GLP-1 receptor agonist, and uses thereof

Abstract

The present invention relates to a compound having a novel structure that binds to the glucagon-like peptide-1 receptor (GLP-1R) and acts as an agonist or a modulator thereof, a preparation method thereof, and uses thereof. The compound of the present invention can bind to the GLP-1 receptor and exhibit agonist activity thereof, and thus may be usefully employed for the treatment or prevention of GLP-1 receptor activity-associated diseases.

Description

GLP-1 RECEPTOR AGONIST, AND USES THEREOF

[0001] The present invention relates to a compound having a novel structure that binds to the glucagon-like peptide-1 receptor (GLP-1R) and acts as an agonist or a modulator thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a preparation method thereof, and uses thereof.

[0002] Diabetes is a metabolic disease caused by a lack of insulin secretion or action, and may be broadly categorized into type 1 and type 2 depending on the mechanism. Type 1 diabetes is caused by autoimmune destruction of the beta cells of the pancreas, resulting in a deficiency of insulin that should be secreted. Type 2 diabetes, also known as non-insulin-dependent diabetes, primarily occurs when the amount of insulin produced in response to an increase in blood sugar is insufficient for cells to absorb glucose effectively, thereby failing to lower blood sugar levels adequately. Treatment of type 1 diabetes requires insulin therapy, involving the external administration of insulin, while type 2 diabetes is treated with a single or multiple agents or insulin therapy, depending on the severity of the disease.

[0003] Currently known oral diabetes medications include insulin secretagogues, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, and sodium-glucose co-transporter 2 (SGLT-2) selective inhibitors. Despite the positive aspects of maintaining sustained glycemic normalization, many of the oral diabetes medications currently in clinical use have limited efficacy or cause a variety of side effects, including hypoglycemia, diarrhea, weight gain, cardiovascular problems, and liver toxicity when taken long-term. In addition, insulin administration, the last treatment method, requires subcutaneous injections 2-3 times daily, which is inconvenient and has the potential to cause hypoglycemia, which is the biggest side effect. To address these issues, GLP-1 receptor agonists have recently emerged as the next generation of diabetes treatments.

[0004] GLP-1 (glucagon-like peptide-1) is a 30-amino acid long incretin hormone that is secreted by L-cells in the intestine in response to food intake. GLP-1 not only directly enhances meal-induced insulin secretion from pancreatic beta cells, but also plays an important role in controlling postprandial blood glucose by promoting glucose-dependent insulin secretion by the pancreas in healthy individuals (ChemMedChem 13 (2018) 662-671).

[0005] GLP-1 inhibits glucagon secretion, which causes the liver to produce less glucose. GLP-1 also delays gastric emptying, slows small intestinal motility, and delays food absorption. GLP-1 receptor agonists, such as GLP-1, its analogues or oral low-molecular-weight compounds, have shown great promise in clinical trials for the treatment of metabolic syndrome including type 2 diabetes, nonalcoholic steatohepatitis (NASH), obesity, and cardiovascular disease, and induce numerous biological effects such as stimulation of insulin secretion, inhibition of glucagon secretion, inhibition of gastric emptying, inhibition of gastric or intestinal motility, and induction of weight loss ((i) Cardiovascular Diabetology 2014, 13:142; (ii) Front. Endocrinol. 14 (2023) 1085799; (iii) Mol. Metab. 57 (2022) 101351). It also has a pancreatic protective function even on long-term use, and can maintain normal blood sugar levels for long periods of time without the risk of hypoglycemia.

[0006] Therefore, the present inventors conducted extensive research on a GLP-1 receptor agonist having a novel structure, and completed the present invention by confirming that the compound described below has excellent effects as a GLP-1 receptor agonist.

[0007] An object of the present invention is to provide a compound having a novel structure that binds to the glucagon-like peptide-1 receptor (GLP-1R) and acts as an agonist thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0008] Another object of the present invention is to provide a preparation method of the compound.

[0009] Still another object of the present invention is to provide uses of the compound. Specifically, the present invention aims to provide a pharmaceutical composition comprising a compound having a novel structure that binds to the glucagon-like peptide-1 receptor (GLR-1R) and acts as an agonist thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, uses thereof for the manufacture of a medicament for preventing or treating a GLP-1 receptor activity-associated disease, and a method for preventing or treating a GLP-1 receptor activity-associated disease comprising administering a therapeutically effective amount of the compounds.

[0010] The present inventors found a compound having a novel structure that binds to the glucagon-like peptide-1 receptor (GLP-1R) and acts as an agonist thereof, and employed to inhibit or treat a GLP-1 receptor activity-associated disease, thereby completing the present invention.

[0011] These will be described in detail below. All combinations of various elements disclosed in the present invention fall within the scope of the present invention. In addition, it cannot be considered that the scope of the present invention is limited by specific descriptions described below.

[0012] GLP-1 receptor agonist

[0013] The present invention provides a compound represented by the following Chemical Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0014] [Chemical Formula I]

[0015]

[0016] in Chemical Formula I above,

[0017] A1to A4are each independently CRAor N;

[0018] RAis -H, -C1-4alkyl, -C1-4haloalkyl, or -halo;

[0019] ring X is or ;

[0020] RX1is -C1-4alkyl, -C1-4alkylene-O-C1-4alkyl, -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl), wherein one or more H in the -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl) ring may be substituted with -C1-4alkyl, -CN, -C1-4cyanoalkyl, -C1-4haloalkyl, or -halo;

[0021] p is 0, 1, 2, 3, or 4;

[0022] RX2is -(CH2)q-C(=O)OH or -(CH=CH)-C(=O)OH;

[0023] q is 0, 1, or 2;

[0024] RX3and RX4are each independently -C1-4alkyl, -C1-4haloalkyl, or -halo;

[0025] ring Y is or ;

[0026] Y1is NRYor O;

[0027] RYis -H, -C1-4alkyl, -C(=O)-C1-4alkyl, or -C(=O)-O-C1-4alkyl;

[0028] L is -CH2-O- or -O-CH2-, wherein the carbon of -CH2-O- is connected to ring Z and the oxygen of -O-CH2- is connected to ring Z; and

[0029] ring Z is phenyl or a 6-membered heteroaryl, wherein one or more H of the phenyl or 6-membered heteroaryl ring may be substituted with -C1-4alkyl, -C1-4cyanoalkyl, -C1-4aminoalkyl, -C1-4hydroxyalkyl, -C1-4haloalkyl, -CN, -OC1-4alkyl, -OC1-4haloalkyl, -S(=O)2-C1-4alkyl, or -halo.

[0030] In addition, according to an embodiment of the present invention, the compound represented by Chemical Formula I of the present invention may be in the following ranges:

[0031] A1to A3are each independently CRAor N;

[0032] A4is CRA;

[0033] RAis -H, -C1-4haloalkyl, or -halo;

[0034] ring X is or ;

[0035] RX1is -C1-4alkyl, -C1-4alkylene-O-C1-4alkyl, -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl), wherein one or more H in the -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl) ring may be substituted with -C1-4alkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, or -halo;

[0036] p is 0, 1, or 2;

[0037] RX2is -C(=O)OH or -(CH=CH)-C(=O)OH;

[0038] RX3and RX4are each independently -C1-4haloalkyl or -halo;

[0039] ring Y is or ;

[0040] Y1is NRYor O;

[0041] RYis -H, -C1-4alkyl, -C(=O)-C1-4alkyl, or -C(=O)-O-C1-4alkyl;

[0042] L is -CH2-O- or -O-CH2-, wherein the carbon of -CH2-O- is connected to ring Z and the oxygen of -O-CH2- is connected to ring Z; and

[0043] ring Z is phenyl or pyridinyl, wherein one or more H of the phenyl or pyridinyl ring may be substituted with -H, -C1-4alkyl, -C1-4haloalkyl, -CN, -OC1-4alkyl, -OC1-4haloalkyl, -S(=O)2-C1-4alkyl, or -halo.

[0044] In addition, the present invention provides a compound represented by the following Chemical Formula II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0045] [Chemical Formula II]

[0046]

[0047] in Chemical Formula II above,

[0048] A1to A4are each independently CRAor N;

[0049] RAis -H, -C1-4alkyl, -C1-4haloalkyl, or -halo;

[0050] ring X is or ;

[0051] RX1is -C1-4alkyl, -C1-4alkylene-O-C1-4alkyl, -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl), wherein one or more H in the -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl) ring may be substituted with -C1-4alkyl, -CN, -C1-4cyanoalkyl, -C1-4haloalkyl, or -halo;

[0052] p is 0, 1, 2, 3, or 4;

[0053] RX2is -(CH2)q-C(=O)OH or -(CH=CH)-C(=O)OH;

[0054] q is 0, 1, or 2;

[0055] RX3and RX4are each independently -C1-4alkyl, -C1-4haloalkyl, or -halo;

[0056] Y1is NRYor O;

[0057] RYis -H, -C1-4alkyl, -C(=O)-C1-4alkyl, or -C(=O)-O-C1-4alkyl;

[0058] L is -CH2-O- or -O-CH2-, wherein the carbon of -CH2-O- is connected to ring Z and the oxygen of -O-CH2- is connected to ring Z; and

[0059] ring Z is phenyl or a 6-membered heteroaryl, wherein one or more H of the phenyl or 6-membered heteroaryl ring may be substituted with -C1-4alkyl, -C1-4cyanoalkyl, -C1-4aminoalkyl, -C1-4hydroxyalkyl, -C1-4haloalkyl, -CN, -OC1-4alkyl, -OC1-4haloalkyl, -S(=O)2-C1-4alkyl, or -halo.

[0060] In addition, the present invention provides a compound represented by the following Chemical Formula III, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0061] [Chemical Formula III]

[0062]

[0063] in Chemical Formula III above,

[0064] A1to A4are each independently CRAor N;

[0065] RAis -H, -C1-4alkyl, -C1-4haloalkyl, or -halo;

[0066] ring X is or ;

[0067] RX1is -C1-4alkyl, -C1-4alkylene-O-C1-4alkyl, -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl), wherein one or more H in the -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl) ring may be substituted with -C1-4alkyl, -CN, -C1-4cyanoalkyl, -C1-4haloalkyl, or -halo;

[0068] p is 0, 1, 2, 3, or 4;

[0069] RX2is -(CH2)q-C(=O)OH or -(CH=CH)-C(=O)OH;

[0070] q is 0, 1, or 2;

[0071] RX3and RX4are each independently -C1-4alkyl, -C1-4haloalkyl, or -halo;

[0072] L is -CH2-O- or -O-CH2-, wherein the carbon of -CH2-O- is connected to ring Z and the oxygen of -O-CH2- is connected to ring Z; and

[0073] ring Z is phenyl or a 6-membered heteroaryl, wherein one or more H of the phenyl or 6-membered heteroaryl ring may be substituted with -C1-4alkyl, -C1-4cyanoalkyl, -C1-4aminoalkyl, -C1-4hydroxyalkyl, -C1-4haloalkyl, -CN, -OC1-4alkyl, -OC1-4haloalkyl, -S(=O)2-C1-4alkyl, or -halo.

