GLP-1 receptor agonist, and uses thereof

Abstract

The present disclosure 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 disclosure 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, thereby failing to lower blood sugar levels. 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, a pharmaceutical composition for preventing or treating a GLP-1 receptor activity-associated disease, 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] is a single bond or a double bond;

[0018] X1and X2are each independently C or N;

[0019] Rx is -C1-4alkyl;

[0020] Y1is C(=O) or S(=O)2;

[0021] Y2is CH or CH2;

[0022] Z1and Z2are each independently C or N;

[0023] RV1and RV2are each independently -H or -C1-4alkyl;

[0024] U1and U2are each independently NH, O, or N;

[0025] U3is C(=O) or CRU;

[0026] RUis -H, -C1-4alkyl, -C1-4haloalkyl, or -halo;

[0027] W is CH or N;

[0028] RW1and RW2are each independently -H or -C1-4alkyl;

[0029] ring A is -phenyl, -(5-6 membered heteroaryl), or -(5-10 membered heterohydroaryl), wherein -CH2- of the -(5-10 membered heterohydroaryl) ring may be substituted with -C(=O)-, and at least one H of the -phenyl, -(5-6 membered heteroaryl), or -(5-10 membered heterohydroaryl) ring may be substituted with -C1-4alkyl, -C1-4hydroxyalkyl, -C1-4aminoalkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, -(3-6 membered cycloalkyl), -CN, -NH2, -NH-(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), -NO2, -OH, -O-C1-4alkyl, or -halo, wherein at least one H of the -C1-4alkyl, -C1-4hydroxyalkyl, -C1-4aminoalkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, -NH2, -NH-(C1-4alkyl), or -N(C1-4alkyl)(C1-4alkyl) may be substituted with deuterium;

[0030] LAis -(C0-2alkylene)- or -C(=O)-;

[0031] RAis -H, -O-C1-4alkyl, -N=S(=O)R1R2, -N=S(=NH)(C1-4alkyl)(C1-4alkyl), -NH-S(=O)2-(C1-4alkyl), -NH-C(=O)-C(=O)-N(C1-4alkyl)(C1-4alkyl), or -(NH)n-(4-6 membered heterocycloalkyl), wherein the -(NH)n-(4-6 membered heterocycloalkyl) ring may contain one or more N, O, S, S(=O)2, or S(=O)(NH) in the ring, and at least one H of the -(NH)n-(4-6 membered heterocycloalkyl) ring may be substituted with -C1-4alkyl or -S(=O)2-C1-4alkyl;

[0032] n is 0, 1, or 2;

[0033] R1and R2are each independently -C1-4alkyl, -NH2, -NH-(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), or -(3-6 membered cycloalkyl), wherein at least one H of the -C1-4alkyl, -NH2, -NH-(C1-4alkyl), or -N(C1-4alkyl)(C1-4alkyl) may be substituted with deuterium; or R1and R2may be linked to each other to form, together with S atom, -(4-6 membered monocyclic ring) or -(6-11 membered spirocyclic ring), wherein the -(4-6 membered monocyclic ring) or -(6-11 membered spirocyclic ring) may contain one or more N, O, or S in the ring, and may be saturated or unsaturated, and at least one H of the -(4-6 membered monocyclic ring) or -(6-11 membered spirocyclic ring) may be substituted with -C1-4alkyl, -C1-4haloalkyl, -O-C1-4alkyl, -halo, -C(=O)-(C1-4alkyl), or -(4-6 membered heterocycloalkyl), wherein at least one H of the -(4-6 membered heterocycloalkyl) may be substituted with -C1-4alkyl;

[0034] LBis -(C0-2alkylene)- or -CRL1RL2-;

[0035] RL1and RL2are each independently -H or -C1-4alkyl; and

[0036] ring B is -phenyl, -(5-6 membered heteroaryl), -(6-10 membered hydroaryl), -(5-10 membered heterohydroaryl), -(5-6 membered cycloalkyl), or -(5-6 membered heterocycloalkyl), wherein -CH2- of the -(6-10 membered hydroaryl) or -(5-10 membered heterohydroaryl) ring may be substituted with -C(=O)-, and at least one H of the -phenyl, -(5-6 membered heteroaryl), -(6-10 membered hydroaryl), -(5-10 membered heterohydroaryl), -(5-6 membered cycloalkyl), or -(5-6 membered heterocycloalkyl) ring may be substituted with -C1-4alkyl, -C1-4hydroxyalkyl, -C1-4aminoalkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, -CN, -NO2, -NH2, -NH-(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), -N=S(=O)(C1-4alkyl)(C1-4alkyl), -O-C1-4alkyl, -halo, or -(3-6 membered cycloalkyl), wherein at least one H of the -C1-4alkyl, -C1-4hydroxyalkyl, -C1-4aminoalkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, -NH2, -NH-(C1-4alkyl), or -N(C1-4alkyl)(C1-4alkyl) may be substituted with deuterium.

[0037] According to the present invention,

[0038] moiety is or ; and Rx may be -methyl.

[0039] In addition, according to the present invention,

[0040] moiety may be or .

[0041] In addition, according to the present invention,

[0042] moiety may be or .

[0043] In addition, according to the present invention,

[0044] moiety is , , or ; and RUmay be -CF3.

[0045] In addition, according to the present invention,

[0046] ring A is , , , , , or , wherein at least one H of the ring A may be substituted with -C1-4alkyl, -C1-4haloalkyl, -(3-6 membered cycloalkyl), -CN, -NH2, -NH-(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), -NO2, -OH, -O-C1-4alkyl, or -halo, wherein at least one H of the -C1-4alkyl may be substituted with deuterium.

[0047] In addition, according to the present invention,

[0048] ring B is , , , or , wherein at least one H of the ring B may be substituted with -C1-4alkyl, -C1-4haloalkyl, -CN, -N=S(=O)(C1-4alkyl)(C1-4alkyl), -O-C1-4alkyl, -halo, or -(3-6 membered cycloalkyl), wherein at least one H of the -C1-4alkyl may be substituted with deuterium.

[0049] In addition, according to the present invention,

[0050] LA-RAis -LA-N=S(=O)R1R2; LAis -(C0-2alkylene)- or -C(=O)-; and R1and R2are each independently -C1-4alkyl, -N(C1-4alkyl)(C1-4alkyl), or -(3-6 membered cycloalkyl), wherein at least one H of the -C1-4alkyl may be substituted with deuterium.

[0051] In addition, according to the present invention,

[0052] LA-RAis , , , , , , , , , , , , , , , , , , or ; and RA1may be CH2, NH, or O.

[0053] In addition, the present invention provides a compound represented by the following Chemical Formula II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0054] [Chemical Formula II]

[0055]

[0056] in Chemical Formula II above,

[0057] is a single bond or a double bond;

[0058] X1and X2are each independently C or N;

[0059] Rx is -C1-4alkyl;

[0060] Y1is C(=O) or S(=O)2;

[0061] Y2is CH or CH2;

[0062] Z1and Z2are each independently C or N;

[0063] RV1and RV2are each independently -H or -C1-4alkyl;

[0064] U1and U2are each independently NH, O, or N;

[0065] U3is C(=O) or CRU;

[0066] RUis -H, -C1-4alkyl, -C1-4haloalkyl, or -halo;

[0067] W is CH or N;

[0068] RW1and RW2are each independently -H or -C1-4alkyl;

[0069] ring A is -phenyl, -(5-6 membered heteroaryl), or -(5-10 membered heterohydroaryl), wherein -CH2- of the -(5-10 membered heterohydroaryl) ring may be substituted with -C(=O)-, and at least one H of the -phenyl, -(5-6 membered heteroaryl), or -(5-10 membered heterohydroaryl) ring may be substituted with -C1-4alkyl, -C1-4hydroxyalkyl, -C1-4aminoalkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, -(3-6 membered cycloalkyl), -CN, -NH2, -NH-(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), -NO2, -OH, -O-C1-4alkyl, or -halo, wherein at least one H of the -C1-4alkyl, -C1-4hydroxyalkyl, -C1-4aminoalkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, -NH2, -NH-(C1-4alkyl), or -N(C1-4alkyl)(C1-4alkyl) may be substituted with deuterium;

[0070] LAis -(C0-2alkylene)- or -C(=O)-;

[0071] R1and R2are each independently -C1-4alkyl, -NH2, -NH-(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), or -(3-6 membered cycloalkyl), wherein at least one H of the -C1-4alkyl, -NH2, -NH-(C1-4alkyl), or -N(C1-4alkyl)(C1-4alkyl) may be substituted with deuterium; or R1and R2may be linked to each other to form, together with S atom, -(4-6 membered monocyclic ring) or -(6-11 membered spirocyclic ring), wherein the -(4-6 membered monocyclic ring) or -(6-11 membered spirocyclic ring) may contain one or more N, O, or S in the ring, and may be saturated or unsaturated, and at least one H of the -(4-6 membered monocyclic ring) or -(6-11 membered spirocyclic ring) may be substituted with -C1-4alkyl, -C1-4haloalkyl, -O-C1-4alkyl, -halo, -C(=O)-(C1-4alkyl), or -(4-6 membered heterocycloalkyl), wherein at least one H of the -(4-6 membered heterocycloalkyl) may be substituted with -C1-4alkyl;

[0072] LBis -(C0-2alkylene)- or -CRL1RL2-;

[0073] RL1and RL2are each independently -H or -C1-4alkyl; and

[0074] ring B is -phenyl, -(5-6 membered heteroaryl), -(6-10 membered hydroaryl), -(5-10 membered heterohydroaryl), -(5-6 membered cycloalkyl), or -(5-6 membered heterocycloalkyl), wherein -CH2- of the -(6-10 membered hydroaryl) or -(5-10 membered heterohydroaryl) ring may be substituted with -C(=O)-, and at least one H of the -phenyl, -(5-6 membered heteroaryl), -(6-10 membered hydroaryl), -(5-10 membered heterohydroaryl), -(5-6 membered cycloalkyl), or -(5-6 membered heterocycloalkyl) ring may be substituted with -C1-4alkyl, -C1-4hydroxyalkyl, -C1-4aminoalkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, -CN, -NO2, -NH2, -NH-(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), -N=S(=O)(C1-4alkyl)(C1-4alkyl), -O-C1-4alkyl, -halo, or -(3-6 membered cycloalkyl), wherein at least one H of the -C1-4alkyl, -C1-4hydroxyalkyl, -C1-4aminoalkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, -NH2, -NH-(C1-4alkyl), or -N(C1-4alkyl)(C1-4alkyl) may be substituted with deuterium.

[0075] 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.

[0076] [Table 1]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130] 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.

[0131] 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.

[0132] In the present invention, "halo" may be F, Cl, Br or I.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] In the present invention, "cyanoalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (-CN).

[0137] 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, azetidine, 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, 3-pyrroline, thiopyran, pyrone, oxetane, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-oxaspiro[3.3]heptane, 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.

[0138] 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".

[0139] 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, furan, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, pyridine, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, indazole, 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".

[0140] In the present invention, "hydroarene" or "hydroaryl" is one in which one or more double bonds in the aromatic hydrocarbon ring are saturated.

[0141] In the present invention, "heterohydroarene" or "heterohydroaryl" is one in which one or more double bonds in the "heteroarene" or "heteroaryl" ring are saturated.

[0142] 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.

[0143] The compounds represented by Chemical Formula I or II 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 Formula I or II may be separated by column chromatography, HPLC, or the like. Otherwise, each stereoisomer of the compounds represented by Chemical Formula I or II may be stereospecifically synthesized using optically pure starting materials and / or reagents with known configurations.

[0144] In the present invention, "stereoisomer" includes diastereomers and optical isomers, wherein optical isomers include not only enantiomers but also mixtures and racemates of enantiomers.

[0145] 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.

[0146] 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.

[0147] Preparation method of GLP-1 receptor agonist

[0148] The present invention provides a preparation method of compounds represented by Chemical Formula I or II, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0149] Preferred methods of preparing the compounds represented by Chemical Formula I or II of the present invention, stereoisomers thereof or pharmaceutically acceptable salts thereof are as shown in the following Reaction Scheme 1 to Reaction Scheme 15, which may also include modifications as will be apparent to those skilled in the art.

