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] R1is -H or -C1-4alkyl;

[0020] Y is or ;

[0021] Y1to Y4are each independently C, CRY1, CRY2RY3, C(=O), or N;

[0022] Y5and Y6are each independently C or NH;

[0023] RY1to RY3are each independently -H, -C1-4alkyl, or -(3- to 6-membered cycloalkyl);

[0024] Z1and Z2are each independently C or N;

[0025] R2is -H or -C1-4alkyl;

[0026] W is CH or N;

[0027] R3and R4are each independently -H or -C1-4alkyl;

[0028] Ring A is , , , or ;

[0029] A1is C(=O) or S(=O)2;

[0030] A2to A4are each independently CH2, C(=O), or O;

[0031] A5to A8are each independently CRA4or N;

[0032] RA1is -H, -C1-4alkyl, -C1-4haloalkyl, -(3- to 6-membered cycloalkyl), or -(4- to 6-membered heterocycloalkyl), wherein at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl, -C1-4haloalkyl, or -halo;

[0033] RA2and RA3are -H, -C1-4alkyl, -C1-4aminoalkyl, -C1-4hydroxyalkyl, -C1-4alkyl-O-C1-4alkyl, and RA2and RA3are linked to each other to form a -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring together with the carbon atom, wherein the -(4- to 6-membered heterocycloalkyl) ring contains an oxygen or nitrogen atom in the ring, and at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl;

[0034] RA4is -H, -C1-4alkyl, -C1-4haloalkyl, -O-C1-4alkyl, or -halo;

[0035] Ring B is or ;

[0036] RB1to RB3are each independently -H, -C1-4alkyl, -C1-4haloalkyl, -CN, -OH, -O-C1-4alkyl, -halo, or -(3- to 6-membered cycloalkyl);

[0037] RB4to RB6are each independently -H or -C1-4alkyl;

[0038] Ring C is , , or ; and

[0039] RC1and RC2are each independently -H, -C1-4alkyl, -C1-4haloalkyl, or -halo.

[0040] In the present invention, the compound represented by the chemical formula I may be within the following range:

[0041] is a single bond or a double bond;

[0042] X1is N;

[0043] X2is C;

[0044] R1is -C1-4alkyl;

[0045] Y is or ;

[0046] Z1and Z2are each independently C or N;

[0047] R2is -H or -C1-4alkyl;

[0048] W is CH or N;

[0049] R3and R4are each independently -H or -C1-4alkyl;

[0050] Ring A is , , , or ;

[0051] A1is C(=O) or S(=O)2;

[0052] A2to A4are each independently CH2, C(=O), or O;

[0053] A5to A8are each independently CRA4or N;

[0054] RA1is -H, -C1-4alkyl, -C1-4haloalkyl, -(3- to 6-membered cycloalkyl), or -(4- to 6-membered heterocycloalkyl), wherein at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl, -C1-4haloalkyl, or -halo;

[0055] RA2and RA3are -H, -C1-4alkyl, or -C1-4aminoalkyl, and RA2and RA3are linked to each other to form a -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring together with the carbon atom, wherein the -(4- to 6-membered heterocycloalkyl) ring contains a nitrogen atom in the ring, and at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl;

[0056] RA4is -H, -C1-4alkyl, -O-C1-4alkyl, or -halo;

[0057] Ring B is or ;

[0058] RB1to RB3are each independently -H, -C1-4alkyl, -CN, -O-C1-4alkyl, -halo, or -(3- to 6-membered cycloalkyl);

[0059] RB4to RB6are each independently -H or -C1-4alkyl;

[0060] Ring C is , , or ; and

[0061] RC1and RC2are each independently -C1-4haloalkyl.

[0062] According to an embodiment of the present invention,

[0063] Ring A is , , , , , , , , or ;

[0064] RA1is -H, -C1-4alkyl, -C1-4haloalkyl, -(3- to 6-membered cycloalkyl), or -(4- to 6-membered heterocycloalkyl), wherein at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl, -C1-4haloalkyl, or -halo;

[0065] RA2and RA3are -H, -C1-4alkyl, or -C1-4aminoalkyl, and RA2and RA3are linked to each other to form a -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring together with the carbon atom, wherein the -(4- to 6-membered heterocycloalkyl) ring contains a nitrogen atom in the ring, and at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl;

[0066] RA4is -H, -C1-4alkyl, -O-C1-4alkyl, or -halo.

[0067] According to an embodiment of the present invention,

[0068] Ring B is , , or ;

[0069] RB1to RB3are each independently -H, -C1-4alkyl, -CN, -O-C1-4alkyl, -halo, or -(3- to 6-membered cycloalkyl);

[0070] RB4to RB6are each independently -H or -C1-4alkyl.

[0071] According to an embodiment of the present invention,

[0072] Ring C is , , or .

[0073] In addition, the present invention provides a compound represented by the following Chemical Formula II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0074] [Chemical Formula II]

[0075]

[0076] in Chemical Formula II above,

[0077] is a single bond or a double bond;

[0078] R1is -H or -C1-4alkyl;

[0079] Z1and Z2are each independently C or N;

[0080] R2is -H or -C1-4alkyl;

[0081] W is CH or N;

[0082] R3and R4are each independently -H or -C1-4alkyl;

[0083] Ring A is , , , or ;

[0084] A1is C(=O) or S(=O)2;

[0085] A2to A4are each independently CH2, C(=O), or O;

[0086] A5to A8are each independently CRA4or N;

[0087] RA1is -H, -C1-4alkyl, -C1-4haloalkyl, -(3- to 6-membered cycloalkyl), or -(4- to 6-membered heterocycloalkyl), wherein at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl, -C1-4haloalkyl, or -halo;

[0088] RA2and RA3are -H, -C1-4alkyl, -C1-4aminoalkyl, -C1-4hydroxyalkyl, -C1-4alkyl-O-C1-4alkyl, and RA2and RA3are linked to each other to form a -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring together with the carbon atom, wherein the -(4- to 6-membered heterocycloalkyl) ring contains an oxygen or nitrogen atom in the ring, and at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl;

[0089] RA4is -H, -C1-4alkyl, -C1-4haloalkyl, -O-C1-4alkyl, or -halo;

[0090] Ring B is or ;

[0091] RB1to RB3are each independently -H, -C1-4alkyl, -C1-4haloalkyl, -CN, -OH, -O-C1-4alkyl, -halo, or -(3- to 6-membered cycloalkyl);

[0092] RB4to RB6are each independently -H or -C1-4alkyl;

[0093] Ring C is , , or ; and

[0094] RC1and RC2are each independently -H, -C1-4alkyl, -C1-4haloalkyl, or -halo.

[0095] In addition, the present invention provides a compound represented by the following Chemical Formula III, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0096] [Chemical Formula III]

[0097]

[0098] in Chemical Formula III above,

[0099] is a single bond or a double bond;

[0100] R1is -H or -C1-4alkyl;

[0101] R2is -H or -C1-4alkyl;

[0102] R3and R4are each independently -H or -C1-4alkyl;

[0103] Ring A is , , , or ;

[0104] A1is C(=O) or S(=O)2;

[0105] A2to A4are each independently CH2, C(=O), or O;

[0106] A5to A8are each independently CRA4or N;

[0107] RA1is -H, -C1-4alkyl, -C1-4haloalkyl, -(3- to 6-membered cycloalkyl), or -(4- to 6-membered heterocycloalkyl), wherein at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl, -C1-4haloalkyl, or -halo;

[0108] RA2and RA3are -H, -C1-4alkyl, -C1-4aminoalkyl, -C1-4hydroxyalkyl, -C1-4alkyl-O-C1-4alkyl, and RA2and RA3are linked to each other to form a -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring together with the carbon atom, wherein the -(4- to 6-membered heterocycloalkyl) ring contains an oxygen or nitrogen atom in the ring, and at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl;

[0109] RA4is -H, -C1-4alkyl, -C1-4haloalkyl, -O-C1-4alkyl, or -halo.

[0110] 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.

[0111] [Table 1]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140] 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.

[0141] 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.

[0142] In the present invention, "halo" may be F, Cl, Br or I.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] In the present invention, "cyanoalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).

[0147] In the present invention, the term "heterocycloalkyl" may mean a ring containing 1 to 5 heteroatoms selected from N, O and S as atoms forming the ring, and may be saturated or partially unsaturated. Herein, when unsaturated, the heterocycloalkyl may be referred to as a heterocycloalkene. Unless otherwise stated, the heterocycloalkyl may be a single ring or multiple rings such as spiro rings, bridged rings or fused rings. Further, "3 to 12-membered heterocycloalkyl" may mean a heterocycloalkyl containing 3 to 12 atoms forming a ring. Examples of the heterocycloalkyl may include, but are not limited to, pyrrolidine, piperidin, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridine, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1S,4S)-2-azabicyclo[2.2.2]octane, or (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane, and the like.

[0148] 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".

[0149] In the present invention, "heteroarene" may be a ring containing one or more of O, N, P, Si, and S as heterogeneous elements. The number of ring-forming carbon atoms of the heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. The polycyclic heteroarene may have, for example, a bicyclic or tricyclic structure. Examples of the heteroarene include, but not limited to, thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine,N-arylcarbazole,N-heteroarylcarbazole,N-alkylcarbazole, benzoxazole, benzoimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilole, dibenzofuran, and the like. In an embodiment of the present invention, the heteroarene may also include a bicyclic heterocyclo-arene including an arene ring fused to a heterocycloalkyl ring or a heteroarene fused to a cycloalkyl ring. In the present specification, a moiety obtained by removing one hydrogen atom from the above "heteroarene" is referred to as "heteroaryl".

[0150] In the present invention, "hydroarene" or "hydroaryl" is one in which one or more double bonds in the aromatic hydrocarbon ring are saturated.

[0151] In the present invention, "heterohydroarene" or "heterohydroaryl" is one in which one or more double bonds in the "heteroarene" or "heteroaryl" ring are saturated.

[0152] 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.

[0153] The compounds represented by Chemical Formula I to III 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 to III may be separated by column chromatography, HPLC, or the like. Otherwise, each stereoisomer of the compounds represented by Chemical Formula I to III may be stereospecifically synthesized using optically pure starting materials and / or reagents with known configurations.

[0154] In the present invention, "stereoisomer" includes diastereomers and optical isomers, wherein optical isomers include not only enantiomers but also mixtures and racemates of enantiomers.

[0155] 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.

[0156] 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.

[0157] Preparation method of GLP-1 receptor agonist

[0158] The present disclosure provides a preparation method of compounds represented by Chemical Formulas I to III, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0159] Preferred methods of preparing the compounds represented by Chemical Formulas I to III of the present disclosure, stereoisomers thereof or pharmaceutically acceptable salts thereof are as shown in the following Reaction Scheme 1 to Reaction Scheme 12, which may also include modifications as will be apparent to those skilled in the art.

[0160] [Reaction Scheme 1]

[0161]

[0162] As shown in Reaction Scheme 1 above, 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 the 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.

[0163] [Reaction Scheme 1-1]

[0164]

[0165] The hydrazine compound 1-1 in Reaction Scheme 1 above may be purchased or prepared according to Reaction Scheme 1-1 above. In detail, Compound 1-1 may be synthesized by using Compound 1-1-1 through Sandmeyer reaction according to Reaction Scheme 1-1 above.