[0074] In addition, the present invention provides a compound represented by the following Chemical Formula IV, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0075] [Chemical Formula IV]

[0076]

[0077] in Chemical Formula IV above,

[0078] A1to A4are each independently CRAor N;

[0079] RAis -H, -C1-4alkyl, -C1-4haloalkyl, or -halo;

[0080] RX1is -C1-4alkyl, -C1-4alkylene-O-C1-4alkyl, -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl), wherein one or more H in the -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl) ring may be substituted with -C1-4alkyl, -CN, -C1-4cyanoalkyl, -C1-4haloalkyl, or -halo;

[0081] p is 0, 1, 2, 3, or 4;

[0082] RX2is -(CH2)q-C(=O)OH or -(CH=CH)-C(=O)OH;

[0083] q is 0, 1, or 2;

[0084] RX3is -C1-4alkyl, -C1-4haloalkyl, or -halo;

[0085] ring Y is or ;

[0086] Y1is NRYor O;

[0087] RYis -H, -C1-4alkyl, -C(=O)-C1-4alkyl, or -C(=O)-O-C1-4alkyl;

[0088] L is -CH2-O- or -O-CH2-, wherein the carbon of -CH2-O- is connected to ring Z and the oxygen of -O-CH2- is connected to ring Z; and

[0089] ring Z is phenyl or a 6-membered heteroaryl, wherein one or more H of the phenyl or 6-membered heteroaryl ring may be substituted with -C1-4alkyl, -C1-4cyanoalkyl, -C1-4aminoalkyl, -C1-4hydroxyalkyl, -C1-4haloalkyl, -CN, -OC1-4alkyl, -OC1-4haloalkyl, -S(=O)2-C1-4alkyl, or -halo.

[0090] In addition, the present invention provides a compound represented by the following Chemical Formula V, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0091] [Chemical Formula V]

[0092]

[0093] in Chemical Formula V above,

[0094] A1to A4are each independently CRAor N;

[0095] RAis -H, -C1-4alkyl, -C1-4haloalkyl, or -halo;

[0096] RX1is -C1-4alkyl, -C1-4alkylene-O-C1-4alkyl, -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl), wherein one or more H in the -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl) ring may be substituted with -C1-4alkyl, -CN, -C1-4cyanoalkyl, -C1-4haloalkyl, or -halo;

[0097] p is 0, 1, 2, 3, or 4;

[0098] RX4is -C1-4alkyl, -C1-4haloalkyl, or -halo;

[0099] ring Y is or ;

[0100] Y1is NRYor O;

[0101] RYis -H, -C1-4alkyl, -C(=O)-C1-4alkyl, or -C(=O)-O-C1-4alkyl;

[0102] L is -CH2-O- or -O-CH2-, wherein the carbon of -CH2-O- is connected to ring Z and the oxygen of -O-CH2- is connected to ring Z; and

[0103] ring Z is phenyl or a 6-membered heteroaryl, wherein one or more H of the phenyl or 6-membered heteroaryl ring may be substituted with -C1-4alkyl, -C1-4cyanoalkyl, -C1-4aminoalkyl, -C1-4hydroxyalkyl, -C1-4haloalkyl, -CN, -OC1-4alkyl, -OC1-4haloalkyl, -S(=O)2-C1-4alkyl, or -halo.

[0104] In addition, according to an embodiment of the present invention, specific compounds of the present invention may be any one selected from the compounds described in Table 1 below.

[0105] [Table 1]

[0106]

[0107] In the present invention, "alkyl" may refer to a straight-chain or branched-chain acyclic, cyclic, or saturated hydrocarbon in which the carbon atoms are connected, unless otherwise specified. For example, "C1-4alkyl" may mean an alkyl containing 1 to 4 carbon atoms. The acyclic alkyl may include, for example, methyl, ethyl,n-propyl,n-butyl, isopropyl,sec-butyl, isobutyl,tert-butyl, and the like, but is not limited to thereto. The cyclic alkyl may be used interchangeably with "cycloalkyl" in the present specification, and may include, as an example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, but is not limited thereto.

[0108] In the present invention, "alkenyl" and "alkynyl" may refer to a straight-chain or branched-chain acyclic, cyclic, or unsaturated hydrocarbon to which they are bonded. For example, "C1-4alkenyl" may indicate an unsaturated hydrocarbon of 1 to 4 carbon atoms with at least one double bond, and "C1-4alkynyl" may indicate an unsaturated hydrocarbon of 1 to 4 carbon atoms with at least one triple bond.

[0109] In the present invention, "alkoxy" may refer to -(O-alkyl) as an alkyl ether group, wherein the alkyl is the same as defined above. For example, "C1-4alkoxy" may mean an alkoxy containing C1-4alkyl, i.e. -(O-C1-4alkyl); and examples of the alkoxy may include, but are not limited to, methoxy, ethoxy,n-propoxy, isopropoxy,n-butoxy, isobutoxy,sec-butoxy,tert-butoxy, and the like.

[0110] In the present invention, "halo" may be F, Cl, Br or I.

[0111] In the present invention, "haloalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with at least one halo as defined herein. Examples of the haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl orn-butyl independently substituted with at least one halogen such as F, Cl, Br, or I.

[0112] In the present invention, "hydroxyalkyl" may refer to a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with -OH. Examples of the hydroxyalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl orn-butyl independently substituted with at least one hydroxy.

[0113] In the present invention, "aminoalkyl" may refer to a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with amino (-NR'R''). Herein, R' and R'' may each independently be selected from the group consisting of hydrogen and C1-4alkyl, and the selected R' and R'' may each independently be substituted or unsubstituted.

[0114] In the present invention, "cyanoalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (-CN).

[0115] In the present invention, "cycloalkyl" may refer to a hydrocarbon ring that does not contain a hetero atom (N, O, P, P(=O), S, or the like) in the ring, and may be saturated or partially unsaturated. Herein, when unsaturated, the cycloalkyl may be referred to as a cycloalkenyl. Unless otherwise stated, the cycloalkyl may be a single ring or multiple rings such as spiro rings, bridged rings or fused rings.

[0116] In the present invention, the term "heterocycloalkyl" may mean a ring containing 1 to 5 heteroatoms selected from N, O and S as atoms forming the ring, and may be saturated or partially unsaturated. Herein, when unsaturated, the heterocycloalkyl may be referred to as a heterocycloalkene. Unless otherwise stated, the heterocycloalkyl may be a single ring or multiple rings such as spiro rings, bridged rings or fused rings. Further, "3 to 12-membered heterocycloalkyl" may mean a heterocycloalkyl containing 3 to 12 atoms forming a ring. Examples of the heterocycloalkyl may include, but are not limited to, pyrrolidine, piperidin, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1S,4S)-2-azabicyclo[2.2.2]octane, or (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane, and the like.

[0117] In the present invention, "arene" may mean an aromatic hydrocarbon ring. The arene may be monocyclic arene or polycyclic arene. The number of ring-forming carbon atoms in the arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less. Examples of arene may include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quaterbenzene, quinquebenzene, sexibenzene, triphenylene, pyrene, benzofluoranthene, chrysene, and the like. In the present specification, a moiety obtained by removing one hydrogen atom from the above "arene" is referred to as "aryl".

[0118] In the present invention, "heteroarene" may be a ring containing one or more of O, N, P, Si, and S as heterogeneous elements. The number of ring-forming carbon atoms of the heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. The polycyclic heteroarene may have, for example, a bicyclic or tricyclic structure. Examples of the heteroarene include, but not limited to, thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine,N-arylcarbazole,N-heteroarylcarbazole,N-alkylcarbazole, benzoxazole, benzoimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilole, dibenzofuran, and the like. In an embodiment of the present invention, the heteroarene may also include a bicyclic heterocyclo-arene including an arene ring fused to a heterocycloalkyl ring or a heteroarene fused to a cycloalkyl ring. In the present specification, a moiety obtained by removing one hydrogen atom from the above "heteroarene" is referred to as "heteroaryl".

[0119] In the present invention, "hydroarene" or "hydroaryl" is one in which one or more double bonds in the aromatic hydrocarbon ring are saturated.

[0120] In the present invention, "heterohydroarene" or "heterohydroaryl" is one in which one or more double bonds in the "heteroarene" or "heteroaryl" ring are saturated.

[0121] In the present invention, "ring" may be a single ring or multiple rings. The multiple rings may be spiro rings, bridged rings, or fused rings.

[0122] The compounds represented by Chemical Formulas I to V of the present invention may contain at least one asymmetric carbon and thus may be present as a racemate, a racemic mixture, a single enantiomer, a diastereomeric mixture and each diastereomer. These stereoisomers may be separated by conventional techniques, and for example, the compounds represented by Chemical Formulas I to V may be separated by column chromatography, HPLC, or the like. Otherwise, each stereoisomer of the compounds represented by Chemical Formulas I to V may be stereospecifically synthesized using optically pure starting materials and / or reagents with known configurations.

[0123] In the present invention, "stereoisomer" means a compound that has the same chemical formula or molecular formula but is sterically different. In the present invention, the stereoisomer includes optical isomer, enantiomer, diasteromer, cis / trans isomer, rotamer, and atropisomer. Each of these isomers, racemates, and mixtures thereof are also included within the scope of the present invention. For example, since the compound of Chemical Formulas I to V of the present invention is not specified in stereochemical structure, the compound may include the stereoisomers of Chemical Formulas I to V. Unless otherwise specified, a solid bond ( ) connected to an asymmetric carbon atom may include a wedge solid bond ( ) or a wedge dashed bond ( ) representing the absolute arrangement of stereocenters.