[0150] [Reaction Scheme 1]

[0151]

[0152] According to the above Reaction Scheme 1, Compound 1-3 is prepared through a cyclization reaction between Compounds 1-1 and 1-2, then Compound 1-4 is prepared through reaction with phenylchloroformate, and Compound 1-5 is prepared through addition of 2,2-dimethoxyethanamine. Then, the desired compound 1-6 may be synthesized by cyclization under acid conditions using methanesulfonic acid. This compound serves as a core framework for the synthesis of the desired GLP-1 receptor agonist derivative, which is used in the subsequent synthesis of all compounds.

[0153] [Reaction Scheme 1-1]

[0154]

[0155] [Reaction Scheme 1-2]

[0156]

[0157] The hydrazine compound 1-1 in Reaction Scheme 1 above may be purchased or prepared according to Reaction Scheme 1-1 or Reaction Scheme 1-2. Specifically, Compound 1-1-1 may be synthesized into Compound 1-1-2 through Sandmeyer reaction according to Reaction Scheme 1-1. Otherwise, according to Reaction Scheme 1-2, ketone compound 1-2-1 may be used as a starting material, tert-butyl carbazate may be introduced under acid conditions to prepare Compound 1-2-2, followed by reduction to prepare Compound 1-2-3, and deprotection to synthesize the desired hydrazine compound 1-2-4, which may be used in the reaction.

[0158] [Reaction Scheme 2]

[0159]

[0160] According to Reaction Scheme 2 above, Compounds 2-1 and 1-6 may be subjected to a copper-mediated coupling reaction to prepare Compound 2-2, and then sulfoximine may be introduced using a palladium coupling reaction to prepare Compound 2-3, followed by deprotection of the protecting group using trifluoroacid, or the like, to prepare Compound 2-4. Then, the desired compound 2-6 may be finally synthesized through an amide coupling reaction with Compound 2-5.

[0161] Compound 2-6 prepared by Reaction Scheme 2 may be Compounds according to Examples1 to 92,121, 124 to 138,143 to 158, 166 to 172, 177, 179 to 181, 185 to 187, 189, 190, 193 to 198, 204 to 206, 208 to 213, 217 to 223, 225 to 228, 231 to 249, 252, 254 to 258, 260, 261, 263 to 400, 404 to 466, 468 to 489, 493 to 496, 500, 509 to 518, 520 to 522, 525 to 557, 562 to 570, 574 to 576, 580 to 583, 586 to 588, 596 to 601, 606, 607, etc.

[0162] [Reaction Scheme 3]

[0163]

[0164] According to Reaction Scheme 3 above, Compounds 3-1 and 1-6 may be subjected to a copper-mediated coupling reaction to prepare Compound 3-2, followed by a hydration reaction to obtain Compound 3-3 and an amide coupling reaction to introduce sulfoximine, thereby preparing Compound 3-4. Then, the deprotection process as in Reaction Scheme 2 may be performed to prepare Compound 3-5, followed by an amide coupling process with Compound 2-5, thereby preparing Compound 3-6.

[0165] Compound 3-6 prepared by Reaction Scheme 3 above may be compounds according to Examples93 to 101, 159 to 165, 173, 176, 178, 188, 191, 192, 250, 251, 571, 572, 584, 585, 589 to 594, 608 to 619, etc.

[0166] [Reaction Scheme 4]

[0167]

[0168] According to Reaction Scheme 4 above, Compounds 4-1 and 1-6 may be subjected to a copper-mediated coupling reaction to prepare Compound 4-2, followed by a reductive amination reaction to introduce sulfoximine, thereby obtaining Compound 4-3. Then, the deprotection process as in Reaction Scheme 2 above may be performed to prepare Compound 4-4, followed by an amide coupling process with Compound 2-5, thereby preparing Compound 4-5.

[0169] Compound 4-5 prepared by Reaction Scheme 4 above may be compounds according to Examples102 to 105, etc.

[0170] [Reaction Scheme 5]

[0171]

[0172] According to Reaction Scheme 5 above, the nitro functional group of Compound 2-3-1 obtainable in Reaction Scheme 2 may be reduced using zinc to prepare Compound 5-1, followed by a reductive amination reaction to prepare Compound 5-2. Then, the deprotection process as in Reaction Scheme 2 may be performed to prepare Compound 5-3, followed by an amide coupling process with Compound 2-5, thereby preparing Compound 5-4.

[0173] Compound 5-4 prepared by Reaction Scheme 5 above may be compounds according to Examples108, 109, etc.

[0174] [Reaction Scheme 6]

[0175]

[0176] According to Reaction Scheme 6 above, the nitro functional group of Compound 2-6-1 obtainable in Reaction Scheme 2 may be reduced using zinc to prepare Compound 6-1, followed by a reductive amination reaction to prepare Compound 6-2.

[0177] Compounds 6-1 and 6-2 prepared by Reaction Scheme 6 may be compounds according to Examples106,etc., respectively.

[0178] [Reaction Scheme 7]

[0179]

[0180] According to Reaction Scheme 7 above, the protecting group of Compound 3-2 obtainable in Reaction Scheme 3 may be deprotected using trifluoroacid, etc., to prepare Compound 7-2, followed by an amide coupling reaction with Compound 2-5, thereby preparing Compound 7-3. Then, the desired compound 7-4 may be prepared through a hydration reaction and an amide coupling reaction.

[0181] Compounds 7-2 and 7-3 prepared by Reaction Scheme 7 above may be compounds according to Examples117, 118,etc., and Compound 7-4 may be compounds according to Examples110 to 114, 119, 120, etc.

[0182] [Reaction Scheme 8]

[0183]

[0184] According to Reaction Scheme 8 above, Compound 7-3 obtainable in Reaction Scheme 7 may be subjected to coupling reaction with Compound 8-1 to prepare Compound 8-2.

[0185] Compound 8-2 prepared by Reaction Scheme 8 above may be compounds according to Examples115, 116, etc.

[0186] [Reaction Scheme 9]

[0187]

[0188] According to Reaction Scheme 9 above, Compound 7-3 obtainable in Reaction Scheme 7 may be subjected to coupling reaction with Compound 9-1 to prepare Compound 9-2, followed by deprotection of the protecting group using palladium / carbon, thereby preparing the desired compound 9-3.

[0189] Compound 9-3 prepared by Reaction Scheme 9 above may be compounds according to Example123,etc.

[0190] [Reaction Scheme 10]

[0191]

[0192] According to Reaction Scheme 10 above, Compound 10-2 may be synthesized by coupling various sulfone groups to the amine of Compound 10-1 prepared after reducing the nitro group of Compound 3-3-1 obtainable in Reaction Scheme 3, and Compound 10-3 may be prepared by deprotection of the protecting group using trifluoroacid or the like. Then, Compound 10-3 may be subjected to an amide coupling reaction with Compound 2-5 to prepare the desired compound 10-4.

[0193] Compound 10-4 prepared by Reaction Scheme 10 above may be compounds according to Examples140, 141, etc.

[0194] [Reaction Scheme 11]

[0195]

[0196] According to Reaction Scheme 11 above, the protecting group of Compound 3-3-2 obtainable in Reaction Scheme 3 may be deprotected with palladium / carbon to prepare Compound 11-1, followed by coupling with a sulfone group to prepare Compound 11-2. The protecting group of Compound 11-2 may be deprotected with trifluoroacid, or the like, to prepare Compound 11-3, followed by an amide coupling reaction with Compound 2-5, thereby preparing the desired compound 11-4.

[0197] Compound 11-4 prepared by Reaction Scheme 11 above may be compounds according to Example139, etc.

[0198] [Reaction Scheme 12]

[0199]

[0200] According to Reaction Scheme 12 above, Compound 2-2 obtainable in Reaction Scheme 2 may be subjected to a palladium-mediated coupling reaction to introduce Compound 12-1, thereby preparing Compound 12-2. The protecting group (-Cbz) of the prepared Compound 12-2 may be deprotected to prepare Compound 12-3, followed by a reductive amination reaction, thereby synthesizing Compound 12-4. Then, the protecting group (-Boc) may be deprotected using trifluoro acid, etc., to prepare Compound 12-5, followed by an amide coupling reaction with Compound 2-5, thereby preparing Compound 12-6.

[0201] Compound 12-6 prepared by Reaction Scheme 12 above may be compounds according to Examples492, 497 to 499, 508, 519, 595, 602 to 605, etc.

[0202] [Reaction Scheme 13]

[0203]

[0204] According to Reaction Scheme 13 above, Compound 1-6 obtainable in Reaction Scheme 1 and Compound 13-1 may be subjected to a copper-mediated coupling reaction to prepare Compound 13-2. Compound 13-3 may be prepared by introducing various alkyl substituents to amine, followed by deprotection of the protecting group (-Cbz), thereby synthesizing Compound 13-4. Compound 13-5 may be synthesized by introducing various sulfoximine functional groups to the obtained Compound 13-4, followed by a deprotection process using trifluoroacid to prepare Compound 13-6, and an amide coupling process with Compound 2-5, thereby preparing the desired compound 13-7.

[0205] Compound 13-7 prepared by Reaction Scheme 13 above may be compounds according to Examples122, 142, 175, 182 to 184, 199 to 203, 214 to 216, 229, 230, 259, 262, 401 to 403, 467, 501 to 507, 573,etc.

[0206] [Reaction Scheme 13-1]

[0207]

[0208] Compound 13-1 used in Reaction Scheme 13 above may be prepared according to Reaction Scheme 13-1. Specifically, Compound 13-1-2 may be prepared by protecting the amine functional group of Compound 13-1-1, followed by hydration with the boronic ester group to synthesize boronic acid compound 13-1, which can be used in Reaction Scheme 13 above.

[0209] [Reaction Scheme 14]

[0210]

[0211] According to Reaction Scheme 14 above, Compound 1-6 obtainable in Reaction Scheme 1 and Compound 14-1 may be subjected to a copper-mediated coupling reaction to prepare Compound 14-2. Then, Compound 14-3 may be prepared through a deprotection process using trifluoroacid, and the desired compound 14-4 may be prepared through an amide coupling process with Compound 2-5.

[0212] Compound 14-4 prepared by Reaction Scheme 14 above may be compounds according to Examples491, 523, 524, 577 to 579, etc.

[0213] [Reaction Scheme 14-1]

[0214]

[0215] Compound 14-1 used in Reaction Scheme 14 above may be prepared according to Reaction Scheme 14-1. Specifically, Compound 14-1 may be synthesized by substituting the boronic acid functional group of Compound 14-1-1 with various sulfoximines, which may be used in Reaction Scheme 14 above.

[0216] [Reaction Scheme 15]

[0217]

[0218] According to Reaction Scheme 15 above, Compound 1-6 obtainable in Reaction Scheme 1 and Compound 15-1 may be subjected to a copper-mediated coupling reaction to prepare Compound 15-2. Then, Compound 15-3 may be prepared through a deprotection process using trifluoroacid, and the desired compound 15-4 may be prepared through an amide coupling process with Compound 2-5.

[0219] Compound 15-4 prepared by Reaction Scheme 15 above may be compounds according to Examples253, 558 to 561, etc.

[0220] [Reaction Scheme 15-1]

[0221]

[0222] Compound 15-1 used in Reaction Scheme 15 above may be prepared according to Reaction Scheme 15-1. Specifically, 2-bromo-2,2-difluoroacetyl chloride may be added to the amine functional group of Compound 15-1-1 to prepare Compound 15-1-2, followed by a copper-mediated addition and oxidation reaction of a 1,2-diamine compound having various R1 and R2 substituents, thereby synthesizing oxamide compound 15-1, which may be used in Reaction Scheme 15 above.

[0223] Uses of GLP-1 receptor agonist

[0224] The present invention provides uses of the compounds represented by Chemical Formula I or II, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0225] [Chemical Formula I]

[0226]

[0227] [Chemical Formula II]

[0228]

[0229] wherein Chemical Formula I or II is as defined above.

[0230] According to an embodiment of the present invention, the present invention provides a pharmaceutical composition comprising the compounds represented by Chemical Formula I or II, stereoisomers thereof, or pharmaceutically acceptable salts thereof as active ingredients.

[0231] 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 Formula I or II as shown above, stereoisomers thereof, or pharmaceutically acceptable salts thereof as active ingredients.