[0166] [Reaction Scheme 2]

[0167]

[0168] As shown in Reaction Scheme 2 above, Compound 2-2 is prepared by palladium-mediated coupling of Compound 2-1 and Compound 1-6, followed by deprotection using trifluoroacid, etc., as a protecting group to prepare Compound 2-3. Lastly, the desired compound 2-5 may be synthesized through an amide coupling reaction with Compound 2-4. Here, A1to A4may be null or represent C, O, S, etc.

[0169] Compound 2-5 prepared by Reaction Scheme 2 above may include Compounds of Examples1 to 14, 16 to 25, 36 to 39, 51 to 53, 57 to 60, 68 to 71,etc.

[0170] [Reaction Scheme 2-1]

[0171]

[0172] Compound 2-1 in Reaction Scheme 2 above may be prepared according to Reaction Scheme 2-1. In detail, Compound 2-1 may be synthesized by reacting Compound 2-1-1 with a halogenated alkyl compound. Here, A1to A4may be null or C, O, S, etc.

[0173] [Reaction Scheme 3]

[0174]

[0175] As shown in Reaction Scheme 3 above, Compound 3-2 is prepared by a copper-mediated coupling reaction between Compound 3-1 and Compound 1-6, followed by deprotection using trifluoroacid, etc., as a protecting group, to prepare Compound 3-3. Lastly, the desired compound 3-4 may be synthesized through an amide coupling reaction with Compound 2-4.

[0176] Compound 3-4 prepared by Reaction Scheme 3 above may include Compounds of Examples26 to 29, etc.

[0177] [Reaction Scheme 3-1]

[0178]

[0179] Compound 3-1 in Reaction Scheme 3 above may be prepared according to Reaction Scheme 3-1. In detail, Compound 3-1-1 may be reacted with a halogenated alkyl compound, followed by a deprotection reaction of the protecting group to prepare Compound 3-1-3. Lastly, the deprotected amine may be alkylated to synthesize Compound 3-1.

[0180] [Reaction Scheme 4]

[0181]

[0182] As shown in Reaction Scheme 4 above, Compound 4-2 may be prepared by a copper-mediated coupling reaction between Compound 4-1 and Compound 1-6, followed by deprotection of the protecting group through a hydrogenolysis reaction to synthesize Compound 4-3. Next, Compound 4-4 may be obtained by introducing an alkyl group through a reductive amination reaction, followed by deprotection and amide coupling as shown in Reaction Scheme 1 to prepare Compound 4-6.

[0183] Compound 4-6 prepared using Reaction Scheme 4 may include Compounds of Examples30, 31, 54, and 55, etc.

[0184] [Reaction Scheme 4-1]

[0185]

[0186] Compound 4-1 in Reaction Scheme 4 above may be prepared according to Reaction Scheme 4-1. In detail, Compound 4-1 may be synthesized by reacting Compound 4-1-1 with a halogenated alkyl compound.

[0187] [Reaction Scheme 5]

[0188]

[0189] As shown in Reaction Scheme 5 above, Compound 5-2 is prepared by a copper-mediated coupling reaction between Compound 5-1 and Compound 1-6, followed by deprotection of using trifluoroacid, etc., as a protecting group, to prepare Compound 5-3. Lastly, the desired compound 5-4 may be synthesized through an amide coupling reaction with Compound 2-4.

[0190] Compound 5-4 prepared by Reaction Scheme 5 above may include Compounds of Examples32 and 33, etc.

[0191] [Reaction Scheme 5-1]

[0192]

[0193] Compound 5-1 in Reaction Scheme 5 above may be prepared according to Reaction Scheme 5-1. In detail, Compound 5-1 may be synthesized by substituting a boronic acid ester for the halogen of Compound 5-1-1, followed by a hydration reaction on the ester.

[0194] [Reaction Scheme 6]

[0195]

[0196] As shown in Reaction Scheme 6 above, Compound 6-2 may be prepared through an amide coupling process between Compound 2-3 obtained in Reaction Scheme 2 and Compound 6-1. Subsequently, a hydrated amine may be added to the nitro functional group of Compound 6-2 to synthesize Intermediate 6-3. Then, Compound 6-4 may be prepared through a cyclization reaction under acidic conditions. Compound 6-5 may then be prepared through an intracyclic substitution reaction using hydrazine.

[0197] Compounds 6-4 and 6-5 prepared by Reaction Scheme 6 above may include Compounds34 and 35, etc., respectively.

[0198] [Reaction Scheme 6-1]

[0199]

[0200] Compound 6-1 in Reaction Scheme 6 above may be prepared according to Reaction Scheme 6-1. In detail, Compound 6-1-2 may be prepared by introducing an alkylcyanide group to the nitrogen of Compound 6-1-1, and Compound 6-1-3, which has a three-membered ring, may be prepared using a chiral ring sulfate compound. Lastly, Compound 6-1 may be synthesized by hydration of the ester.

[0201] [Reaction Scheme 7]

[0202]

[0203] As shown in Reaction Scheme 7 above, Compound 7-2 may be synthesized by a copper-mediated coupling reaction between Compound 7-1 and Compound 1-6. Compound 7-4 may then be prepared through deprotection and amide coupling processes as shown in Reaction Scheme 2.

[0204] Compound 7-4 prepared using Reaction Scheme 7 above may include Compounds of Examples15, 48 to 50, 63 to 66, 81 to 89, 92 to 96, 129 to 136, 146 to 148, 156 to 160, 164 to 168, 177 to 188, 191 to 194, 201, 202, 208 to 211, 220 to 227, and 260 to 265, etc.

[0205] [Reaction Scheme 7-1]

[0206]

[0207] Compound 7-1 in Reaction Scheme 7 above may be prepared according to Reaction Scheme 7-1. In detail, Compound 7-1-3 may be prepared through an electrophilic substitution reaction between Compounds 7-1-1 and 7-1-2, followed by an acid-mediated cyclization reaction to prepare Compound 7-4. Then, Compound 7-1 may be synthesized through an alkylation reaction.

[0208] [Reaction Scheme 8]

[0209]

[0210] Compound 8-1 may be synthesized by adding 1,1'-carbonyldiimidazole (CDI) to Compound 1-3 prepared in Reaction Scheme 1, and then Compound 8-2 may be added to prepare Urea Compound 8-3. Subsequently, Compound 8-5 may be prepared through deprotection and amide coupling processes as in Reaction Scheme 2.

[0211] Compound 8-5 prepared using Reaction Scheme 8 may include Compounds of Examples236to239,250, and251, etc.

[0212] [Reaction Scheme 8-1]

[0213]

[0214] Compound 8-2 in Reaction Scheme 8 above may be prepared according to Reaction Scheme 8-1. In detail, Aniline Compound 8-2 may be prepared by performing a Staudinger reaction on Compound 8-2-1 using sodium azide.

[0215] [Reaction Scheme 9]

[0216]

[0217] As shown in Reaction Scheme 9 above, Compound 9-2 may be obtained through a copper-mediated coupling reaction between Compound 9-1 and Compound 1-6 prepared in Reaction Scheme 1. Subsequently, Compound 9-4 may be prepared through deprotection and amide coupling processes as in Reaction Scheme 2.

[0218] Compound 9-4 prepared by Reaction Scheme 9 above may include Compounds of Examples56, 61, 62, 67, 72 to 80, 90, 91, 97 to 128, 141 to 145, 150 to 155, 172 to 176, 189, 190, 195 to 200, 203, 204, 212 to 215, etc.

[0219] [Reaction Scheme 9-1]

[0220]

[0221] Compound 9-1 in Reaction Scheme 9 above may be prepared according to Reaction Scheme 9-1. In detail, Compound 9-1-2 may be prepared by using thionyl chloride on Carboxylic Acid Compound 9-1-1, followed by the addition of Compound 9-1-3 to synthesize Amide Compound 9-1-4. Then, the cyclic compound 9-1 may be prepared through an intramolecular Friedel-Crafts alkylation reaction under acid conditions.

[0222] [Reaction Scheme 10]

[0223]

[0224] Compound 9-1 prepared in Reaction Scheme 9-1 may be subjected to a Staudinger reaction using sodium azide to prepare Aniline Compound 10-1, which may then be reacted with Compound 8-1 prepared in Reaction Scheme 8, to synthesize Urea Compound 10-2. Subsequently, Compound 10-4 may be prepared through deprotection and amide coupling processes as in Reaction Scheme 2.

[0225] Compound 10-4 prepared using Reaction Scheme 10 may include Compounds of Examples228 and 240 to 249, etc.

[0226] [Reaction Scheme 11]

[0227]

[0228] As shown in Reaction Scheme 11, Compound 11-2 may be obtained through a copper-mediated coupling reaction between Compound 11-1 and Compound 1-6 prepared in Reaction Scheme 1. Subsequently, Compound 11-4 may be prepared through deprotection and amide coupling processes as in Reaction Scheme 2.

[0229] Compounds 11-4 prepared using Reaction Scheme 11 above may include Compounds of Examples205 to 207, 216 to 219, 229 to 235, 252 to 259, 266, etc.

[0230] [Reaction Scheme 11-1]

[0231]

[0232] Compound 11-1 in Reaction Scheme 11 above may be prepared according to Reaction Scheme 11-1. In detail, Compound 11-1-1 may be subjected to an alkylation reaction to prepare Compound 11-1-2, followed by a reaction with Compound 11-1-3 to prepare Compound 11-1, which forms a spiro ring at the amide α-position.

[0233] [Reaction Scheme 12]

[0234]

[0235] As shown in Reaction Scheme 12 above, Compound 12-2 is prepared by a copper-mediated coupling reaction between Compound 12-1 and Compound 1-6, followed by deprotection the protecting group using trifluoroacid, etc., to prepare Compound 12-3. Lastly, the desired Compound 12-4 may be synthesized through an amide coupling reaction with Compound 2-4.

[0236] Compounds 12-4 prepared using Reaction Scheme 12 above may include Compounds of Examples43, 44,137 to 140, 149, 161 to163, 169 to 171, etc.

[0237] [Reaction Scheme 12-1]

[0238]

[0239] Compound 12-1 in Reaction Scheme 12 above may be prepared according to Reaction Scheme 12-1. In detail, Compound 12-1 may be prepared by an alkylation reaction on the amine of Compound 12-1-1.

[0240] Uses of GLP-1 receptor agonist

[0241] The present invention provides uses of the compounds represented by Chemical Formula I to III, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0242] [Chemical Formula I]

[0243]

[0244] [Chemical Formula II]

[0245]

[0246] [Chemical Formula III]

[0247]

[0248] According to an embodiment of the present invention, the present invention provides a pharmaceutical composition comprising the compounds represented by Chemical Formula I to III, stereoisomers thereof, or pharmaceutically acceptable salts thereof as active ingredients.

[0249] 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 to III as shown above, stereoisomers thereof, or pharmaceutically acceptable salts thereof as active ingredients.

[0250] 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, heart disease, stroke, diabetic nephropathy, dementia, Parkinson's disease, depression, alcoholism, inflammatory bowel disease, and multiple sclerosis, etc.

[0251] Examples of the glucagon-like peptide-1 (GLP-1) mediated diseases may comprise endocrine, nutritional, and metabolic diseases; immune, inflammatory, and fibrotic diseases; mental and behavioral disorders; neurodegenerative diseases; circulatory diseases; or renal diseases.

