Pyrazolopyridine derivatives with GLP-1 receptor agonist activity

Abstract

The present invention provides a compound that acts as a GLP-1 receptor agonist, exhibiting similar activity to GLP-1 peptide, and is non-invasively administered with improved activity, metabolic stability, and bioavailability; and also provides a preventive or therapeutic agent for non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus) or obesity, containing the compound as an active ingredient. [Solution] The present invention provides a compound represented by the following formula (I), or a salt thereof, or a solvate thereof, in which an indole ring or a pyrrolo[2,3-b]pyridine ring and a pyrazolopyridine skeleton are bonded via substituents. TIFF2026048784000220.tif3567

Description

[Technical Field]

[0001] This invention relates to compounds or salts thereof that have the same effect as GLP-1 as GLP-1 receptor agonists, or solvates thereof. It also relates to preventive or therapeutic agents for non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus) or obesity that contain these compounds as active ingredients. [Background technology]

[0002] Glucagon-like peptide-1 (GLP-1) is an incretin secreted from L cells in the small intestine when nutrients pass through the digestive tract. It is known to exert a variety of effects via the GLP-1 receptor, including glucose-dependent insulin secretion promotion, glucagon secretion inhibition, gastric emptying delay, and appetite suppression. GLP-1 analogs are already in practical use as diabetes medications and are considered one of the most effective diabetes treatments due to their potent HbA1c-lowering and weight-reducing effects. However, all of these require invasive subcutaneous administration. Therefore, the creation of GLP-1 receptor agonists that can be administered non-invasively is highly anticipated. For example, attempts have been made to improve the bioavailability of GLP-1 analogs such as semaglutide when administered orally using absorption enhancers (sodium N-(8-(2-hydroxybenzoyl)amino)caprylate: SNAC) (Patent Document 1), and to create small molecule GLP-1 receptor agonists (Patent Documents 2 and 3). However, further improvements are needed in the pharmaceutical properties, including activity, metabolic stability, and bioavailability.

[0003] Two compounds are known for use in chemical libraries as 2-[(2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl)carbonyl]-1H-indol.

[0004] [ka]

[0005] Furthermore, Patent Document 4 describes the following pyrazolopyridine derivatives as compounds useful for the prevention and treatment of sleep disorders (sleeping sickness) and leishmaniasis caused by parasitism by eukaryotes such as flagellates (blastocrithidia): Trypanosomatidae.

[0006] [ka] [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Publication No. 2012 / 080471 [Patent Document 2] International Publication No. 2009 / 111700 [Patent Document 3] International Publication No. 2010 / 114824 [Patent Document 4] International Publication No. 2016 / 038045 [Overview of the project] [Problems that the invention aims to solve]

[0008] The problem that the present invention aims to solve is to provide a compound or salt thereof, or a solvate thereof, that has the same effect as GLP-1 peptide as a GLP-1 receptor agonist, can be administered non-invasively, and has improved activity, metabolic stability, and bioavailability; and also to provide a preventive or therapeutic agent for non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus) or obesity, containing such a compound or salt thereof as an active ingredient. [Means for solving the problem]

[0009] The inventors of the present invention have conducted intensive research to solve such problems, and as a result, they have found that a compound represented by the formula (I) in which an indole ring and a pyrazolopyridine skeleton are bonded via a substituent has the same action as the GLP-1 peptide as a GLP-1 receptor agonist, and thus have completed the present invention.

[0010] That is, in one aspect of the present invention, the following invention is provided. [1] Formula (I): [Chemical formula] [In the formula, X represents -N= or -CR , 1-6 , Qb , 6-10 , 1-6 , 1-6 , 1-6 , 1-6 , , 1-6 , 6-10 , 1 , 1-6 , Qa , 1-6 , 2 =; R a is selected from a hydrogen atom, a halogen atom, and C 1-6 alkyl; Y is selected from -C(=O)-, -CHR-, and -S(=O)2-; R represents a hydrogen atom or C 1-6 alkyl; Q 1 represents C 6-10 aryl or a 5- to 10-member heteroaryl, where C 6-10 aryl and the 5- to 10-member heteroaryl may be substituted with 1 to 5 substituents independently selected from a halogen atom, C 1-6 alkyl (where C 1-6 alkyl may be substituted with one or more halogen atoms), and C 1-6 alkoxy; Q 2 represents a 3- to 12-member heterocyclyl or a 5- to 10-member heteroaryl, where the 3- to 12-member heterocyclyl and the 5- to 10-member heteroaryl may be substituted with 1 to 3 substituents independently selected from a halogen atom, C 1-6 alkyl (where C 1-6 alkyl may be substituted with one or more halogen atoms), C 1-6 alkoxy, and -NR Qa R Qb and further, two C 1-6 ​3-8 It may also form a carbon ring; R Qa and R Qb These are, independently, hydrogen atoms and C 1-6 Alkyl, and (C 1-6 Selected from alkyl)carbonyl; R 1 , R 2 , and R 3 These are, independently, hydrogen atoms and C 1-6 Alkyl (where C 1-6 Alkyls are halogen atoms, C 1-6 Selected from (may be substituted with one or more substituents independently selected from alkoxy and hydroxyl); R 4 , R 5 , and R 6 These are, independently, a hydrogen atom, a halogen atom, and C 1-6 Selected from alkyl groups; R 7 and R 8 These are, independently, hydrogen atoms or C 1-6 This represents alkyl, where C 1-6 Alkyls are halogen atoms and C 3-15 It may be substituted with one or more substituents independently selected from cycloalkyl, or R 7 and R 8 They come together with the carbon atoms to which they bond, C 3-15 A cycloalkane ring may be formed, or R 7 and R 8 C formed by these together 3-15 A cycloalkane ring consists of 1 to 3 carbon atoms. 1-6 It may also be substituted with alkyl, where C 1-6 Alkyl is a halogen atom, hydroxyl, -NR 7a R 7b , C 1-6 R may be substituted with one or more substituents independently selected from alkoxys and 3- to 12-membered heterocyclines, 7a and R 7b These are, independently, hydrogen atoms and C 1-6 Alkyl, and (C 1-6Selected from alkyl)carbonyl; n1 represents an integer between 0 and 3; n2 represents an integer between 0 and 5; R 9 These are equations (IIa), (IIb), (IIc), (IId): [ka] , -CO2R 9f , and -C(=O)-NR 9g R 9h Selected from the groups represented by; R 9a , R 9b , R 9c , R 9d , and R 9g These are, independently, hydrogen atoms and C 1-6 Alkyl (where C 1-6 Alkyls are halogen atoms and C 1-6 (May be substituted with one or more substituents independently selected from the alkoxy), and (C 1-6 Selected from alkyl)carbonyl, R 9e C may be substituted with a hydrogen atom or one or more halogen atoms. 1-6 Represents alkyl, R 9f is a hydrogen atom or C 1-6 Represents alkyl, R 9h C is a hydrogen atom. 1-6 Alkyl, (C 1-6 Alkyl)carbonyl, cyano, or -S(=O) n3 -R 9i n3 represents an integer between 0 and 2, and R 9i C 1-6 Represents alkyl; Z 1 These are equations (IIIa), (IIIb), (IIIc), (IIId), and (IIIe): [ka] Selected from the groups represented by; R za C is a hydrogen atom. 1-6 Alkyl, and (C 1-6 Selected from alkyl)carbonyl, Rzb and R zc each independently represents a hydrogen atom or C 1-6 alkyl, n4 represents an integer from 1 to 3, and n5 and n6 each independently represent an integer from 0 to 10 (* represents the bonding site to the pyrazolopyridine skeleton, ** represents the bonding site to Z 2 respectively); Z 2 is selected from C 1-6 alkyl, C 3-15 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, where C 3-15 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl are Group A: Group A: a) oxo, b) a halogen atom, c) cyano, d) -NR zd R ze ; where R zd and R ze each independently are selected from a hydrogen atom, C 1-6 alkyl and (C 1-6 alkyl)carbonyl, where C 1-6 alkyl may be substituted with one or more substituents independently selected from hydroxy, a halogen atom, and C 1-6 alkoxy, e) -C(=O)-NR zf R zg ; where R zf and R zg each independently are selected from a hydrogen atom, C 1-6 alkyl, and (C 1-6 alkyl)carbonyl, where C 1-6 alkyl may be substituted with one or more substituents independently selected from hydroxy, a halogen atom, and C 1-6 alkoxy,<0​​​​​​​1-6 Representing alkyl, g)C 1-6 alkyl; here, C 1-6 Alkyl is a halogen atom, hydroxyl, -NR zi R zj , C 1-6 It may be substituted with one or more substituents independently selected from alkoxys and 3- to 12-membered heterocyclyls, where R zi and R zj These are, independently, hydrogen atoms or C 1-6 Alkyl groups are represented by 3-12 member heterocyclyl groups, which are hydroxylated and C. 1-6 It may be substituted with one or more substituents independently selected from alkyl groups and 3- to 12-membered heterocyclines. h)C 1-6 Alkoxy; here C 1-6 Alkoxy compounds consist of a hydroxyl atom, a halogen atom, and C 1-6 It may be substituted with one or more substituents independently selected from the alkoxy. i) 3-12 member heterocyclyl; where 3-12 member heterocyclyl is C 1-6 Alkyl and (C 1-6 It may be substituted with one or more substituents independently selected from the alkyl)carbonyl. j)C 6-10 Ariel; here C 6-10 Aaryl is one or more (C 1-6 It may be substituted with an alkyl)carbonyl, and k) A 5-10 member heteroaryl; where a 5-10 member heteroaryl is C 1-6 Alkyl, C 1-6 Alkoxy, -NR zk R zl , and may be substituted with one or more substituents independently selected from 3- to 12-membered heterocyclyls, where R zk and R zl These are, independently, hydrogen atoms and C 1-6 Alkyl, and (C 1-6 Selected from alkyl)carbonyl, 3-12 membered heterocyclines are C 1-6 Alkyl and (C1-6 It may be substituted with one or more substituents independently selected from the alkyl)carbonyl. [May be substituted with 1 to 5 substituents independently selected from the original compound.] A compound represented by , a salt thereof, or a solvate thereof.