[0232] The glucagon-like peptide-1 (GLP-1) receptor activity-associated disease comprises metabolic, immune, inflammatory, fibrotic, neurodegenerative diseases, circulatory diseases and renal diseases, and specifically comprises 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, cardiovascular disease, stroke, diabetic nephropathy, dementia, Parkinson's disease, depression, alcoholism, inflammatory bowel disease, and multiple sclerosis, etc.

[0233] Examples of the glucagon-like peptide-1 (GLP-1) receptor activity-associated diseases may comprise endocrine, nutritional, and metabolic diseases; immune, inflammatory, and fibrotic diseases; mental and behavioral disorders; neurodegenerative diseases; circulatory diseases; or renal diseases.

[0234] The 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 disorder is depression or alcoholism, the neurodegenerative disease is dementia or Parkinson's disease, the circulatory disease is stroke or cardiovascular disease, and the renal disease is diabetic nephropathy.

[0235] The pharmaceutically acceptable salts are as described above in the pharmaceutically acceptable salts of the compounds represented by Chemical Formula I or II of the present invention.

[0236] 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 Formula I or II, stereoisomers thereof 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 Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA, and may be formulated into various formulations depending on each disease or component.

[0237] 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 Formula I or II of the present invention is about 1 to 1000 mg / kg, preferably 5 to 100 mg / kg, and may be divided and administered once or several times a day.

[0238] 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 Formula I or II, stereoisomers thereof or pharmaceutically acceptable salts thereof.

[0239] 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 Formula I or II, stereoisomers thereof or pharmaceutically acceptable salts thereof.

[0240] The term "therapeutically effective amount" used herein refers to an amount of the compounds represented by Chemical Formula I or II effective for the prevention or treatment of GLP-1 receptor activity-associated diseases.

[0241] 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 Formula I or II, stereoisomers thereof or pharmaceutically acceptable salts thereof.

[0242] 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 Formula I or II. 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 Formula I or II, wherein the additional active agent may exhibit synergistic or adjuvant effects together with the compounds represented by Chemical Formula I or II above.

[0243] In addition, the present invention provides uses of compounds represented by Chemical Formula I or II, 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 Formula I or II 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.

[0244] In addition, the present invention provides uses of compounds represented by Chemical Formula I or II, stereoisomers thereof, or pharmaceutically acceptable salts thereof for the treatment of GLP-1 receptor activity-associated diseases.

[0245] Matters described in the uses, compositions, and treatment methods of the present invention are equally applied unless they contradict each other.

[0246] The compounds represented by Chemical Formula I or II of the present invention, stereoisomers thereof, or pharmaceutically acceptable salts thereof 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).

[0247] Hereinafter, the present disclosure 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 disclosure, and the scope of the present disclosure is not limited only to these Examples.

[0248] Equipment and Analysis Conditions Used for LC / MS

[0249] The LC / MS retention times and LC / MS mass spectrometry results of the compounds prepared in the Examples were measured under the conditions shown in Table 2 below.

[0250] [Table 2]

[0251]

[0252] Preparation of Compounds according to Examples

[0253] Specific methods for preparing compounds represented by Chemical Formula I or II are described as follows.

[0254] Example 1: Synthesis of 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0255] [Step 1] Synthesis of tert-butyl (4S)-3-amino-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0256]

[0257] Tert-Butyl (2S)-3-cyano-2-methyl-4-oxo-piperidine-1-carboxylate (100.0 %, 3.0 g, 12.6 mmol), (4-fluoro-3,5-dimethyl-phenyl)hydrazine hydrochloride (100.0 %, 2.4 g, 12.6 mmol), and hydrochloric acid (2.0 M solution in water, 12.6 mL, 25.2 mmol) were dissolved in ethanol (100 mL) at room temperature, and the solution was stirred at the same temperature for 2 hours. 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 and concentrated by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = from 5 % to 30 %) to obtain the title compound (3.8 g, 81.3 %) as an orange solid.

[0258] [Step 2] Synthesis of tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(phenoxycarbonylamino)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0259]

[0260] The tert-butyl (4S)-3-amino-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.0 %, 4.4 g, 11.8 mmol) prepared in Step 1 and pyridine (100.00 % solution, 1.4 mL, 17.7 mmol) were dissolved in ethyl acetate (150 mL) at room temperature. Phenyl carbonochloridate (100.00 % solution, 2.2 mL, 17.6 mmol) was added to the solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride 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 and concentrated by column chromatography (SiO2, 80 g cartridge; ethyl acetate / hexane = from 5 % to 20 %) to obtain the title compound (5.0 g, 86.0 %) as a pale orange solid.

[0261] [Step 3] Synthesis of tert-butyl (4S)-3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0262]

[0263] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(phenoxycarbonylamino)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.0 %, 1.0 g, 2.0 mmol) prepared in Step 2 and 2,2-dimethoxyethane-amine (100.0 % solution, 1.1 mL, 10.1 mmol) were dissolved in acetonitrile (5 mL) at room temperature, and stirred at the same temperature for 18 hours. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain the title compound (0.700 g, 68.48 %) as a pale yellow solid.

[0264] [Step 4] Synthesis of tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0265]

[0266] The tert-butyl (4S)-3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.0 %, 0.8 g, 1.5 mmol) prepared in Step 3 was dissolved in tetrahydrofuran (15 mL), and methanesulfonic acid (100.0 % solution, 0.1 mL, 1.5 mmol) was added at room temperature. The resulting mixture was stirred at 70℃ for 1 hour, and then cooled to room temperature to terminate the reaction. 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 and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = from 0% to 60 %) to obtain the title compound (0.6 g, 83.3 %) as a white solid.

[0267] [Step 5] Synthesis of tert-butyl (4S)-3-[3-(4-bromophenyl)-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0268]

[0269] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.0 %, 0.2 g, 0.5 mmol) prepared in Step 4, (4-bromophenyl)boronic acid (100.0 %, 0.18 g, 0.9 mmol), copper(II) acetate (100.0 % solution, 0.07 mL, 0.7 mmol) and molecular sieve 4Å (150 mg) were dissolved in N,N-dimethylformamide (5 mL), and pyridine (100.0 % solution, 0.08 mL, 1.0 mmol) was added at room temperature, followed by stirring for 18 hours at 70℃. Then, the reaction mixture was cooled to room temperature to terminate the reaction. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, extracted with ethyl acetate, filtered through a plastic filter to remove the solid residue and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = from 0% to 80 %) to obtain the title compound (150.0 mg, 55.5 %) as a pale yellow solid.

[0270] [Step 6] Synthesis of tert-butyl (4S)-3-[3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0271]

[0272] The tert-butyl (4S)-3-[3-(4-bromophenyl)-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.0 %, 50.0 mg, 0.08 mmol) prepared in Step 5, imino-dimethyl-oxo-λ6-sulfane (100.0 %, 10.0 mg, 0.11 mmol), JohnPhos (100.0 %, 8.0 mg, 0.03 mmol), tris(dibenzylideneacetone) dipalladium(0)(Pd2(dba)3, 100.0 %, 8.0 mg, 0.01 mmol) and sodium tert-butoxide, 99.9% (100.0%, 12.0 mg, 0.1 mmol) was dissolved in 1,4-dioxane (2 mL) at room temperature. The solution was stirred at 80℃ for 2 hours, and then cooled to room temperature to terminate the reaction. A saturated aqueous ammonium chloride 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 and concentrated by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = from 100 % to 95 %) to obtain the title compound (45.0 mg, 88.2 %) as a pale yellow solid.

[0273] [Step 7] Synthesis of 1-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]phenyl]-3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one

[0274]

[0275] The tert-butyl (4S)-3-[3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.0 %, 0.04 g, 0.07 mmol) prepared in Step 6 was dissolved in dichloromethane (1 mL) at room temperature. Trifluoroacetic acid (100.0 % solution, 0.3 mL, 3.9 mmol) was added to the solution, and stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was poured onto the resulting concentrate, which was then extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (0.04 g, 103.0 %, pale yellow oil).

[0276] [Step 8] Synthesis of 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0277]

[0278] The 1-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]phenyl]-3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one (100.0 %, 36.0 mg, 0.07 mmol) obtained in Step 7, 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (100.0 %, 32.0 mg, 0.08 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.0 %, 30.0 mg, 0.08 mmol) were dissolved in N,N-dimethylformamide (1 mL) at room temperature. Then, N,N-diisopropylethylamine (100.0 % solution, 0.07 mL, 0.4 mmol) was added to the solution, and the mixture was stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride 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 and concentrated by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = from 100 % to 95 %) to obtain the title compound (45.0 mg, 70.5 %) as a pale yellow solid.

[0279] LC / MS (ES)m / z 902.41 [M + H]+;LC / MS retention time3.52 (min);LC / MS analysis conditions#1

[0280] Synthesis of Examples 2 to 80, 121, 124 to 138, 143 to 158, 166 to 172, 177, 179 to 181, 185 to 187, 189, 190, 193 to 198, 204 to 206, 208 to 213, 217 to 223, 225 to 228, 231 to 249, 252, 254 to 258, 260, 261, 263 to 400, 404 to 466, 468 to 489, 493 to 496, 500, 509 to 518, 520 to 522, 525 to 557, 562 to 570, 574 to 576, 580 to 583, 586 to 588, 596 to 601, 606, and 607

[0281] The following compounds in Table 3 were each prepared according to the same reactions as described in Steps 1 to 8 of Example 1, except that hydrazines having various substituents were used instead of the (4-fluoro-3,5-dimethylphenyl)hydrazine in Step 1 of Example 1, various boronic acids were used instead of the (4-bromophenyl)boronic acid used in Step 5 of Example 1, and various sulfoximine reagents were used instead of the imino-dimethyl-oxo-λ6-sulfane used in Step 6 of Example 1. The prepared compounds, along with the LC / MS retention times and LC / MS mass spectrometry results of each compound, are shown in Table 3 below.

[0282] [Table 3]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466] Synthesis of Examples 81 to 88

[0467] Compounds of Examples 81 to 88 were each prepared according to the same reactions as described in Steps 1 to 8 of Example 1, except that aniline was used as a starting material instead of hydrazine in Step 1 of Example 1. Synthesis method A of hydrazine is described below, and the compounds prepared therefrom and the LC / MS retention times and LC / MS mass spectrometry results of each compound are shown in Table 4 below.

[0468] A: Synthesis of (4-chloro-3-methyl-phenyl)hydrazine

[0469]

[0470] 4-Chloro-3-methyl-aniline (100.0 %, 1416.0 mg, 10.0 mmol) and hydrochloric acid (100.0 % solution, 2.5 mL, 72.0 mmol) were dissolved in water (0.5 mL) at 0℃. Then, sodium nitrite (100.0 % solution, 0.4 mL, 11.0 mmol) was added to the solution and stirred at the same temperature for 2 hours. Tin chloride dihydrate (100.0%, 4.5 g, 20.0 mmol) and hydrochloric acid (100.0% solution, 5 mL, 144.0 mmol) were added to the reaction mixture and stirred at the same temperature for an additional 3 hours. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The precipitated solid was filtered, washed with hexane, and dried to obtain the title compound (1.05 g, 67.05%) as a yellow solid.

[0471] [Table 4]

[0472]

[0473]

[0474]

[0475] Synthesis of Examples 89 to 92

[0476] Compounds of Examples 89 to 92 were each prepared according to the same reactions as described in Steps 1 to 8 of Example 1, except that ketone was used as a starting material instead of hydrazine in Step 1 of Example 1. Synthesis method B of hydrazine is described below, and the compounds prepared therefrom and the LC / MS retention times and LC / MS mass spectrometry results of each compound are shown in Table 5 below.

[0477] B: Synthesis of 1-(4-fluorophenyl)ethylhydrazine

[0478] [Step 1] Synthesis of tert-butyl N-[(Z)-1-(4-fluorophenyl)ethylideneamino]carbamate

[0479]

[0480] A solution of 1-(4-fluorophenyl)ethanone (100.0 % solution, 0.4 mL, 3.6 mmol), tert-butyl carbazate (100.0 %, 0.5 g, 3.6 mmol), and acetic acid (100.0 % solution, 0.04 mL, 0.7 mmol) dissolved in methanol (40 mL) at room temperature was stirred at the same temperature. After the solvent was removed from the reaction mixture under reduced pressure, the precipitated solid was filtered, washed with hexane, and dried to obtain the title compound (0.9 g, 98.6%) as a white solid.

