmol) were added and stirred at 100°C for 4 hours. After the reaction was completed, water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography to prepare 69 mg of the title compound in a liquid phase. (Yield: 63.91%)

[0230] 1H-NMR (600 MHz, CDCl3) δ 7.89 (d, 1H), 7.84 (s, 1H), 7.58-7.53 (m, 2H), 7.48 (d, 1H), 7.22 (d, 1H), 7.10 (s, 1H), 6.97 (d, 1H), 6.77-6.74 (m, 1H), 6.69 (d, 1H), 5.49 (s, 2H), 4.19-4.16 (m, 2H), 4.13-4.08 (m, 4H), 3.93- 3.92 (m, 6H), 2.67-2.60 (m, 4H), 2.30 (s, 2H), 2.11-2.07 (m, 2H), 0.89-0.85 (m, 2H), 0.71-0.66 (m, 2H)

[0231] [Step 5] 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2-methoxy-4-(trifluoro)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0232] Methyl 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylate (69 mg, 0.10 mmol) was added to a mixed solution of tetrahydrofuran (2 ml) and methanol (1 ml). Then, 2 M sodium hydroxide aqueous solution (0.34 mL, 0.68 mmol) was added dropwise, and the mixture was stirred at 50°C for 4 hours. When the reaction was complete, the mixture was concentrated under reduced pressure, and water was added to terminate the reaction. 1 N hydrogen chloride aqueous solution was added to neutralize the pH to 6-7, and then extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography to prepare 4.3 mg of the title compound. (Yield: 26.14%)

[0233]

[0234] Example 17. 2-(7-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0235] The title compound was obtained in the same manner as in Example 16, except that 4-chloro-2-methoxybenzyl alcohol was used instead of 2-methoxy-4-(trifluoromethyl)benzyl alcohol. (Yield: 8.21%)

[0236]

[0237] Example 18. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((4-fluoro-2-methoxybenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0238] The title compound was obtained in the same manner as in Example 16, except that (4-fluoro-2-methoxyphenyl)methanol was used instead of 2-methoxy-4-(trifluoromethyl)benzyl alcohol. (Yield: 18.33%)

[0239]

[0240] Example 19. 2-(7-(6-((4-chloro-2-methoxybenzyl)oxy)-5-fluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0241] The title compound was obtained in the same manner as in Example 17, except that 2,6-dichloro-3-fluoropyridine was used instead of 2-bromo-6-fluoropyridine. (Yield: 15.57%)

[0242]

[0243] Example 20. 2-(7-(6-((4-chloro-2-methoxybenzyl)oxy)-3,5-difluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0244] The title compound was obtained in the same manner as in Example 17, except that 2-bromo-3,5,6-trifluoropyridine was used instead of 2-bromo-6-fluoropyridine. (Yield: 36.85%)

[0245]

[0246] Example 21. 2-(7-(6-((4-chloro-2-(methylthio)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0247] The title compound was obtained in the same manner as in Example 16, except that (4-chloro-2-(methylthio)phenyl)methanol was used instead of 2-methoxy-4-(trifluoromethyl)benzyl alcohol. (Yield: 17.37%)

[0248]

[0249] Example 22. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0250] The title compound was obtained in the same manner as in Example 6, except that cyclopropyl(3-fluoro-4-(hydromethyl)phenyl)methanone was used instead of 4-chloro-2-methoxybenzyl alcohol. (Yield: 14.14%)

[0251]

[0252] Example 23. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.3]hept-5-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0253] [Step 1] 2-Bromo-6-((2,4-dichlorobenzyl)oxy)pyridine

[0254] 2,4-Dichlorobenzyl alcohol (1.57 g, 8.85 mmol) was added to toluene (17.7 ml), and 2-bromo-6-fluoropyridine (1.56 g, 8.85 mmol), 18-crown-6-ether (116.98 mg, 0.44 mmol), and potassium hydroxide (0.75 g, 13.28 mmol) were added and stirred at room temperature for 24 hours. When the reaction was completed, water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography to prepare 2.70 g of the title compound. (Yield: 91.6%)

[0255] 1H NMR (400MHz, CDCl3) δ 7.50-7.42 (m, 3H), 7.27-7.25 (m, 1H), 7.10 (d, 1H), 6.76 (d, 1H), 5.42 (s, 2H)