[0011] [2]Q 1 However, these are phenyl or pyridyl, where phenyl and pyridyl are halogen atoms and C 1-6 The compounds described in [1], their salts, or solvates thereof, substituted with 1 to 4 substituents independently selected from alkyl.

[0012] [3]R 7 and R 8 Are both hydrogen atoms?; R 7 and R 8 Both are C 1-6 Is it alkyl?; R 7 is a hydrogen atom and R 8 C 1-6 It is alkyl; or R 7 and R 8 They come together with the carbon atoms to which they bond, C 3-8 It forms a cycloalkane ring, and here the formed C 3-8 A cycloalkane ring consists of 1-2 carbon atoms. 1-6 It may also be substituted with alkyl, where C 1-6 Alkyl is hydroxy, C 1-6 The compounds described in [1] or [2], salts thereof, or solvates thereof, which may be substituted with one or more substituents independently selected from alkoxys and 3- to 12-membered heterocyclines.

[0013] [4]Z 2 However, C 1-6 Alkyl, C 3-15 Cycloalkyl, 3-12 member heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, where C 3-15 Cycloalkyl, 3-12 member heterocyclyl, C6-10 Aryls, and 5-10 member heteroaryls, belong to group B: Group B: a) Oxo, b) Halogen atom, c)-NR zd1 R ze1 ; Here R zd1 and R ze1 These are, independently, hydrogen atoms and C 1-6 Alkyl, and (C 1-6 Selected from alkyl)carbonyl, where C 1-6 Alkyl is C 1-6 It may be substituted with one or more substituents independently selected from the alkoxy. d)-S(=O) n7 -R zh1 Here, n7 represents an integer between 0 and 2, and R zh1 C 1-6 Representing alkyl, e)C 1-6 alkyl; here, C 1-6 Alkyl is a halogen atom, hydroxyl, -NR zi R zj , C 1-6 It may be substituted with one or more substituents independently selected from alkoxys and 3- to 12-membered heterocyclyls, where R zi and R zj These are, independently, hydrogen atoms or C 1-6 Alkyl groups are represented by 3-12 member heterocyclyl groups, which are hydroxylated and C. 1-6 It may be substituted with one or more substituents independently selected from alkyl groups and 3- to 12-membered heterocyclines. f)C 1-6 Alkoxy; here C 1-6 The alkoxy may be substituted with one or more hydroxyls. g) 3-12 member heterocyclils; where 3-12 member heterocyclils are 1 or more (C 1-6 It may be substituted with an alkyl)carbonyl, and h) A 5-10 member heteroaryl; where a 5-10 member heteroaryl is C 1-6 Alkyl and -NR zk1 R zl1may be substituted with one or more substituents independently selected therefrom, wherein R zk1 and R zl1 are independently selected from a hydrogen atom and C 1-6 alkyl, and may be substituted with 1 to 4 substituents independently selected from any one of [1] to [3], a salt thereof, or a solvate of any of them.

[0014] [5] The compound, salt thereof, or solvate of any of them according to any one of [1] to [4], wherein Y is -C(=O)-.

[0015] [6] The compound, salt thereof, or solvate of any of them according to any one of [1] to [5], wherein R 1 is a hydrogen atom.

[0016] [7] The compound, salt thereof, or solvate of any of them according to any one of [1] to [6], wherein both n1 and n2 are 0.

[0017] [8] The compound, salt thereof, or solvate of any of them according to any one of [1] to [7], wherein R 9 is of formula (IIb):

Chemical formula

[0018] [9] The compound, salt thereof, or solvate of any of them according to any one of [1] to [8], wherein X is -N=, -CH=, or -CF=. <​​​​​​​​​​​​​The binding sites with (each are represented).

[0020]

[11] A pharmaceutical composition containing, as an active ingredient, a compound described in any one of [1] to

[10] , a salt thereof, or a solvate of any of them.

[0021]

[12] A preventive or therapeutic agent for non-insulin-dependent diabetes (type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes (type 1 diabetes), diabetic complications, obesity, hypertension, dyslipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, Parkinson's disease, or dementia, containing, as an active ingredient, a compound described in any one of [1] to

[10] , a salt thereof, or a solvate of any of them. Here, examples of dementia include Alzheimer's disease. ​​​​​​​​​​​​​​​​​The compounds, salts thereof, or solvates thereof according to the present invention have similar activity to GLP-1 peptides as GLP-1 receptor agonists, and are expected to have sufficient bioavailability when administered orally. These provide non-peptide, insulin-independent (type 2 diabetes) or obesity preventive or therapeutic agents. [Brief explanation of the drawing]

[0026] [Figure 1] The results of powder X-ray diffraction measurements of the sodium salt hydrate crystals of compound 1 obtained in Example 163 (Sample 160a) are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). [Figure 2] The results of powder X-ray diffraction measurements of the sodium salt hydrate crystals of compound 1 obtained in Example 163 (Sample 160b) are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). [Figure 3] The results of powder X-ray diffraction measurements of the crystal of Example Compound 66 (Sample 161a) obtained in Example 163 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 4] The results of powder X-ray diffraction measurements of the crystal of Example Compound 66 (Sample 161b) obtained in Example 163 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 5] The results of powder X-ray diffraction measurements of the calcium salt hydrate crystals of Example Compound 67 obtained in Example 163 (Sample 162a) are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 6] The results of powder X-ray diffraction measurements of the calcium salt hydrate crystals of Example Compound 67 (Sample 162b) obtained in Example 163 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 7] The results of thermogravimetric and differential thermal analysis of the sodium salt hydrate crystals of compound 1 obtained in Example 164 are shown. The horizontal axis represents temperature (°C), the right vertical axis represents the weight change (%) of the sample in thermogravimetric analysis, and the left vertical axis represents the heat flow observed in differential thermal analysis. [Figure 8]The results of thermogravimetric and differential thermal analysis of the calcium salt hydrate crystals of Example Compound 67 obtained in Example 164 are shown. The horizontal axis represents temperature (°C), the right vertical axis represents the weight change (%) of the sample in thermogravimetric analysis, and the left vertical axis represents the heat flow observed in differential thermal analysis. [Figure 9] Effects of example compound 67 and exenatide on insulin secretion after intravenous glucose administration in male cynomolgus monkeys. The area under the insulin curve is shown as mean ± standard error (n=6). Each drug was administered using a crossover design. * indicates a statistically significant difference compared to the solvent group (P<0.025), and ** indicates a statistically significant difference compared to the solvent group (P<0.005) (Williams test). Each drug concentration represents the mean value of the measured plasma drug concentration. [Figure 10] Effects of Example Compound 67 and exenatide on plasma glucose levels after intravenous glucose administration in male cynomolgus monkeys. The area under the plasma glucose curve is shown as mean ± standard error (n=6). Each drug was administered using a crossover design. * indicates a statistically significant difference compared to the solvent group (P<0.025), and ** indicates a statistically significant difference compared to the solvent group (P<0.005) (Williams test). Each drug concentration represents the mean value of the measured plasma drug concentration. [Figure 11] Effects of example compound 67 and exenatide on food intake in male cynomolgus monkeys. Food intake is shown as mean ± standard deviation (n=6). Each drug was administered using a crossover design. * indicates a statistically significant difference compared to the solvent group (P<0.025), and ** indicates a statistically significant difference compared to the solvent group (P<0.005) (Williams test). [Figure 12] Plasma drug concentration profiles after oral administration of this substance to cynomolgus monkeys. The average values ​​for n=2 are shown for both plasma concentrations and each dose. [Modes for carrying out the invention]