[0124] The compound represented by Chemical Formulas I to V of the present invention may be present in the form of a "pharmaceutically acceptable salt". Thus, pharmaceutically acceptable salts of the compound represented by Chemical Formulas I to V above are included in the scope of the compound of the present invention. The term "pharmaceutically acceptable salt" as used herein refers to a concentration having a relatively non-toxic and harmless effective effect on patients, which includes any organic acid or inorganic acid addition salt of the compound represented by Chemical Formulas I to V in which side effects caused by these salts do not reduce the beneficial efficacy of the compound.

[0125] In the present invention, a pharmaceutically acceptable salt may mean a salt commonly used in the pharmaceutical industry, for example, inorganic ion salts prepared with calcium, potassium, sodium, magnesium, and the like, inorganic acid salts prepared with hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, and the like, organic acid salts prepared with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, and the like, sulfonic acid salts prepared with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and the like, amino acid salts prepared with glycine, arginine, lysine, and the like, and amine salts prepared with tromethamine, trimethylamine, triethylamine, ammonia, pyridine, picoline, and the like, but the types of salts meant in the present invention are not limited to these listed salts.

[0126] Preferred salts in the present invention include inorganic ion salts prepared with calcium, potassium, sodium, magnesium, and the like, or amine salts prepared with tromethamine, trimethylamine, triethylamine, ammonia, pyridine, picoline, and the like.

[0127] Preparation method of GLP-1 receptor agonist

[0128] The present invention provides a preparation method of compounds represented by the following Chemical Formulas I to V, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0129] Preferred methods of preparing the compounds represented by Chemical Formulas I to V of the present invention, stereoisomers thereof, or pharmaceutically acceptable salts thereof are as shown in the following Reaction Schemes 1, 2, 2-1, 2-2, 2-3, 3, and 3-1, which include modifications as will be apparent to those skilled in the art:

[0130] [Reaction Scheme 1]

[0131]

[0132] According to the above Reaction Scheme 1, Compound 1-3 may be prepared through a substitution reaction between Compounds 1-1 and 1-2, and then Compound 1-4 may be prepared using palladium carbon. Then, Compound 1-6 may be prepared through amide coupling with Compound 1-5, Compound 1-7 may be prepared under acid conditions, and then Compound 1-8 may be prepared by removing the amine protecting group. This compound serves as a core skeleton for the synthesis of the desired GLP-1 receptor agonist derivative, which is used in the synthesis of subsequent compounds.

[0133] [Reaction Scheme 2]

[0134]

[0135] According to the above Reaction Scheme 2, Compound 2-3 may be prepared through a coupling reaction or substitution reaction of Compounds 2-1 and 2-2, and then Compound 2-4 may be prepared through a coupling reaction with Compound 1-8 prepared in Reaction Scheme 1. Then, the alkyl group may be removed through a hydrolysis reaction or under acid conditions to prepare Compound 2-5.

[0136] Compound 2-5 prepared by the above Reaction Scheme 2 may be Compounds 9, 13, 14, 15, 16, 17, 18, 19, 20, 23, 24, 25, 26, 27, 31, 33, 35, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 52, etc.

[0137] [Reaction Scheme 2-1]

[0138]

[0139] According to the above Reaction Scheme 2-1, Compound 2-3 and Compound 2-1-1 may be subjected to a palladium coupling reaction to prepare Compound 2-1-2, and then the amine protecting group may be removed to prepare Compound 2-1-3. Then, Compound 2-1-5 may be prepared through a substitution reaction with Compound 2-1-4, and then the alkyl group may be removed under acid conditions to prepare Compound 2-1-6.

[0140] Compound 2-1-6 prepared by the above Reaction Scheme 2-1 may be Compounds 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 22, 29, 34, 37, etc.

[0141] [Reaction Scheme 2-2]

[0142]

[0143] According to the above Reaction Scheme 2-2, Compound 2-2-2 may be prepared through a substitution reaction between Compound 2-1-3 prepared in the above Reaction Scheme 2-1 and Compound 2-2-1, and then Compound 2-2-3 may be prepared by removing the alkyl group under the same acid conditions as in Reaction Scheme 2-1.

[0144] Compound 2-2-3 prepared by the above Reaction Scheme 2-2 may be Compounds 21, 32, etc.

[0145] [Reaction Scheme 2-3]

[0146]

[0147] According to the above Reaction Scheme 2-3, Compound 2-3-2 may be prepared through a substitution reaction between Compound 2-1-3 prepared in the above Reaction Scheme 2-1 and Compound 2-3-1, and then Compound 2-3-3 may be prepared by removing the alkyl group under the same conditions as in Reaction Scheme 2-1.

[0148] Compound 2-3-3 prepared by the above Reaction Scheme 2-3 may be Compound 28, etc.

[0149] [Reaction Scheme 3]

[0150]

[0151] According to the above Reaction Scheme 3, Compound 3-2 may be prepared through a palladium-mediated coupling reaction of Compound 2-3 prepared in the above Reaction Scheme 2 and Compound 3-1, and then Compound 3-4 may be prepared through a substitution reaction with Compound 3-3. Then, after removing the amine protecting group, Compound 3-6 may be prepared through a reductive amination reaction, and Compound 3-7 may be prepared by removing the alkyl group under the same conditions as in Reaction Scheme 2.

[0152] Compound 3-7 prepared by the above Reaction Scheme 3 may be Compounds 36, 51, 53, etc.

[0153] [Reaction Scheme 3-1]

[0154]

[0155] According to the above Reaction Scheme 3-1, Compound 3-1-1 may be prepared by removing the alkyl group from Compound 3-4, which is prepared in the above Reaction Scheme 3, under the same conditions as in Reaction Scheme 2.

[0156] Compound 3-1-1 prepared by the above Reaction Scheme 3-1 may be Compound 30, etc.

[0157] Uses of GLP-1 receptor agonist

[0158] The present invention provides uses of the compounds represented by Chemical Formulas I to V, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0159] [Chemical Formula I]

[0160]

[0161] [Chemical Formula II]

[0162]

[0163] [Chemical Formula III]

[0164]

[0165] [Chemical Formula IV]

[0166]

[0167] [Chemical Formula V]

[0168]

[0169] wherein Chemical Formulas I to V are as defined above.

[0170] According to an embodiment of the present invention, the present invention provides a pharmaceutical composition comprising the compounds represented by Chemical Formulas I to V, stereoisomers thereof, or pharmaceutically acceptable salts thereof as active ingredients.

[0171] In addition, according to an embodiment of the present invention, the present invention provides a pharmaceutical composition for the prevention or treatment of a glucagon-like peptide-1 (GLP-1) receptor activity-associated disease, comprising the compounds represented by Chemical Formulas I to V as shown above, stereoisomers thereof, or pharmaceutically acceptable salts thereof as active ingredients.

[0172] The glucagon-like peptide-1 (GLP-1) receptor activity-associated disease may comprise metabolic, immune, inflammatory, fibrotic, neurodegenerative diseases, circulatory diseases and renal diseases, and specifically comprise all symptoms or diseases associated with abnormal activity of GLP-1 receptors, including type 2 diabetes, obesity, non-alcoholic fatty liver disease, polycystic ovary syndrome, heart disease, stroke, diabetic nephropathy, dementia, Parkinson's disease, depression, alcoholism, inflammatory bowel disease, and multiple sclerosis, etc.

[0173] Examples of the glucagon-like peptide-1 (GLP-1)-mediated diseases may comprise endocrine, nutritional, and metabolic diseases; immune, inflammatory, and fibrotic diseases; mental and behavioral disorders; neurodegenerative diseases; circulatory diseases; or renal diseases.

[0174] The endocrine, nutritional and metabolic diseases may be type 2 diabetes, obesity or polycystic ovary syndrome, the immune, inflammatory and fibrotic diseases may be inflammatory bowel disease, non-alcoholic fatty liver disease or multiple sclerosis, the mental and behavioral disorder may be depression or alcoholism, the neurodegenerative disease may be dementia or Parkinson's disease, the circulatory disease may be stroke or cardiovascular disease, and the renal disease may be diabetic nephropathy.

[0175] The pharmaceutically acceptable salts are as described above in the pharmaceutically acceptable salts of the compounds represented by Chemical Formulas I to V of the present invention.

[0176] For administration, the pharmaceutical composition of the present invention may further comprise at least one or more pharmaceutically acceptable carrier in addition to the compounds represented by Chemical Formulas I to V, stereoisomers or pharmaceutically acceptable salts thereof. The pharmaceutically acceptable carrier may be saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, or a mixture of one or more of these ingredients, and, if necessary, may contain other conventional additives such as antioxidants, buffers, bacteriostatic agents, and the like. Further, diluents, dispersants, surfactants, binders and lubricants may be additionally added and may be formulated into injectable formulations such as aqueous solutions, suspensions, emulsions, and the like, pills, capsules, granules or tablets. Accordingly, the pharmaceutical composition of the present invention may be a patch, liquid, pill, capsule, granule, tablet, suppository, or the like. These formulations may be prepared by conventional methods used for formulation in the art or a method disclosed in the document [see, Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA], and may be formulated into various formulations depending on each disease or component.

[0177] The composition of the present invention may be administered orally or parenterally (for example, intravenous, subcutaneous, intraperitoneal or topical application) according to the desired method, and the dosage varies depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease. The daily dosage of the compounds represented by Chemical Formulas I to V of the present invention is about 1 to 1000 mg / kg, preferably 10 to 200 mg / kg, and may be divided and administered once or several times a day.

[0178] The pharmaceutical composition of the present invention may further comprise at least one active ingredient exhibiting the same or similar efficacy in addition to the compounds represented by Chemical Formulas I to V, stereoisomers or pharmaceutically acceptable salts thereof.

[0179] The present invention provides a method for preventing or treating GLP-1 receptor activity-associated diseases comprising administering a therapeutically effective amount of the compounds represented by Chemical Formulas I to V, stereoisomers or pharmaceutically acceptable salts thereof.

[0180] The term "therapeutically effective amount" used herein refers to an amount of the compounds represented by Chemical Formulas I to V effective for the prevention or treatment of GLP-1 receptor activity-associated diseases.

[0181] In addition, the present invention provides a method for binding to the glucagon-like peptide-1 receptor (GLP-1R) and acting as an agonist thereof by administering to a mammal, including a human, the compounds represented by Chemical Formulas I to V, stereoisomers or pharmaceutically acceptable salts thereof.