[0256] [Step 2] tert-Butyl 6-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate

[0257] 2-Bromo-6-((2,4-dichlorobenzyl)oxy)pyridine (1300 mg, 3.90 mmol) was added to a mixed solution of dioxane (8.68 ml) and distilled water (4.34 ml), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane (318.8 mg, 0.39 mmol), potassium carbonate (1.62 g, 11.71 mmol), and tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (1.5 g, 4.69 mmol) were added and stirred at 90°C for 24 hours. After the reaction was completed, water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography to prepare 1.34 g of the title compound. (Yield: 77.02%)

[0258] 1H NMR (400MHz, CDCl3) δ 7.94-7.86 (m, 2H), 7.63-7.57 (m, 1H), 7.55-7.46 (m, 2H), 7.31-7.22 (m, 2H), 6.93 (s, 1H), 6.78-6.71 (m, 1H), 6.68 (s, 1H), 5.48 (s, 2H), 4.56-4.53 (m, 2H), 4.39-4.35 (m, 4H), 3.20-3.11 (m, 2H), 2.38-2.32 (m, 2H), 0.91-0.86 (m, 3H), 0.73-0.67 (m, 2H)

[0259] [Step 3] 6-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.3]hept-5-ene

[0260] tert-Butyl 6-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (1.34 g, 3.00 mmol) was added to dichloromethane (10 ml), and trifluoroacetic acid (4.45 g, 39.04 mmol) was added. The mixture was stirred at room temperature for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, water was added to stop the reaction, and the mixture was neutralized with a saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the extracted organic layer was dried over anhydrous magnesium sulfate and then filtered. The obtained filtrate was concentrated under reduced pressure to prepare 1.20 g of the title compound as a brown liquid without purification.

[0261] MS m / z 347.1 [M+H]+

[0262] [Step 4] Methyl 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.3]hept-5-en-2-yl)-1H-benzo[d]imidazole-6-carboxylate

[0263] Methyl 2-chloro-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Reference Example 1, 25.78 mg, 0.085 mmol) was added to dimethylformaldehyde (2 ml), and 6-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.3]hept-5-ene (38.32 mg, 0.11 mmol), potassium carbonate (23.46 mg, 0.17 mmol), and cesium fluoride (12.89 mg, 0.08 mmol) were added and stirred at 100°C for 12 hours. After the reaction was completed, water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography to prepare 27 mg of the title compound in a liquid phase. (Yield: 51.76%)

[0264] 1H NMR (400MHz, CDCl3) δ 7.94-7.86 (m, 2H), 7.63-7.57 (m, 1H), 7.55-7.46 (m, 2H), 7.31-7.22 (m, 2H), 6.93 (s, 1H), 6.78-6.71 (m, 1H), 6.68 (s, 1H), 5.48 (s, 2H), 4.56-4.53 (m, 2H), 4.39-4.35 (m, 4H), 3.20-3.11 (m, 2H), 2.38-2.32 (m, 2H), 0.91-0.86 (m, 3H), 0.73-0.67 (m, 2H)

[0265] [Step 5] 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.3]hept-5-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0266] Methyl 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.3]hept-5-en-2-yl)-1H-benzo[d]imidazole-6-carboxylate (26.4 mg, 0.043 mmol) was added to a mixed solution of tetrahydrofuran (1 ml) and methanol (0.5 ml), and 2 M Sodium hydroxide aqueous solution (0.17 mL, 0.348 mmol) was added dropwise and stirred at 40°C for 1 hour. When the reaction was complete, the mixture was concentrated under reduced pressure, and water was added to terminate the reaction. 1 N aqueous hydrogen chloride solution was added to neutralize the pH to 6-7, and then extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography to prepare 12.7 mg of the title compound in a liquid phase. (Yield: 49.24%)

[0267]

[0268] Example 24. 2-(7-(6-((4-bromo-2-methoxybenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0269] The title compound was obtained in the same manner as in Example 17, except that 4-bromo-2-methoxybenzyl alcohol was used instead of 4-chloro-2-methoxybenzyl alcohol. (Yield: 5.01%)

[0270]

[0271] Example 25. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(3-fluoro-6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0272] The title compound was prepared in the same manner as in Example 16, except that 2-bromo-3,6-difluoropyridine was used instead of 2-bromo-6-fluoropyridine. (Yield: 68%)