[0027] The present invention will be described in a less restrictive manner below. definition In this invention, "halogen atom" means a fluorine atom, chlorine atom, bromine atom, iodine atom, etc. In this invention, when the halogen atom is a substituent such as an aryl (for example, X in formula (I) is -CR), a R when = a ), preferred halogen atoms include fluorine atoms and chlorine atoms. In the present invention, when the halogen atom is a substituent such as alkyl (for example, Q in formula (I) 1 C 6-10 Aryl or 5-10 member heteroaryls 1-6 When substituted with alkyl, and further substituted therewith, preferred halogen atoms include fluorine and chlorine atoms. C having halogen atoms as substituents 1-6 Specific examples of alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, pentafluoroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, heptafluoropropyl, 3,3,3-trifluoropropyl, 2,3-dichloropropyl, 1-fluoro-3-bromopropyl, 4-bromobutyl, 3,3,3,4,4-pentafluorobutyl, 4,4-dichlorobutyl, 5-iodopentyl, 5,5-difluoropentyl, 6-chlorohexyl, and 6,6,6-trifluorohexyl.

[0028] In the present invention, "C 1-6 "Alkyl" refers to linear and branched alkyl groups having 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, and 2-ethylbutyl.

[0029] In the present invention, "C 1-6 "Axoxy" is C 1-6 This refers to an alkyl-O- group, where C 1-6Alkyl is as defined above. For example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, 1-methylpropoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy, 2-ethylbutoxy, etc. may be mentioned.

[0030] In the present invention, “(C 1-6 alkyl)carbonyl” means a (C 1-6 alkyl)-C(O)- group, where C 1-6 alkyl is as defined above. For example, methylcarbonyl (acetyl), ethylcarbonyl (propionyl), n-propylcarbonyl, i-propylcarbonyl, n-butylcarbonyl, i-butylcarbonyl, sec-butylcarbonyl, t-butylcarbonyl, 1-methylpropylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, 2-methylbutylcarbonyl, 1,1-dimethylpropylcarbonyl, 1-ethylpropylcarbonyl, n-hexylcarbonyl, 4-methylpentylcarbonyl, 2-ethylbutylcarbonyl, etc. may be mentioned.

[0031] In the present invention, “C 6-10 aryl” means an aromatic carbocyclic group, which may have a non-aromatic part in addition to the aromatic part. The ring may be monocyclic or bicyclic aryl condensed with a benzene ring or a monocyclic aryl ring. For example, phenyl, 1-naphthyl, 2-naphthyl, azulenyl, isochromanyl, 2,4-dihydro-1H -isoquinolin-3-onyl, 1,3-dihydrobenzimidazol-2-onyl, etc. may be mentioned, and preferably phenyl may be mentioned.

[0032] In the present invention, "heteroaryl" means an aromatic 5-10 membered cyclic group containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur atoms in the atoms constituting the ring, and may have a non-aromatic portion in addition to the aromatic portion. The ring may be monocyclic or a bicyclic heteroaryl formed by condensation with a benzene ring or a monocyclic heteroaryl ring. Examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolidinyl, imidazopyridyl, benzoisoxazolyl, and benzoisothiazolyl.

[0033] In the present invention, "heterocyclyl" means a non-aromatic cyclic group containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may be fully saturated or partially unsaturated. The ring may be a monocyclic, bicyclic, or spirocyclic ring with 3 to 12 members, preferably 3 to 10 members. Examples include oxetanil, azetidinil, 3,7-dioxa-9-azabicyclo[3.3.1]nonanil, piperazinil, piperidinil, morpholinil, thiomorpholinil, pyrrolidinil, tetrahydropyranil, tetrahydrofuranil, 2-oxa-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2-thia-6-azaspiro[3.3]heptyl, oxazolidinil, thiazolidinil, imidazolidinil, pyrazolidinil, thianil, oxanil, thioxanil, indolinil, isoindolinil, tetrahydroindolinil, quinuclidinil, azepinil, and tropanil.

[0034] In the present invention, "C 3-15 A "cycloalkyl" is a monovalent group derived by removing one hydrogen atom of any choice from a cyclic saturated aliphatic hydrocarbon having 3 to 15 carbon atoms. 3-8 "Cycloalkyl" refers to cycloalkyl compounds with 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-6 A "cycloalkyl" is a cycloalkyl group with 3 to 6 carbon atoms. The two groups together form a carbon atom. 3-15 When a cycloalkane ring is formed, the group becomes a divalent group. Examples include cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, cycloheptane-1,1-diyl, and cyclooctane-1,1-diyl.

[0035] The groups on the two carbon atoms come together as C 3-8 When a carbon ring is formed, the ring forms a fused ring. For example, a ring structure in which two carbon atoms are linked by -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2-. Furthermore, the cyclic hydrocarbons in the cycloalkane ring, carbocyclic ring, and cycloalkyl group may be crosslinked rings. 3-15 Examples of crosslinking rings in cycloalkyls include bicyclo[1.1.0]butane, bicyclo[3.2.1]octane, bicyclo[5.2.0]nonane, bicyclo[4.3.2]undecane, and tricyclo[2.2.1.0]. 2,6 ]heptane, tricyclo[4.3.1.1 2,5 ]Undecane, Tricyclo[3.3.1.1 3,7 Decane (adamantane), tricyclo[3.3.1.1 3,7 Decane-2-ylidene (2-adamantylidene), pentacyclo[4.2.0.0 2,5 .0 3,8 .0 4,7 Examples include octane (cubane), which consists of a cross-linking ring.3-15 Examples of cycloalkyls include bicyclo[1.1.0]butyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, bicyclo[4.3.2]undecyl, and tricyclo[2.2.1.0]. 2,6 ]heptyl, tricyclo[4.3.1.1 2,5 Examples include undecyl, adamantyl, 2-adamantylidenyl, and cubenyl.

[0036] The present invention provides a compound represented by formula (I), a salt thereof, or a solvate thereof. [ka]

[0037] X is -N= or -CR a = represents; R a These are hydrogen atoms, halogen atoms, and C 1-6 Selected from alkyl groups, X is preferably -N=, -CH=, or -CF=, and more preferably -CH=.

[0038] Y is selected from -C(=O)-, -CHR-, and -S(=O)2-; R is a hydrogen atom or C 1-6 Represents alkyl.

[0039] Q 1 C 6-10 Represents an aryl or a 5- to 10-membered heteroaryl, where C 6-10 Aryl and 5-10 member heteroaryls contain halogen atoms, C 1-6 Alkyl (where C 1-6 Alkyl may be substituted with one or more halogen atoms), and C 1-6 It may be substituted with 1 to 5 substituents independently selected from the alkoxy. Q 1 The is preferably phenyl or pyridyl, where phenyl or pyridyl is a halogen atom and C 1-6 It is substituted with 1 to 4 substituents independently selected from the alkyl group. More preferably, Q 1is a halogen atom and C 1-6 This is a phenyl molecule substituted with 2-3 substituents independently selected from the alkyl group.