[0182] The method for preventing or treating GLP-1 receptor activity-associated diseases of the present invention comprises not only dealing with the disease itself prior to the onset of symptoms, but also inhibiting or avoiding the symptoms thereof by administering the compounds represented by Chemical Formulas I to V, stereoisomers or pharmaceutically acceptable salts thereof. In the management of a disease, the prophylactic or therapeutic dose of a particular active ingredient may vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. The dosage and frequency of administration may vary depending on the age, weight and response of the individual patient. Suitable dosage regimens can be readily selected by those skilled in the art who will naturally take these factors into account. In addition, the method for preventing or treating GLP-1 receptor activity-associated diseases of the present invention may further administering a therapeutically effective amount of an additional active agent that is helpful in treating the diseases together with the compounds represented by Chemical Formulas I to V, wherein the additional active agent may exhibit synergistic or adjuvant effects together with the compounds represented by Chemical Formulas I to V above.

[0183] In addition, the present invention provides uses of compounds represented by Chemical Formulas I to V, stereoisomers thereof, or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of GLP-1 receptor activity-associated diseases. The compounds represented by Chemical Formulas I to V for the manufacture of medicaments may be mixed with acceptable adjuvants, diluents, carriers, and the like, and may be prepared as a combined preparation with other active agents to have a synergistic effect of the active ingredients.

[0184] In addition, the present invention provides uses of compounds represented by Chemical Formulas I to V, stereoisomers thereof, or pharmaceutically acceptable salts thereof for the treatment of GLP-1 receptor activity-associated diseases.

[0185] Matters described in the uses, compositions, and treatment methods of the present invention are equally applied unless they contradict each other.

[0186] The compounds represented by Chemical Formulas I to V of the present invention, stereoisomers thereof, or pharmaceutically acceptable salts thereof may have remarkably excellent effects in preventing or treating GLP-1 receptor activity-associated diseases by binding to the glucagon-like peptide-1 receptor (GLP-1R).

[0187] Hereinafter, the present invention will be described in more detail through Examples and Experimental Examples. However, these Examples and the like are only presented as examples of the present invention, and the scope of the present invention is not limited only to these Examples.

[0188] Preparation of Compounds according to Examples

[0189] Specific methods for preparing compounds represented by Chemical Formulas I to V are described as follows.

[0190] Example 6: Synthesis of 2-[[5-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydrooxazin-2-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (Compound 6)

[0191] [Step 1] Synthesis of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile

[0192]

[0193] A solution of 2-bromo-6-fluoro-pyridine (1.000 g, 5.682 mmol), 3-fluoro-4-(hydroxymethyl)benzonitrile (1.030 g, 6.815 mmol), and cesium carbonate (2.220 g, 6.814 mmol) dissolved inN,N-dimethylformamide (8.5 mL) at room temperature was stirred at 90℃ for 18 hours, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 24 g cartridge; 10%-aqueous ethyl acetate solution / 90%-aqueous hexane solution = 0% to 30%) and concentrated to obtain the desired compound (1.300 g, 74.50%) as a white solid.

[0194] [Step 2] Synthesis of tert-butyl 5-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydrooxazine-2-carboxylate

[0195]

[0196] A solution of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (200.000 mg, 0.651 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydrooxazine-2-carboxylate (243.000 mg, 0.781 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (42.000 mg, 0.064 mmol), and potassium carbonate (180.000 mg, 1.302 mmol) dissolved in 1,4-dioxane (1.85 mL) / water (0.650 mL) at room temperature was stirred at 100℃ for 2 hours. Then, the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 50%) and concentrated to obtain the desired compound (122.000 mg, 45.54%) as a pale yellow solid.

[0197] [Step 3] Synthesis of 4-[[6-(3,6-dihydro-2H-oxazin-5-yl)-2-pyridyl]oxymethyl]-3-fluoro-benzonitrile; 2,2,2-trifluoroacetic acid

[0198]

[0199] To a solution of tert-butyl 5-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydrooxazine-2-carboxylate (398.000 mg, 0.967 mmol) dissolved in dichloromethane (4.8 mL) at room temperature, 2,2,2-trifluoroacetic acid (1.5 mL, 19.602 mmol) was added and the mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the obtained product was used without further purification (395.000 mg, 96.00%, dark brown solid).

[0200] [Step 4]Synthesis of tert-butyl 2-[[5-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydrooxazin-2-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0201]

[0202] A solution of 4-[[6-(3,6-dihydro-2H-oxazin-5-yl)-2-pyridyl]oxymethyl]-3-fluoro-benzonitrile; 2,2,2-trifluoroacetic acid (100.000 mg, 0.235 mmol), tert-butyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (79.000 mg, 0.235 mmol), potassium carbonate (195.000 mg, 1.411 mmol), and potassium iodide (20.000 mg, 0.120 mmol) dissolved in acetonitrile (1.1 mL) at room temperature was stirred at 50℃ for 5 hours. Then, the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; hexane / ethyl acetate = 50% to 100%) and concentrated to obtain the desired compound (123.000 mg, 85.52%) as a pale yellow solid.

[0203] [Step 5]Synthesis of 2-[[5-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydrooxazin-2-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid

[0204]

[0205] To a solution of tert-butyl 2-[[5-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydrooxazin-2-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (123.000 mg, 0.201 mmol) dissolved in dichloromethane (2 mL) at room temperature, trifluoroacetic acid (0.54 mL, 7.057 mmol) was added and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the desired compound (15.000 mg, 13.43%) as a yellow solid.

[0206] 1H NMR(400 MHz, CDCl3)δ8.24 (s, 1H), 8.06 (dd,J= 1.4, 8.5 Hz, 1H), 7.84 (d,J= 8.5 Hz, 1H), 7.60-7.57 (m, 2H), 7.43 (d,J= 8.0 Hz, 1H), 7.36 (dd,J= 1.2, 9.2 Hz, 1H), 6.95 (d, 7.5 Hz, 1H), 6.71 (d,J= 8.2 Hz, 1H), 6.64 (s, 1H), 5.47 (s, 2H), 5.22-5.21 (m, 1H), 4.74-4.69 (m, 4H), 4.65-4.60 (m, 1H), 4.52 (s, 2H), 4.40-4.35 (m, 1H), 3.63 (s, 2H), 2.76-2.72 (m, 1H), 2.47-2.41 (m, 1H);LRMS(ES) m / z 556.1 (M++1).

[0207] Examples 1 to 5, 7, 8, 10 to 12, 21, 22, 28, 29, 32, 34 and 37

[0208] Compounds according to Examples 1, 2, 3, 4, 5, 7, 8, 10, 11, 12, 21, 22, 28, 29, 32, 34 and 37 were prepared according to substantially the same process as the synthesis ofCompound 6described above, and the name,1H-NMR and MS analysis results of respective compounds according to Examples are shown in Table 2 below.

[0209] [Table 2]

[0210]

[0211] Example 9: Synthesis of 2-[[3-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (Compound 9)

[0212] [Step 1] Synthesis of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile

[0213]

[0214] A solution of 2-bromo-6-fluoro-pyridine (3.0 g, 17.0 mmol), 3-fluoro-4-(hydroxymethyl)benzonitrile (3.09 g, 20.5 mmol), and cesium carbonate (6.66 g, 20.5 mmol) dissolved inN,N-dimethylformamide (25 mL) at room temperature was stirred at 90℃ for 18 hours, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 40 g cartridge; 10%-aqueous ethyl acetate solution / 90%-aqueous hexane solution = 0% to 30%) and concentrated to obtain the desired compound (3.87 g, 73.9%) as a white solid.

[0215] [Step 2] Synthesis of methyl 4-nitro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate

[0216]

[0217] A solution of methyl 3-fluoro-4-nitro-benzoate (5.0 g, 25.1 mmol), [(2S)-oxetan-2-yl]methanamine (2.4 g, 27.6 mmol), and potassium carbonate (6.94 g, 50.2 mmol) dissolved in dimethyl sulfoxide (63 mL) at room temperature was stirred at 90℃ for 18 hours, and then the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = 0% to 40%) and concentrated to obtain the desired compound (6.69 g, 100.00%) as an orange solid.

[0218] [Step 3] Synthesis of methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate

[0219]

[0220] A solution of methyl 4-nitro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (3.64 g, 13.7 mmol) and Pd / C (10%, 200 mg) dissolved in methanol (200 mL) at room temperature was stirred under a hydrogen balloon at room temperature for 3 hours. The reaction mixture was filtered through a pad of Celite to remove solids, then the solvent was removed from the obtained filtrate under reduced pressure, and the obtained product was used without further purification (3.2 g, 99.1%, colorless gel).

[0221] [Step 4] Synthesis of 2-(3-tert-butoxycarbonyl-3-azabicyclo[4.1.0]heptan-6-yl)acetic acid

[0222]

[0223] A solution of tert-butyl 6-(2-methoxy-2-oxo-ethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (10.0 g, 37.1 mmol) and aqueous sodium hydroxide solution (2 M, 37 mL, 371 mmol) dissolved in methanol (37 mL) was stirred at room temperature for 6 hours. 1 M aqueous hydrochloric acid solution was added to the reaction mixture until the pH reached 3 to 4. The precipitated solid was filtered, washed with distilled water, and dried to obtain the desired compound (8.88 g, 93.7%) as a white solid.

[0224] [Step 5] Synthesis of tert-butyl 6-[2-[4-methoxycarbonyl-2-[[(2S)-oxetan-2-yl]methylamino]anilino]-2-oxo-ethyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate

[0225]

[0226] A solution of 2-(3-tert-butoxycarbonyl-3-azabicyclo[4.1.0]heptan-6-yl)acetic acid (600 mg, 2.35 mmol), methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (555 mg, 2.35 mmol), EDC·HCl (901 mg, 4.70 mmol), and 4-(dimethylamino)pyridine (57 mg, 0.470 mmol) dissolved in dichloromethane (11 mL) at room temperature was stirred at room temperature. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 40 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (1.10 g, 98.8%) as a white foam solid.

[0227] [Step 6] Synthesis of methyl 2-[(3-tert-butoxycarbonyl-3-azabicyclo[4.1.0]heptan-6-yl)methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0228]

[0229] A solution of tert-butyl 6-[2-[4-methoxycarbonyl-2-[[(2S)-oxetan-2-yl]methylamino]anilino]-2-oxo-ethyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate (2.1 g, 4.43 mmol) dissolved in acetic acid (44 mL) at room temperature was stirred at 90℃ for 3 hours, and then the reaction was terminated by lowering the temperature to room temperature. The reaction mixture was concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 24 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (2.0 g, 99.0%) as a white foam solid.