[0273]

[0274] Example 26. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(3,5-difluoro-6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0275] The title compound was prepared in the same manner as in Example 16, except that 2-bromo-3,5,6-trifluoropyridine was used instead of 2-bromo-6-fluoropyridine. (Yield: 54%)

[0276]

[0277] Example 27. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(3,5-difluoro-6-((2-methoxy-4-methylbenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0278] The title compound was prepared in the same manner as in Example 26, except that (2-methoxy-4-methylphenyl)methanol was used instead of 2-methoxy-4-(trifluoromethyl)benzyl alcohol. (Yield: 21%)

[0279]

[0280] Example 28. 2-(7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0281] The title compound was prepared in the same manner as in Example 17, except that (4-chloro-2-(difluoromethoxy)phenyl)methanol was used instead of (4-chloro-2-methoxyphenyl)methanol. (Yield: 46.9%)

[0282]

[0283] Example 29. 2-(7-(6-((4-chloro-2-methoxybenzyl)oxy)-3-fluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0284] The title compound was prepared in the same manner as in Example 25, except that (4-chloro-2-methoxyphenyl)methanol was used instead of 2-methoxy-4-(trifluoromethyl)benzyl alcohol. (Yield: 45%)

[0285]

[0286] Example 30. 2-(7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)-3,5-difluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0287] The title compound was prepared in the same manner as in Example 20, except that (4-chloro-2-(difluoromethoxy)phenyl)methanol was used instead of (2-methoxy-4-chlorophenyl)methanol. (Yield: 32%)

[0288]

[0289] Example 31. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2-(difluoromethoxy)-4-fluorobenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0290] The title compound was prepared in the same manner as in Example 28, except that (2-(difluoromethoxy)-4-fluorophenyl)methanol was used instead of (4-chloro-2-(difluoromethoxy)phenyl)methanol. (Yield: 49%)

[0291]

[0292] Example 32. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2-(difluoromethoxy)-4-methoxybenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0293] The title compound was prepared in the same manner as in Example 28, except that (2-(difluoromethoxy)-4-methoxyphenyl)methanol was used instead of (4-chloro-2-(difluoromethoxy)phenyl)methanol. (Yield: 3%)

[0294]

[0295] Example 33. 2-(7-(6-((4-chloro-2-methylbenzyl)oxy)-3,5-difluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0296] The title compound was prepared in the same manner as in Example 30, except that (4-chloro-2-methylphenyl)methanol was used instead of (4-chloro-2-(difluoromethoxy)phenyl)methanol. (Yield: 21%)

[0297]

[0298] Example 34. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2-(difluoromethoxy)-4-methoxybenzyl)oxy)-3,5-difluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0299] The title compound was prepared in the same manner as in Example 30, except that (2-(difluoromethoxy)-4-methoxyphenyl)methanol was used instead of (4-chloro-2-(difluoromethoxy)phenyl)methanol. (Yield: 42%)

[0300]

[0301] Example 35. 2-(7-(6-((2,4-bis(difluoromethoxy)benzyl)oxy)-3,5-difluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0302] The title compound was prepared in the same manner as in Example 30, except that (2,4-bis(difluoromethoxy)phenyl)methanol was used instead of (4-chloro-2-(difluoromethoxy)phenyl)methanol. (Yield: 78%)

[0303]

[0304] Example 36. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((4-cyclopropyl-2-methoxybenzyl)oxy)-3,5-difluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0305] The title compound was prepared in the same manner as in Example 30, except that (4-cyclopropyl-2-methoxyphenyl)methanol was used instead of (4-chloro-2-(difluoromethoxy)phenyl)methanol. (Yield: 24%)

[0306]

[0307] Example 37. 2-(6-(6-((4-chloro-2-methoxybenzyl)oxy)-5-fluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0308] The title compound was prepared in the same manner as in Example 6, except that 2,6-dichloro-3-fluoropyridine was used instead of 2-bromo-6-fluoropyridine. (Yield: 84%)

[0309]

[0310] Example 38. 2-(6-(6-((4-chloro-2-methoxybenzyl)oxy)-3-fluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0311] The title compound was prepared in the same manner as in Example 6, except that 2-bromo-3,6-difluoropyridine was used instead of 2-bromo-6-fluoropyridine. (Yield: 28%)