[0481] [Step 2] Synthesis of tert-butyl N-[1-(4-fluorophenyl)ethylamino]carbamate

[0482]

[0483] The tert-butyl N-[(Z)-1-(4-fluorophenyl)ethylidene amino]carbamate (100.0 %, 0.9 g, 3.6 mmol) prepared in Step 1 and acetic acid (100.0 % solution, 0.02 mL, 0.4 mmol) were dissolved in acetonitrile (35 mL) at room temperature. Sodium cyanoborohydride (100.0 %, 0.4 g, 7.1 mmol) was added to the solution, and the mixture was heated under reflux for 6 hours. The reaction mixture was then cooled to room temperature to terminate the reaction. A 2N sodium hydroxide aqueous solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.9 g, 99.2 %, clear oil).

[0484] [Step 3] Synthesis of 1-(4-fluorophenyl)ethylhydrazine

[0485]

[0486] The tert-butyl N-[1-(4-fluorophenyl)ethylamino]carbamate (100.0 %, 0.9 g, 3.5 mmol) prepared in Step 2 and hydrogen chloride (4.0 M solution, 1.8 mL, 7.1 mmol) were dissolved in dichloromethane (35 mL) at room temperature, and stirred at the same temperature. After the solvent was removed from the reaction mixture under reduced pressure, the precipitated solid was filtered, washed with hexane, and dried to obtain the title compound (0.65 g, 96.3 %) as a white solid.

[0487] [Table 5]

[0488]

[0489]

[0490] Example 93: Synthesis of N-[dimethyl(oxo)-λ6-sulfanylidene]-4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]benzamide

[0491] [Step 1] Synthesis of tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-methoxycarbonylphenyl)-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0492]

[0493] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.0 %, 1.0 g, 2.3 mmol) prepared in Step 4 of Example 1, (4-methoxycarbonylphenyl) boronic acid (100.0 %, 0.82 g, 4.6 mmol), copper(II) acetate (100.0 % solution, 0.3 mL, 3.4 mmol), and molecular sieve 4Å (150 mg) were dissolved in N,N-dimethylformamide (2 mL) at room temperature. Pyridine (100.0% solution, 0.4 mL, 4.95 mmol) was added to the solution, followed by stirring for 18 hours at 80℃. Then, the resulting mixture was cooled to room temperature to terminate the reaction. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, extracted with ethyl acetate, filtered through a plastic filter to remove the solid residue and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24 g cartridge; ethyl acetate / hexane = from 0% to 100 %) to obtain the title compound (0.98 g, 75.2 %) as a white solid.

[0494] [Step 2] Synthesis of 4-[3-[(4S)-5-tert-butoxycarbonyl-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]benzoic acid

[0495]

[0496] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-methoxycarbonylphenyl)-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.0 %, 0.1 g, 0.2 mmol) prepared in Step 1 was dissolved in methanol (2 mL) at room temperature. Sodium hydroxide (2.0 M solution, 0.2 mL, 0.3 mmol) was added to the solution and stirred at 50℃ for 3 hours, and then the resulting mixture was cooled to room temperature to terminate the reaction. A 1N aqueous hydrochloric acid 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 obtained product was used without further purification (90.0 mg, 92.2 %, white solid).

[0497] [Step 3] Synthesis of tert-butyl (4S)-3-[3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]carbamoyl]phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0498]

[0499] The 4-[3-[(4S)-5-tert-butoxycarbonyl-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]benzoic acid (100.0 %, 25.0 mg, 0.05 mmol) prepared in Step 2, imino-dimethyl-oxo-λ6-sulfane (100.0 %, 5.0 mg, 0.05 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.0 %, 25.0 mg, 0.07 mmol) were dissolved in N,N-dimethylformamide (1 mL) at room temperature. Then, N,N-diisopropylethylamine (DIPEA, 100.0 % solution, 0.02 mL, 0.1 mmol) was added to the solution, and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride 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 and concentrated by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = from 100 % to 95 %) to obtain the title compound (26.0 mg, 91.7 %) as a pale yellow solid.

[0500] [Step 4] Synthesis of N-[dimethyl(oxo)-λ6-sulfanylidene]-4-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]benzamide

[0501]

[0502] The tert-butyl (4S)-3-[3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]carbamoyl]phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.0 %, 0.03 g, 0.04 mmol) prepared in Step 3 was dissolved in dichloromethane (1 mL) at room temperature. Trifluoroacetic acid (100.0 % solution, 0.3 mL, 3.9 mmol) was added to the solution, and stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was poured onto the resulting concentrate, which was then extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (0.02 g, 99.7 %, pale yellow solid).

[0503] [Step 5] Synthesis of N-[dimethyl(oxo)-λ6-sulfanylidene]-4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]benzamide

[0504]

[0505] The N-[dimethyl(oxo)-λ6-sulfanylidene]-4-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]benzamide (100.0 %, 25.0 mg, 0.05 mmol) prepared in Step 4, 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (100.0 %, 22.0 mg, 0.05 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.0 %, 20.0 mg, 0.05 mmol) were dissolved in N,N-dimethylformamide (0.5 mL) at room temperature. Then, N,N-diisopropyl ethylamine (DIPEA, 100.0% solution, 0.05 mL, 0.3 mmol) was added to the solution, and stirred at the same temperature. A saturated aqueous ammonium chloride 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 and concentrated by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = from 100 % to 95 %) to obtain the title compound (25.0 mg, 57.7 %) as a pale yellow solid.

[0506] LC / MS (ES)m / z 931.2 [M + H]+;LC / MS retention time3.66 (min);LC / MS analysis conditions#1

[0507] Synthesis of Examples 94 to 101, 159 to 165, 173, 176, 178, 188, 191, 192, 250, 251, 571, 572, 584, 585, 589 to 594, and 608 to 619

[0508] The following compounds in Table 6 were each prepared according to the same reactions as described in Steps 1 to 5 of Example 93, except that a boronic acid with a fluorine added at position 3 was used instead of the (4-methoxycarbonyl)phenyl boronic acid used in Step 1 of Example 93, and various sulfoximine reagents were used instead of the imino-dimethyl-oxo-λ6-sulfane used in Step 3 of Example 93. The prepared compounds, along with the LC / MS retention times and LC / MS mass spectrometry results of each compound, are shown in Table 6 below.

[0509] [Table 6]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525] Example 102: Synthesis of 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-[[[dimethyl(oxo)-λ6-sulfanylidene]amino]methyl]phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0526] [Step 1] Synthesis of tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-formylphenyl)-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0527]

[0528] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.0 %, 0.06 g, 0.1 mmol) prepared in Step 4 of Example 1, (4-formylphenyl) boronic acid (100.0 %, 50.0 mg, 0.3 mmol), copper(II) acetate (100.0 % solution, 0.02 mL, 0.2 mmol), and molecular sieve 4Å (150 mg) were dissolved in N,N-dimethylformamide (1.5 mL). Pyridine (100.0 % solution, 0.03 mL, 0.4 mmol) was added at room temperature and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, extracted with ethyl acetate, filtered through a plastic filter to remove the solid residue and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = from 0% to 40 %) to obtain the title compound (55.0 mg, 74.2 %) as a yellow solid.

[0529] [Step 2] Synthesis of tert-butyl (4S)-3-[3-[4-[[[dimethyl(oxo)-λ6-sulfanylidene]amino]methyl]phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0530]

[0531] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-formylphenyl)-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.0 %, 0.03 g, 0.06 mmol) prepared in Step 1 and imino-dimethyl-oxo-λ6-sulfane (100.0 %, 10.0 mg, 0.1 mmol) were dissolved in 1,2-dichloroethane (1 mL) at room temperature. Sodium triacetoxyborohydride (100.0 %, 35.0 mg, 0.2 mmol) was added to the solution and 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 washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = from 100 % to 60 %) to obtain the title compound (0.03 g, 73.0 %) as a white solid.

[0532] [Step 3] Synthesis of 1-[4-[[[dimethyl(oxo)-λ6-sulfanylidene]amino]methyl]phenyl]-3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one

[0533]

[0534] The tert-butyl (4S)-3-[3-[4-[[[dimethyl(oxo)-λ6-sulfanylidene]amino]methyl]phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.0 %, 0.03 g, 0.04 mmol) prepared in Step 2 was dissolved in dichloromethane (1 mL) at room temperature. Trifluoroacetic acid (100.0 % solution, 0.3 mL, 3.9 mmol) was added to the solution, and stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was poured onto the resulting concentrate, which was then extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (0.02 g, 100.1 %, pale yellow solid).

[0535] [Step 4] Synthesis of 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-[[[dimethyl(oxo)-λ6-sulfanylidene]amino]methyl]phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0536]

[0537] The 1-[4-[[[dimethyl(oxo)-λ6-sulfanylidene]amino]methyl]phenyl]-3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one (100.0 %, 25.0 mg, 0.05 mmol) prepared in Step 3, 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (100.0 %, 22.0 mg, 0.05 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.0 %, 20.0 mg, 0.05 mmol) were dissolved in N,N-dimethylformamide (0.5 mL) at room temperature. Then, N,N-diisopropylethylamine (DIPEA, 100.0 % solution, 0.05 mL, 0.3 mmol) was added to the solution, and the mixture was stirred at the same temperature. A saturated aqueous ammonium chloride 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 and concentrated by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = from 100 % to 95 %) to obtain the title compound (18.0 mg, 41.1 %) as a pale yellow solid.

[0538] LC / MS (ES)m / z 917.4 [M + H]+;LC / MS retention time2.66 (min);LC / MS analysis conditions#1

[0539] Synthesis of Examples 103 to 105

[0540] Compounds of Examples 103 to 105 were each prepared according to the same reactions as described in Steps 1 to 4 of Example 102, except that (3-fluoro-4-formylphenyl)boronic acid, (3-formylphenyl)boronic acid, and (4-fluoro-3-formylphenyl)boronic acid were used instead of the (4-formylphenyl)boronic acid used in Step 1 of Example 102. The compounds prepared in Examples 103 to 105, along with the LC / MS retention times and LC / MS mass spectrometry results of each compound, are shown in Table 7 below.

[0541] [Table 7]

[0542]

[0543]

[0544] Example 106: Synthesis of 3-[(1S,2S)-1-[2-[(4S)-3-[3-[3-amino-4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0545]

[0546] The 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3-nitro-phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one (100.0 %, 0.03 g, 0.03 mmol) prepared in the same manner as in Step 8 of Example 1 was dissolved in tetrahydrofuran (0.2 mL) / water (0.2 mL) at room temperature. Zinc powder (100.0 %, 0.01 g, 0.2 mmol) and ammonium chloride (100.0 %, 8 mg, 0.2 mmol) were added to the solution, and stirred at the same temperature for 2 hours. The reaction mixture was filtered through a plastic filter to remove solids, the filtrate was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was poured onto the resulting concentrate, which was then extracted with dichloromethane. 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 and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = from 0 % to 30 %) to obtain the title compound (0.03 g, 86.1 %) as a yellow solid.

[0547] LC / MS (ES)m / z 918.3 [M + H]+;LC / MS retention time3.38 (min);LC / MS analysis conditions#1

[0548] Example 108: Synthesis of 3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethyl-phenyl)-3-[3-[3-(dimethylamino)-4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]phenyl]-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0549] [Step 1] Synthesis of tert-butyl (4S)-3-[3-[3-amino-4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]phenyl]-2-oxo-imidazol-1-yl]-2-(4-chloro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0550]

[0551] The tert-butyl (4S)-2-(4-chloro-3,5-dimethyl-phenyl)-3-[3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3-nitro-phenyl]-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.0 %, 0.03 g, 0.05 mmol) prepared in the same manner as in Step 6 of Example 1, zinc powder (100.0 %, 0.02 g, 0.2 mmol), and ammonium chloride (100.0 %, 0.01 g, 0.2 mmol) were dissolved in tetrahydrofuran (0.1 mL) / water (0.1 mL) at room temperature, and stirred at the same temperature for 2 hours. The reaction mixture was filtered through a plastic filter to remove solids, then the solvent was removed from the obtained filtrate under reduced pressure, and the obtained product was used without further purification (0.03 g, 99.9 %, white solid).