[0252] 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.

[0253] The pharmaceutically acceptable salts are as described above in the pharmaceutically acceptable salts of the compounds represented by Chemical Formula I to III of the present invention.

[0254] 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 to III, 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.

[0255] 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 to III 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.

[0256] 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 to III, stereoisomers thereof or pharmaceutically acceptable salts thereof.

[0257] 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 to III, stereoisomers thereof or pharmaceutically acceptable salts thereof.

[0258] The term "therapeutically effective amount" used herein refers to an amount of the compounds represented by Chemical Formula I to III effective for the prevention or treatment of GLP-1 receptor activity-associated diseases.

[0259] 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 to III, stereoisomers thereof or pharmaceutically acceptable salts thereof.

[0260] 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 to III. 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 to III, wherein the additional active agent may exhibit synergistic or adjuvant effects together with the compounds represented by Chemical Formula I to III above.

[0261] In addition, the present invention provides uses of compounds represented by Chemical Formula I to III, 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 to III 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.

[0262] Matters described in the uses, compositions, and treatment methods of the present invention are equally applied unless they contradict each other.

[0263] The compounds represented by Chemical Formula I to III 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).

[0264] 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.

[0265] LC / MS Equipment and Analysis Conditions

[0266] The LC / MS retention time and LC / MS mass spectrometry results of the compounds prepared in Examples were measured under the conditions listed in Table 2.

[0267] [Table 2]

[0268]

[0269] Preparation of Compounds of Examples

[0270] Specific preparation methods for compounds represented by Chemical Formulas I to III are as follows.

[0271] Example 1: 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-(1'-methyl-2'-oxo-spiro[cyclobutane-1,3'-indoline]-6'-yl)-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

[0272] [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

[0273]

[0274] Tert-Butyl (2S)-3-cyano-2-methyl-4-oxo-piperidine-1-carboxylate (100.00%, 3.000 g, 12.590 mmol), (4-fluoro-3,5-dimethyl-phenyl)hydrazine hydrochloride (100.00%, 2.400 g, 12.589 mmol), and hydrochloric acid (2.00 M solution in water, 12.6 mL, 25.200 mmol) were dissolved in ethanol (100 mL) at room temperature, and 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 by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = 5% to 30%) and concentrated to obtain the title compound (3.830 g, 81.25%) as an orange solid.

[0275] [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

[0276]

[0277] 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 (100.00%, 4.400 g, 11.750 mmol) prepared in Step 1 and pyridine (100.00% solution, 1.43 mL, 17.680 mmol) were dissolved in ethyl acetate (150 mL) at room temperature, followed by the addition of phenyl carbonochloridate (100.00% solution, 2.2 mL, 17.536 mmol) and stirring 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 by column chromatography (SiO2, 80 g cartridge; ethyl acetate / hexane = 5% to 20%) and concentrated to obtain the title compound (5.000 g, 86.02%) as a pale orange solid.

[0278] [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

[0279]

[0280] 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 (100.00%, 1.000 g, 2.022 mmol) prepared in Step 2 and 2,2-dimethoxyethaneamine (100.00% solution, 1.1 mL, 10.096 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.

[0281] [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

[0282]

[0283] 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 (100.00%, 0.770 g, 1.523 mmol) prepared in Step 3 was dissolved in tetrahydrofuran (15 mL), and methanesulfonic acid (100.00% solution, 0.1 mL, 1.541 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 by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 60%) and concentrated to obtain the title compound (0.560 g, 83.29%) as a white solid.

[0284] [Step 5] Synthesis of 6'-bromo-1'-methyl-spiro[cyclobutane-1,3'-indoline]-2'-one

[0285]

[0286] 6'-Bromospiro[cyclobutane-1,3'-indoline]-2'-one (100.00%, 0.500 g, 1.983 mmol) and cesium carbonate (100.00%, 2.000 g, 6.138 mmol) were dissolved in acetonitrile (10 mL) at room temperature, followed by the addition of iodomethane (100.00% solution, 0.4 mL, 6.425 mmol) and stirring 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 obtained product was used without further purification (0.400 g, 75.79%, white solid).

[0287] [Step 6] Synthesis of tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(1'-methyl-2'-oxo-spiro[cyclobutane-1,3'-indoline]-6'-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0288]

[0289] 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%, 70.000 mg, 0.159 mmol) prepared in Step 4 and the 6'-bromo-1'-methyl-spiro[cyclobutane-1,3'-indoline]-2'-one (100.00%, 90.000 mg, 0.338 mmol) prepared in Step 5, trans-N,N'-dimethylcyclohexane-1,2-diamine (100.00%, 16.000 mg, 0.113 mmol), potassium carbonate (100.00%, 70.000 mg, 0.706 mmol), copper iodide (100.00%, 5.000 mg, 0.026 mmol), and 1-methyl-2-pyrrolidinone (100.00% solution, 1.5 mL, 15.585 mmol) were dissolved in 1-methylpyrrolidin-2-one (1 mL) at room temperature, stirred at 130℃ for 3 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 by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 80%) and concentrated to obtain the title compound (0.080 g, 80.51%) as a white solid.

[0290] [Step 7] Synthesis of 6'-[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]-1'-methyl-spiro[cyclobutane-1,3'-indoline]-2'-one

[0291]

[0292] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(1'-methyl-2'-oxo-spiro[cyclobutane-1,3'-indoline]-6'-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00%, 0.025 g, 0.040 mmol) prepared in Step 6 was dissolved in dichloromethane (1 mL) at room temperature, followed by the addition of trifluoroacetic acid (100.00% solution, 0.3 mL, 3.920 mmol) and stirring 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, 99.97%, pale yellow solid).

[0293] [Step 8] 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-(1'-methyl-2'-oxo-spiro[cyclobutane-1,3'-indoline]-6'-yl)-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

[0294]

[0295] The 6'-[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]-1'-methyl-spiro[cyclobutane-1,3'-indoline]-2'-one(100.00%, 40.000 mg, 0.078 mmol) prepared 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 (100.00%, 35.000 mg, 0.085 mmol), and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (100.00%, 45.000 mg, 0.086 mmol) were dissolved in acetonitrile (1 mL) at room temperature, followed by the addition of N,N-diisopropylethylamine (100.00% solution, 0.07 mL, 0.402 mmol) and stirring 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 by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 80%) and concentrated to obtain the title compound (0.032 g, 44.57%) as a pale yellow solid.

[0296] LC / MS (ES)m / z 920.38 [M+H]+;LC / MS retention time4.35 (min);LC / MS analysis condition#1

[0297] Examples 2 to 14, 16 to 25, 36 to 39, 51 to 53, 57 to 60, and 68 to 71

[0298] The following Compounds of Examples were prepared, respectively, in the same manner as described in Steps 1 to 8 of Example 1, except that various spiroindolinone reagents were used instead of the 6'-bromo-1'-methyl-spiro[cyclobutane-1,3'-indoline]-2'-one in Step 5 of Example 1 and various hydrazine compounds were used in Step 1 of Example 1. The prepared Compounds and the LC / MS retention time and LC / MS mass analysis results thereof are shown in Table 3 below.

[0299] [Table 3]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313] Example 26: Synthesis of 3-[(1S,2S)-1-[2-[(4S)-3-[3-(1,1'-dimethyl-2-oxo-spiro[indoline-3,3'-pyrrolidine]-5-yl)-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

[0314] [Step 1] Synthesis of tert-butyl 5-bromo-1-methyl-2-oxo-spiro[indoline-3,3'-pyrrolidine]-1'-carboxylate

[0315]

[0316] Tert-butyl 5-bromo-2-oxo-spiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (100.00%, 0.700 g, 1.906 mmol) and cesium carbonate (100.00%, 2.000 g, 6.138 mmol) were dissolved in acetonitrile (10 mL) at room temperature, followed by the addition of iodomethane (100.00% solution, 0.4 mL, 6.425 mmol) and stirring 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 obtained product was used without further purification (0.600 g, 82.54%, white solid).

[0317] [Step 2] Synthesis of 5-bromo-1-methyl-spiro[indoline-3,3'-pyrrolidine]-2-one

[0318]

[0319] The tert-butyl 5-bromo-1-methyl-2-oxo-spiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (100.00%, 0.100 g, 0.262 mmol) prepared in Step 1 was dissolved in dichloromethane (1 mL) at room temperature, followed by the addition of trifluoroacetic acid (100.00% solution, 0.3 mL, 3.920 mmol) and stirring 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 resulting concentrate was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (0.074 g, 100.40%, pale yellow solid).

[0320] [Step 3] Synthesis of 5-bromo-1,1'-dimethyl-spiro[indoline-3,3'-pyrrolidine]-2-one

[0321]

[0322] The 5-bromo-1-methyl-spiro[indoline-3,3'-pyrrolidine]-2-one (100.00%, 74.000 mg, 0.263 mmol) prepared in Step 2, formaldehyde (37.00% solution, 0.05 mL, 0.502 mmol), and N,N-diisopropylethylamine (100.00% solution, 0.09 mL, 0.517 mmol) were dissolved in dichloromethane (1 mL) at room temperature, followed by the addition of sodium triacetyloxyborohydride (100.00%, 160.000 mg, 0.759 mmol) and stirring 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 by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 100% to 90%) and concentrated to obtain the title compound (0.070 g, 90.09%) as a white solid.

[0323] [Step 4] Synthesis of tert-butyl (4S)-3-[3-(1,1'-dimethyl-2-oxo-spiro[indoline-3,3'-pyrrolidine]-5-yl)-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

[0324]

[0325] 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%, 70.000 mg, 0.159 mmol) prepared in Step 4 of Example 1 and the 5-bromo-1,1'-dimethyl-spiro[indoline-3,3'-pyrrolidine]-2-one (100.00%, 70.000 mg, 0.237 mmol) prepared in Step 3 were dissolved in 1-methylpyrrolidin-2-one (1 mL) at room temperature. Trans-N,N'-dimethylcyclohexane-1,2-diamine (100.00%, 16.000 mg, 0.113 mmol), potassium carbonate (100.00%, 70.000 mg, 0.706 mmol) and copper iodide (100.00%, 5.000 mg, 0.026 mmol) were added to the dissolved solution and stirred at 130℃ for 3 hours, and 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 by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = 100% to 90%) and concentrated to obtain the title compound (0.050 g, 48.09%) as a white solid.

[0326] [Step 5] Synthesis of 5-[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]-1,1'-dimethyl-spiro[indoline-3,3'-pyrrolidine]-2-one

[0327]

[0328] The tert-butyl (4S)-3-[3-(1,1'-dimethyl-2-oxo-spiro[indoline-3,3'-pyrrolidine]-5-yl)-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%, 0.025 g, 0.038 mmol) prepared in Step 4 was dissolved in dichloromethane (1 mL) at room temperature, followed by the addition of trifluoroacetic acid (100.00% solution, 0.3 mL, 3.920 mmol) and stirring 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 resulting concentrate was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (0.021 g, 96.70%, pale yellow solid).