[0230] [Step 7] Synthesis of methyl 2-(3-azabicyclo[4.1.0]heptan-6-ylmethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate; 2,2,2-trifluoroacetic acid

[0231]

[0232] A solution of methyl 2-[(3-tert-butoxycarbonyl-3-azabicyclo[4.1.0]heptan-6-yl)methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (2.0 g, 4.39 mmol) and 2,2,2-trifluoroacetic acid (6.72 mL, 87.8 mmol) dissolved in dichloromethane (22 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 24 g cartridge; methanol / dichloromethane = 0% to 20%) and concentrated to obtain the desired compound (1.52 g, 73.8%) as a pale yellow foam solid.

[0233] [Step 8] Synthesis of methyl 2-[[3-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0234]

[0235] A solution of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (400 mg, 1.30 mmol), methyl 2-(3-azabicyclo[4.1.0]heptan-6-ylmethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate; 2,2,2-trifluoroacetic acid (611 mg, 1.30 mmol), RuPhos palladium G3(109 mg, 0.130 mmol), and cesium carbonate (1.27 g, 3.91 mmol) dissolved in 1,4-dioxane (3 mL) at room temperature was stirred at 100℃ for 18 hours, and then the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (460 mg, 60.7%) as a white foam solid.

[0236] [Step 9] Synthesis of 2-[[3-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid

[0237]

[0238] A solution of methyl 2-[[3-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (307 mg, 0.528 mmol) and 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (2.0 M in H2O, 0.554 mL, 1.11 mmol) dissolved in acetonitrile (5 mL) at room temperature was stirred at 38℃ for 18 hours, and then the reaction was terminated by lowering the temperature to room temperature. 1 M hydrochloric acid was added to the reaction mixture until the pH reached 3 to 4, then distilled water was poured in, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (250 mg, 83.4%) as a pale yellow foam solid.

[0239] 1H NMR(400 MHz, CDCl3):δ8.18 (d,J= 12.1 Hz, 1H), 8.09 (d,J= 4.9 Hz, 1H), 8.00-7.88 (m, 1H), 7.59 (td,J= 7.5, 3.1 Hz, 1H), 7.50-7.39 (m, 2H), 7.33 (d,J= 9.3 Hz, 2H), 6.21-6.07 (m, 2H), 5.41 (t,J= 4.9 Hz, 2H), 5.33-5.17 (m, 1H), 4.55-4.72 (m, 2H), 4.44 (dt,J= 9.2, 6.0 Hz, 1H), 4.32 (dt,J= 9.2, 5.9 Hz, 1H), 4.05-3.87 (m, 1H), 3.73-3.57 (m, 1H), 3.35 (t,J= 9.8 Hz, 1H), 3.29-3.19 (m, 1H), 2.89-2.71 (m, 1H), 2.61-2.38 (m, 1H), 2.32 (br. s, 1H), 1.90 (br. s, 1H), 1.52-1.42 (m, 4H), 1.37 (br. s, 1H);LRMS(ES) m / z 568.6 (M++1).

[0240] Examples 13 to 18, 45 and 46

[0241] Compounds according to Examples 13 to 18, 45, and 46 were prepared according to substantially the same process as the synthesis ofCompound 9described above, and the name,1H-NMR and MS analysis results of respective compounds according to Examples are shown in Table 3 below.

[0242] [Table 3]

[0243]

[0244] Example 19: Synthesis of 2-[[(1R,6R)-3-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (Compound 19)

[0245] [Step 1] Synthesis of 2-[(1R,6R)-3-tert-butoxycarbonyl-3-azabicyclo[4.1.0]heptan-6-yl]acetic acid

[0246]

[0247] A solution of tert-butyl (1R,6R)-6-(2-methoxy-2-oxo-ethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (1.000 g, 3.71 mmol) and sodium hydroxide (2.00 M solution, 18.6 mL, 37.1 mmol) dissolved in methanol (18 mL) at room temperature was stirred at the same temperature for 6 hours. 1 M aqueous hydrochloric acid solution was added to the reaction mixture until the pH reached 3 to 4. The precipitated solid was filtered, washed with distilled water, and dried to obtain the desired compound (805 mg, 84.9%) as a white solid.

[0248] [Step 2] Synthesis of tert-butyl (1R,6R)-6-[2-[4-methoxycarbonyl-2-[[(2S)-oxetan-2-yl]methylamino]anilino]-2-oxo-ethyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate

[0249]

[0250] A solution of 2-[(1R,6R)-3-tert-butoxycarbonyl-3-azabicyclo[4.1.0]heptan-6-yl]acetic acid (500 mg, 1.96 mmol), methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (463 mg, 1.96 mmol), EDC·HCl (751 mg, 3.92 mmol), and 4-(dimethylamino)pyridine (48 mg, 0.392 mmol) dissolved in dichloromethane (5 mL) at room temperature was stirred at the same temperature for 18 hours. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (928 mg, 100%).

[0251] [Step 3] Synthesis of methyl 2-[[(1R,6R)-3-tert-butoxycarbonyl-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0252]

[0253] A solution of tert-butyl (1R,6R)-6-[2-[4-methoxycarbonyl-2-[[(2S)-oxetan-2-yl]methylamino]anilino]-2-oxo-ethyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate (928 mg, 1.96 mmol) dissolved in acetic acid (20 mL) at room temperature was stirred at 90℃ for 3 hours, and then the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (732 mg, 82%) as a pale yellow foam solid.

[0254] [Step 4] Synthesis of methyl 2-[[(1R,6R)-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate; 2,2,2-trifluoroacetic acid

[0255]

[0256] A solution of methyl 2-[[(1R,6R)-3-tert-butoxycarbonyl-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (732 mg, 1.61 mmol) and 2,2,2-trifluoroacetic acid (2.46 mL, 32.1 mmol) dissolved in dichloromethane (8 mL) at room temperature was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 20%) and concentrated to obtain the desired compound (592.9 mg, 78.6%) as a pale yellow foam solid.

[0257] [Step 5] Synthesis of methyl 2-[[(1R,6R)-3-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0258]

[0259] A solution of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (150 mg, 0.488 mmol), methyl 2-[[(1R,6R)-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate; 2,2,2-trifluoroacetic acid (229 mg, 0.488 mmol), RuPhos palladium G3(20 mg, 0.024 mmol), and cesium carbonate (477 mg, 1.465 mmol) dissolved in 1,4-dioxane (2 mL) at room temperature was stirred at 100℃ for 18 hours, and then the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (70.2 mg, 24.7%) as a pale yellow solid.

[0260] [Step 6] Synthesis of 2-[[(1R,6R)-3-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid

[0261]

[0262] A solution of methyl 2-[[(1R,6R)-3-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (70 mg, 0.120 mmol) and 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (2.0 M solution, 0.126 mL, 0.253 mmol) dissolved in acetonitrile (1.2 mL) at room temperature was stirred at 38℃ for 18 hours, and then the reaction was terminated by lowering the temperature to room temperature. 1 M hydrochloric acid was added to the reaction mixture until the pH reached 3 to 4, then distilled water was poured in, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2plate, 20x20x1 mm; methanol / dichloromethane = 10%) and concentrated to obtain the desired compound (21 mg, 30.7%) as a pale yellow solid.

[0263] 1H NMR(400 MHz, CDCl3): 8.18 (s, 1H), 8.03-8.13 (m, 1H), 7.77-7.92 (m, 1H), 7.57-7.65 (m,J= 7.5, 7.5 Hz, 1H), 7.39-7.49 (m, 2H), 7.35 (dd,J= 9.2, 1.2 Hz, 1H), 6.21 (d,J= 8.2 Hz, 1H), 6.15 (d,J= 7.8 Hz, 1H), 5.43 (d,J= 5.4 Hz, 2H), 5.17-5.27 (m, 1H), 4.55-4.73 (m, 2H), 4.45 (d,J= 9.0 Hz, 2H), 3.90-4.04 (m, 1H), 3.57-3.71 (m, 1H), 3.33-3.43 (m, 1H), 3.19-3.31 (m, 1H), 2.74-2.89 (m, 1H), 2.46-2.61 (m, 1H), 2.24-2.34 (m, 1H), 1.84-1.99 (m, 1H), 1.58 (br. s, 4H), 1.30-1.38 ppm (m, 1H);LRMS(ES) m / z 568.1 (M++1).

[0264] Examples 35, 38 to 44, 50, and 52

[0265] Compounds according to Examples 35, 38 to 44, 50, and 52 were prepared according to substantially the same process as the synthesis ofCompound 19described above, and the name,1H-NMR and MS analysis results of respective compounds according to Examples are shown in Table 4 below.

[0266] [Table 4]

[0267]

[0268] Example 20: Synthesis of 2-[[(1S,6S)-3-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (Compound 20)

[0269] [Step 1] Synthesis of 2-[(1S,6S)-3-tert-butoxycarbonyl-3-azabicyclo[4.1.0]heptan-6-yl]acetic acid

[0270]

[0271] A solution of tert-butyl (1S,6S)-6-(2-methoxy-2-oxo-ethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (1.0 g, 3.71 mmol) and sodium hydroxide (2.0 M solution, 18.6 mL, 37.13 mmol) dissolved in methanol (18 mL) at room temperature was stirred at the same temperature for 6 hours. 1 M aqueous hydrochloric acid solution was added to the reaction mixture until the pH reached 3 to 4. The precipitated solid was filtered, washed with distilled water, and dried to obtain the desired compound (820 mg, 86.5%) as a white solid.

[0272] [Step 2] Synthesis of tert-butyl (1S,6S)-6-[2-[4-methoxycarbonyl-2-[[(2S)-oxetan-2-yl]methylamino]anilino]-2-oxo-ethyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate

[0273]

[0274] A solution of 2-[(1S,6S)-3-tert-butoxycarbonyl-3-azabicyclo[4.1.0]heptan-6-yl]acetic acid (500 mg, 1.96 mmol), methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (463 mg, 1.96 mmol), EDC·HCl (751 mg, 3.92 mmol), and 4-(dimethylamino)pyridine (48 mg, 0.392 mmol) dissolved in dichloromethane (5 mL) at room temperature was stirred at the same temperature. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (928 mg, 99.9%).