[0312]

[0313] Example 39. 2-(6-(6-((4-chloro-2-methoxybenzyl)oxy)-3,5-difluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0314] The title compound was prepared in the same manner as in Example 6, except that 2-bromo-3,5,6-trifluoropyridine was used instead of 2-bromo-6-fluoropyridine. (Yield: 47%)

[0315]

[0316] Example 40. 2-(6-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)-3,5-difluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0317] The title compound was prepared in the same manner as in Example 39, except that (4-chloro-2-(difluoromethoxy)phenyl)methanol was used instead of (4-chloro-2-methoxyphenyl)methanol. (Yield: 65%)

[0318]

[0319] Example 41. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(3,5-difluoro-6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0320] The title compound was prepared in the same manner as in Example 14, except that 2-bromo-3,5,6-trifluoropyridine was used instead of 2-bromo-6-fluoropyridine. (Yield: 55%)

[0321]

[0322] Example 42. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(3,5-difluoro-6-((2-methoxy-4-methylbenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0323] The title compound was prepared in the same manner as in Example 39, except that (2-methoxy-4-methylphenyl)methanol was used instead of (4-chloro-2-methoxyphenyl)methanol. (Yield: 68%)

[0324]

[0325] Example 43. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2-(difluoromethoxy)-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0326] The title compound was prepared in the same manner as in Example 16, except that (2-(difluoromethoxy)-4-(trifluoro)phenyl)methanol was used instead of (2-methoxy-4-(trifluoromethyl)phenyl)methanol. (Yield: 55%)

[0327]

[0328] Example 44. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(6-((4-cyclopropyl-2-methoxybenzyl)oxy)-3,5-difluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0329] The title compound was prepared in the same manner as in Example 39, except that (4-cyclopropyl-2-methoxyphenyl)methanol was used instead of (4-chloro-2-methoxyphenyl)methanol. (Yield: 10%)

[0330]

[0331] Example 45. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(6-((2-(difluoromethoxy)-4-(trifluoromethyl)benzyl)oxy)-3,5-difluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0332] The title compound was prepared in the same manner as in Example 39, except that (2-(difluoromethoxy)-4-(trifluoro)phenyl)methanol was used instead of (4-chloro-2-methoxyphenyl)methanol. (Yield: 61%)

[0333]

[0334] Example 46. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2-(difluoromethoxy)-4-(trifluoromethyl)benzyl)oxy)-3-fluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0335] The title compound was prepared in the same manner as in Example 29, except that (2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)methanol was used instead of (4-chloro-2-methoxyphenyl)methanol. (Yield: 53%)

[0336]

[0337] Example 47. 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(6-((2-(difluoromethoxy)-4-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid

[0338] The title compound was prepared in the same manner as in Example 39, except that (2-(difluoromethoxy)-4-fluorophenyl)methanol was used instead of (4-chloro-2-methoxyphenyl)methanol. (Yield: 10%)

[0339]

[0340] Example 48. 2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0341] The title compound was prepared in the same manner as in Example 39, except that 3-fluoro-4-(hydroxymethyl)benzonitrile was used instead of (4-chloro-2-methoxyphenyl)methanol. (Yield: 7%)

[0342]

[0343] The structures of the compounds prepared in the above examples are summarized in Table 1 below.

[0344] [Table 1]

[0345]

[0346]

[0347]

[0348]

[0349] The NMR measurement results of the final compounds obtained in the above examples are summarized and shown in Table 2 below.

[0350] [Table 2]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356] Evaluation of the compounds of the present invention

[0357] Experimental Example 1: cAMP activity test

[0358] The efficacy of the GLP-1 receptor agonist of the compound according to the present invention was measured by evaluating cAMP production using CHO (Eurofins, HTS163C2) cell lines in which the human GLP-1 receptor is overexpressed.