[0552] [Step 2] Synthesis of tert-butyl (4S)-2-(4-chloro-3,5-dimethyl-phenyl)-3-[3-[3-(dimethylamino)-4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]phenyl]-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0553]

[0554] The tert-butyl (4S)-3-[3-[3-amino-4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]phenyl]-2-oxo-imidazol-1-yl]-2-(4-chloro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.0 %, 0.03 g, 0.05 mmol) prepared in Step 1, sodium triacetyloxyboron (100.0 %, 0.03 g, 0.14 mmol), and formaldehyde (36.5 % solution in water, 7 μL, 0.07 mmol) were dissolved in dichloromethane (1 mL) at room temperature, and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = from 0% to 50 %) to obtain the title compound (0.01 g, 40.0 %) as a white solid.

[0555] [Step 3] Synthesis of 1-[(4S)-2-(4-chloro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[3-(dimethylamino)-4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]phenyl]imidazol-2-one

[0556]

[0557] The tert-butyl (4S)-2-(4-chloro-3,5-dimethyl-phenyl)-3-[3-[3-(dimethylamino)-4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]phenyl]-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.0 %, 0.01 g, 0.02 mmol) prepared in Step 2 and trifluoroacetic acid (100.0 % solution, 0.05 mL, 0.4 mmol) were dissolved in dichloromethane (1 mL) at room temperature, and stirred at the same temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and concentrated under reduced pressure. The obtained product was used without further purification (0.01 g, 98.0 %, white solid).

[0558] [Step 4] Synthesis of 3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethyl-phenyl)-3-[3-[3-(dimethylamino)-4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]phenyl]-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0559]

[0560] The 1-[(4S)-2-(4-chloro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[3-(dimethylamino)-4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]phenyl]imidazol-2-one (100.0 %, 0.01 g, 0.02 mmol) prepared in Step 3, 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (100.0 %, 9 mg, 0.02 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.0 %, 0.01 g, 0.04 mmol), and N,N-diisopropylethylamine (100.0 % solution, 9 μL, 0.05 mmol) were dissolved in N,N-dimethylformamide (1 mL) at room temperature, and stirred at the same temperature. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = from 0 % to 80 %), and the resulting product was further purified and concentrated by chromatography (SiO2plate, 20x20x1 mm; methanol / dichloromethane = 5 %) to obtain the title compound (0.02 g, 90.0 %) as a white solid.

[0561] LC / MS (ES)m / z 972.5 [M + H]+;LC / MS retention time2.67 (min);LC / MS analysis conditions#1

[0562] Synthesis of Example 109

[0563] A compound of Example 109 was prepared according to the same reactions as described in Steps 1 to 4 of Example 108, except that (4-methoxyphenyl)hydrazine was used instead of the (4-chloro-3,5-dimethylphenyl)hydrazine in Step 1 of Example 1 for the synthesis of Example 108. The prepared compounds, along with the LC / MS retention times and LC / MS mass spectrometry results of each compound, are shown in Table 8 below.

[0564] [Table 8]

[0565]

[0566] Example 110: Synthesis of N-(azetidin-1-yl)-4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]-2-fluoro-benzamide

[0567] [Step 1] Synthesis of tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(3-fluoro-4-methoxycarbonyl-phenyl)-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0568]

[0569] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.0 %, 0.2 g, 0.5 mmol) prepared in Step 4 of Example 1, (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (100.0 %, 441.5 mg, 1.0 mmol), copper(II) acetate (100.0 %, 272.4 mg, 1.5 mmol), and molecular sieve 4Å (150 mg) were dissolved in N,N-dimethylformamide (5 mL). Pyridine (100.0% solution, 0.2 mL, 2.0 mmol) was added to the solution at room temperature, followed by stirring for 18 hours at 80℃. Then, the resulting mixture was cooled to room temperature to terminate the reaction. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, extracted with ethyl acetate, filtered through a plastic filter to remove the solid residue and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = from 0% to 80 %) to obtain the title compound (0.13 g, 22.4 %) as a pale yellow solid.

[0570] [Step 2] Synthesis of methyl 2-fluoro-4-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]benzoate

[0571]

[0572] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(3-fluoro-4-methoxycarbonyl-phenyl)-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.0 %, 0.13 g, 0.2 mmol) prepared in Step 1 was dissolved in dichloromethane (2.2 mL) at room temperature. Trifluoroacetic acid (100.0 % solution, 0.3 mL, 4.5 mmol) was added to the solution, and stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was poured onto the resulting concentrate, which was then extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (0.1 g, 90.4 %, white solid).

[0573] [Step 3] Synthesis of methyl 4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]-2-fluoro-benzoate

[0574]

[0575] The methyl 2-fluoro-4-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]benzoate (100.0 %, 110.5 mg, 0.2 mmol) prepared in Step 2, 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (100.0 %, 138.3 mg, 0.3 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.0 %, 127.8 mg, 0.3 mmol) were dissolved in N,N-dimethylformamide (2.2 mL) at room temperature. N,N-diisopropylethylamine (100.0 % solution, 0.1 mL, 0.7 mmol) was added to the solution, and the mixture was stirred at the same temperature for 20 hours. A saturated aqueous ammonium chloride 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 and concentrated by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = from 100 % to 95 %) to obtain the title compound (0.18 g, 90.6 %) as a white solid.

[0576] [Step 4] Synthesis of 4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]-2-fluoro-benzoic acid

[0577]

[0578] The methyl 4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]-2-fluoro-benzoate (100.0 %, 0.2 g, 0.2 mmol) prepared in Step 3, and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100.0 %, 64.0 mg, 0.5 mmol) were dissolved in acetonitrile (0.5 mL) at room temperature, was stirred at the same temperature for 20 hours. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = from 0% to 5%) to obtain the title compound (50.4 mg, 25.1 %) as a white solid.

[0579] [Step 5] Synthesis of N-(azetidin-1-yl)-4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]-2-fluoro-benzamide

[0580]

[0581] The 4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]-2-fluoro-benzoic acid (100.0 %, 23.6 mg, 0.03 mmol) prepared in Step 4, azetidine-1-amine; dihydrochloride (100.0 %, 5.9 mg, 0.04 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (100.0 %, 15.4 mg, 0.04 mmol) were dissolved in N,N-dimethylformamide (2.2 mL) at room temperature. Then, N,N-diisopropylethylamine (100.0 % solution, 0.01 mL, 0.08 mmol) was added to the solution, and stirred at the same temperature for 20 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. 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 and concentrated by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = from 0 % to 10 %) to obtain the title compound (9.2 mg, 36.7 %) as a white solid.

[0582] LC / MS (ES)m / z 927.5 [M + H]+;LC / MS retention time3.81 (min);LC / MS analysis conditions#2

[0583] Synthesis of Examples 111 to 114, and 117 to 120

[0584] The following compounds in Table 9 were each prepared according to the same reactions as described in Steps 1 to 5 of Example 110, except that a boronic acid with a fluorine added at position 3 was used instead of the (4-methoxycarbonylphenyl) boronic acid used in Step 1 of Example 110, and various hydrazine reagents were used instead of the azetidine-1-amine used in Step 5 of Example 110. The prepared compounds, along with the LC / MS retention times and LC / MS mass spectrometry results of each compound, are shown in Table 9 below.

[0585] [Table 9]

[0586]

[0587]

[0588]

[0589] Example 115: Synthesis of 4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]-N-methylsulfonyl-benzamide

[0590]

[0591] The 4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]benzoic acid (100.00 %, 16.000 mg, 0.019 mmol) prepared in Step 4 of Example 110, and methanesulfonamide (100.00 %, 5.000 mg, 0.053 mmol) were dissolved in dichloromethane (0.5 mL) at room temperature. Then, N,N-dimethylpyridin-4-amine (DMAP, 100.00 %, 6.000 mg, 0.049 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 100.00 %, 8.000 mg, 0.042 mmol) were added to the solution, and stirred at the same temperature. A saturated aqueous ammonium chloride 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 and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = from 5 % to 50 %) to obtain the title compound (0.010 g, 57.33 %) as a pale yellow solid.

[0592] LC / MS (ES)m / z 932.2 [M + H]+;LC / MS retention time3.58 (min);LC / MS analysis conditions#1

[0593] Synthesis of Example 116

[0594] A compound of Example 116 was prepared according to the same reactions as described in Example 115, except that a boronic acid with a fluorine added was used instead of the 4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]benzoic acid used in Example 115. The prepared compounds, along with the LC / MS retention times and LC / MS mass spectrometry results of each compound, are shown in Table 10 below.

[0595] [Table 10]

[0596]

[0597] Example 123: Synthesis of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-[4-(1-imino-1-oxo-1,4-thiazinane-4-carbonyl)phenyl]-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0598] [Step 1] Synthesis of tert-butyl N-[4-[4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]benzoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate

[0599]

[0600] At room temperature, 4-(3-((4S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)benzoic acid (100.0 %, 51.3 mg, 0.06 mmol), tert-butyl(1-oxo-1λ6-thiomorpholin-1-ylidene)carbamate (100.0 %, 18.3 mg, 0.078 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.0 %, 46.8 mg, 0.09 mmol) were dissolved in N,N-dimethylformamide (1 mL). Then, N,N-diisopropylethylamine (DIPEA, 100.0 % solution, 0.0418 mL, 0.18 mmol) was added to the solution, and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride 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 and concentrated by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = from 100 % to 95 %) to obtain the title compound (63.4 mg, 100.0 %) as a pale yellow solid.

[0601] [Step 2] Synthesis of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-[4-(1-imino-1-oxo-1,4-thiazinane-4-carbonyl)phenyl]-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0602]

[0603] Tert-Butyl N-[4-[4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]benzoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate (100.00 %, 64.300 mg, 0.060 mmol) and trifluoroacetic acid (100.00 % solution, 0.092 mL, 1.202 mmol) were dissolved in dichloromethane (1.17 mL) at room temperature, and stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, followed by extraction with dichloromethane. 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 and concentrated by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = from 0 % to 5 %) to obtain the title compound (45.700 mg, 78.40 %) as a white solid.

[0604] LC / MS (ES)m / z 972.0 [M + H]+;LC / MS retention time5.47 (min);LC / MS analysis conditions#2

[0605] Example 140: Synthesis of N-[4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]phenyl]methanesulfonamide

[0606] [Step 1] Synthesis of tert-butyl (4S)-3-[3-(4-aminophenyl)-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0607]

[0608] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(4-nitrophenyl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 0.050 g, 0.089 mmol) prepared in Step 5 of Example 1 was dissolved in tetrahydrofuran (0.2 mL) / water (0.2 mL) at room temperature. Then, zinc dust (100.00 %, 0.030 g, 0.459 mmol) and ammonium chloride (100.00 %, 0.025 g, 0.467 mmol) were added and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was filtered through a plastic filter to remove solids, then the solvent was removed from the obtained filtrate under reduced pressure, and the obtained product was used without further purification (0.031 g, 65.49 %, black solid).

[0609] [Step 2] Synthesis of tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-[4-(methanesulfonamido)phenyl]-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0610]

[0611] The tert-butyl (4S)-3-[3-(4-aminophenyl)-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 50.000 mg, 0.094 mmol) prepared in Step 1 and triethylamine (100.00 % solution, 0.02 mL, 0.143 mmol) were dissolved in dichloromethane (1 mL) at room temperature. Then, methanesulfonyl chloride (100.00 % solution, 0.01 mL, 0.129 mmol) was added to the solution and 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 chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = from 0% to 40 %) to obtain the title compound (27.000 mg, 47.09 %) as a white solid.

[0612] [Step 3] Synthesis of N-[4-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]phenyl]methanesulfonamide

[0613]

[0614] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-[4-(methanesulfonamido)phenyl]-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 0.025 g, 0.041 mmol) prepared in Step 2 was dissolved in dichloromethane (1 mL) at room temperature. Then, trifluoroacetic acid (100.00 % solution, 0.3 mL, 3.920 mmol) was added to the solution, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was poured onto the resulting concentrate, which was then extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (0.021 g, 100.50 %, pale yellow solid).