[0040] Q 2 represents a 3-12 member heterocyclyl or a 5-10 member heteroaryl, where the 3-12 member heterocyclyl and 5-10 member heteroaryl are halogen atoms, C 1-6 Alkyl (where C 1-6 Alkyl may be substituted with one or more halogen atoms), C 1-6 Alkoxy and -NR Qa R Qb It may be substituted with 1 to 3 substituents independently selected from, and furthermore, 2 C 1-6 Alkyl groups, together with the carbon atoms to which they are bonded, C 3-8 It may also form a carbon ring; R Qa and R Qb These are, independently, hydrogen atoms and C 1-6 Alkyl, and (C 1-6 Selected from alkyl)carbonyl. Preferably, Q 2 i) represents a 6-membered heterocyclyl, where a 6-membered heterocyclyl has 1 or more C 1-6 It may also be substituted with alkyl, and furthermore, two C 1-6 Alkyl groups, together with the carbon atoms to which they are bonded, C 3-8 ii) may form a carbon ring, or represent a 5-6 member heteroaryl group, where the 5-6 member heteroaryl group consists of a halogen atom and a C 1-6 Alkyl, C 1-6 Alkoxy and -NR Qc R Qd It may also be substituted with 1 to 3 substituents independently selected from; R Qc and R Qd These are, independently, hydrogen atoms and C 1-6 Selected from alkyl groups. Preferably, Q 2 represents a 5-6 member heterocyclyl or heteroaryl, where a 5-6 member heterocyclyl and a 5-6 member heteroaryl contain 1-3 C 1-6It may be substituted with alkyl.

[0041] R 1 , R 2 , and R 3 These are, independently, hydrogen atoms and C 1-6 Alkyl (where C 1-6 Alkyls are halogen atoms, C 1-6 Selected from (may be substituted with one or more substituents independently selected from alkoxy and hydroxyl). Preferably, R 1 , R 2 , and R 3 The combinations all involve hydrogen atoms;R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 C 1-6 alkyl; and R 1 is a hydrogen atom, R 2 C 1-6 Alkyl, R 3 C 1-6 Selected from alkyl groups.

[0042] R 4 , R 5 , and R 6 These are, independently, a hydrogen atom, a halogen atom, and C 1-6 Selected from alkyl groups. 4 , R 5 , and R 6 Preferably, each is independently a hydrogen atom or a fluorine atom. More preferably, R 4 , R 5 , and R 6 The combinations are all hydrogen atoms; or R 4 is a hydrogen atom, R 5 is a hydrogen atom, R 6 This is a fluorine atom.

[0043] R 7 and R 8 These are, independently, hydrogen atoms or C 1-6 This represents alkyl, where C 1-6 Alkyls are halogen atoms and C 3-15It may be substituted with one or more substituents independently selected from cycloalkyl groups, and further, R 7 and R 8 They come together with the carbon atoms to which they bond, C 3-15 A cycloalkane ring may be formed, or R 7 and R 8 C formed by these together 3-15 A cycloalkane ring consists of 1 to 3 carbon atoms. 1-6 It may also be substituted with alkyl, where C 1-6 Alkyl is a halogen atom, hydroxyl, -NR 7a R 7b , C 1-6 R may be substituted with one or more substituents independently selected from alkoxys and 3- to 12-membered heterocyclines, 7a and R 7b These are, independently, hydrogen atoms and C 1-6 Alkyl, and (C 1-6 Selected from alkyl)carbonyl. 7 and R 8 Preferably, together with the carbon atoms to which they are bonded, C 3-8 It forms a cycloalkane ring, and here the formed C 3-8 Cycloalkyls are composed of 1 or more C 1-6 It may also be substituted with alkyl, where C 1-6 The alkyl group may be substituted with one or more hydroxyls. Also, C 3-8 Cycloalkyl is C 3-6 It is preferable that it be a cycloalkyl group. Preferred C 3-6 An example of a cycloalkyl group is cyclopentyl.

[0044] n1 represents an integer between 0 and 3; n2 represents an integer between 0 and 5. n1 and n2 are preferably between 0 and 2, more preferably between 0 and 1, and even more preferably 0. Furthermore, preferred combinations of n1 and n2 are 0 and 0, 0 and 1, 0 and 2, 1 and 0, 1 and 1, 2 and 0, more preferably 0 and 0, 0 and 1, 1 and 0, 2 and 0, and even more preferably 0 and 0.

[0045] R 9 These are equations (IIa), (IIb), (IIc), (IId): [ka] , -CO2R 9f , and -C(=O)-NR 9g R 9h Selected from the groups represented by; R 9a , R 9b , R 9c , R 9d , and R 9g These are, independently, hydrogen atoms and C 1-6 Alkyl (where C 1-6 Alkyls are halogen atoms and C 1-6 (May be substituted with one or more substituents independently selected from the alkoxy), and (C 1-6 Selected from alkyl)carbonyl, R 9e C may be substituted with one or more substituents independently selected from hydrogen atoms or halogen atoms. 1-6 Represents alkyl, R 9f is a hydrogen atom or C 1-6 Represents alkyl, R 9h C is a hydrogen atom. 1-6 Alkyl, (C 1-6 Alkyl)carbonyl, cyano, or -S(=O) n3 -R 9i n3 represents an integer between 0 and 2, and R 9i C 1-6 Represents alkyl.

[0046] Z 1 These are equations (IIIa), (IIIb), (IIIc), (IIId), and (IIIe): [ka] Selected from the groups represented by; R za C is a hydrogen atom. 1-6 Alkyl, and (C 1-6 Selected from alkyl)carbonyl, R zband R zc These are, independently, hydrogen atoms or C 1-6 The characters represent alkyl groups, n4 represents integers from 1 to 3, and n5 and n6 independently represent integers from 0 to 10.

[0047] * indicates the binding site to the pyrazolopyridine skeleton, ** indicates Z 2 These represent the connection points between them.

[0048] Z 2 C 1-6 Alkyl, C 3-15 Cycloalkyl, 3-12 member heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, where C 3-15 Cycloalkyl, 3-12 member heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryls may be substituted with 1 to 5 substituents independently selected from group A. Group A: a) Oxo, b) Halogen atom, c) Cyano, d)-NR zd R ze ; Here R zd and R ze These are, independently, hydrogen atoms and C 1-6 Alkyl and (C 1-6 Selected from alkyl)carbonyl, where C 1-6 Alkyl is a group of atoms consisting of a hydroxyl atom, a halogen atom, and C 1-6 It may be substituted with one or more substituents independently selected from the alkoxy. e)-C(=O)-NR zf R zg ; Here R zf and R zg These are, independently, hydrogen atoms and C 1-6 Alkyl, and (C 1-6 Selected from alkyl)carbonyl, where C 1-6 Alkyl is a group of atoms consisting of a hydroxyl atom, a halogen atom, and C 1-6 It may be substituted with one or more substituents independently selected from the alkoxy. f)-S(=O) n7 -R zh Here, n7 represents an integer between 0 and 2, and R zh is a hydrogen atom or C 1-6 Representing alkyl, g)C 1-6 alkyl; here, C 1-6 Alkyl is a halogen atom, hydroxyl, -NR zi R zj , C 1-6 It may be substituted with one or more substituents independently selected from alkoxys and 3- to 12-membered heterocyclyls, where R zi and R zj These are, independently, hydrogen atoms or C 1-6 Alkyl groups are represented by 3-12 member heterocyclyl groups, which are hydroxylated and C. 1-6 It may be substituted with one or more substituents independently selected from alkyl groups and 3- to 12-membered heterocyclines. h)C 1-6 Alkoxy; here C 1-6 Alkoxy compounds consist of a hydroxyl atom, a halogen atom, and C 1-6 It may be substituted with one or more substituents independently selected from the alkoxy. i) 3-12 member heterocyclyl; where 3-12 member heterocyclyl is C 1-6 Alkyl and (C 1-6 It may be substituted with one or more substituents independently selected from the alkyl)carbonyl. j)C 6-10 Ariel; here C 6-10 Aaryl is one or more (C 1-6 It may be substituted with an alkyl)carbonyl, and k) A 5-10 member heteroaryl; where a 5-10 member heteroaryl is C 1-6 Alkyl, C 1-6 Alkoxy, -NR zk R zl , and may be substituted with one or more substituents independently selected from 3- to 12-membered heterocyclyls, where R zk and R zl These are, independently, hydrogen atoms and C 1-6Alkyl, and (C 1-6 Selected from alkyl)carbonyl, 3-12 membered heterocyclines are C 1-6 Alkyl and (C 1-6 It may be substituted with one or more substituents independently selected from the alkyl)carbonyl group.

[0049] R zd , R ze , R zf and R zg C in 1-6 If the alkyl group is substituted with a hydroxyl group, C 1-6 The alkyl is preferably C 2-6 It is alkyl, and more preferably C 2-4 It is alkyl.