[0359] Specifically, the cells were seeded at 3500 cells / 25 μL / well in a half 96 well plate (Corning, #3688) using Ham's F-12K medium containing 10% FBS, 50 μg / mg Gentamicin, and 250 μg / ml G418, and cultured in a 37°C, 5% CO2incubator. The next day, 25 μL of the 2x concentration of the test compound which was dissolved in DPBS containing '0.5% BSA and 2 mM IBMX' or '6 μM BETP, 0.5% BSA, and 2 mM IBMX' was added to the cells, and incubated at 37 °C, 5% CO2for 1 hour. cAMP production was evaluated using the HTRF cAMP Gs dynamic kit (Cisbio, 62AM4PEC) according to the manufacturer's instructions as follows. 25 μL / well of cAMP-d2 and anti-cAMP-Cryptate were each added and reacted at room temperature for 1 hour. After the reaction, fluorescence was measured using FlexStation3 (Molecular device, excitation wavelength 314 nm, emission wavelengths 620 nm and 665 nm). The measured value represents fluorescence resonance energy transfer (FRET) and was calculated as the ratio of 620 nm / 665 nm. The measured value was normalized using the value of the vehicle-administered group. The graph was drawn with the y-axis as the fold change value and the x-axis as the concentration value of the test compound, and the EC50value was calculated using GraphPad Prism. For anti-cAMP cryptate, intracellular cAMP competes with cAMP-d2, and the measured fluorescence resonance energy transfer (FRET) signal is inversely proportional to intracellular cAMP. The activity of the compounds was calculated as the degree of change in the fluorescence resonance energy transfer (FRET) signal, and the EC50of the compounds is shown in the table below.

[0360] Example No.EC50(nM)Example No.EC50(nM)Example No.EC50(nM)15172.33327228188.6349.139.6196.4352.649.1201.613613.3523.4216.2374.963.52241.1383.9755.0239.6392.5816.02424010.6916.0251.1419.51018263.1425.21138272.1432.91225281.84432.81331.5291.34515.41420.9308.9462.61518.5316.84730.4163324.24810.4