[0615] [Step 4] Synthesis of N-[4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]phenyl]methanesulfonamide

[0616]

[0617] The N-[4-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]phenyl]methanesulfonamide (100.00 %, 25.000 mg, 0.049 mmol) prepared in Step 3, 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (100.00 %, 22.000 mg, 0.053 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (100.00 %, 20.000 mg, 0.053 mmol) were dissolved in N,N-dimethylformamide (0.5 mL) at room temperature. Then, N,N-diisopropylethylamine (100.00 % solution, 0.045 mL, 0.258 mmol) was added to the solution and stirred at the same temperature. A saturated aqueous ammonium chloride 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 and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = from 5 % to 50 %) to obtain the title compound (0.023 g, 51.96 %) as a pale yellow solid.

[0618] LC / MS (ES)m / z 905.62 [M + H]+;LC / MS retention time3.81 (min);LC / MS analysis conditions#1

[0619] Synthesis of Example 141

[0620] A compound of Example 141 was prepared according to the same reactions as described in Steps 1 to 4 of Example 140, except that tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(3-methoxy-4-nitrophenyl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate was used instead of the tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(4-nitrophenyl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate used in Step 1 of Example 140. The prepared compounds, along with the LC / MS retention times and LC / MS mass spectrometry results of each compound, are shown in Table 11 below.

[0621] [Table 11]

[0622]

[0623] Example 139: Synthesis of N-[[4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]phenyl]methyl]methanesulfonamide

[0624] [Step 1] Synthesis of tert-butyl (4S)-3-[3-[4-(benzyloxycarbonylaminomethyl)phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0625]

[0626] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 0.500 g, 1.133 mmol) prepared in Step 4 of Example 1, [4-(benzyloxycarbonylaminomethyl)phenyl]boronic acid (100.00 %, 650.000 mg, 2.280 mmol), copper acetate (100.00 %, 200.000 mg, 1.632 mmol), and molecular sieve 4Å (150 mg) were dissolved in N,N-dimethylformamide (8 mL). Pyridine (100.0% solution, 0.19 mL, 2.349 mmol) was added to the solution at room temperature and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, extracted with ethyl acetate, filtered through a plastic filter to remove the solid residue and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = from 0% to 40 %) to obtain the title compound (400.000 mg, 51.88 %) as a white solid.

[0627] [Step 2] Synthesis of tert-butyl (4S)-3-[3-[4-(aminomethyl)phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0628]

[0629] The tert-butyl (4S)-3-[3-[4-(benzyloxycarbonylaminomethyl)phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 100.000 mg, 0.147 mmol) prepared in Step 1 and palladium on carbon (10%) (100.00 % solution, 0.0042 mL, 0.470 mmol) were dissolved in methanol (2 mL) at room temperature and stirred with a hydrogen balloon attached. The reaction mixture was filtered through a celite pad to remove solids, then the solvent was removed from the obtained filtrate under reduced pressure, and the obtained product was used without further purification (40.000 mg, 49.82%, white solid).

[0630] [Step 3] Synthesis of tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-[4-(methanesulfonamidomethyl)phenyl]-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0631]

[0632] The tert-butyl (4S)-3-[3-[4-(aminomethyl)phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 50.000 mg, 0.091 mmol) prepared in Step 2 and triethylamine (100.00 % solution, 0.019 mL, 0.136 mmol) were dissolved in dichloromethane (1 mL) at room temperature, and methanesulfonyl chloride (100.00 % solution, 0.008 mL, 0.103 mmol) was added to the solution and 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 chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = from 0% to 40 %) to obtain the title compound (27.000 mg, 47.25 %) as a white solid.

[0633] [Step 4] Synthesis of N-[[4-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]phenyl]methyl]methanesulfonamide

[0634]

[0635] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-[4-(methanesulfonamidomethyl)phenyl]-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 0.025 g, 0.040 mmol) prepared in Step 3 was dissolved in dichloromethane (1 mL) at room temperature, and trifluoroacetic acid (100.00 % solution, 0.3 mL, 3.920 mmol) was added to the solution and stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was poured onto the resulting concentrate, which was then extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (0.021 g, 100.00 %, pale yellow solid).

[0636] [Step 5] Synthesis of N-[[4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]phenyl]methyl]methanesulfonamide

[0637]

[0638] The N-[[4-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]phenyl]methyl]methanesulfonamide (100.00 %, 25.000 mg, 0.048 mmol) prepared in Step 4, 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (100.00 %, 22.000 mg, 0.053 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (100.00 %, 20.000 mg, 0.053 mmol) were dissolved in N,N-dimethylformamide (0.5 mL) at room temperature. Then, N,N-diisopropylethylamine (100.00 % solution, 0.045 mL, 0.258 mmol) was added to the solution and stirred at the same temperature. A saturated aqueous ammonium chloride 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 and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = from 5 % to 70 %) to obtain the title compound (0.021 g, 48.00 %) as a pale yellow solid.

[0639] LC / MS (ES)m / z 921.23 [M + H]+;LC / MS retention time3.92 (min);LC / MS analysis conditions#1

[0640] Example 492: Synthesis of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-[4-[(4-methyl-1-oxo-1,4-thiazinan-1-ylidene)amino]phenyl]-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0641] [Step 1] Synthesis of benzyl 1-[4-[3-[(4S)-5-tert-butoxycarbonyl-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]phenyl]imino-1-oxo-1,4-thiazinane-4-carboxylate

[0642]

[0643] The tert-butyl (4S)-3-[3-(4-bromophenyl)-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 500.000 mg, 0.838 mmol) prepared in Step 5 of Example 1, benzyl 1-imino-1-oxo-1,4-thiazinane-4-carboxylate (100.00 %, 585.000 mg, 2.180 mmol), tris(dibenzylideneacetone) dipalladium(0)(Pd2(dba)3, 100.00 %, 155.000 mg, 0.169 mmol), Johnphos (100.00 %, 150.000 mg, 0.503 mmol), and sodium tert-butoxide (100.00 %, 240.000 mg, 2.497 mmol) were dissolved in 1,4-dioxane (5 mL) at room temperature, followed by stirring at 80℃ for 1 hour. Then, the reaction mixture was cooled to room temperature to terminate the reaction. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, extracted with ethyl acetate, filtered through a plastic filter to remove the solid residue and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = from 0 % to 20 %) to obtain the title compound (500.000 mg, 76.09 %) as a yellow solid.

[0644] [Step 2] Synthesis of tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[2-oxo-3-[4-[(1-oxo-1,4-thiazinan-1-ylidene)amino]phenyl]imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0645]

[0646] The benzyl 1-[4-[3-[(4S)-5-tert-butoxycarbonyl-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]phenyl]imino-1-oxo-1,4-thiazinane-4-carboxylate (100.00 %, 500.000 mg, 0.638 mmol) prepared in Step 1 and palladium on activated carbon (10.00 %, 68.000 mg, 0.064 mmol) were dissolved in methanol (6.5 mL) at room temperature, and stirred at the same temperature for 18 hours with a hydrogen balloon attached. The reaction mixture was filtered through a celite pad to remove solids, then the solvent was removed from the obtained filtrate under reduced pressure, and the obtained product was used without further purification (240.000 mg, 57.91 %, white solid).

[0647] [Step 3] Synthesis of tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-[4-[(4-methyl-1-oxo-1,4-thiazinan-1-ylidene)amino]phenyl]-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0648]

[0649] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[2-oxo-3-[4-[(1-oxo-1,4-thiazinan-1-ylidene)amino]phenyl]imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 40.000 mg, 0.062 mmol) prepared in Step 2, formaldehyde (37.00 % solution, 0.012 mL, 0.121 mmol), and N,N-diisopropylethylamine (100.00 % solution, 0.02 mL, 0.115 mmol) were dissolved in dichloromethane (300 μL) at room temperature, and sodium triacetoxyborohydride (100.00 %, 40.000 mg, 0.190 mmol) was added to the solution and 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 washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = from 0 % to 30 %) to obtain the title compound (20.000 mg, 48.95 %) as a yellow solid.

[0650] [Step 4] Synthesis of 1-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[4-[(4-methyl-1-oxo-1,4-thiazinan-1-ylidene)amino]phenyl]imidazol-2-one

[0651]

[0652] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-[4-[(4-methyl-1-oxo-1,4-thiazinan-1-ylidene)amino]phenyl]-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 20.000 mg, 0.030 mmol) prepared in Step 3 and trifluoroacetic acid (100.00 % solution, 0.035 mL, 0.283 mmol) were dissolved in dichloromethane (300 μL) at room temperature, and stirred at the same temperature for 18 hours. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The obtained product was used without further purification (17.000 mg, 100.00 %, yellow solid).

[0653] [Step 5] Synthesis of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-[4-[(4-methyl-1-oxo-1,4-thiazinan-1-ylidene)amino]phenyl]-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0654]

[0655] The 1-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[4-[(4-methyl-1-oxo-1,4-thiazinan-1-ylidene)amino]phenyl]imidazol-2-one (100.00 %, 17.000 mg, 0.030 mmol) obtained in Step 4, 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (100.00 %, 15.000 mg, 0.036 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 100.00 %, 17.000 mg, 0.033 mmol), and N,N-diisopropylethylamine (100.00 % solution, 0.026 mL, 0.149 mmol) were dissolved in acetonitrile (300 μL) at room temperature, and stirred at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, extracted with ethyl acetate, filtered through a plastic filter to remove the solid residue and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = from 0 % to 20 %) to obtain the title compound (25.000 mg, 86.61 %) as a pale yellow solid.

[0656] LC / MS (ES)m / z 957.63 [M + H]+;LC / MS retention time2.72 (min);LC / MS analysis conditions#1

[0657] Synthesis of Examples 497 to 499, 508, 519, 595, and 602 to 605

[0658] Compounds of Examples 497 to 499, 508, 519, 595, and 602 to 605 were each prepared according to the same reactions as described in Steps 1 to 5 of Example 492, except that various heterocyclic sulfoximine reagents were used instead of the benzyl 1-imino-1-oxo-1,4-thiazinane-4-carboxylate in Step 1 of Example 492. The prepared compounds, along with the LC / MS retention times and LC / MS mass spectrometry results of each compound, are shown in Table 12 below.

[0659] [Table 12]

[0660]

[0661]

[0662]

[0663]

[0664] Example 501: Synthesis of 3-[1-[2-[(4S)-3-[3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3-(methylamino)phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(tetrahydropyran-4-yl)-indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0665] [Step 1] Synthesis of benzyl N-[2-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[0666]

[0667] 2-Bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (100.00 %, 3.000 g, 10.070 mmol), benzyl carbonochloridate (100.00 % solution, 1.717 mL, 12.080 mmol), and sodium hydrogen bicarbonate (100.00 %, 1.015 g, 12.080 mmol) were dissolved in tetrahydrofuran (50 mL) at room temperature, and stirred at the same temperature for 4 hours. A saturated aqueous ammonium chloride 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 and concentrated by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = from 0% to 100 %) to obtain the title compound (3.500 g, 80.46 %) as a pale yellow liquid.

[0668] [Step 2] Synthesis of [3-(benzyloxycarbonylamino)-4-bromo-phenyl]boronic acid

[0669]

[0670] The benzyl N-[2-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (100.00 %, 0.300 g, 0.700 mmol) prepared in Step 1, ammonium acetate (100.00 %, 0.268 g, 3.472 mmol), and sodium periodate (100.00 %, 0.743 g, 3.471 mmol) were dissolved in acetone (3 mL) / water (3 mL) at room temperature, and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, extracted with ethyl acetate, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The obtained product was used without further purification (0.243 g, 100.00 %, white solid).

[0671] [Step 3] Synthesis of tert-butyl (4S)-3-[3-[3-(benzyloxycarbonylamino)-4-bromo-phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0672]

[0673] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 1.350 g, 3.060 mmol) prepared in Step 4 of Example 1, the [3-(benzyloxycarbonylamino)-4-bromo-phenyl]boronic acid (100.00 %, 1.605 g, 4.586 mmol) prepared in Step 2, copper acetate (100.00 %, 0.750 g, 6.116 mmol), pyridine (100.00 % solution, 0.9892 mL, 12.230 mmol), and molecular sieve 4Å (50 mg) were dissolved in N,N-dimethylformamide (16 mL) at room temperature, and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = from 0% to 100 %) to obtain the title compound (1.500 g, 65.80 %) as a white solid.