[0050] C 1-6 Even if the alkoxy is substituted with one or more hydroxyls, C 1-6 The alkyl is preferably C 2-6 It is alkyl, and more preferably C 2-4 It is alkyl. Preferably, Z 2 i) 1 or more -NR zd R ze Even if replaced by C 3-15 ii) A cycloalkyl group, which may be substituted with 1 to 3 substituents independently selected from the C group. 6-10 The selection is made from aryls and 5-10 member heteroaryls which may be substituted with 1-3 substituents independently selected from group iii)D. More preferably, Z 2 i) C may be substituted with 1 to 3 substituents independently selected from the C group. 6-10 The selection is made from aryls and 5-10 member heteroaryls which may be substituted with 1-3 substituents independently selected from group D. C group: a) halogen atoms, b)-NR zd2 R ze2 ; Here R zd2 and R ze2 These are, independently, hydrogen atoms and C 1-6Alkyl, and (C 1-6 Selected from alkyl)carbonyl, where C 1-6 Alkyl is defined as having 1 or more C 1-6 It may be substituted with an alkoxy. c)-S(=O) n7 -R zh1 Here, n7 represents an integer between 0 and 2, and R zh1 C 1-6 Representing alkyl, d)C 1-6 Alkyl, e)C 1-6 Alkoxy; here C 1-6 The alkoxy may be substituted with one or more hydroxyls. f) 5-10 member heteroaryls; where a 5-10 member heteroaryl is -NR zk1 R zl1 It may be substituted with one or more substituents independently selected from R, where R zk1 and R zl1 These are, independently, hydrogen atoms and C 1-6 Selected from alkyl groups. Group D: a) Oxo, b) Halogen atom, c)C 1-6 alkyl; here, C 1-6 Alkyl is a halogen atom, hydroxyl, C 1-6 It may be substituted with one or more substituents independently selected from alkoxys and 3- to 12-membered heterocyclines, where the 3- to 12-membered heterocycline is one or more C 1-6 It may be substituted with alkyl, and d) Heterocyclines with 3 to 12 members.

[0051] The compound represented by formula (I) of the present invention is Z 1 The base is represented by equation (IIIa), where Y is represented by -C(=O)-, and R 9 is the group represented by formula (IIb), and R 9b is a hydrogen atom, and R 7 and R 8 These, together with the carbon atoms they bond to, form 1 to 3 C 1-6C substituted with alkyl 3-15 A cycloalkane ring is formed, and the 1 to 3 C 1-6 It is preferable that the alkyl group is unsubstituted.

[0052] Next, examples of methods for producing compounds represented by formula (I), their salts, or solvates thereof will be explained using the following schemes.

[0053] Compounds represented by formula (I), their salts, or solvates thereof are produced by i) general method A1 or general method A2, ii) general method B, and iii) general method C. This method is used for compounds represented by formula (I), Z 1 The base is represented by equation (IIIa), where Y is represented by -C(=O)-, and R 9 is the group represented by formula (IIb), and R 9b This is an example of a preferred method for producing the compound represented by formula (Ia), where is a hydrogen atom.

[0054] Also, R 7 and R 8 These, together with the carbon atoms they bond to, form 1 to 3 C 1-6 C substituted with alkyl 3-15 When a cycloalkane ring is formed, the 1 to 3 C 1-6 Alkyl compounds are an example of a preferred manufacturing method when they are unsubstituted.

[0055] Furthermore, if the starting material or target product in a certain step undergoes an undesirable chemical transformation under the reaction conditions of that step, the target product for that step can be obtained, for example, by protecting and deprotecting the functional group. For the selection of protecting groups and the methods of protection and deprotection, see, for example, TW Greene, PGMWuts, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons, Inc., New York (2007). Some methods of protecting and deprotecting functional groups are also described in the following scheme.

[0056] <General manufacturing method A1> Compound f can be synthesized by the general method A1 shown in the following scheme. [ka] During the ceremony, P 2 is a hydrogen atom or C 1-6 Represents alkyl, P 1a represents the protecting group of an amino acid, P 3a and P 3b Independently, C 1-6 Represents alkyl, or P 3a and P 3b However, they may also form a 5-7 membered 1,3-dioxacycloalkane ring together with the oxygen atom to which they are bonded and the carbon atom to which the oxygen atom is bonded. 1 cyano or -CO-OP 2 Represents Y 2 This represents =O or =NH, and X 1 This represents a leaving group. Examples of amino protecting groups include formyl, (C 1-6 Alkyl)carbonyl (acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.), carbamoyl, C 1-6 Examples include alkoxycarbonyls (methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, etc.), substituted silyls (trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, etc.), aralkyloxycarbonyls (benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, etc.), allyls, and aralkyls. Examples of leaving groups include halogen atoms, acetyloxy, trifluoroacetyloxy, methanesulfonyloxy, and p-toluenesulfonyloxy.

[0057] Process A1-1a : Compound a1 can be obtained by reacting compound a with a base. Examples of bases include metal hydrides such as sodium hydride, potassium hydride, and lithium hydride; and metal alkoxides such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-pentoxide, with metal alkoxides such as potassium t-butoxide being preferred. Examples of solvents include ether-based solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane, with THF being preferred. The reaction temperature is typically -30°C to 30°C, preferably -10°C to 10°C. The reaction time is usually 15 minutes to 5 hours, preferably 30 minutes to 3 hours. Compound a1 may be isolated, or it may be subjected to step A1-1b without isolation. Compound a can be purchased commercially from companies such as Aldlab Chemicals, LLC and Tokyo Chemical Industry. It can also be synthesized by referring to Bioorganic Medicinal Chemistry, 1999, 7, 795-809, CN 103086955. Compound a1 may also be obtained as an alkali metal salt, such as a potassium salt, by contact with the base used in the reaction, and such salts can also be subjected to the next step.

[0058] Process A1-1b : Compound b can be obtained by reacting compound a1 with compound a2. This reaction is preferably carried out in the presence of an acid. Examples of acids include hydrochloric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, and salts of a weak base and a strong acid, such as pyridine hydrochloride. Suitable solvents include hydrocarbon solvents (such as hexane, heptane, benzene, toluene, and xylene) and alcoholic solvents (such as methanol and ethanol). The presence of water in the system is also acceptable. The reaction temperature is typically 40°C to 200°C, preferably 60°C to 150°C. The reaction time is typically 6 minutes to 30 hours, preferably 30 minutes to 3 hours. Compound a2 can be purchased commercially as a salt with hydrogen chloride added to Alfa Aesar, etc. Referring to Synlett, 2011, 17, 2555-2558, compound a2, in which the hydrazine portion is protected with t-butoxycarbonyl, can also be used after deprotecting it with an acid such as methanesulfonic acid. Furthermore, referring to the Journal of Medicinal Chemistry 2003, 46, 1546-1553, compound: Q 1 -NH2 can also be used as a starting material for synthesis.

[0059] Process A1-2 : Compound c can be obtained by reacting compound b with compound b1 or compound b2 in the presence of a base. Examples of bases include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.), nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine, pyrazine, pyridazine, etc.), metal hydrides such as sodium hydride, potassium hydride, and lithium hydride; and metal alkoxides such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-pentoxide. When compound b2 is used, a metal alkoxide such as potassium t-butoxide is preferred. Suitable solvents include alcohol-based solvents such as methanol and ethanol; ether-based solvents such as THF and diethyl ether; ester-based solvents such as ethyl acetate and methyl acetate; nitrile-based solvents such as acetonitrile, benzonitrile, and benzyl cyanide; and amide-based solvents such as N,N-dimethylacetamide (DMA), N,N-dimethylimidazolidinone (DMI), and DMF. However, amide-based solvents such as DMA are preferred. The reaction temperature is typically -50°C to 70°C, preferably -30°C to 50°C. The reaction time is typically 15 minutes to 72 hours, preferably 1 hour to 30 hours. Compound b1 can be purchased commercially from companies such as Enamine LTD. Also, referencing WO2006 / 048727, compound: H2NCH2CH(OP 3a )(OP 3b It can also be synthesized by reacting ) with phosgene or triphosgene. Compound b2 can be purchased commercially from companies such as UkrOrgSyntez Ltd. Also, referring to WO99 / 50262, compound: H2NCH2CH(OP 3a )(OP 3b It can also be synthesized by reacting it with diisocyanates such as CDI.