[0329] [Step 6] Synthesis of 3-[(1S,2S)-1-[2-[(4S)-3-[3-(1,1'-dimethyl-2-oxo-spiro[indoline-3,3'-pyrrolidine]-5-yl)-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

[0330]

[0331] The 5-[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]-1,1'-dimethyl-spiro[indoline-3,3'-pyrrolidine]-2-one (100.00%, 40.000 mg, 0.072 mmol) prepared in Step 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-carboxylic acid (100.00%, 35.000 mg, 0.085 mmol) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (100.00%, 45.000 mg, 0.086 mmol) were dissolved in acetonitrile (1 mL) at room temperature, followed by the addition of N,N-diisopropylethylamine (100.00% solution, 0.07 mL, 0.402 mmol) and stirring 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 by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = 100% to 95%) and concentrated to obtain the title compound (0.035 g, 51.22%) as a pale yellow solid.

[0332] LC / MS (ES)m / z 949.41 [M+H]+;LC / MS retention time2.86 (min);LC / MS analysis condition#1

[0333] Examples 27 to 29

[0334] The following Compounds of Examples were prepared, respectively, in the same manner as described in Steps 1 to 6 of Example 26, except that various spirocyclic indolinones containing amines were used instead of the tert-butyl 5-bromo-2-oxo-spiro[indoline-3,3'-pyrrolidine]-1'-carboxylate used in Step 1 of Example 26. The prepared Compounds and the LC / MS retention time and LC / MS mass analysis results thereof are shown in Table 4 below.

[0335] [Table 4]

[0336]

[0337] Example 30: Synthesis of 3-[(1S,2S)-1-[2-[(4S)-3-[3-(1,1'-dimethyl-2'-oxo-spiro[azetidine-3,3'-indoline]-6'-yl)-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

[0338] [Step 1] Synthesis of benzyl 6'-bromo-1'-methyl-2'-oxo-spiro[azetidine-3,3'-indoline]-1-carboxylate

[0339]

[0340] Benzyl 6'-bromo-2'-oxo-spiro[azetidine-3,3'-indoline]-1-carboxylate (100.00%, 0.300 g, 0.775 mmol) and cesium carbonate (100.00%, 0.950 g, 2.916 mmol) were dissolved in acetonitrile (10 mL) at room temperature, followed by the addition of iodomethane (100.00% solution, 0.2 mL, 3.213 mmol) and stirring 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 obtained product was used without further purification (0.250 g, 80.43%, white solid).

[0341] [Step 2] Synthesis of benzyl 6'-[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]-1'-methyl-2'-oxo-spiro[azetidine-3,3'-indoline]-1-carboxylate

[0342]

[0343] 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 and the benzyl 6'-bromo-1'-methyl-2'-oxo-spiro[azetidine-3,3'-indoline]-1-carboxylate (100.00%, 150.000 mg, 0.374 mmol) prepared in Step 1 were dissolved in 1-methylpyrrolidin-2-one (1 mL) at room temperature. Trans-N,N'-dimethylcyclohexane-1,2-diamine (100.00%, 20.000 mg, 0.141 mmol), potassium carbonate (100.00%, 70.000 mg, 0.706 mmol), and copper iodide (100.00%, 5.000 mg, 0.026 mmol) were added to the dissolved solution, stirred at 130℃ for 3 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 by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 50%) and concentrated to obtain the title compound (0.150 g, 86.93%) as a white solid.

[0344] [Step 3] Synthesis of tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(1'-methyl-2'-oxo-spiro[azetidine-3,3'-indoline]-6'-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0345]

[0346] The benzyl 6'-[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]-1'-methyl-2'-oxo-spiro[azetidine-3,3'-indoline]-1-carboxylate (100.00%, 130.000 mg, 0.171 mmol) prepared in Step 2 and Pd / C (10%, 100.00% solution, 0.0042 mL, 0.470 mmol) were dissolved in methanol (1 mL) at room temperature, and stirred at the same temperature with a hydrogen balloon attached. The reaction mixture was filtered through a Celite pad to remove solids, and the solvent was removed from the filtrate under reduced pressure. The resulting product was used without further purification (105.000 mg, 98.02%, white solid).

[0347] [Step 4] Synthesis of tert-butyl (4S)-3-[3-(1,1'-dimethyl-2'-oxo-spiro[azetidine-3,3'-indoline]-6'-yl)-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

[0348]

[0349] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(1'-methyl-2'-oxo-spiro[azetidine-3,3'-indoline]-6'-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00%, 50.000 mg, 0.080 mmol) prepared in Step 3, formaldehyde (37.00% solution, 0.02 mL, 0.201 mmol), and N,N-diisopropylethylamine (100.00% solution, 0.03 mL, 0.172 mmol) were dissolved dichloromethane (1 mL) at room temperature, followed by the addition of sodium triacetyloxyborohydride (100.00%, 50.000 mg, 0.237 mmol) and stirring 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 by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = 100% to 80%) and concentrated to obtain the title compound (0.050 g, 97.82%) as a white solid.

[0350] [Step 5] Synthesis of 6'-[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]-1,1'-dimethyl-spiro[azetidine-3,3'-indoline]-2'-one

[0351]

[0352] The tert-butyl (4S)-3-[3-(1,1'-dimethyl-2'-oxo-spiro[azetidine-3,3'-indoline]-6'-yl)-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, 0.078 mmol) prepared in Step 4 was dissolved in dichloromethane (1 mL) at room temperature, followed by the addition of trifluoroacetic acid (100.00% solution, 0.3 mL, 3.920 mmol) and stirring 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 added to the resulting concentrate, followed by extraction with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (0.040 g, 94.79%, pale yellow solid).

[0353] [Step 6] Synthesis of 3-[(1S,2S)-1-[2-[(4S)-3-[3-(1,1'-dimethyl-2'-oxo-spiro[azetidine-3,3'-indoline]-6'-yl)-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

[0354]

[0355] The 6'-[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]-1,1'-dimethyl-spiro[azetidine-3,3'-indoline]-2'-one (100.00%, 30.000 mg, 0.055 mmol) prepared in Step 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-carboxylic acid (100.00%, 30.000 mg, 0.073 mmol), and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (100.00%, 30.000 mg, 0.058 mmol) were dissolved in acetonitrile (1 mL) at room temperature, followed by the addition of N,N-diisopropylethylamine (100.00% solution, 0.05 mL, 0.287 mmol) and stirring 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 by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = 100% to 70%) and concentrated to obtain the title compound (0.032 g, 61.79%) as a pale yellow solid.

[0356] LC / MS (ES)m / z 935.27 [M+H]+;LC / MS retention time2.66 (min);LC / MS analysis condition#1

[0357] Examples 31, 54, and 55

[0358] The following Compounds of Examples were prepared in the same manner as described in Steps 1 to 6 of Example 30, except that acetaldehyde was used instead of formaldehyde in Step 4 of Example 30. The prepared Compounds and the LC / MS retention time and LC / MS mass analysis results thereof are shown in Table 5 below.

[0359] [Table 5]

[0360]

[0361] Example 32: Synthesis of 3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(1'-methyl-2'-oxo-spiro[cyclobutane-1,3'-indoline]-6'-yl)-2-oxo-imidazol-1-yl]-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

[0362] [Step 1] Synthesis of 6'-bromo-1'-methyl-spiro[cyclobutane-1,3'-indoline]-2'-one

[0363]

[0364] 6'-Bromospiro[cyclobutane-1,3'-indoline]-2'-one (100.00%, 0.200 g, 0.800 mmol), iodomethane (100.00% solution, 0.14848 mL, 2.380 mmol), and cesium carbonate (100.00%, 0.775 g, 2.380 mmol) were dissolved in acetonitrile (5 mL) at room temperature, and stirred at the same temperature for 18 hours. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 100%) and concentrated to obtain the title compound (0.200 g, 90.00%) as a white solid.

[0365] [Step 2] Synthesis of 1'-methyl-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclobutane-1,3'-indoline]-2'-one

[0366]

[0367] The 6'-bromo-1'-methyl-spiro[cyclobutane-1,3'-indoline]-2'-one (100.00%, 0.394 g, 1.481 mmol) prepared in Step 1, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (100.00%, 0.451 g, 1.777 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (100.00%, 0.054 g, 0.074 mmol), and potassium acetate (100.00%, 0.291 g, 2.962 mmol) were dissolved in 1,4-dioxane (10 mL) at room temperature. The dissolved solution was stirred at 100℃ for 18 hours, and then cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 100%) and concentrated to obtain the title compound (0.464 g, 100.00%) as a white solid.

[0368] [Step 3] Synthesis of (1'-methyl-2'-oxo-spiro[cyclobutane-1,3'-indoline]-6'-yl)boronic acid

[0369]

[0370] The 1'-methyl-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclobutane-1,3'-indoline]-2'-one (100.00%, 0.505 g, 1.612 mmol) prepared in Step 2, ammonium acetate (100.00%, 0.497 g, 6.447 mmol), and sodium periodate (100.00%, 1.379 g, 6.447 mmol) were dissolved in acetone (8 mL) / water (8 mL) at room temperature, and stirred at the same temperature for 18 hours. The reaction mixture was filtered through a pad of celite to remove solids, the filtrate was concentrated under reduced pressure to remove the solvent, and the concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 100%) and concentrated to obtain the title compound (0.270 g, 72.46%) as a pale yellow solid.

[0371] [Step 4] Synthesis of tert-butyl (4S)-2-(4-chloro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(1'-methyl-2'-oxo-spiro[cyclobutane-1,3'-indoline]-6'-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0372]

[0373] The (1'-methyl-2'-oxo-spiro[cyclobutane-1,3'-indoline]-6'-yl)boronic acid (100.00%, 0.076 g, 0.328 mmol) prepared in Step 3 and the tert-butyl (4S)-2-(4-chloro-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%, 0.100 g, 0.218 mmol) prepared in Step 4 of Example 1, copper acetate (100.00%, 0.089 g, 0.725 mmol), and pyridine (100.00% solution, 0.69 g, 0.873 mmol) were dissolved in N,N-dimethylformamide (1 mL) at room temperature, stirred at 60℃ for 18 hours, and then cooled to room temperature to terminate the reaction. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, followed by extraction with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 100%) and concentrated to obtain the title compound (0.140 g, 90%) as a white solid.

[0374] [Step 5] Synthesis of 6'-[3-[(4S)-2-(4-chloro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]-1'-methyl-spiro[cyclobutane-1,3'-indoline]-2'-one

[0375]

[0376] The tert-butyl (4S)-2-(4-chloro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(1'-methyl-2'-oxo-spiro[cyclobutane-1,3'-indoline]-6'-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00%, 0.118 g, 0.184 mmol) synthesized in Step 4 and trifluoroacetic acid (100.00% solution, 0.4558 mL, 3.682 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, followed by extraction with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (0.100 g, 100.40%, white solid).

[0377] [Step 6] Synthesis of 3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(1'-methyl-2'-oxo-spiro[cyclobutane-1,3'-indoline]-6'-yl)-2-oxo-imidazol-1-yl]-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

[0378]

[0379] The 6'-[3-[(4S)-2-(4-chloro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]-1'-methyl-spiro[cyclobutane-1,3'-indoline]-2'-one (100.00%, 0.100 g, 0.200 mmol) prepared in Step 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-carboxylic acid (100.00%, 0.098 g, 0.239 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 100.00%, 0.105 g, 0.203 mmol) and N,N-diisopropylethylamine (100.00% solution, 0.0962 mL, 0.552 mmol) were dissolved in acetonitrile (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, followed by extraction with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 100%) and concentrated to obtain the title compound (0.054 g, 30.00%) as a white solid.