[0674] [Step 4] Synthesis of tert-butyl (4S)-3-[3-[3-[benzyloxycarbonyl(methyl)amino]-4-bromo-phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0675]

[0676] The tert-butyl (4S)-3-[3-[3-(benzyloxycarbonylamino)-4-bromo-phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 0.300 g, 0.402 mmol) prepared in Step 3, iodomethane (100.00 % solution, 0.1 mL, 1.610 mmol), and sodium hydride (60.00 %, 0.064 g, 1.600 mmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature, and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = from 0% to 100 %) to obtain the title compound (0.192 g, 62.81 %) as a white solid.

[0677] [Step 5] Synthesis of tert-butyl (4S)-3-[3-[4-bromo-3-(methylamino)phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0678]

[0679] The tert-butyl (4S)-3-[3-[3-[benzyloxycarbonyl(methyl)amino]-4-bromo-phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 0.254 g, 0.334 mmol) prepared in Step 4, palladium-activated carbon (100.00 %, 0.036 g, 0.033 mmol), and palladium-activated carbon ethylenediamine complex (100.00 %, 0.036 g, 0.033 mmol) were dissolved in tetrahydrofuran (2 mL) and stirred at room temperature. Then, the resulting mixture was stirred for 5 hours with a hydrogen balloon attached. The reaction mixture was filtered through a celite pad to remove solids, then the solvent was removed from the obtained filtrate under reduced pressure, and the concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = from 0% to 50 %) to obtain the title compound (0.143 g, 68.29 %) as a white solid.

[0680] [Step 6] Synthesis of tert-butyl (4S)-3-[3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3-(methylamino)phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0681]

[0682] The tert-butyl (4S)-3-[3-[4-bromo-3-(methylamino)phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 0.050 g, 0.080 mmol) prepared in Step 5, imino-dimethyl-oxo-λ6-sulfane (100.00 %, 0.015 g, 0.156 mmol), tris(dibenzylideneacetone)dipalladium (100.00 %, 0.015 g, 0.016 mmol), JohnPhos (100.00 %, 0.014 g, 0.048 mmol), and sodium tert-butoxide (100.00%, 0.023 g, 0.240 mmol) were dissolved in 1,4-dioxane (1 mL) at room temperature, followed by stirring at 80℃ for 3 hours. Then, the reaction mixture was cooled to room temperature to terminate the reaction. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = from 0% to 100 %) to obtain the title compound (0.051 g, 100.00 %) as a pale yellow solid.

[0683] [Step 7] Synthesis of (1-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3-(methylamino)phenyl]-3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one

[0684]

[0685] The tert-butyl (4S)-3-[3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3-(methylamino)phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 0.052 g, 0.082 mmol) prepared in Step 6 and trifluoroacetic acid (100.00 % solution, 0.2026 mL, 1.637 mmol) were dissolved in dichloromethane (1 mL) at room temperature, and stirred at the same temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The obtained product was used without further purification (0.044 g, 100.40 %, pale yellow liquid).

[0686] [Step 8] Synthesis of 3-[1-[2-[(4S)-3-[3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3-(methylamino)phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(tetrahydropyran-4-yl)-indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0687]

[0688] The 1-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3-(methylamino)phenyl]-3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one (100.00 %, 0.044 g, 0.082 mmol) prepared in Step 7, 1-[1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-5-(tetrahydropyran-4-yl)-indole-2-carboxylic acid (100.00 %, 0.039 g, 0.106 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 100.00 %, 0.047 g, 0.090 mmol), and N,N-diisopropylethylamine (100.00 % solution, 0.0428 mL, 0.246 mmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature, and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = from 0 % to 100 %) to obtain the title compound (0.050 g, 68.00 %) as a white solid.

[0689] LC / MS (ES)m / z 889.5 [M + H]+;LC / MS retention time2.80 (min);LC / MS analysis conditions#1

[0690] Synthesis of Examples 122, 142, 175, 182 to 184, 199 to 203, 214 to 216, 229, 230, 259, 262, 401 to 403, 467, 502 to 507, and 573

[0691] The following Examples 122, 142, 175, 182 to 184, 199 to 203, 214 to 216, 229, 230, 259, 262, 401 to 403, 467, 502 to 507, and 573 were each prepared according to the same reactions as described in Steps 1 to 8 of Example 501, except that hydrazines having various substituents were used instead of the (4-fluoro-3,5-dimethylphenyl)hydrazine in Step 3 of Example 501 and that various sulfoximine reagents were used instead of the imino-dimethyl-oxo-λ6-sulfane used in Step 6 of Example 501. The prepared compounds, along with the LC / MS retention times and LC / MS mass spectrometry results of each compound, are shown in Table 13 below.

[0692] [Table 13]

[0693]

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703] Preparation Example 1: Synthesis of 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-2-fluoro-phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0704] [Step 1] Synthesis of (4-bromo-3-fluoro-phenyl)imino-dimethyl-oxo-λ6-sulfane

[0705]

[0706] Imino-dimethyl-oxo-λ6-sulfane (100.00 %, 200.000 mg, 2.147 mmol), copper iodide (100.00 %, 0.041 g, 0.215 mmol), and 4-(dimethylamino)pyridine (100.00 %, 0.262 g, 2.147 mmol) were dissolved in methanol (2.6 mL) at room temperature, and (4-bromo-3-fluoro-phenyl)boronic acid (100.00 %, 0.705 g, 3.221 mmol) was added and 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 washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = from 0% to 80 %) to obtain the title compound (406.000 mg, 71.05 %) as a colorless oil.

[0707] [Step 2] Synthesis of tert-butyl (4S)-3-[3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-2-fluoro-phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0708]

[0709] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 100.000 mg, 0.227 mmol) prepared in Step 4 of Example 1, the (4-bromo-3-fluoro-phenyl)imino-dimethyl-oxo-λ6-sulfane (100.00 %, 0.121 g, 0.453 mmol) prepared in Step 1, trans-N,N'-dimethylcyclohexane-1,2-diamine (100.00 %, 0.016 g, 0.113 mmol), potassium carbonate (100.00 %, 0.067 g, 0.680 mmol), and copper iodide (CuI, 100.00 %, 0.004 g, 0.023 mmol) were dissolved in 1-methylpyrrolidin-2-one (2.3 mL) at room temperature, and stirred at 110℃ for 3 hours. Then, the reaction mixture was cooled to room temperature to terminate the reaction. A saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = from 0% to 80 %) to obtain the title compound (133.000 mg, 93.70 %) as a pale yellow foam solid.

[0710] [Step 3] Synthesis of 1-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-2-fluoro-phenyl]-3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one

[0711]

[0712] The tert-butyl (4S)-3-[3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-2-fluoro-phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 133.000 mg, 0.212 mmol) prepared in Step 2, and 2,2,2-trifluoroacetic acid (100.00 % solution, 0.3248 mL, 4.244 mmol) were dissolved in dichloromethane (1 mL) at room temperature, and stirred at the same temperature for 3 hours. 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 (112.000 mg, 100.20 %, pale yellow foam solid).

[0713] [Step 4] Synthesis of 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-2-fluoro-phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0714]

[0715] The 1-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-2-fluoro-phenyl]-3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one (100.00 %, 112.000 mg, 0.213 mmol) prepared in Step 3, 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (100.00 %, 0.087 g, 0.213 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 100.00 %, 0.122 g, 0.234 mmol), and N,N-diisopropylethylamine (100.00 % solution, 0.07409 mL, 0.425 mmol) were dissolved in acetonitrile (1 mL) at room temperature, and 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 and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = from 0 % to 5 %) to obtain the title compound (158.000 mg, 80.75 %) as a pale yellow foam solid.

[0716] LC / MS (ES)m / z 920.66 [M + H]+;LC / MS retention time3.49 (min);LC / MS analysis conditions#1

[0717] Synthesis of Examples 491, 523, 524, and 577 to 579

[0718] Compounds of Examples 491, 523, 524, and 577 to 579 were each prepared according to the same reactions as described in Steps 1 to 4 of Preparation Example 1, except that (3-bromo-2-fluorophenyl)boronic acid was used instead of the (4-bromo-2-fluorophenyl)boronic acid used in Step 1 of Preparation Example 1. The prepared compounds, along with the LC / MS retention times and LC / MS mass spectrometry results of each compound, are shown in Table 14 below.

[0719] [Table 14]

[0720]

[0721]

[0722]

[0723] Example 253: Synthesis of N-[4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]phenyl]-N',N'-dimethyl-oxamide

[0724] [Step 1] Synthesis of 2-bromo-N-(4-bromophenyl)-2,2-difluoro-acetamide

[0725]

[0726] 4-Bromoaniline (100.00 %, 0.300 g, 1.744 mmol) and triethylamine (100.00 % solution, 0.47696 mL, 3.488 mmol) were dissolved in dichloromethane (5 mL) at room temperature, and 2-bromo-2,2-difluoro-acetyl chloride (100.00 % solution, 0.16427 mL, 1.744 mmol) was added thereto and stirred at the same temperature. The solvent was removed from the reaction mixture under reduced pressure, and the concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = from 0% to 30 %) to obtain the title compound (0.510 g, 88.90 %) as a white solid.

[0727] [Step 2] Synthesis of N-(4-bromophenyl)-N',N'-dimethyl-oxamide

[0728]

[0729] The 2-bromo-N-(4-bromophenyl)-2,2-difluoro-acetamide (100.00 %, 0.500 g, 1.520 mmol) prepared in Step 1 and copper sulfate (100.00 %, 0.024 g, 0.152 mmol) were dissolved in dimethyl sulfoxide (3 mL) / water (0.3 mL), and N,N,N',N'-tetramethylethylenediamine (100.00 % solution, 0.34187 mL, 2.280 mmol) was added at room temperature, followed by stirring at 110℃ for 18 hours. Then, the reaction mixture was cooled to room temperature to terminate the reaction. Water was added to 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 and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = from 0% to 50 %) to obtain the title compound (0.090 g, 21.84 %) as a yellow solid.

[0730] [Step 3] Synthesis of tert-butyl (4S)-3-[3-[4-[[2-(dimethylamino)-2-oxo-acetyl]amino]phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0731]

[0732] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 0.150 g, 0.113 mmol) prepared in Step 4 of Example 1, copper iodide (100.00 %, 0.013 g, 0.023 mmol), (1S,2S)-(+)-N,N'-dimethylcyclohexane-1,2-diamine (100.00 %, 0.024 g, 0.057 mmol), potassium carbonate (100.00 %, 0.101 g, 0.340 mmol), and the N-(4-bromophenyl)-N',N'-dimethyl-oxamide (100.00 %, 0.092 g, 0.136 mmol) prepared in Step 2 were dissolved in 1-methylpyrrolidin-2-one (5 mL) at room temperature, and stirred at 130℃ for 18 hours. Then, the reaction mixture was cooled to room temperature to terminate the reaction. A saturated aqueous ammonium chloride 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 and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = from 0% to 100 %) to obtain the title compound (0.200 g, 279.60 %) as a brown solid.

[0733] [Step 4] Synthesis of N-[4-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]phenyl]-N',N'-dimethyl-oxamide

[0734]

[0735] The tert-butyl (4S)-3-[3-[4-[[2-(dimethylamino)-2-oxo-acetyl]amino]phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00 %, 0.200 g, 0.317 mmol) prepared in Step 3 and trifluoroacetic acid (100.00 % solution, 0.281 mL, 2.270 mmol) were dissolved in dichloromethane (5 mL) at room temperature, and 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 chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.120 g, 71.30 %, white solid).

[0736] [Step 5] Synthesis of N-[4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]phenyl]-N',N'-dimethyl-oxamide

[0737]

[0738] The N-[4-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]phenyl]-N',N'-dimethyl-oxamide (100.00 %, 0.120 g, 0.226 mmol) prepared in Step 4, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00 %, 0.129 g, 0.339 mmol), N,N-diisopropylethylamine (100.00 % solution, 0.118 mL, 0.677 mmol), and 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (100.00 %, 0.093 g, 0.226 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature, and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = from 0% to 100 %) to obtain the title compound (0.110 g, 52.68 %) as a yellow solid.