[0060] Process A1-3 : Compound d can be obtained by reacting compound c with an acid. Examples of acids include inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acids (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.), and carboxylic acids (formic acid (FA), acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid, fluoroacetic acid, trifluoroacetic acid (TFA), tartaric acid, propionic acid, glutaric acid, etc.). Examples of solvents include ether-based solvents (ether, tetrahydrofuran, dioxane, dimethoxyethane, cyclopentyl methyl ether, etc.), aromatic hydrocarbon-based solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), aliphatic hydrocarbon-based solvents (pentane, hexane, heptane, octane, cyclohexane, etc.), amide-based solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.), alcohol-based solvents (methanol, ethanol, 2,2,2-trifluoroethanol, n-propanol, isopropanol, n-butanol, sec-butanol, pentanol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, etc.), acetate ester-based solvents (methyl acetate, ethyl acetate, isopropyl acetate, etc.), acetonitrile, and mixed solvents thereof, with ether-based solvents such as tetrahydrofuran being preferred. The reaction temperature is typically 0°C to 100°C, preferably 10°C to 80°C. The reaction time is typically 10 minutes to 20 hours, preferably 30 minutes to 5 hours.

[0061] Process A1-4 : a)Z 2 However, C 1-6 Alkyl, C 3-15 If compound d is a cycloalkyl or a 3- to 12-membered heterocycline, compound e can be obtained by reacting compound d1 with compound d1 in the presence of a base. Examples of bases include metal hydrides such as sodium hydride, potassium hydride, and lithium hydride; metal alkoxides such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-pentoxide; and alkyl metals such as butyllithium and ethyllithium. Examples of solvents include ether-based solvents (ether, tetrahydrofuran, dioxane, dimethoxyethane, cyclopentyl methyl ether, etc.), aromatic hydrocarbon-based solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), aliphatic hydrocarbon-based solvents (pentane, hexane, heptane, octane, cyclohexane, etc.), and amide-based solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.), with amide-based solvents such as N,N-dimethylacetamide being preferred. The reaction temperature is typically 0°C to 150°C, preferably 20°C to 120°C. The reaction time is typically 15 minutes to 24 hours, preferably 30 minutes to 5 hours. b)Z 2 However, C 6-10 If compound d is an aryl or a 5-10 membered heteroaryl, compound e can be obtained by reacting compound d with compound d1 in the presence of a base, a copper catalyst, and a ligand. Examples of bases include weakly basic inorganic salts (such as sodium carbonate, potassium carbonate, potassium phosphate, and cesium carbonate) and organic bases (such as triethylamine, pyridine, and tetrabutylammonium fluoride), with weakly basic inorganic salts such as potassium carbonate being preferred. Examples of copper catalysts include copper(I) iodide, copper(I) bromide, copper(I) chloride, copper(II) acetate, copper(II) oxide, and copper(I) trifluoromethanesulfonate, with copper(I) iodide being preferred. Examples of ligands include diamines such as phenanthroline, quinoline-8-ol, 2,2,6,6-tetramethylheptan-3,5-dione, N,N'-dimethylethane-1,2-diamine, trans-cyclohexane-1,2-diamine, and trans-N,N'-dimethylcyclohexane-1,2-diamine, with trans-N,N'-dimethylcyclohexane-1,2-diamine being preferred. Examples of solvents include ether-based solvents (ether, tetrahydrofuran, dioxane, dimethoxyethane, cyclopentyl methyl ether, etc.), aromatic hydrocarbon-based solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), aliphatic hydrocarbon-based solvents (pentane, hexane, heptane, octane, cyclohexane, etc.), amide-based solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.), alcohol-based solvents (methanol, ethanol, 2,2,2-trifluoroethanol, n-propanol, isopropanol, n-butanol, sec-butanol, pentanol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, etc.), acetate ester-based solvents (methyl acetate, ethyl acetate, isopropyl acetate, etc.), and acetonitrile, with amide-based solvents such as N-methylpyrrolidone being preferred. The reaction temperature is typically 30°C to 200°C, preferably 60°C to 160°C. The reaction time is usually 1 to 15 hours, preferably 3 to 9 hours.

[0062] Process A1-5 : Compound f can be obtained by deprotecting compound e. Protecting group P 1a C such as t-butoxycarbonyl 1-6 If it is an alkoxycarbonyl, it is preferable to deprotect it using an acid. Examples of acids include inorganic acids (hydrogen chloride, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acids (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.), and carboxylic acids (formic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid, fluoroacetic acid, trifluoroacetic acid, tartaric acid, propionic acid, glutaric acid, etc.). Examples of solvents include ether-based solvents (tetrahydrofuran, methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, etc.), hydrocarbon-based solvents (hexane, heptane, benzene, toluene, etc.), amide-based solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.), and halogen-based solvents (dichloromethane, chloroform, carbon tetrachloride, etc.), with amide-based solvents such as N-methylpyrrolidone being preferred. The reaction temperature is typically 0°C to 200°C, preferably 10°C to 120°C. The reaction time is usually 30 minutes to 10 hours, preferably 1 to 6 hours. Compound f may be obtained as a salt with the acid used in the reaction, and such a salt can also be subjected to the next step.

[0063] <General manufacturing method A2> Z 2 However, -NR zd R ze C is replaced by 3-15 In the case of bulky groups such as cycloalkyl groups, compound p, which corresponds to compound f, can also be synthesized using general method A2 shown in the following scheme. [ka] In the formula, Z 2a This is an unsubstituted C 3-15 Represents a cycloalkyl or a 3- to 12-membered heterocycline. P 1a and P 2a This represents the protecting group of an amino acid. X 2 , X 3 , X 4 and X 5 Each of these independently represents a leaving group, R 10a and R 10b Independently, C 1-6 Represents alkyl, or R 10a and R 10bHowever, they may combine with the oxygen atom to which they are bonded and the carbon atom to which the oxygen atom is bonded to form a 5- to 7-membered 1,3-dioxacycloalkane ring. Examples of amino protecting groups include formyl, (C 1-6 Alkyl)carbonyl (acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.), carbamoyl, C 1-6 Examples include alkoxycarbonyls (methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, etc.), substituted silyls (trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, etc.), aralkyloxycarbonyls (benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, etc.), allyls, and aralkyls. Examples of leaving groups include halogen atoms, acetyloxy, trifluoroacetyloxy, methanesulfonyloxy, and p-toluenesulfonyloxy.

[0064] Process A2-1 : Compound h can be obtained by reacting compound g with an azide in the presence of a base. Examples of bases include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.). Examples of azides include metal azides such as sodium azide, trimethylsilyl azide, and diphenylphosphoryl azide, with diphenylphosphoryl azide being preferred. Examples of solvents include ether-based solvents (tetrahydrofuran, methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, etc.), hydrocarbon-based solvents (hexane, heptane, benzene, toluene, etc.), and amide-based solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.), with hydrocarbon-based solvents such as toluene being preferred. The reaction temperature is typically 0°C to 150°C, preferably 10°C to 100°C. The reaction time is usually 1 to 10 hours, preferably 2 to 6 hours. Compound g is described, for example, in the Journal of the American Chemical Society, 2016, 138, 1698-1708 and WO2009 / 152133. It can also be purchased commercially from companies such as Enamine Ltd.

[0065] Process A2-2 : Compound i can be obtained by reacting compound b, obtained in step A1-1b, with compound h in the presence of a base. Examples of bases include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.) and nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine, pyrazine, pyridazine, etc.). Suitable solvents include ether-based solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane; and hydrocarbon-based solvents such as hexane, heptane, benzene, and toluene. Bases such as pyridine can also be used as solvents. The reaction temperature is typically 0°C to 60°C, preferably 5°C to 45°C. The reaction time is typically 30 minutes to 50 hours, preferably 2 to 10 hours.

[0066] Process A2-3 : Compound j can be obtained by reacting compound i with compound i1 or compound i2 in the presence of a base. Examples of bases include weakly basic inorganic salts (such as sodium carbonate, potassium carbonate, and cesium carbonate) and metal hydrides (such as sodium hydride and potassium hydride), with weakly basic inorganic salts such as cesium carbonate being preferred. Examples of compound i1 include 1,2-dichloro-1-methoxyethane, 1,2-dichloro-1-ethoxyethane, 1,2-dichloro-1-i-propoxyethane, and 1,2-dichloro-1-t-butoxyethane, with 1,2-dichloro-1-ethoxyethane being preferred. Compound i1 can be purchased commercially from companies such as Tokyo Chemical Industry Co., Ltd. and FCH Group. Examples of compound i2 include 2-chloro-1,1-dimethoxyethane, 2-chloro-1,1-diethoxyethane, 2-bromo-1,1-dimethoxyethane, and 2-bromo-1,1-ethoxyethane. Compound i2 can be purchased commercially from companies such as Tokyo Chemical Industries. Examples of solvents include alcohol-based solvents such as methanol and ethanol; ether-based solvents such as THF and diethyl ether; ester-based solvents such as ethyl acetate and methyl acetate; nitrile-based solvents such as acetonitrile, benzonitrile, and benzyl cyanide; and amide-based solvents such as N,N-dimethylacetamide (DMA), N,N-dimethylimidazolidinone (DMI), and DMF, with amide-based solvents such as DMA being preferred. The reaction temperature is typically 0°C to 60°C, preferably 20°C to 45°C. The reaction time is typically 1 to 72 hours, preferably 12 minutes to 35 hours.