Claims

1.A compound of Chemical Formula 1:[Chemical Formula 1]or a pharmaceutically acceptable salt thereof,in the Chemical Formula 1,X is N, CH or C,is a single bond or a double bond, wherein, when X is N or CH,is a single bond, and when X is C,is a double bond;m1, m2, m3, and m4 are each independently 0 or 1;R1is -(CH2)qRa, q is 1 or 2, Rais C1-6alkyl, C3-6cycloalkyl, 3 to 12 membered heterocycloalkyl, or 5 to 12 membered heteroaryl, and Rais optionally substituted with 1 to 3 substituents selected from the group consisting of C1-6alkyl, halogen, cyano, C1-6cyanoalkyl, and C1-6alkoxy;A is phenyl, 5 to 12 membered heterocycloalkyl, or 5 or 6 membered heteroaryl;B is phenyl, 5 to 12 membered heteroaryl, or 5 to 12 membered heterocycloalkyl;R2is each independently halogen or C1-6alkyl, and o is 0, 1, or 2;L is a direct bond or -CH2O-;R3is each independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkylthio, cyano, C1-6alkoxy, C1-6haloalkoxy, C3-6cycloalkyl, -O-C3-6cycloalkyl, -CO-C3-6cycloalkyl, and 5 or 6 membered heteroaryl, wherein said cycloalkyl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-6alkyl, and C1-6haloalkyl, and p is 0, 1, 2, or 3.2.The compound of Claim 1 or a pharmaceutically acceptable salt thereof, in the Chemical Formula 1, is , and R4and R5are each independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkylthio, cyano, C1-6alkoxy, C1-6haloalkoxy, C3-6cycloalkyl, -O-C3-6cycloalkyl, -CO-C3-6cycloalkyl, and 5- or 6-membered heteroaryl, wherein the cycloalkyl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-6alkyl, and C1-6haloalkyl.3.The compound of Claim 1 or a pharmaceutically acceptable salt thereof, in the Chemical Formula 1, R1is .4.The compound of Claim 1 or a pharmaceutically acceptable salt thereof, in the Chemical Formula 1, is , R1is , and R4and R5are each independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkylthio, cyano, C1-6alkoxy, C1-6haloalkoxy, C3-6cycloalkyl, -O-C3-6cycloalkyl, -CO-C3-6cycloalkyl, and 5- or 6-membered heteroaryl, wherein the cycloalkyl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-6alkyl, and C1-6haloalkyl.5.The compound of Claim 1 or a pharmaceutically acceptable salt thereof, whereinR1is -(CH2)qRa, q is 1 or 2, Rais C3-6cycloalkyl, and Rais substituted with C1-6cyanoalkyl;A is pyridine;B is phenyl;R2is each independently F, and o is 0, 1 or 2;L is -CH2O-; andR3is each independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkylthio, cyano, C1-6alkoxy, C1-6haloalkoxy, C3-6cycloalkyl, -O-C3-6cycloalkyl, -CO-C3-6cycloalkyl, and 5 or 6 membered heteroaryl, and p is 2.6.The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is(1) 2-(7-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(2) 2-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(3) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(4) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(5) 2-(7-(6-((4-chloro-2-methylbenzyl)oxy)pyridin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(6) 2-(6-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(7) 2-(6-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(8) 2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(9) 2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(10) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(11) 2-(6-(6-((2-chloro-4-fluorobenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(12) 2-(6-(6-((2-chloro-4-methoxybenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(13) 2-(6-(6-((2-chloro-4-methylbenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(14) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(15) 2-(6-(6-((4-chloro-2-methylbenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(16) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(17) 2-(7-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(18) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((4-fluoro-2-methoxybenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(19) 2-(7-(6-((4-chloro-2-methoxybenzyl)oxy)-5-fluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(20) 2-(7-(6-((4-chloro-2-methoxybenzyl)oxy)-3,5-difluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(21) 2-(7-(6-((4-chloro-2-(methylthio)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(22) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(23) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(6-((2,4-dichlorobenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.3]hept-5-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(24) 2-(7-(6-((4-bromo-2-methoxybenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(25) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(3-fluoro-6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(26) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(3,5-difluoro-6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(27) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(3,5-difluoro-6-((2-methoxy-4-methylbenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(28) 2-(7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(29) 2-(7-(6-((4-chloro-2-methoxybenzyl)oxy)-3-fluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(30) 2-(7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)-3,5-difluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(31) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2-(difluoromethoxy)-4-fluorobenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(32) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2-(difluoromethoxy)-4-methoxybenzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(33) 2-(7-(6-((4-chloro-2-methylbenzyl)oxy)-3,5-difluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(34) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2-(difluoromethoxy)-4-methoxybenzyl)oxy)-3,5-difluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(35) 2-(7-(6-((2,4-bis(difluoromethoxy)benzyl)oxy)-3,5-difluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(36) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((4-cyclopropyl-2-methoxybenzyl)oxy)-3,5-difluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(37) 2-(6-(6-((4-chloro-2-methoxybenzyl)oxy)-5-fluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(38) 2-(6-(6-((4-chloro-2-methoxybenzyl)oxy)-3-fluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(39) 2-(6-(6-((4-chloro-2-methoxybenzyl)oxy)-3,5-difluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(40) 2-(6-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)-3,5-difluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid,(41) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(3,5-difluoro-6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(42) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(3,5-difluoro-6-((2-methoxy-4-methylbenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(43) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2-(difluoromethoxy)-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(44) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(6-((4-cyclopropyl-2-methoxybenzyl)oxy)-3,5-difluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(45) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(6-((2-(difluoromethoxy)-4-(trifluoromethyl)benzyl)oxy)-3,5-difluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(46) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(7-(6-((2-(difluoromethoxy)-4-(trifluoromethyl)benzyl)oxy)-3-fluoropyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid,(47) 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(6-(6-((2-(difluoromethoxy)-4-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid, or(48) 2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.7.A composition comprising a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.8.A pharmaceutical composition for exhibiting GLP-1 receptor (Glucagon-like peptide-1 receptor) agonist activity, comprising a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.9.The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is for treating or preventing obesity, hypertension, diabetes, hyperlipidemia, hypoglycemia, cardiovascular disorder, coronary artery disease, fatty liver, alcoholic steatohepatitis, chronic kidney disease, insulin resistance, or impaired glucose tolerance.10.A method for exhibiting GLP-1 receptor (Glucagon-like peptide-1 receptor) agonist activity in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.11.The method of claim 10, wherein the method is for treating or preventing obesity, hypertension, diabetes, hyperlipidemia, hypoglycemia, cardiovascular disorder, coronary artery disease, fatty liver, alcoholic steatohepatitis, chronic kidney disease, insulin resistance, or impaired glucose tolerance.

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