[0380] LC / MS (ES)m / z 936.7 [M+H]+;LC / MS retention time4.20 (min);LC / MS analysis condition#1

[0381] Example 33

[0382] The following Compounds of Examples were prepared, respectively, in the same manner as described in Steps 1 to 6 of Example 32, except that 5'-bromospiro[cyclopropane-1,3'-indoline]-2'-one was used instead of 6'-bromospiro[cyclobutane-1,3'-indoline]-2'-one used in Step 1 of Example 32. The prepared Compounds and the LC / MS retention time and LC / MS mass analysis results thereof are shown in Table 6 below.

[0383] [Table 6]

[0384]

[0385] Example 34: Synthesis of 6'-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-[5-(trifluoromethyl)-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]-1'-methyl-spiro[cyclobutane-1,3'-indoline]-2'-one

[0386] [Step 1] Synthesis of ethyl 1-(cyanomethyl)-5-(2,2-dimethyltetrahydropyran-4-yl)indole-2-carboxylate

[0387]

[0388] Ethyl 5-(2,2-dimethyltetrahydropyran-4-yl)-1H-indole-2-carboxylate (100.00%, 3.000 g, 9.954 mmol) and sodium hydride (60.00%, 0.671 g, 16.784 mmol) were dissolved in N,N-dimethylformamide (55 mL), and stirred at 0℃ for 30 minutes. Then, 2-chloroacetonitrile (100.00% solution, 1.420 mL, 22.380 mmol) was added thereto and the resulting mixture was further stirred at room temperature for 18 hours. Water was added to 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 by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 100%) and concentrated to obtain the title compound (2.356 g, 69.54%) as a pale yellow solid.

[0389] [Step 2] Synthesis of ethyl 1-[(1S,2S)-1-cyano-2-methyl-cyclopropyl]-5-(2,2-dimethyltetrahydropyran-4-yl)indole-2-carboxylate

[0390]

[0391] The ethyl 1-(cyanomethyl)-5-(2,2-dimethyltetrahydropyran-4-yl)indole-2-carboxylate (100.00%, 2.400 g, 7.100 mmol) prepared in Step 1, (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (100.00%, 2.435 g, 17.630 mmol), and potassium bis(trimethylsilyl)amide (1.00 M solution, 28.202 mL, 28.202 mmol) were dissolved in tetrahydrofuran (20 mL) at 0℃ and stirred at the same temperature for 5 hours. A saturated aqueous ammonium chloride 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 by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 100%) and concentrated to obtain the title compound (1.900 g, 71.00%) as a brown solid.

[0392] [Step 3] Synthesis of 1-[(1S,2S)-1-cyano-2-methyl-cyclopropyl]-5-(2,2-dimethyltetrahydropyran-4-yl)indole-2-carboxylic acid

[0393]

[0394] The ethyl 1-[(1S,2S)-1-cyano-2-methyl-cyclopropyl]-5-(2,2-dimethyltetrahydropyran-4-yl)indole-2-carboxylate (100.00%, 1.900 g, 4.993 mmol) prepared in Step 2 and sodium hydroxide (5.00 M solution, 3.995 mL, 19.980 mmol) were dissolved in methanol (10 mL) / water (5 mL) / tetrahydrofuran (15 mL) at room temperature, stirred at 50℃ for 3 hours, and then cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and 2N hydrochloric acid aqueous solution was poured to the resulting concentrate, 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 obtained product was used without further purification (1.760 g, 100.00%, white solid).

[0395] [Step 4] Synthesis of (1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(1'-methyl-2'-oxo-spiro[cyclobutane-1,3'-indoline]-6'-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropanecarbonitrile

[0396]

[0397] The 1-[(1S,2S)-1-cyano-2-methyl-cyclopropyl]-5-(2,2-dimethyltetrahydropyran-4-yl)indole-2-carboxylic acid (100.00%, 0.087 g, 0.247 mmol) prepared in Step 3 and the 6'-[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]-1'-methyl-spiro[cyclobutane-1,3'-indoline]-2'-one (100.00%, 0.100 g, 0.200 mmol) prepared in Step 7 of Step Example 1, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (100.00% solution, 0.109 g, 0.209 mmol), and N,N-diisopropylethylamine (100.00% solution, 0.0992 mL, 0.570 mmol) were dissolved in acetonitrile (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, followed by extraction with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 50%) and concentrated to obtain the title compound (0.164 g, 100.00%) as a white solid.

[0398] [Step 5] Synthesis of (1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(1'-methyl-2'-oxo-spiro[cyclobutane-1,3'-indoline]-6'-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-N-hydroxy-2-methyl-cyclopropanecarboxamidine

[0399]

[0400] The (1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(1'-methyl-2'-oxo-spiro[cyclobutane-1,3'-indoline]-6'-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropanecarbonitrile (100.00%, 0.164 g, 0.190 mmol) synthesized in Step 4, hydroxylamine hydrochloride (100.00%, 0.040 g, 0.571 mmol), and N,N-diisopropylethylamine (100.00% solution, 0.09953 mL, 0.571 mmol) were mixed with ethanol (1 mL) at room temperature, heated under reflux for 1 hour, then cooled to room temperature. After removing the solvent from the reaction mixture under reduced pressure, water was added to 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 concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 100%) and concentrated to obtain the title compound (0.044 g, 25.80%) as a white solid.

[0401] [Step 6] Synthesis of 6'-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-[5-(trifluoromethyl)-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]-1'-methyl-spiro[cyclobutane-1,3'-indoline]-2'-one (28442)

[0402]

[0403] The (1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(1'-methyl-2'-oxo-spiro[cyclobutane-1,3'-indoline]-6'-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-N-hydroxy-2-methyl-cyclopropanecarboxamidine (100.00%, 0.044 g, 0.049 mmol) prepared in Step 5 and trifluoroacetic anhydride (100.00% solution, 0.01495 mL, 0.108 mmol) were mixed with tetrahydrofuran (1 mL) at room temperature, heated under reflux for 18 hours, then cooled to room temperature. After removing the solvent from the reaction mixture under reduced pressure, a saturated aqueous sodium bicarbonate solution was poured into 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 concentrate was purified by chromatography (SiO2plate, 20x20x1 mm; ethyl acetate / hexane = 0% to 70%) and concentrated to obtain the title compound (0.026 g, 54.98%) as a white solid.

[0404] LC / MS (ES)m / z 972.4 [M+H]+;LC / MS retention time4.30 (min);LC / MS analysis condition#1

[0405] Example 35: Synthesis of 6'-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-[5-(trifluoromethyl)-4H-1,2,4-triazol-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]-1'-methyl-spiro[cyclobutane-1,3'-indoline]-2'-one

[0406]

[0407] The 6'-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-[5-(trifluoromethyl)-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]-1'-methyl-spiro[cyclobutane-1,3'-indoline]-2'-one (100.00%, 0.010 g, 0.010 mmol) prepared in Step 6 of Example 34 and hydrazine monohydrate (100.00% solution, 0.001 mL, 0.021 mmol) were dissolved in N,N-dimethylformamide (1 mL) at room temperature, and stirred at the same temperature for 2 hours. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by chromatography (SiO2plate, 20x20x1 mm; ethyl acetate / hexane = 80%) and concentrated to obtain the title compound (0.006 g, 60.06%) as a white solid.

[0408] LC / MS (ES)m / z 971.3 [M+H]+;LC / MS retention time4.15 (min);LC / MS analysis condition#1

[0409] Example 187: Synthesis of 6-[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]-4,5-dimethyl-spiro[1,4-benzoxazine-2,1'-cyclopropane]-3-one

[0410] [Step 1] Synthesis of methyl 1-(4-bromo-3-methyl-2-nitro-phenoxy)cyclopropanecarboxylate

[0411]

[0412] 1-Bromo-4-fluoro-2-methyl-3-nitro-benzene (100.00%, 1.000 g, 4.273 mmol), methyl 1-hydroxycyclopropanecarboxylate (100.00%, 744.000 mg, 6.407 mmol) and sodium hydride (60% dispersion in Paraffin Liquid, 342.000 mg, 8.550 mmol) were dissolved in tetrahydrofuran (14 mL) at 0℃ and stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride 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 by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 30%) and concentrated to obtain the title compound (420.000 mg, 29.77%) as a white solid.

[0413] [Step 2] Synthesis of 6-bromo-5-methyl-spiro[4H-1,4-benzoxazine-2,1'-cyclopropane]-3-one

[0414]

[0415] The methyl 1-(4-bromo-3-methyl-2-nitro-phenoxy)cyclopropanecarboxylate (100.00%, 420.000 mg, 1.272 mmol) prepared in Step 1 and iron (100.00%, 710.000 mg, 12.714 mmol) were dissolved in acetic acid (8 mL) at room temperature, stirred at 60℃ for 3 hours, and cooled to room temperature to terminate the reaction. The reaction mixture was filtered through a glass filter to remove solids, and a saturated aqueous sodium bicarbonate solution was poured into the filtrate, 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 by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 30%) and concentrated to obtain the title compound (290.000 mg, 85.02%) as a yellow solid.

[0416] [Step 3] Synthesis of 6-bromo-4,5-dimethyl-spiro[1,4-benzoxazine-2,1'-cyclopropane]-3-one

[0417]

[0418] The 6-bromo-5-methyl-spiro[4H-1,4-benzoxazine-2,1'-cyclopropane]-3-one (100.00%, 100.000 mg, 0.373 mmol) prepared in Step 2, iodomethane (100.00% solution, 0.07 mL, 1.124 mmol) and cesium carbonate (100.00%, 365.000 mg, 1.120 mmol) were dissolved in acetonitrile (2 mL) at room temperature, 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 by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 20%) and concentrated to obtain the title compound (98.000 mg, 93.13%) as a yellow oil.

[0419] [Step 4] Synthesis of tert-butyl (4S)-3-[3-(4,5-dimethyl-3-oxo-spiro[1,4-benzoxazine-2,1'-cyclopropane]-6-yl)-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

[0420]

[0421] 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%, 40.000 mg, 0.091 mmol) prepared in Step 4 of Example 1, the 6-bromo-4,5-dimethyl-spiro[1,4-benzoxazine-2,1'-cyclopropane]-3-one (100.00%, 28.000 mg, 0.099 mmol) prepared in Step 3, trans-N,N'-dimethylcyclohexane-1,2-diamine (100.00%, 6.000 mg, 0.042 mmol), potassium carbonate (100.00%, 27.000 mg, 0.272 mmol) and copper iodide (100.00%, 2.000 mg, 0.011 mmol) were dissolved in 1-methylpyrrolidin-2-one (1 mL) at room temperature. The dissolved solution was stirred at 130℃ for 18 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 by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 80%) and concentrated to obtain the title compound (35.000 mg, 60.11%) as a yellow oil.