[0067] Process A2-4 : Compound k can be obtained by reacting compound j with an acid. Examples of acids include inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acids (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.), and carboxylic acids (formic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid, fluoroacetic acid, trifluoroacetic acid, tartaric acid, propionic acid, glutaric acid, etc.), with sulfonic acids such as methanesulfonic acid being preferred. Examples of solvents include ether-based solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane, with THF being preferred. The reaction temperature is typically 0°C to 100°C, preferably 20°C to 80°C. The reaction time is usually 15 minutes to 6 hours, preferably 30 minutes to 3 hours.

[0068] Process A2-5 : Compound l can be obtained by reacting compound k with compound k1 in the presence of a base. Examples of compound k1 include halogenated carbon atoms such as methyl iodide. 1-6 Alkyl and acetyl chloride halogenated (C 1-6 Examples include alkyl carbonyl. Also, R zd But (C 1-6 When it is an alkyl carbonyl compound, replace compound k1 with ((C 1-6 It is also preferable to use an acid anhydride represented as alkyl)carbonyl)2O, such as acetic anhydride. Examples of bases include metal hydrides such as sodium hydride, potassium hydride, and lithium hydride; and metal alkoxides such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-pentoxide, with metal alkoxides such as potassium pentoxide being preferred. Examples of solvents include ether-based solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane; and hydrocarbon-based solvents such as hexane, heptane, benzene, and toluene, with THF being preferred. The reaction temperature is typically -50°C to 50°C, preferably -40°C to 40°C. The reaction time is usually 1 minute to 2 hours, preferably 3 minutes to 30 minutes.

[0069] Process A2-6 : Compound m can be obtained by deprotecting compound l. Deprotection can be performed by selecting appropriate reagents and reaction conditions depending on the type of protecting group, but when the protecting group is t-butoxycarbonyl, it is preferable to react it with an acid. Examples of acids include inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acids (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.), and carboxylic acids (formic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid, fluoroacetic acid, trifluoroacetic acid, tartaric acid, propionic acid, glutaric acid, etc.), with carboxylic acids such as trifluoroacetic acid being preferred. Examples of solvents include ether-based solvents such as diethyl ether, THF, and dimethoxyethane; halogen-based solvents such as dichloromethane (CH2Cl2), chloroform, and carbon tetrachloride; N,N-dimethylformamide; and acetonitrile, with halogen-based solvents such as CH2Cl2 being preferred. The reaction temperature is typically 0°C to 60°C, preferably 10°C to 40°C. The reaction time is usually 30 minutes to 10 hours, preferably 1 to 5 hours. Compound m may be obtained as a salt with the acid used in the reaction, and such a salt can also be subjected to step A2-7.

[0070] Process A2-7 : Compound n can be obtained by protecting one of the amino acids in compound m. Protection allows for the selection of appropriate reagents and reaction conditions depending on the type of protecting group, but the protecting group is C 1-6 If it is an alkoxycarbonyl, it is preferable to react it with a base. Examples of compounds used for protection include methoxycarbonyl chloride, ethoxycarbonyl chloride, 2,2,2-trichloroethoxycarbonyl chloride, benzoyl chloride (Z-Cl), 9-fluorenylmethyloxycarbonyl chloride (Fmoc-Cl), and di-t-butyl dicarbonate, with di-t-butyl dicarbonate being preferred. Examples of bases include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.) and nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine, pyrazine, pyridazine, etc.), with tertiary amines such as triethylamine being preferred. Examples of solvents include ether-based solvents such as diethyl ether, THF, and dimethoxyethane; halogen-based solvents such as dichloromethane (CH2Cl2), chloroform, and carbon tetrachloride; N,N-dimethylformamide; and acetonitrile, with halogen-based solvents such as CH2Cl2 being preferred. The reaction temperature is typically 0°C to 60°C, preferably 15°C to 40°C. The reaction time is typically 30 minutes to 20 hours, preferably 1 to 5 hours.

[0071] Process A2-8 : Compound o can be obtained by reacting compound n with compound n1 in the presence of a base. As compound n1, for example, halogenated carbon such as methyl iodide. 1-6 Alkyl and acetyl chloride halogenated (C 1-6 Examples include alkyl carbonyl. Also, R ze C 1-6 If it is alkyl, C 1-6 Alkyl is either unsubstituted or C 1-6 It is preferable that the alkoxy group is substituted. This step is carried out in the same manner as step A2-5, and the base, solvent, reaction temperature, and reaction time used in the reaction are also the same as in step A2-5.

[0072] Process A2-9 : Compound p can be obtained by deprotecting compound o. Deprotection allows for the selection of appropriate reagents and reaction conditions depending on the type of protecting group, but protecting group P 1a C such as t-butoxycarbonyl 1-6 If it is an alkoxycarbonyl, it is preferable to deprotect it using an acid. This process is carried out in the same manner as in process A1-5, and the acid, solvent, reaction temperature, and reaction time used in the reaction are also the same as in process A1-5.

[0073] <General manufacturing method B> Compound bf can be synthesized by the general method B shown in the following scheme. [ka] During the ceremony, P 21 is hydroxy, C 1-6 Alkoxy, or -NR 21a R 21b Represents R 21a and R 21b These are, independently, hydrogen atoms and C 1-6 Alkyl, or C 6-10 Represents an arrow, X 21 is a hydrogen atom, a halogen atom, or -Zn-X 21a This represents, X 21a This represents a bromine atom or an iodine atom. X 22 This represents a leaving group. Examples of leaving groups include halogen atoms, acetyloxy, trifluoroacetyloxy, methanesulfonyloxy, and p-toluenesulfonyloxy.

[0074] Process B-1 : Compound BB can be obtained by reacting compound ba with compound ba1 in the presence of a palladium catalyst. As a palladium catalyst, a complex formed in situ by separately adding a palladium compound and a ligand can be used. Alternatively, a separately prepared complex may be used as is. Examples of ligands include 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, trimethylenebis(diphenylphosphine), 2-(di-t-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-(di-t-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl, and 2-di-t-butylphosphino-2',4',6'-triisopropylbiphenyl. Examples of palladium compounds to be combined with the ligand include di-μ-chlorobis[(η-allyl)palladium(II)] and tetrakis(triphenylphosphine)palladium(O). Examples of palladium catalysts usable in this process include tris(dibenzylideneacetone)dipalladium(O), 5,10,15,20-tetraphenyl-21H,23H-porphyricobalt(II), palladium acetate(II), bis(di-t-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, dichlorobis(triphenylphosphine)palladium(II), palladium hydroxide, tetrakis(triphenylphosphine)palladium(O), and di-μ-chlorobis[(η-allyl)palladium(II)]. In step 11, it is preferable to use a complex formed with di-μ-chlorobis[(η-allyl)palladium(II)] as the palladium compound and 2-(di-t-butylphosphin)-2',4',6'-triisopropyl-1,1'-biphenyl as the ligand as the catalyst. This process may also be carried out in the presence of a base. Examples of bases include weakly basic inorganic salts (sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, calcium acetate, etc.), metal hydrides (sodium hydride, potassium hydride, etc.), and metal alkoxides (potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, etc.). Suitable reaction solvents include ether-based solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane, or amide-based solvents such as N,N-dimethylacetamide (DMA), N,N-dimethylimidazolidinone (DMI), and DMF. A mixed solvent with water may also be used. The reaction temperature is typically 10°C to 200°C, preferably 40°C to 130°C. The reaction time is usually 1 minute to 20 hours, preferably 10 minutes to 10 hours. Compound ba can be purchased commercially from Aurora Fine Chemicals, etc. It can also be synthesized, referring to Synthetic Communications, 39(14), 2506-2515, 2009. -COP 21 It can also be obtained by esterifying or amidating compound ba, which is a -COOH group. X 21 -Zn-X 21a Compound ba1 can be purchased commercially from companies such as Focus Synthesis LLC. It can also be synthesized by referring to WO2014 / 201206, etc.