[0275] [Step 3] Synthesis of methyl 2-[[(1S,6S)-3-tert-butoxycarbonyl-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0276]

[0277] A solution of tert-butyl (1S,6S)-6-[2-[4-methoxycarbonyl-2-[[(2S)-oxetan-2-yl]methylamino]anilino]-2-oxo-ethyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate (928 mg, 1.96 mmol) dissolved in acetic acid (20 mL) at room temperature was stirred at 90℃ for 2 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (743 mg, 83.2%) as a pale yellow foam solid.

[0278] [Step 4] Synthesis of methyl 2-[[(1S,6S)-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate; 2,2,2-trifluoroacetic acid

[0279]

[0280] A solution of methyl 2-[[(1S,6S)-3-tert-butoxycarbonyl-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (743 mg, 1.63 mmol) and 2,2,2-trifluoroacetic acid (2.50 mL, 32.6 mmol) dissolved in dichloromethane (8 mL) at room temperature was stirred at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 20%) and concentrated to obtain the desired compound (497 mg, 64.9%) as a pale yellow foam solid.

[0281] [Step 5] Synthesis of methyl 2-[[(1S,6S)-3-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0282]

[0283] A solution of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (150 mg, 0.488 mmol), methyl 2-[[(1S,6S)-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate; 2,2,2-trifluoroacetic acid (229 mg, 0.488 mmol), RuPhos palladium G3(20 mg, 0.024 mmol), and cesium carbonate (477 mg, 1.46 mmol) dissolved in 1,4-dioxane (2 mL) at room temperature was stirred at 100℃ for 18 hours, and then the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (86.0 mg, 30.3%) as a yellow foam solid.

[0284] [Step 6] Synthesis of 2-[[(1S,6S)-3-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid

[0285]

[0286] A solution of methyl 2-[[(1S,6S)-3-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (86 mg, 0.148 mmol) and 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (2.0 M solution, 0.155 mL, 0.311 mmol) dissolved in acetonitrile (1.2 mL) at room temperature was stirred at 38℃ for 18 hours, and then the reaction was terminated by lowering the temperature to room temperature. 1 M hydrochloric acid was added to the reaction mixture until the pH reached 3 to 4, then distilled water was poured in, and the mixture was extracted with ethyl acetate. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2plate, 20x20x1 mm; methanol / dichloromethane = 10%) and concentrated to obtain the desired compound (42 mg, 50%) as a pale yellow solid.

[0287] 1H NMR(400 MHz, CDCl3):δ8.14 (s, 1H), 8.08 (d,J= 7.8 Hz, 1H), 7.93-7.79 (m, 1H), 7.59 (t,J= 7.5 Hz, 1H), 7.47-7.37 (m, 2H), 7.33 (dd,J= 9.3, 1.2 Hz, 1H), 6.17 (d,J= 8.1 Hz, 1H), 6.13 (d,J= 7.8 Hz, 1H), 5.47-5.35 (m, 2H), 5.32-5.25 (m, 1H), 4.61 (d,J= 6.6 Hz, 1H), 4.51 (br. s, 2H), 4.26-4.37 (m, 1H), 3.98-3.85 (m, 1H), 3.65-3.51 (m, 1H), 3.45-3.30 (m, 1H), 3.25 (br. s, 1H), 2.81-2.70 (m, 1H), 2.49-2.36 (m, 2H), 1.86 (d,J= 9.8 Hz, 1H), 1.61-1.42 (m, 4H), 1.37-1.27 (m, 1H);LRMS(ES) m / z 568.1 (M++1).

[0288] Example 23: Synthesis of 2-[[(1R,6R)-3-[3-[(4-cyano-2-fluoro-phenyl)methoxy]phenyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (Compound 23)

[0289] [Step 1] Synthesis of 4-[(3-bromophenoxy)methyl]-3-fluoro-benzonitrile

[0290]

[0291] A solution of 3-bromophenol (500 mg, 2.89 mmol), 4-(bromomethyl)-3-fluoro-benzonitrile (680 mg, 3.18 mmol), tetrabutylammonium chloride (402 mg, 1.44 mmol), and sodium hydroxide (2.0 M solution, 28.9 mL, 57.8 mmol) dissolved in dichloromethane (28.9 mL) at room temperature was stirred at the same temperature. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 30%) and concentrated to obtain the desired compound (769 mg, 86.9%) as a white solid.

[0292] [Step 2] Synthesis of methyl 2-[[(1R,6R)-3-[3-[(4-cyano-2-fluoro-phenyl)methoxy]phenyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0293]

[0294] A solution of methyl 2-[[(1R,6R)-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate; 2,2,2-trifluoroacetic acid (200 mg, 0.426 mmol), 4-[(3-bromophenoxy)methyl]-3-fluoro-benzonitrile (130 mg, 0.426 mmol), RuPhos palladium G3(18 mg, 0.050 equiv., 0.021 mmol), and cesium carbonate (278 mg, 0.852 mmol) dissolved in 1,4-dioxane (1.4 mL) at room temperature was stirred at 100℃ for 18 hours, and then the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (130 mg, 52.5%) as a pale yellow foam solid.

[0295] [Step 3] Synthesis of 2-[[(1R,6R)-3-[3-[(4-cyano-2-fluoro-phenyl)methoxy]phenyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid

[0296]

[0297] A solution of methyl 2-[[(1R,6R)-3-[3-[(4-cyano-2-fluoro-phenyl)methoxy]phenyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (130 mg, 0.224 mmol) and 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (2.0 M aqueous solution, 0.235 mL, 0.470 mmol) dissolved in acetonitrile (2.2 mL) at room temperature was stirred at 38℃ for 18 hours, and the reaction was terminated by lowering the temperature to room temperature. 1 M hydrochloric acid was added to the reaction mixture until the pH reached 3 to 4, then distilled water was poured in, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (39 mg, 30.8%) as a pale yellow foam solid.

[0298] 1H NMR(400 MHz, DMSO-d6)δ8.22-8.13 (m, 1H), 7.95-7.86 (m, 1H), 7.74 (d,J= 3.4 Hz, 3H), 7.63-7.53 (m, 1H), 7.13-7.04 (m, 1H), 6.60-6.51 (m, 2H), 6.46-6.36 (m, 1H), 5.18 (s, 2H), 5.10-5.00 (m, 1H), 4.75-4.59 (m, 2H), 4.54-4.38 (m, 1H), 4.37-4.28 (m, 1H), 3.27-3.18 (m, 1H), 3.07-2.93 (m, 2H), 2.78-2.66 (m, 1H), 2.48-2.35 (m, 2H), 1.88-1.76 (m, 1H), 1.69-1.40 (m, 4H), 1.19-1.12 (m, 2H);LRMS(ES) m / z 567.81 (M++1).

[0299] Examples 24 to 26, 31 and 49

[0300] Compounds according to Examples 24 to 26, 31, and 49 were prepared according to substantially the same process as the synthesis ofCompound 23described above, and the name,1H-NMR and MS analysis results of respective compounds according to Examples are shown in Table 5 below.

[0301] [Table 5]

[0302]

[0303] Example 27: Synthesis of 2-[[(1R,6R)-3-[6-[(4-cyano-2-fluoro-phenoxy)methyl]-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (Compound 27)

[0304] [Step 1] Synthesis of 4-[(6-bromo-2-pyridyl)methoxy]-3-fluoro-benzonitrile

[0305]

[0306] A solution of 2-bromo-6-(bromomethyl)pyridine (500 mg, 1.99 mmol), 3-fluoro-4-hydroxy-benzonitrile (301 mg, 2.19 mmol), tetrabutylammonium chloride (277 mg, 0.996 mmol), and sodium hydroxide (2.0 M, 13 mL, 26.0 mmol) dissolved in dichloromethane (13 mL) at room temperature was stirred at the same temperature. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 30%) and concentrated to obtain the desired compound (593 mg, 96.9%) as a white solid.

[0307] [Step 2] Synthesis of methyl 2-[[(1R,6R)-3-[6-[(4-cyano-2-fluoro-phenoxy)methyl]-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0308]

[0309] A solution of methyl 2-[[(1R,6R)-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate; 2,2,2-trifluoroacetic acid (200 mg, 0.426 mmol), 4-[(6-bromo-2-pyridyl)methoxy]-3-fluoro-benzonitrile (131 mg 0.426 mmol), RuPhos palladium G3(18 mg, 0.021 mmol), and cesium carbonate (278 mg, 0.852 mmol) dissolved in 1,4-dioxane (2.1 mL) at room temperature was stirred at 100℃ for 18 hours, and then the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (165.5 mg, 66.8%) as a pale yellow foam solid.

[0310] [Step 3] Synthesis of 2-[[(1R,6R)-3-[6-[(4-cyano-2-fluoro-phenoxy)methyl]-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid

[0311]

[0312] A solution of methyl 2-[[(1R,6R)-3-[6-[(4-cyano-2-fluoro-phenoxy)methyl]-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (165.5 mg, 0.285 mmol) and 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (2.0 M, 0.299 mL, 0.598 mmol) dissolved in acetonitrile (2.8 mL) at room temperature was stirred at 38℃ for 18 hours and the reaction was terminated by lowering the temperature to room temperature. 1 M hydrochloric acid was added to the reaction mixture until the pH reached 3 to 4, then distilled water was poured in, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (55 mg, 34%) as a pale yellow foam solid.

[0313] 1H NMR(400 MHz, DMSO-d6)δ8.17 (s, 1H), 7.89-7.81 (m, 1H), 7.80-7.73 (m, 1H), 7.68-7.61 (m, 1H), 7.58 (d,J= 8.4 Hz, 1H), 7.53 (dd,J= 7.3, 8.5 Hz, 1H), 7.40 (t,J= 8.6 Hz, 1H), 6.77 (d,J= 8.6 Hz, 1H), 6.69 (d,J= 7.2 Hz, 1H), 5.17 (s, 2H), 5.08-5.00 (m, 1H), 4.71-4.59 (m, 2H), 4.50-4.39 (m, 1H), 4.36-4.26 (m, 1H), 3.88-3.79 (m, 1H), 3.62-3.51 (m, 1H), 3.29-3.20 (m, 1H), 2.76-2.63 (m, 1H), 2.46-2.36 (m, 2H), 1.80-1.68 (m, 1H), 1.60-1.49 (m, 3H), 1.49-1.38 (m, 2H), 1.22-1.13 (m, 1H);LRMS(ES) m / z 568.85 (M++1).