[0422] [Step 5] Synthesis of 6-[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]-4,5-dimethyl-spiro[1,4-benzoxazine-2,1'-cyclopropane]-3-one

[0423]

[0424] The tert-butyl (4S)-3-[3-(4,5-dimethyl-3-oxo-spiro[1,4-benzoxazine-2,1'-cyclopropane]-6-yl)-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%, 35.000 mg, 0.054 mmol) prepared in Step 4 and trifluoroacetic acid (100.00% solution, 0.135 mL, 1.091 mmol) were dissolved in dichloromethane (270 μL) at room temperature and stirred at the same temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (29.500 mg, 99.83%, yellow oil).

[0425] [Step 6] Synthesis of 6-[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]-4,5-dimethyl-spiro[1,4-benzoxazine-2,1'-cyclopropane]-3-one

[0426]

[0427] The tert-butyl (4S)-3-[3-(4,5-dimethyl-3-oxo-spiro[1,4-benzoxazine-2,1'-cyclopropane]-6-yl)-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%, 17.000 mg, 0.026 mmol) prepared in Step 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-carboxylic acid (100.00%, 13.000 mg, 0.032 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (100.00%, 15.000 mg, 0.029 mmol), and N,N-diisopropylethylamine (100.00% solution, 0.023 mL, 0.132 mmol) were dissolved in acetonitrile (300 uL) at room temperature 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 by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 50%) and concentrated to obtain the title compound (5.000 mg, 20.20%) as a white solid.

[0428] LC / MS (ES)m / z 936.8 [M+H]+;LC / MS retention time3.83 (min);LC / MS analysis condition#1

[0429] Examples 15, 48 to 50, 63 to 66, 81 to 89, 92 to 96, 129 to 136, 146 to 148, 156 to 160, 164 to 168, 177 to 186, 188, 191 to 194, 201, 202, 208 to 211, 220 to 227, 260 to 265

[0430] The following Compounds of Examples were prepared, respectively, in the same manner as described in Steps 1 to 6 of Example 187, except that various aryl or heteroaryl compounds substituted with fluoro or nitro were used instead of 1-bromo-4-fluoro-2-methyl-3-nitro-benzene used in Step 1 of Example 187 and various hydrazine compounds were used in Step 1 of Example 1. The prepared Compounds and the LC / MS retention time and LC / MS mass analysis results thereof are shown in Table 7 below.

[0431] [Table 7]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455] Example 250: Synthesis of 1-(4,5-dimethyl-3-oxo-spiro[1,4-benzoxazine-2,1'-cyclopropane]-6-yl)-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]urea

[0456] [Step 1] Synthesis of tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-(imidazole-1-carbonylamino)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0457]

[0458] 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 (100.00%, 200.000 mg, 0.534 mmol) prepared in Step 1 of Example 1 and 1,1'-carbonylbis-1H-imidazole (100.00%, 173.000 mg, 1.067 mmol) were dissolved in N,N-dimethylformamide (890 uL) at room temperature, and the dissolved solution was stirred at the same temperature for 18 hours. The obtained product was used without further purification (250.000 mg, 99.89%, brown oil)

[0459] [Step 2] Synthesis of 6-amino-4,5-dimethyl-spiro[1,4-benzoxazine-2,1'-cyclopropane]-3-one

[0460]

[0461] The 6-bromo-4,5-dimethyl-spiro[1,4-benzoxazine-2,1'-cyclopropane]-3-one (100.00%, 105.000 mg, 0.372 mmol) prepared in Step 3 of Example 187, sodium azide (100.00%, 60.000 mg, 0.923 mmol), copper iodide (100.00%, 71.000 mg, 0.373 mmol), sodium carbonate (100.00%, 80.000 mg, 0.755 mmol), and N,N'-dimethylethylenediamine (100.00% solution, 0.07 mL, 0.650 mmol) were dissolved in N,N-dimethylformamide (1.9 mL) at room temperature. The resulting solution was stirred at 110℃ for 18 hours and 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 extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the title compound (80.000 mg, 98.49%) as a brown oil.

[0462] [Step 3] Synthesis of tert-butyl (4S)-3-[(4,5-dimethyl-3-oxo-spiro[1,4-benzoxazine-2,1'-cyclopropane]-6-yl)carbamoylamino]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0463]

[0464] The 6-amino-4,5-dimethyl-spiro[1,4-benzoxazine-2,1'-cyclopropane]-3-one (100.00%, 30.000 mg, 0.137 mmol) prepared in Step 2 and the tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-(imidazole-1-carbonylamino)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (0.30 M solution in DMF, 0.45819 mL, 0.137 mmol) prepared in Step 1 were mixed at room temperature, and the reaction 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 dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the title compound (15.800 mg, 18.58%) as a brown solid.

[0465] [Step 4] Synthesis of 1-(4,5-dimethyl-3-oxo-spiro[1,4-benzoxazine-2,1'-cyclopropane]-6-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]urea

[0466]

[0467] The tert-butyl (4S)-3-[(4,5-dimethyl-3-oxo-spiro[1,4-benzoxazine-2,1'-cyclopropane]-6-yl)carbamoylamino]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00%, 37.000 mg, 0.060 mmol) prepared in Step 3 and trifluoroacetic acid (100.00% solution, 0.15 mL, 1.212 mmol) were dissolved in dichloromethane (300 uL) at room temperature, and stirred at the same temperature for 15 minutes. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (31.000 mg, 99.96%, orange solid).

[0468] [Step 5] Synthesis of 1-(4,5-dimethyl-3-oxo-spiro[1,4-benzoxazine-2,1'-cyclopropane]-6-yl)-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]urea

[0469]

[0470] The 1-(4,5-dimethyl-3-oxo-spiro[1,4-benzoxazine-2,1'-cyclopropane]-6-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]urea (100.00%, 16.000 mg, 0.031 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%, 15.000 mg, 0.036 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (100.00%, 32.000 mg, 0.062 mmol), and N,N-diisopropylethylamine (100.00% solution, 0.054 mL, 0.310 mmol) were dissolved in acetonitrile (300 uL) at room temperature, and stirred at the same temperature. A saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with ethyl acetate. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 50%) and concentrated to obtain the title compound (17.000 mg, 60.42%) as a white solid.

[0471] LC / MS (ES)m / z 912.91 [M+H]+;LC / MS retention time3.47 (min);LC / MS analysis condition#1

[0472] Examples 236 to 239, and 251

[0473] The following Compounds of Examples were prepared, respectively, in the same manner as described in Steps 1 to 5 of Example 250, except that various spiro rings containing amines were used instead of the 6-bromo-4,5-dimethyl-spiro[1,4-benzoxazine-2,1'-cyclopropane]-3-one used in Step 1 of Example 250. The prepared Compounds and the LC / MS retention time and LC / MS mass analysis results thereof are shown in Table 8 below.

[0474] [Table 8]

[0475]

[0476]

[0477] Example 113: Synthesis of 3-[(1S,2S)-1-[5-(2,2-dimethyltetrahydropyran-4-yl)-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(8-fluoro-2-methyl-3-oxo-spiro[1H-isoquinoline-4,1'-cyclopropane]-7-yl)-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

[0478] [Step 1] Synthesis of (1-(4-bromo-3-fluoro-phenyl)cyclopropanecarbonyl chloride

[0479]

[0480] 1-(4-Bromo-3-fluoro-phenyl)cyclopropanecarboxylic acid (100.00%, 1.000 g, 3.860 mmol) and thionyl chloride (1.00 M solution, 4.246 mL, 4.246 mmol) were mixed at room temperature, and the resulting mixture was heated under reflux for 4 hours and then cooled to room temperature to terminate the reaction. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product was then used without further purification (1.071 g, 99.98%, white solid).

[0481] [Step 2] Synthesis of (1-(4-bromo-3-fluoro-phenyl)-N-methyl-cyclopropanecarboxamide

[0482]

[0483] The 1-(4-bromo-3-fluoro-phenyl)cyclopropanecarbonyl chloride (100.00%, 0.500 g, 1.802 mmol) prepared in Step 1, methanamine (2.00 M in THF solution, 3.6033 mL, 7.207 mmol), and triethylamine (100.00% solution, 1.51 mL, 10.800 mmol) were dissolved in dichloromethane (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 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 (0.490 g, 99.95%, brown solid).

[0484] [Step 3] Synthesis of 7-bromo-8-fluoro-2-methyl-spiro[1H-isoquinoline-4,1'-cyclopropane]-3-one

[0485]

[0486] The 1-(4-bromo-3-fluoro-phenyl)-N-methyl-cyclopropanecarboxamide (100.00%, 0.490 g, 1.801 mmol) prepared in Step 2, paraformaldehyde (100.00%, 0.108 g, 3.596 mmol), and Eaton's reagent (100.00% solution, 3 mL, 12.602 mmol) were mixed and stirred at room temperature, and then stirred again at 80℃ for 2 hours. The resulting mixture was cooled to room temperature to terminate the reaction. The reaction mixture was neutralized with 2N aqueous sodium hydroxide solution and extracted with dichloromethane. The extract was filtered through a plastic filter and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 100%) and concentrated to obtain the title compound (0.214 g, 41.83%) as a white solid.

[0487] [Step 4] Synthesis of tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(8-fluoro-2-methyl-3-oxo-spiro[1H-isoquinoline-4,1'-cyclopropane]-7-yl)-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0488]

[0489] 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%, 0.300 g, 0.700 mmol) obtained in Step 4 of Example 1 and the 7-bromo-8-fluoro-2-methyl-spiro[1H-isoquinoline-4,1'-cyclopropane]-3-one (100.00%, 0.232 g, 0.816 mmol) obtained in Step 3, copper iodide (100.00%, 0.013 g, 0.068 mmol), (1S,2S)-(+)-N,N'-dimethylcyclohexane-1,2-diamine (100.00%, 0.048 g, 0.340 mmol) and potassium carbonate (100.00%, 0.282 g, 2.038 mmol) were dissolved in 1-methylpyrrolidin-2-one (5 mL) at room temperature, followed by stirring at 130℃ for 18 hours, and the resulting mixture was then cooled to room temperature to terminate the reaction. A saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 100%) and concentrated to obtain the title compound (0.438 g, 100.00%) as a pale yellow solid.

[0490] [Step 5] Synthesis of 8-fluoro-7-[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]-2-methyl-spiro[1H-isoquinoline-4,1'-cyclopropane]-3-one

[0491]

[0492] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(8-fluoro-2-methyl-3-oxo-spiro[1H-isoquinoline-4,1'-cyclopropane]-7-yl)-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00%, 0.438 g, 0.679 mmol) prepared in Step 4 and trifluoroacetic acid (100.00% solution, 1.682 mL, 13.586 mmol) were dissolved in dichloromethane (4 mL) at room temperature, followed by stirring at the same temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (0.370 g, 100.00%, pale yellow liquid).

[0493] [Step 6] Synthesis of 3-[(1S,2S)-1-[5-(2,2-dimethyltetrahydropyran-4-yl)-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(8-fluoro-2-methyl-3-oxo-spiro[1H-isoquinoline-4,1'-cyclopropane]-7-yl)-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

[0494]

[0495] The 8-fluoro-7-[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]-2-methyl-spiro[1H-isoquinoline-4,1'-cyclopropane]-3-one (100.00%, 0.370 g, 0.680 mmol) prepared in Step 5, 5-(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%, 0.363 g, 0.883 mmol) benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 100.00%, 0.389 g, 0.747 mmol), and N,N-diisopropylethylamine (100.00% solution, 0.355 mL, 2.040 mmol) were dissolved in acetonitrile (4 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 and extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 100%) and concentrated to obtain the title compound (0.318 g, 50.00%) as a white solid.