[0739] LC / MS (ES)m / z 925.58 [M + H]+;LC / MS retention time3.70 (min);LC / MS analysis conditions#1

[0740] Synthesis of Examples 558 to 561

[0741] Compounds of Examples 558 to 561 were each prepared according to the same reactions as described in Steps 1 to 5 of Example 253, except that ethylenediamine having various substituents was used instead of the N,N,N',N'-tetramethylethylenediamine used in Step 2 of Example 253. The prepared compounds, along with the LC / MS retention times and LC / MS mass spectrometry results of each compound, are shown in Table 15 below.

[0742] [Table 15]

[0743]

[0744]

[0745] The NMR analysis data for the compounds corresponding to Examples 1, 3, 9, 29, 46, 50, 75, 76, and 96 above are shown in Table 16 below.

[0746] [Table 16]

[0747]

[0748]

[0749] Activity measurement and analysis protocol of compounds of present disclosure

[0750] <Experimental Example 1> cAMP activity test (in vitro)

[0751] The activation of GLP-1R by the compounds of Examples 1 to 114 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 cells 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 logarithm of the agonist concentration and the EC50was determined by fitting the data to an S-shaped equation. The final results were calculated using the GraphPad Prism 4.0 program to obtain respective EC50values. The EC50values of the compounds of Examples 1 to 114 are shown in Table 17 below. Note: EC50range: +++++: 1 < EC50≤ 10; ++++: 10 < EC50≤ 100; +++: 100 < EC50≤ 1000; ++: 1000 < EC50≤ 5000; +: EC50> 5000

[0752] <Experimental Example 2> cAMP activity test (in vitro,1% BSA added)

[0753] The activation of GLP-1R by the compounds of Examples 115 to 619 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) containing 1% BSA (GenDEPOT, A0100-005) 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 cells 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 logarithm of the agonist concentration and the EC50was determined by fitting the data to an S-shaped equation. The final results were calculated using the GraphPad Prism 4.0 program to obtain respective EC50values. The EC50values of the compounds of Examples 115 to 619 are shown in Table 17 below. Note: EC50range: +++++: 1 < EC50≤ 10; ++++: 10 < EC50≤ 100; +++: 100 < EC50≤ 1000; ++: 1000 < EC50≤ 5000; +: EC50> 5000

[0754] [Table 17]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763] As described in Table 17 above, the agonist assay results for cAMP confirmed that the compounds of the present invention exhibited excellent agonist activity for cAMP.

[0764] As described above, the present invention has been described in detail through preferred Examples, Preparation Example 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,is a single bond or a double bond;X1and X2are each independently C or N;Rx is -C1-4alkyl;Y1is C(=O) or S(=O)2;Y2is CH or CH2;Z1and Z2are each independently C or N;RV1and RV2are each independently -H or -C1-4alkyl;U1and U2are each independently NH, O, or N;U3is C(=O) or CRU;RUis -H, -C1-4alkyl, -C1-4haloalkyl, or -halo;W is CH or N;RW1and RW2are each independently -H or -C1-4alkyl;ring A is -phenyl, -(5-6 membered heteroaryl), or -(5-10 membered heterohydroaryl), wherein -CH2- of the -(5-10 membered heterohydroaryl) ring may be substituted with -C(=O)-, and at least one H of the -phenyl, -(5-6 membered heteroaryl), or -(5-10 membered heterohydroaryl) ring may be substituted with -C1-4alkyl, -C1-4hydroxyalkyl, -C1-4aminoalkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, -(3-6 membered cycloalkyl), -CN, -NH2, -NH-(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), -NO2, -OH, -O-C1-4alkyl, or -halo, wherein at least one H of the -C1-4alkyl, -C1-4hydroxyalkyl, -C1-4aminoalkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, -NH2, -NH-(C1-4alkyl), or -N(C1-4alkyl)(C1-4alkyl) may be substituted with deuterium;LAis -(C0-2alkylene)- or -C(=O)-;RAis -H, -O-C1-4alkyl, -N=S(=O)R1R2, -N=S(=NH)(C1-4alkyl)(C1-4alkyl), -NH-S(=O)2-(C1-4alkyl), -NH-C(=O)-C(=O)-N(C1-4alkyl)(C1-4alkyl), or -(NH)n-(4-6 membered heterocycloalkyl), wherein the -(NH)n-(4-6 membered heterocycloalkyl) ring may contain one or more N, O, S, S(=O)2, or S(=O)(NH) in the ring, and at least one H of the -(NH)n-(4-6 membered heterocycloalkyl) ring may be substituted with -C1-4alkyl or -S(=O)2-C1-4alkyl;n is 0, 1, or 2;R1and R2are each independently -C1-4alkyl, -NH2, -NH-(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), or -(3-6 membered cycloalkyl), wherein at least one H of the -C1-4alkyl, -NH2, -NH-(C1-4alkyl), or -N(C1-4alkyl)(C1-4alkyl) may be substituted with deuterium; or R1and R2may be linked to each other to form, together with S atom, -(4-6 membered monocyclic ring) or -(6-11 membered spirocyclic ring), wherein the -(4-6 membered monocyclic ring) or -(6-11 membered spirocyclic ring) may contain one or more N, O, or S in the ring, and may be saturated or unsaturated, and at least one H of the -(4-6 membered monocyclic ring) or -(6-11 membered spirocyclic ring) may be substituted with -C1-4alkyl, -C1-4haloalkyl, -O-C1-4alkyl, -halo, -C(=O)-(C1-4alkyl), or -(4-6 membered heterocycloalkyl), wherein at least one H of the -(4-6 membered heterocycloalkyl) may be substituted with -C1-4alkyl;LBis -(C0-2alkylene)- or -CRL1RL2-;RL1and RL2are each independently -H or -C1-4alkyl; andring B is -phenyl, -(5-6 membered heteroaryl), -(6-10 membered hydroaryl), -(5-10 membered heterohydroaryl), -(5-6 membered cycloalkyl), or -(5-6 membered heterocycloalkyl), wherein -CH2- of the -(6-10 membered hydroaryl) or -(5-10 membered heterohydroaryl) ring may be substituted with -C(=O)-, and at least one H of the -phenyl, -(5-6 membered heteroaryl), -(6-10 membered hydroaryl), -(5-10 membered heterohydroaryl), -(5-6 membered cycloalkyl), or -(5-6 membered heterocycloalkyl) ring may be substituted with -C1-4alkyl, -C1-4hydroxyalkyl, -C1-4aminoalkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, -CN, -NO2, -NH2, -NH-(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), -N=S(=O)(C1-4alkyl)(C1-4alkyl), -O-C1-4alkyl, -halo, or -(3-6 membered cycloalkyl), wherein at least one H of the -C1-4alkyl, -C1-4hydroxyalkyl, -C1-4aminoalkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, -NH2, -NH-(C1-4alkyl), or -N(C1-4alkyl)(C1-4alkyl) may be substituted with deuterium.2.The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, whereinmoietyisor; andRx is -methyl.3.The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, whereinmoietyisor.4.The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, whereinmoietyisor.5.The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, whereinmoietyis,, or; andRUis -CF3.6.The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, whereinring A is,,,,, or, wherein at least one H of the ring A may be substituted with -C1-4alkyl, -C1-4haloalkyl, -(3-6 membered cycloalkyl), -CN, -NH2, -NH-(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), -NO2, -OH, -O-C1-4alkyl, or -halo, wherein at least one H of the -C1-4alkyl may be substituted with deuterium.7.The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, whereinring B is,,, or, wherein at least one H of the ring B may be substituted with -C1-4alkyl, -C1-4haloalkyl, -CN, -N=S(=O)(C1-4alkyl)(C1-4alkyl), -O-C1-4alkyl, -halo, or -(3-6 membered cycloalkyl), wherein at least one H of the -C1-4alkyl may be substituted with deuterium.8.The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, whereinLA-RAis -LA-N=S(=O)R1R2;LAis -(C0-2alkylene)- or -C(=O)-; andR1and R2are each independently -C1-4alkyl, -N(C1-4alkyl)(C1-4alkyl), or -(3-6 membered cycloalkyl), wherein at least one H of the -C1-4alkyl may be substituted with deuterium.9.The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, whereinLA-RAis,,,,,,,,,,,,,,,,,, or; andRA1is CH2, NH, or O.10.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,is a single bond or a double bond;X1and X2are each independently C or N;Rx is -C1-4alkyl;Y1is C(=O) or S(=O)2;Y2is CH or CH2;Z1and Z2are each independently C or N;RV1and RV2are each independently -H or -C1-4alkyl;U1and U2are each independently NH, O, or N;U3is C(=O) or CRU;RUis -H, -C1-4alkyl, -C1-4haloalkyl, or -halo;W is CH or N;RW1and RW2are each independently -H or -C1-4alkyl;ring A is -phenyl, -(5-6 membered heteroaryl), or -(5-10 membered heterohydroaryl), wherein -CH2- of the -(5-10 membered heterohydroaryl) ring may be substituted with -C(=O)-, and at least one H of the -phenyl, -(5-6 membered heteroaryl), or -(5-10 membered heterohydroaryl) ring may be substituted with -C1-4alkyl, -C1-4hydroxyalkyl, -C1-4aminoalkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, -(3-6 membered cycloalkyl), -CN, -NH2, -NH-(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), -NO2, -OH, -O-C1-4alkyl, or -halo, wherein at least one H of the -C1-4alkyl, -C1-4hydroxyalkyl, -C1-4aminoalkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, -NH2, -NH-(C1-4alkyl), or -N(C1-4alkyl)(C1-4alkyl) may be substituted with deuterium;LAis -(C0-2alkylene)- or -C(=O)-;R1and R2are each independently -C1-4alkyl, -NH2, -NH-(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), or -(3-6 membered cycloalkyl), wherein at least one H of the -C1-4alkyl, -NH2, -NH-(C1-4alkyl), or -N(C1-4alkyl)(C1-4alkyl) may be substituted with deuterium; or R1and R2may be linked to each other to form, together with S atom, -(4-6 membered monocyclic ring) or -(6-11 membered spirocyclic ring), wherein the -(4-6 membered monocyclic ring) or -(6-11 membered spirocyclic ring) may contain one or more N, O, or S in the ring, and may be saturated or unsaturated, and at least one H of the -(4-6 membered monocyclic ring) or -(6-11 membered spirocyclic ring) may be substituted with -C1-4alkyl, -C1-4haloalkyl, -O-C1-4alkyl, -halo, -C(=O)-(C1-4alkyl), or -(4-6 membered heterocycloalkyl), wherein at least one H of the -(4-6 membered heterocycloalkyl) may be substituted with -C1-4alkyl;LBis -(C0-2alkylene)- or -CRL1RL2-;RL1and RL2are each independently -H or -C1-4alkyl; andring B is -phenyl, -(5-6 membered heteroaryl), -(6-10 membered hydroaryl), -(5-10 membered heterohydroaryl), -(5-6 membered cycloalkyl), or -(5-6 membered heterocycloalkyl), wherein -CH2- of the -(6-10 membered hydroaryl) or -(5-10 membered heterohydroaryl) ring may be substituted with -C(=O)-, and at least one H of the -phenyl, -(5-6 membered heteroaryl), -(6-10 membered hydroaryl), -(5-10 membered heterohydroaryl), -(5-6 membered cycloalkyl), or -(5-6 membered heterocycloalkyl) ring may be substituted with -C1-4alkyl, -C1-4hydroxyalkyl, -C1-4aminoalkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, -CN, -NO2, -NH2, -NH-(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), -N=S(=O)(C1-4alkyl)(C1-4alkyl), -O-C1-4alkyl, -halo, or -(3-6 membered cycloalkyl), wherein at least one H of the -C1-4alkyl, -C1-4hydroxyalkyl, -C1-4aminoalkyl, -C1-4cyanoalkyl, -C1-4haloalkyl, -NH2, -NH-(C1-4alkyl), or -N(C1-4alkyl)(C1-4alkyl) may be substituted with deuterium.11.A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following compounds:.12.A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof as an active ingredient, and comprising a pharmaceutically acceptable carrier.13.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 11, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof as an active ingredient.14.The pharmaceutical composition of claim 13, whereinthe 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.15.The pharmaceutical composition of claim 14, 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.16.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 11, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof as an active ingredient.17.Use of the compound according to any one of claims 1 to 11, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating a glucagon-like peptide-1 (GLP-1) receptor activity-associated disease.18.Use of the compound according to any one of claims 1 to 11, 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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