[0314] Example 33: Synthesis of 2-[[(1R,6R)-3-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-3-fluoro-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (Compound 33)

[0315] [Step 1] Synthesis of 4-[(5,6-difluoro-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile

[0316]

[0317] A solution of 6-bromo-2,3-difluoro-pyridine (300 mg, 1.55 mmol), 3-fluoro-4-(hydroxymethyl)benzonitrile (257 mg, 1.70 mmol), and palladium(II) acetate (35 mg, 0.155 mmol), racemic-2-di-t-butylphosphino-1,1'-binaphthyl, 98% trixiephos (123 mg, 0.309 mmol), and cesium carbonate (1.01 g, 3.09 mmol) dissolved in 1,4-dioxane (5.1 mL) at room temperature was stirred at 100℃ for 18 hours, and then the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (212 mg, 51.9%) as a white solid.

[0318] [Step 2] Synthesis of methyl 2-[[(1R,6R)-3-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-3-fluoro-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0319]

[0320] A solution of 4-[(5,6-difluoro-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (100 mg, 0.379 mmol), methyl 2-[[(1R,6R)-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate; 2,2,2-trifluoroacetic acid (187 mg, 0.397 mmol), and potassium carbonate (105 mg, 0.757 mmol) dissolved in dimethyl sulfoxide (1.3 mL) at room temperature was stirred at 90℃ for 3 hours, and then the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (149 mg, 66%) as a pale yellow foam solid.

[0321] [Step 3] Synthesis of 2-[[(1R,6R)-3-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-3-fluoro-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid

[0322]

[0323] A solution of methyl 2-[[(1R,6R)-3-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-3-fluoro-2-pyridyl]-3-azabicyclo[4.1.0]heptan-6-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (149.7 mg, 0.250 mmol) and 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (2.0 M, 0.262 mL, 0.524 mmol) dissolved in acetonitrile (2.5 mL) at room temperature was stirred at 38℃ for 18 hours, and the reaction was terminated by lowering the temperature to room temperature. 1 M hydrochloric acid was added to the reaction mixture until the pH reached 3 to 4, then distilled water was poured in, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (46 mg, 31.5%) as a white foam solid.

[0324] 1H NMR(400 MHz, CDCl3)δ8.20 (s, 1H), 8.10 (d,J= 7.9 Hz, 1H), 7.99-7.84 (m, 1H), 7.58 (t,J= 7.5 Hz, 1H), 7.45 (dd,J= 1.2, 7.9 Hz, 1H), 7.35 (dd,J= 1.4, 9.2 Hz, 1H), 7.21 (dd,J= 8.4, 12.2 Hz, 1H), 6.20 (dd,J= 1.7, 8.4 Hz, 1H), 5.40 (s, 2H), 5.28-5.18 (m, 1H), 4.73-4.61 (m, 3H), 4.56 (br. s, 1H), 4.48 (td,J= 6.0, 9.1 Hz, 1H), 3.86 (d,J= 13.4 Hz, 1H), 3.67-3.58 (m, 1H), 3.32 (br. s, 1H), 3.23 (ddd,J= 2.7, 10.1, 12.9 Hz, 1H), 2.86 (br. s, 1H), 2.57 (d,J= 2.6 Hz, 1H), 2.40-2.31 (m, 1H), 2.07 (br. s, 1H), 1.70-1.59 (m, 1H), 1.53 (t,J= 13.1 Hz, 3H), 1.43-1.34 (m, 1H);LRMS(ES) m / z 586.05 (M++1).

[0325] Examples 47 and 48

[0326] Compounds according to Examples 47 and 48 were prepared according to substantially the same process as the synthesis ofCompound 33described above, and the name,1H-NMR and MS analysis results of respective compounds according to Examples are shown in Table 6 below.

[0327] [Table 6]

[0328]

[0329] Example 36: Synthesis of 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-methyl-3,6-dihydropyridazin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (Compound 36)

[0330] [Step 1] Synthesis of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile

[0331]

[0332] A solution of 2-bromo-6-fluoro-pyridine (1.000 g, 5.682 mmol), 3-fluoro-4-(hydroxymethyl)benzonitrile (1.030 g, 6.815 mmol), and cesium carbonate (2.220 g, 6.814 mmol) dissolved inN,N-dimethylformamide (8.5 mL) at room temperature was stirred at 90℃ for 18 hours, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 24 g cartridge; 10%-aqueous ethyl acetate solution / 90%-aqueous hexane solution = 0% to 30%) and concentrated to obtain the desired compound (1.300 g, 74.50%) as a white solid.

[0333] [Step 2] Synthesis of tert-butyl 4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydro-1H-pyridazine-2-carboxylate

[0334]

[0335] A solution of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (300.000 mg, 0.977 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1H-pyridazine-2-carboxylate (303.000 mg, 0.977 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (64.000 mg, 0.098 mmol), and cesium carbonate (637.000 mg, 1.955 mmol) dissolved in 1,4-dioxane (2.8 mL) / water (0.980 mL) at room temperature was stirred at 100℃ for 2 hours. Then, the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 50%) and concentrated to obtain the desired compound (175.000 mg, 43.65%) as a light brown solid.

[0336] [Step 3]Synthesis of methyl 2-[[2-tert-butoxycarbonyl-4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydropyridazin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0337]

[0338] A solution of tert-butyl 4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydro-1H-pyridazine-2-carboxylate (0.218 g, 0.531 mmol), methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (164.000 mg, 0.557 mmol), potassium carbonate (440 mg, 3.184 mmol), and potassium iodide (79.000 mg, 0.476 mmol) dissolved in acetonitrile (2.4 mL) at room temperature was stirred at 35℃ for 4 hours. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; hexane / ethyl acetate = 0% to 50%) and concentrated to obtain the desired compound (203.000 mg, 57.15%) as a light brown solid.

[0339] [Step 4]Synthesis of methyl 2-[[5-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydro-1H-pyridazin-2-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate; 2,2,2-trifluoroacetic acid

[0340]

[0341] To a solution of methyl 2-[[2-tert-butoxycarbonyl-4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydropyridazin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (50.000 mg, 0.075 mmol) dissolved in dichloromethane (374 μL) at room temperature, 2,2,2-trifluoroacetic acid (0.143 mL, 1.869 mmol) was added and stirred at the same temperature for 3 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (51.000 mg, 99.92%, brown solid).

[0342] [Step 5] Synthesis of methyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-methyl-3,6-dihydropyridazin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0343]

[0344] A solution of methyl 2-[[5-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydro-1H-pyridazin-2-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate; 2,2,2-trifluoroacetic acid (100.00%, 0.070 g, 0.123 mmol) dissolved in methanol (10 mL) was stirred at room temperature for 30 hours. Then,N-ethyldiisopropylamine (100.00% solution, 0.043 mL, 0.247 mmol), formaldehyde (37% solution, 0.014 mL, 0.380 mmol), and sodium triacetoxyborohydride (0.078 g, 0.368 mmol) were added and further stirred at the same temperature overnight. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 5%) and concentrated to obtain the desired compound (0.021 g, 29.28%) as a white solid.

[0345] [Step 6] Synthesis of 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-methyl-3,6-dihydropyridazin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid

[0346]

[0347] To a solution of methyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-methyl-3,6-dihydropyridazin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (7.700 mg, 0.013 mmol) dissolved in acetonitrile (0.265 mL) at room temperature, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (1.00 M solution, 0.053 mL, 0.053 mmol) was added, and the mixture was stirred at the same temperature for 18 hours. Then, hydrogen chloride (1.00 M solution, 0.05287 mL, 0.053 mmol) was added to the reaction mixture at room temperature, and the mixture was stirred for 5 minutes to complete the reaction. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (4.000 mg, 53.23%) as a pink solid.

[0348] 1H NMR(400 MHz, CDCl3)δ8.12 (s, 1H), 7.96-7.82 (m, 1H), 7.73 (d,J= 8.4 Hz, 1H), 7.62-7.57 (m, 2H), 7.44 (d,J= 8.0 Hz, 1H), 7.36 (d,J= 9.3 Hz, 1H), 7.02 (d,J= 7.4 Hz, 1H), 6.74 (d,J= 8.2 Hz, 1H), 6.67 (s, 1H), 5.51 (s, 2H), 5.22-5.18 (m, 1H), 5.00-4.30 (m, 6H), 3.64 (br s, 2H), 2.75 (br s, 4H), 2.50 (br, s, 1H), 2.12 (s, 2H);LRMS(ES) m / z 569.0 (M++1).

[0349] Examples 30, 51 and 53

[0350] Compounds according to Examples 30, 51 and 53 were prepared according to substantially the same process as the synthesis ofCompound 36described above, and the name,1H-NMR and MS analysis results of respective compounds according to Examples are shown in Table 7 below.

[0351] [Table 7]

[0352]

[0353] Activity measurement and analysis protocol of compounds according to present invention

[0354] <Experimental Example 1> cAMP activity test (in vitro)

[0355] Activation of GLP-1R by the compounds was quantified by measuring an increase in cAMP in a human GLP-1R overexpressing CHO-K1 cell line (Eurofins, 95-0062C2). Cells were plated at 30,000 cells / well in 96-well plates (Corning, 3903) using plating medium (Eurofins, 93-0563R2B) and incubated overnight at 37℃, 5% CO2. The next day, the medium was removed, then 1X DPBS (WELGENE, LB001-02) was added at 30 μL / well, and compounds prepared at 3 times the final concentration for measurement were added at 15 μL / well. Six points of dosage were set for each compound. The products were incubated for 30 minutes at 37℃, 5% CO2. Next, intracellular cAMP concentrations were measured and detected using the HitHunter® cAMP Assay for Small Molecules (Eurofins, 90-0075SM10) according to the manufacturer's protocol. The response was plotted against the log of the agonist concentration and the EC50was determined by fitting the data to a sigmoidal equation. The final results were calculated using the GraphPad Prism 4.0 program to obtain respective EC50values. The EC50values of the compounds are shown in Table 8 below. Note: EC50range: +++++: 0.1 nM < EC50≤ 10 nM; ++++: 10 nM < EC50≤ 100 nM; +++: 100 nM < EC50≤ 1000 nM; ++: 1000 nM < EC50≤ 5000 nM; +: EC50> 5000 nM

[0356] [Table 8]

[0357]

[0358] As described in Table 8 above, the agonist assay results for cAMP confirmed that the compounds of the present invention exhibited excellent agonist activity for cAMP.