[0496] LC / MS (ES)m / z 938.8 [M+H]+;LC / MS retention time3.65 (min);LC / MS analysis condition#1

[0497] Examples 56, 61, 62, 67, 72 to 80, 90, 91, 97 to 112, 114 to 128, 141 to 145, 150 to 155, 172 to 176, 189, 190, 195 to 200, 203, 204, and 212 to 215

[0498] The following Compounds of Examples were prepared, respectively, in the same manner as described in Steps 1 to 6 of Example 113, except that various cyclopropanecarboxylic acid reagents were used instead of the 1-(4-bromo-3-fluoro-phenyl)cyclopropanecarboxylic acid in Step 1 of Example 113 and various hydrazine compounds were used in Step 1 of Example 1. The prepared Compounds and the LC / MS retention time and LC / MS mass analysis results thereof are shown in Table 9 below.

[0499] [Table 9]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533] Example 241: Synthesis of 1-[(4S)-5-[5-(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]-3-(8-fluoro-2-methyl-3-oxo-spiro[1H-isoquinolin-4,1'-cyclopropane]-7-yl)urea

[0534] [Step 1] Synthesis of 7-amino-8-fluoro-2-methyl-spiro[1H-isoquinoline-4,1'-cyclopropane]-3-one

[0535]

[0536] The 7-bromo-8-fluoro-2-methyl-spiro[1H-isoquinoline-4,1'-cyclopropane]-3-one (100.00%, 0.180 g, 0.630 mmol) prepared in Step 3 of Example 113, sodium azide (100.00%, 0.103 g, 1.584 mmol), copper iodide (100.00%, 0.014 g, 0.076 mmol), and sodium carbonate (100.00%, 0.105 g, 1.267 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature, and N,N'-dimethylethylenediamine (100.00% solution, 0.11933 mL, 1.109 mmol) was added to the dissolved solution. The resulting mixture was stirred at 110℃ for 5 hours and cooled to room temperature to terminate the reaction. A saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (0.140 g, 100.00%, brown solid).

[0537] [Step 2] Synthesis of tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-(imidazole-1-carbonylamino)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0538]

[0539] 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 (100.00%, 0.500 g, 1.000 mmol) prepared in Step 2 of Example 1 and 1,1'-carbonylbis-1H-imidazole (100.00%, 0.433 g, 2.671 mmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature, and stirred at the same temperature for 18 hours. The obtained product was used without further purification (0.626 g, 100.00%, brown liquid).

[0540] [Step 3] Synthesis of tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[(8-fluoro-2-methyl-3-oxo-spiro[1H-isoquinoline-4,1'-cyclopropane]-7-yl)carbamoylamino]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0541]

[0542] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-(imidazole-1-carbonylamino)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00%, 0.125 g, 0.267 mmol) prepared in Step 2 and the 7-amino-8-fluoro-2-methyl-spiro[1H-isoquinoline-4,1'-cyclopropane]-3-one (100.00%, 0.118 g, 0.534 mmol) prepared in Step 1 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 and extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 100%) and concentrated to obtain the title compound (0.142 g, 85.60%) as a white solid.

[0543] [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-(8-fluoro-2-methyl-3-oxo-spiro[1H-isoquinoline-4,1'-cyclopropane]-7-yl)urea

[0544]

[0545] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[(8-fluoro-2-methyl-3-oxo-spiro[1H-isoquinoline-4,1'-cyclopropane]-7-yl)carbamoylamino]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00%, 0.142 g, 0.229 mmol) prepared in Step 3 and trifluoroacetic acid (100.00% solution, 0.5656 mL, 4.569 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 and extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (0.119 g, 99.92%, pale yellow liquid).

[0546] [Step 5] Synthesis of 1-[(4S)-5-[5-(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]-3-(8-fluoro-2-methyl-3-oxo-spiro[1H-isoquinoline-4,1'-cyclopropane]-7-yl)urea

[0547]

[0548] The 1-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(8-fluoro-2-methyl-3-oxo-spiro[1H-isoquinoline-4,1'-cyclopropane]-7-yl)urea (100.00%, 0.059 g, 0.110 mmol) prepared in Step 4, 5-(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%, 0.061 g, 0.147 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 100.00%, 0.065 g, 0.125 mmol), and N,N-diisopropylethylamine (100.00% solution, 0.0592 mL, 0.340 mmol) were dissolved in acetonitrile (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 and extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 100%) and concentrated to obtain the title compound (0.039 g, 38.00%) as a white solid.

[0549] LC / MS (ES)m / z 914.5 [M+H]+;LC / MS retention time3.50 (min);LC / MS analysis condition#1

[0550] Examples 228 and 240, and 242 to 249

[0551] The following Compounds of Examples were prepared, respectively, in the same manner as described in Steps 1 to 5 of Example 241, except that variously substituted isoquinoline reagents were used instead of 7-bromo-8-fluoro-2-methyl-spiro[1H-isoquinoline-4,1'-cyclopropane]-3-one in Step 1 of Example 241. The prepared Compounds and the LC / MS retention time and LC / MS mass analysis results thereof are shown in Table 10 below.

[0552] [Table 10]

[0553]

[0554]

[0555]

[0556]

[0557] Example 207: Synthesis of 3-[(1S,2S)-1-[5-(2,2-dimethyltetrahydropyran-4-yl)-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(1-methyl-2-oxo-spiro[4H-quinolin-3,1'-cyclopropane]-6-yl)-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

[0558] [Step 1] Synthesis of 6-bromo-1-methyl-3,4-dihydroquinolin-2-one

[0559]

[0560] 6-Bromo-3,4-dihydro-1H-quinolin-2-one (100.00% solution, 1.000 g, 4.423 mmol), iodomethane (100.00% solution, 0.41306 mL, 6.635 mmol), and potassium tert-butoxide (100.00% solution, 0.745 g, 6.639 mmol) were dissolved in N,N-dimethylformamide (20 mL) at room temperature, and the dissolved solution was stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (1.062 g, 99.99%, brown liquid).

[0561] [Step 2] Synthesis of 6-bromo-1-methyl-spiro[4H-quinoline-3,1'-cyclopropane]-2-one

[0562]

[0563] The 6-bromo-1-methyl-3,4-dihydroquinolin-2-one (100.00%, 1.062 g, 4.423 mmol) prepared in Step 1 and lithium bis(trimethylsilyl)amide (1.00 M solution, 11.058 mL, 11.058 mmol) were dissolved in tetrahydrofuran (15 mL), and the dissolved solution was stirred at -78℃ for 0.5 hours. 1,2-Dibromoethane (100.00% solution, 1.1488 mL, 13.270 mmol) was added thereto, followed by stirring at room temperature for 2 hours, then at 70℃ for 18 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and water was added to the resulting concentrate, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 100%) and concentrated to obtain the title compound (0.120 g, 10.19%) as a white solid.

[0564] [Step 3] Synthesis of tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(1-methyl-2-oxo-spiro[4H-quinoline-3,1'-cyclopropane]-6-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0565]

[0566] 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%, 0.100 g, 0.200 mmol) prepared in Step 4 of Example 1 and the 6-bromo-1-methyl-spiro[4H-quinoline-3,1'-cyclopropane]-2-one (100.00%, 0.072 g, 0.272 mmol) prepared in Step 2, copper iodide (100.00%, 0.004 g, 0.023 mmol), (1S,2S)-(+)-N,N'-dimethylcyclohexane-1,2-diamine (100.00%, 0.016 g, 0.113 mmol), and potassium carbonate (100.00%, 0.094 g, 0.680 mmol) were dissolved in 1-methylpyrrolidin-2-one (2 mL) at room temperature, and the dissolved solution was stirred at 130℃ for 18 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 dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 100%) and concentrated to obtain the title compound (0.048 g, 30.00%) as a white solid.

[0567] [Step 4] Synthesis of (6-[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]-1-methyl-spiro[4H-quinoline-3,1'-cyclopropane]-2-one

[0568]

[0569] The tert-butyl (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(1-methyl-2-oxo-spiro[4H-quinoline-3,1'-cyclopropane]-6-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00%, 0.048 g, 0.077 mmol) prepared in Step 3 and trifluoroacetic acid (100.00% solution, 0.1892 mL, 1.528 mmol) were dissolved in dichloromethane (1 mL) at room temperature, and the dissolved solution was stirred at the same temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (0.040 g, 99.17%, pale yellow liquid).

[0570] [Step 5] Synthesis of 3-[(1S,2S)-1-[5-(2,2-dimethyltetrahydropyran-4-yl)-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(1-methyl-2-oxo-spiro[4H-quinoline-3,1'-cyclopropane]-6-yl)-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

[0571]

[0572] The 6-[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]-1-methyl-spiro[4H-quinoline-3,1'-cyclopropane]-2-one (100.00%, 0.040 g, 0.080 mmol) prepared in Step 4, 5-(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%, 0.041 g, 0.099 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 100.00%, 0.043 g, 0.084 mmol), and N,N-diisopropylethylamine (100.00% solution, 0.0397 mL, 0.228 mmol) were dissolved in acetonitrile (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 and extracted with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 100%) and concentrated to obtain the title compound (0.036 g, 50.00%) as a white solid.

[0573] LC / MS (ES)m / z 920.5 [M+H]+;LC / MS retention time3.90 (min);LC / MS analysis condition#1

[0574] Examples 205, 206, and 216 to 219, 229 to 235, 252 to 259, and 266

[0575] The following Compounds of Examples were prepared, respectively, in the same manner as described in Steps 1 to 5 of Example 207, except that variously substituted quinoline reagents were used instead of 6-bromo-3,4-dihydro-1H-quinolin-2-one in Step 1 of Example 207. The prepared Compounds and the LC / MS retention time and LC / MS mass analysis results thereof are shown in Table 11 below.

[0576] [Table 11]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587] Example 138: Synthesis of 7-(3-((S)-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)-1-ethylspiro[benzo[d][1,3]oxazine-4,1'-cyclobutane]-2(1H)-one

[0588] [Step 1] Synthesis of 7-bromo-1-ethylspiro[benzo[d][1,3]oxazine-4,1'-cyclobutane]-2(1H)-one

[0589]

[0590] 7-Bromospiro[benzo[d][1,3]oxazine-4,1'-cyclobutane]-2(1H)-one (100.00%, 134.1 mg, 0.5 mmol) and cesium carbonate (100.00%, 488.7 mg, 1.5 mmol) were dissolved in acetonitrile (2.5 mL) at room temperature. Iodoethane (100.00% solution, 120.6 μL, 1.5 mmol) was added 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 obtained product was used without further purification (0.141 g, 95.51%, white solid).

[0591] [Step 2] Synthesis of tert-butyl (4S)-3-(3-(1-ethyl-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,1'-cyclobutane]-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0592]

[0593] 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%, 106.7 mg, 0.233 mmol) prepared in Step 4 of Example 1 and the 7-bromo-1-ethylspiro[benzo[d][1,3]oxazine-4,1'-cyclobutane]-2(1H)-one (100.00%, 75.9 mg, 0.2563 mmol) prepared in Step 1 were dissolved in 1-methylpyrrolidin-2-one (1 mL) at room temperature. Trans-N,N'-dimethylcyclohexane-1,2-diamine (100.00%, 16.6 mg, 0.1165 mmol), potassium carbonate (100.00%, 96.6 mg, 0.699 mmol), and copper iodide (100.00%, 7.1 mg, 0.0466 mmol) were added to the dissolved solution, stirred at 130℃ for 3 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 by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = 100% to 90%) and concentrated to obtain the title compound (0.140 g, 89.27%) as a white solid.

[0594] [Step 3] Synthesis of 1-ethyl-7-(3-((4S)-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)spiro[benzo[d][1,3]oxazine-4,1'-cyclobutane]-2(1H)-one

[0595]

[0596] The tert-butyl (4S)-3-(3-(1-ethyl-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,1'-cyclobutane]-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (100.00%, 152.8 mg, 0.233 mmol) prepared in Step 2 was dissolved in dichloromethane (2.33 mL) at room temperature, and trifluoroacetic acid (100.00% solution, 356.6 μL, 4.66 mmol) was added 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 aqueous layer, and then concentrated under reduced pressure. The obtained product was used without further purification (120 mg, 92.68%, pale yellow solid).

[0597] [Step 4] Synthesis of 7-(3-((S)-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)-1-ethylspiro[benzo[d][1,3]oxazine-4,1'-cyclobutane]-2(1H)-one

[0598]

[0599] The 1-ethyl-7-(3-((4S)-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)spiro[benzo[d][1,3]oxazine-4,1'-cyclobutane]-2(1H)-one (100.00%, 40.000 mg, 0.072 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%, 133.5 mg, 0.233 mmol), and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (100.00%, 181.9 mg, 0.3029 mmol) were dissolved in acetonitrile (2.33 mL) at room temperature. Triethylamine (100.00% solution, 162.4 μL, 1.165 mmol) was added to the dissolved solution and 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 by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = 100% to 95%) and concentrated to obtain the title compound (0.177 g, 78.62%) as a pale yellow solid.

[0600] LC / MS (ES)m / z 950.85 [M+H]+;LC / MS retention time4.42 (min);LC / MS analysis condition#2

[0601] Examples 43, 44, 137, 139, 140, 149, 161 to 163, and 169 to 171

[0602] The following compounds according to Examples were prepared, respectively, in the same manner as described in Steps 1 to 4 of Example 138, except that 8-bromo-1-ethylspiro[benzo[d][1,3]oxazine-4,1'-cyclobutane]-2(1H)-one was used instead of the 7-bromo-1-ethylspiro[benzo[d][1,3]oxazine-4,1'-cyclobutane]-2(1H)-one used in Step 1 of Example 138, and various alkylating reagents were used instead of iodoethane. The prepared Compounds and the LC / MS retention time and LC / MS mass analysis results thereof are shown in Table 12 below.

[0603] [Table 12]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609] Activity measurement and analysis protocol of compounds of present disclosure

[0610] <Experimental Example 1> cAMP activity test (in vitro)

[0611] The activation of GLP-1R by the compounds of Examples 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 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 are shown in Table 13 below. Note: EC50range: +++++: 1 < EC50≤ 10; ++++: 10 < EC50≤ 100; +++: 100 < EC50≤ 1000; ++: 1000 < EC50≤ 5000; +: EC50> 5000

[0612] [Table 13]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620] As described in Table 13 above, the agonist assay results for cAMP confirmed that the compounds of the present invention exhibited excellent agonist activity for cAMP.

[0621] As described above, the present invention has been described in detail through preferred Examples and Experimental Examples, but the scope of the present invention is not limited to the specific compounds according to Examples and should be interpreted by the claims. Further, those skilled in the art should understand that many modifications and variations can be made without departing from the scope of the present invention.

Claims

1.A compound represented by the following Chemical Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:[Chemical Formula I]in Chemical Formula I above,is a single bond or a double bond;X1and X2are each independently C or N;R1is -H or -C1-4alkyl;Y isor;Y1to Y4are each independently C, CRY1, CRY2RY3, C(=O), or N;Y5and Y6are each independently C or NH;RY1to RY3are each independently -H, -C1-4alkyl, or -(3- to 6-membered cycloalkyl);Z1and Z2are each independently C or N;R2is -H or -C1-4alkyl;W is CH or N;R3and R4are each independently -H or -C1-4alkyl;Ring A is,,, or;A1is C(=O) or S(=O)2;A2to A4are each independently CH2, C(=O), or O;A5to A8are each independently CRA4or N;RA1is -H, -C1-4alkyl, -C1-4haloalkyl, -(3- to 6-membered cycloalkyl), or -(4- to 6-membered heterocycloalkyl), wherein at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl, -C1-4haloalkyl, or -halo;RA2and RA3are -H, -C1-4alkyl, -C1-4aminoalkyl, -C1-4hydroxyalkyl, -C1-4alkyl-O-C1-4alkyl, and RA2and RA3are linked to each other to form a -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring together with the carbon atom, wherein the -(4- to 6-membered heterocycloalkyl) ring contains an oxygen or nitrogen atom in the ring, and at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl;RA4is -H, -C1-4alkyl, -C1-4haloalkyl, -O-C1-4alkyl, or -halo;Ring B isor;RB1to RB3are each independently -H, -C1-4alkyl, -C1-4haloalkyl, -CN, -OH, -O-C1-4alkyl, -halo, or -(3- to 6-membered cycloalkyl);RB4to RB6are each independently -H or -C1-4alkyl;Ring C is,, or; andRC1and RC2are each independently -H, -C1-4alkyl, -C1-4haloalkyl, or -halo.2.The compound represented by the chemical formula I, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, whereinis a single bond or a double bond;X1is N;X2is C;R1is -C1-4alkyl;Y isor;Z1and Z2are each independently C or N;R2is -H or -C1-4alkyl;W is CH or N;R3and R4are each independently -H or -C1-4alkyl;Ring A is,,, or;A1is C(=O) or S(=O)2;A2to A4are each independently CH2, C(=O), or O;A5to A8are each independently CRA4or N;RA1is -H, -C1-4alkyl, -C1-4haloalkyl, -(3- to 6-membered cycloalkyl), or -(4- to 6-membered heterocycloalkyl), wherein at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl, -C1-4haloalkyl, or -halo;RA2and RA3are -H, -C1-4alkyl, or -C1-4aminoalkyl, and RA2and RA3are linked to each other to form a -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring together with the carbon atom, wherein the -(4- to 6-membered heterocycloalkyl) ring contains a nitrogen atom in the ring, and at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl;RA4is -H, -C1-4alkyl, -O-C1-4alkyl, or -halo;Ring B isor;RB1to RB3are each independently -H, -C1-4alkyl, -CN, -O-C1-4alkyl, -halo, or -(3- to 6-membered cycloalkyl);RB4to RB6are each independently -H or -C1-4alkyl;Ring C is,, or; andRC1and RC2are each independently -C1-4haloalkyl.3.The compound represented by the chemical formula I, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, whereinRing A is,,,,,,,, or;RA1is -H, -C1-4alkyl, -C1-4haloalkyl, -(3- to 6-membered cycloalkyl), or -(4- to 6-membered heterocycloalkyl), wherein at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl, -C1-4haloalkyl, or -halo;RA2and RA3are -H, -C1-4alkyl, or -C1-4aminoalkyl, and RA2and RA3are linked to each other to form a -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring together with the carbon atom, wherein the -(4- to 6-membered heterocycloalkyl) ring contains a nitrogen atom in the ring, and at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl;RA4is -H, -C1-4alkyl, -O-C1-4alkyl, or -halo.4.The compound represented by the chemical formula I, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, whereinRing B is,, or;RB1to RB3are each independently -H, -C1-4alkyl, -CN, -O-C1-4alkyl, -halo, or -(3- to 6-membered cycloalkyl);RB4to RB6are each independently -H or -C1-4alkyl.5.The compound represented by the chemical formula I, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, whereinRing C is,, or.6.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;R1is -H or -C1-4alkyl;Z1and Z2are each independently C or N;R2is -H or -C1-4alkyl;W is CH or N;R3and R4are each independently -H or -C1-4alkyl;Ring A is,,, or;A1is C(=O) or S(=O)2;A2to A4are each independently CH2, C(=O), or O;A5to A8are each independently CRA4or N;RA1is -H, -C1-4alkyl, -C1-4haloalkyl, -(3- to 6-membered cycloalkyl), or -(4- to 6-membered heterocycloalkyl), wherein at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl, -C1-4haloalkyl, or -halo;RA2and RA3are -H, -C1-4alkyl, -C1-4aminoalkyl, -C1-4hydroxyalkyl, -C1-4alkyl-O-C1-4alkyl, and RA2and RA3are linked to each other to form a -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring together with the carbon atom, wherein the -(4- to 6-membered heterocycloalkyl) ring contains an oxygen or nitrogen atom in the ring, and at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl;RA4is -H, -C1-4alkyl, -C1-4haloalkyl, -O-C1-4alkyl, or -halo;Ring B isor;RB1to RB3are each independently -H, -C1-4alkyl, -C1-4haloalkyl, -CN, -OH, -O-C1-4alkyl, -halo, or -(3- to 6-membered cycloalkyl);RB4to RB6are each independently -H or -C1-4alkyl;Ring C is,, or; andRC1and RC2are each independently -H, -C1-4alkyl, -C1-4haloalkyl, or -halo.7.A compound represented by the following Chemical Formula III, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:[Chemical Formula III]in Chemical Formula III above,is a single bond or a double bond;R1is -H or -C1-4alkyl;R2is -H or -C1-4alkyl;R3and R4are each independently -H or -C1-4alkyl;Ring A is,,, or;A1is C(=O) or S(=O)2;A2to A4are each independently CH2, C(=O), or O;A5to A8are each independently CRA4or N;RA1is -H, -C1-4alkyl, -C1-4haloalkyl, -(3- to 6-membered cycloalkyl), or -(4- to 6-membered heterocycloalkyl), wherein at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl, -C1-4haloalkyl, or -halo;RA2and RA3are -H, -C1-4alkyl, -C1-4aminoalkyl, -C1-4hydroxyalkyl, -C1-4alkyl-O-C1-4alkyl, and RA2and RA3are linked to each other to form a -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring together with the carbon atom, wherein the -(4- to 6-membered heterocycloalkyl) ring contains an oxygen or nitrogen atom in the ring, and at least one H of the -(3- to 6-membered cycloalkyl) or -(4- to 6-membered heterocycloalkyl) ring may be substituted with -C1-4alkyl;RA4is -H, -C1-4alkyl, -C1-4haloalkyl, -O-C1-4alkyl, or -halo.8.A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following compounds:.9.A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof as an active ingredient, and comprising a pharmaceutically acceptable carrier.10.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 8, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof as an active ingredient.11.The pharmaceutical composition of claim 10, 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.12.The pharmaceutical composition of claim 11, 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.13.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 8, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof as an active ingredient.14.Use of the compound according to any one of claims 1 to 8, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in preventing or treating a glucagon-like peptide-1 (GLP-1) receptor activity-associated disease.15.Use of the compound according to any one of claims 1 to 8, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof for use in preventing or treating a glucagon-like peptide-1 (GLP-1) receptor activity-associated disease.

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