[0359] As described above, the present invention has been described in detail through preferred Examples and Experimental Examples, but the scope of the present invention is not limited to the specific compounds according to Examples and should be interpreted by the claims. Further, those skilled in the art should understand that many modifications and variations can be made without departing from the scope of the present invention.

Claims

1.A compound represented by the following Chemical Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:[Chemical Formula I]in Chemical Formula I above,A1to A4are each independently CRAor N;RAis -H, -C1-4alkyl, -C1-4haloalkyl, or -halo;ring X isor;RX1is -C1-4alkyl, -C1-4alkylene-O-C1-4alkyl, -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl), wherein one or more H in the -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl) ring may be substituted with -C1-4alkyl, -CN, -C1-4cyanoalkyl, -C1-4haloalkyl, or -halo;p is 0, 1, 2, 3, or 4;RX2is -(CH2)q-C(=O)OH or -(CH=CH)-C(=O)OH;q is 0, 1, or 2;RX3and RX4are each independently -C1-4alkyl, -C1-4haloalkyl, or -halo;ring Y isor;Y1is NRYor O;RYis -H, -C1-4alkyl, -C(=O)-C1-4alkyl, or -C(=O)-O-C1-4alkyl;L is -CH2-O- or -O-CH2-, wherein the carbon of -CH2-O- is connected to ring Z and the oxygen of -O-CH2- is connected to ring Z; andring Z is phenyl or a 6-membered heteroaryl, wherein one or more H of the phenyl or 6-membered heteroaryl ring may be substituted with -C1-4alkyl, -C1-4cyanoalkyl, -C1-4aminoalkyl, -C1-4hydroxyalkyl, -C1-4haloalkyl, -CN, -OC1-4alkyl, -OC1-4haloalkyl, -S(=O)2-C1-4alkyl, or -halo.2.The compound of claim 1, whereinA1to A3are each independently CRAor N;A4is CRA;RAis -H, -C1-4haloalkyl, or -halo;ring X isor;RX1is -C1-4alkyl, -C1-4alkylene-O-C1-4alkyl, -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl), wherein one or more H in the -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl) ring may be substituted with -C1-4alkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, or -halo;p is 0, 1, or 2;RX2is -C(=O)OH or -(CH=CH)-C(=O)OH;RX3and RX4are each independently -C1-4haloalkyl or -halo;ring Y isor;Y1is NRYor O;RYis -H, -C1-4alkyl, -C(=O)-C1-4alkyl, or -C(=O)-O-C1-4alkyl;L is -CH2-O- or -O-CH2-, wherein the carbon of -CH2-O- is connected to ring Z and the oxygen of -O-CH2- is connected to ring Z; andring Z is phenyl or pyridinyl, wherein one or more H of the phenyl or pyridinyl ring may be substituted with -H, -C1-4alkyl, -C1-4haloalkyl, -CN, -OC1-4alkyl, -OC1-4haloalkyl, -S(=O)2-C1-4alkyl, or -halo.3.A compound represented by the following Chemical Formula II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:[Chemical Formula II]in Chemical Formula II above,A1to A4are each independently CRAor N;RAis -H, -C1-4alkyl, -C1-4haloalkyl, or -halo;ring X isor;RX1is -C1-4alkyl, -C1-4alkylene-O-C1-4alkyl, -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl), wherein one or more H in the -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl) ring may be substituted with -C1-4alkyl, -CN, -C1-4cyanoalkyl, -C1-4haloalkyl, or -halo;p is 0, 1, 2, 3, or 4;RX2is -(CH2)q-C(=O)OH or -(CH=CH)-C(=O)OH;q is 0, 1, or 2;RX3and RX4are each independently -C1-4alkyl, -C1-4haloalkyl, or -halo;Y1is NRYor O;RYis -H, -C1-4alkyl, -C(=O)-C1-4alkyl, or -C(=O)-O-C1-4alkyl;L is -CH2-O- or -O-CH2-, wherein the carbon of -CH2-O- is connected to ring Z and the oxygen of -O-CH2- is connected to ring Z; andring Z is phenyl or a 6-membered heteroaryl, wherein one or more H of the phenyl or 6-membered heteroaryl ring may be substituted with -C1-4alkyl, -C1-4cyanoalkyl, -C1-4aminoalkyl, -C1-4hydroxyalkyl, -C1-4haloalkyl, -CN, -OC1-4alkyl, -OC1-4haloalkyl, -S(=O)2-C1-4alkyl, or -halo.4.A compound represented by the following Chemical Formula III, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:[Chemical Formula III]in Chemical Formula III above,A1to A4are each independently CRAor N;RAis -H, -C1-4alkyl, -C1-4haloalkyl, or -halo;ring X isor;RX1is -C1-4alkyl, -C1-4alkylene-O-C1-4alkyl, -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl), wherein one or more H in the -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl) ring may be substituted with -C1-4alkyl, -CN, -C1-4cyanoalkyl, -C1-4haloalkyl, or -halo;p is 0, 1, 2, 3, or 4;RX2is -(CH2)q-C(=O)OH or -(CH=CH)-C(=O)OH;q is 0, 1, or 2;RX3and RX4are each independently -C1-4alkyl, -C1-4haloalkyl, or -halo;L is -CH2-O- or -O-CH2-, wherein the carbon of -CH2-O- is connected to ring Z and the oxygen of -O-CH2- is connected to ring Z; andring Z is phenyl or a 6-membered heteroaryl, wherein one or more H of the phenyl or 6-membered heteroaryl ring may be substituted with -C1-4alkyl, -C1-4cyanoalkyl, -C1-4aminoalkyl, -C1-4hydroxyalkyl, -C1-4haloalkyl, -CN, -OC1-4alkyl, -OC1-4haloalkyl, -S(=O)2-C1-4alkyl, or -halo.5.A compound represented by the following Chemical Formula IV, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:[Chemical Formula IV]in Chemical Formula IV above,A1to A4are each independently CRAor N;RAis -H, -C1-4alkyl, -C1-4haloalkyl, or -halo;RX1is -C1-4alkyl, -C1-4alkylene-O-C1-4alkyl, -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl), wherein one or more H in the -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl) ring may be substituted with -C1-4alkyl, -CN, -C1-4cyanoalkyl, -C1-4haloalkyl, or -halo;p is 0, 1, 2, 3, or 4;RX2is -(CH2)q-C(=O)OH or -(CH=CH)-C(=O)OH;q is 0, 1, or 2;RX3is -C1-4alkyl, -C1-4haloalkyl, or -halo;ring Y isor;Y1is NRYor O;RYis -H, -C1-4alkyl, -C(=O)-C1-4alkyl, or -C(=O)-O-C1-4alkyl;L is -CH2-O- or -O-CH2-, wherein the carbon of -CH2-O- is connected to ring Z and the oxygen of -O-CH2- is connected to ring Z; andring Z is phenyl or a 6-membered heteroaryl, wherein one or more H of the phenyl or 6-membered heteroaryl ring may be substituted with -C1-4alkyl, -C1-4cyanoalkyl, -C1-4aminoalkyl, -C1-4hydroxyalkyl, -C1-4haloalkyl, -CN, -OC1-4alkyl, -OC1-4haloalkyl, -S(=O)2-C1-4alkyl, or -halo.6.A compound represented by the following Chemical Formula V, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:[Chemical Formula V]in Chemical Formula V above,A1to A4are each independently CRAor N;RAis -H, -C1-4alkyl, -C1-4haloalkyl, or -halo;RX1is -C1-4alkyl, -C1-4alkylene-O-C1-4alkyl, -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl), wherein one or more H in the -(CH2)p-(3-6 membered cycloalkyl), -(CH2)p-(3-10 membered heterocycloalkyl), or -(CH2)p-(5-6 membered heteroaryl) ring may be substituted with -C1-4alkyl, -CN, -C1-4cyanoalkyl, -C1-4haloalkyl, or -halo;p is 0, 1, 2, 3, or 4;RX4is -C1-4alkyl, -C1-4haloalkyl, or -halo;ring Y isor;Y1is NRYor O;RYis -H, -C1-4alkyl, -C(=O)-C1-4alkyl, or -C(=O)-O-C1-4alkyl;L is -CH2-O- or -O-CH2-, wherein the carbon of -CH2-O- is connected to ring Z and the oxygen of -O-CH2- is connected to ring Z; andring Z is phenyl or a 6-membered heteroaryl, wherein one or more H of the phenyl or 6-membered heteroaryl ring may be substituted with -C1-4alkyl, -C1-4cyanoalkyl, -C1-4aminoalkyl, -C1-4hydroxyalkyl, -C1-4haloalkyl, -CN, -OC1-4alkyl, -OC1-4haloalkyl, -S(=O)2-C1-4alkyl, or -halo.7.A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following compounds:.8.A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof as an active ingredient, and comprising a pharmaceutically acceptable carrier.9.A pharmaceutical composition for the prevention or treatment of a glucagon-like peptide-1 (GLP-1) receptor activity-associated disease, comprising the compound according to any one of claims 1 to 7, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof as an active ingredient.10.The pharmaceutical composition of claim 9, wherein the glucagon-like peptide-1 (GLP-1) receptor activity-associated disease is selected from the group consisting of endocrine, nutritional and metabolic diseases; immune, inflammatory and fibrotic diseases; mental and behavioral disorders; neurodegenerative diseases; circulatory diseases; and renal diseases.11.The pharmaceutical composition of claim 10, whereinthe endocrine, nutritional and metabolic diseases are type 2 diabetes, obesity or polycystic ovary syndrome,the immune, inflammatory and fibrotic diseases are inflammatory bowel disease, non-alcoholic fatty liver disease or multiple sclerosis,the mental and behavioral disorders are depression or alcoholism,the neurodegenerative diseases are dementia or Parkinson's disease,the circulatory diseases are stroke or cardiovascular disease, andthe renal diseases are diabetic nephropathy.12.A method for preventing or treating a glucagon-like peptide-1 (GLP-1) receptor activity-associated disease comprising administering a therapeutically effective amount of the compound according to any one of claims 1 to 7, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof as an active ingredient.13.Use of the compound according to any one of claims 1 to 7, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof for preparing a medicament for preventing or treating a glucagon-like peptide-1 (GLP-1) receptor activity-associated disease.14.Use of the compound according to any one of claims 1 to 7, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof for preventing or treating a glucagon-like peptide-1 (GLP-1) receptor activity-associated disease.

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