[0075] Process B-2 : Compound bc can be obtained by reacting compound bb with compound bb1 in the presence of a base. Examples of bases include metal hydrides such as sodium hydride and potassium hydride, and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide, with potassium hydroxide being preferred. Examples of reaction solvents include amide solvents such as N,N-dimethylacetamide (DMA), N,N-dimethylimidazolidinone (DMI), and DMF, with DMI being preferred. A mixed solvent with water may also be used. The reaction temperature is typically -10°C to 100°C, preferably 0°C to 45°C. The reaction time is usually 30 minutes to 10 hours, preferably 1 to 5 hours. Compound bb can be purchased commercially from companies such as Aquila Pharmatech LLC. It can also be synthesized by referring to WO2013 / 010904, Organic Letters, 7(18), 3965-3968, 2005, US5998438, etc.

[0076] Process B-3 : Compound bd can be obtained by reacting compound bc with hydroxyamine (H2NOH). Examples of reaction solvents include aprotic polar solvents such as dimethyl sulfoxide (DMSO), dimethylformamide, dimethylacetamide, and 1-methyl-2-pyrrolidinone, as well as alcoholic solvents such as methanol and ethanol, with DMSO being preferred. A mixed solvent with water may also be used. The reaction temperature is typically -10°C to 100°C, preferably 20°C to 45°C. The reaction time is usually 2 to 72 hours, preferably 3 to 36 hours. Compound bd may be subjected to step B-4 without isolation or purification.

[0077] Process B-4 : Compound be can be obtained by reacting compound bd with triphosgene, chlorocarbonate esters (such as methyl chlorocarbonate, ethyl chlorocarbonate, isopropyl chlorocarbonate, etc.), and carbonyldiimidazole, preferably carbonyldiimidazole, in the presence of a base. Examples of bases include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, 1,8-diazabicycloundeca-7-ene (DBU), DABCO, etc.) and metal hydroxides (sodium hydroxide, potassium hydroxide), with tertiary amines such as DBU being preferred. Examples of solvents include aprotic polar solvents such as dimethyl sulfoxide (DMSO), dimethylformamide, dimethylacetamide, and 1-methyl-2-pyrrolidinone; alcoholic solvents such as methanol and ethanol; and etheric solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane, with DMSO being preferred. The reaction temperature is typically -10°C to 100°C, preferably 20°C to 45°C. The reaction time is usually 10 minutes to 10 hours, preferably 15 minutes to 2 hours.

[0078] Process B-5 : P 21 Compound bf can be obtained by deprotecting compound be, which is protected with a base, using a base. Examples of bases include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide, and metal alkoxides such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-pentoxide. Suitable solvents include alcoholic solvents such as methanol, ethanol, methoxyethanol, and t-butyl alcohol; etheric solvents such as THF and diethyl ether; and amide solvents such as N,N-dimethylacetamide (DMA), N,N-dimethylimidazolidinone (DMI), and DMF. A mixed solvent with water may also be used. The reaction temperature is typically -20°C to 120°C, preferably 20°C to 100°C. The reaction time is usually 20 minutes to 10 hours, preferably 30 minutes to 5 hours. Note that steps B-1, B-2, B-3, B-4, and B-5 can be performed in any order. For example, compound bc can be obtained by sequentially applying compound ba to steps B-2 and B-1. Compound bf can be obtained by sequentially applying compound ba to steps B-2, B-3, B-4, B-5, and B-1. Compound bf can be obtained by sequentially applying compound ba to steps B-2, B-3, B-4, B-1, and B-5.

[0079] Process B-Aa and Process B-Ab : Also, X 21 However, if it is a halogen atom, compound bb can also be obtained by subjecting compound ba to steps B-Aa and B-Ab below, and this may then be subjected to step B-2. [ka] In the formula, R Qc and R Qd These are, independently, hydrogen atoms or C 1-6 Represents alkyl, or R Qc and R Qd However, they may combine with the oxygen atom to which they are bonded and the boron atom to which the oxygen atom is bonded to form 1,3,2-dioxaboloranyl or 1,3,2-dioxaborinanyl.

[0080] Process B-Aa : The organoboron compound baa can be obtained by reacting compound ba with compound ba2 or compound Ba3 in the presence of a palladium catalyst. This step may also be carried out in the presence of a base. This process is carried out in the same manner as in process B-1, and the palladium catalyst, base, solvent, reaction temperature, and reaction time used in the reaction are also the same as in process B-1. Examples of compound ba2 include pinacolborane and 4,6,6-trimethyl-1,3,2-dioxaborinane. Examples of compound ba3 include diboronic acid, pinacoldiborane (4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborane)), bis(neopentylglycolato)diboron, and bis(hexyleneglycolato)diboron. These compounds can be purchased commercially from companies such as Tokyo Chemical Industry. They can also be synthesized using i) pinacol and ii) diborane, a BH3·THF complex, or a BH3·dimethyl sulfide complex, with reference to Journal of the American Chemical Society, 131(45), 16346-16347, 2009 and Organic Synthesis, 77, 176-185, 2000. The organoboron compound baa may be subjected to step B-Ab without isolation.

[0081] Process B-Ab : Compound bb can be obtained by reacting the organoboron compound baa with compound ba1 in the presence of a base. Examples of bases include weakly basic inorganic salts (such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate), with sodium carbonate being preferred. The solvent, reaction temperature, and reaction time used in the reaction are the same as in step B-1. Furthermore, compound bb can also be obtained by converting compound ba1 to an organoboron compound, similar to the conversion from compound ba to compound baa, and then reacting this with compound ba.

[0082] Process BB : Also, compound bb1 is X 21 -(CH2) n1 When represented as -CH2-CN, compound bca, which corresponds to compound bc obtained in step B-2, is subjected to the following step BB, that is, by reacting it with compound bc1 in the presence of a base, R 7 and R8 They come together with the carbon atoms to which they bond, C 3-15 It forms a cycloalkane ring, and also R 7 and R 8 C formed by these together 3-15 A cycloalkane ring consists of 1 to 3 carbon atoms. 1-6 Compound bcb, which corresponds to compound bc and may be substituted with alkyl, can be obtained and then subjected to step B-3. [ka] In the formula, R 7c , R 7e and n8 R 7d Each of these is independently a hydrogen atom or C 1-6 It represents an alkyl group, and n8 represents an integer between 0 and 3. Examples of bases include sodium hydride, potassium hydride, lithium bis(trimethylsilyl)amide (LiHMDS), and metal hydrides such as sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), and lithium 2,2,6,6-tetramethylpyrrolidide, with KHMDS being preferred. Examples of solvents include ether-based solvents such as THF, diethyl ether, and dioxane, and amide-based solvents such as N,N-dimethylacetamide (DMA), N,N-dimethylimidazolidinone (DMI), DMF, and N,N'-dimethylpropyleneurea (DMPU), with amide-based solvents such as DMPU being preferred. The reaction temperature is, for example, -20°C to 40°C, preferably -10°C to 10°C. The reaction time is, for example, 30 minutes to 8 hours, preferably 1 to 4 hours. Compound bc1 can be purchased commercially from companies such as CGeneTech.Inc. It can also be synthesized by referring to Organic Letters, 12(17), 3938-3941, 2010.

[0083] <General manufacturing method C> Process C-1 : [ka] Compound (Ia) can be obtained by condensing compound f (or compound p) and compound bf using a condensing agent in the presence of a base. Examples of condensing agents include BOP-based condensing agents such as benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazole-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP®), PyAOP, BroP, PyCloP, PyBroP®, and DEPBT, as well as 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholium chloride n-hydrate (DMT-MM) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium Examples include tetrafluoroborate (TBTU), [dimethylamino(triazolo[4,5-b]pyridine-3-yloxy)methylidene]-dimethylazanium hexafluorophosphate (HATU), and ethyl (hydroxyimino)cyanoacetate (Oxyma), with HATU being preferred. Examples of bases include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.) and nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine, pyrazine, pyridazine, etc.), with tertiary amines such as diisopropylethylamine being preferred. Examples of solvents include ether-based solvents such as THF, diethyl ether, and dioxane, and aprotic polar solvents such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide, and 1-methyl-2-pyrrolidinone, with aprotic polar solvents such as DMF being preferred. The reaction temperature is, for example, 0°C to 80°C, preferably 20°C to 60°C. The reaction time is, for example, 1 minute to 10 hours, preferably 30 minutes to 5 hours. Furthermore, compound (Ia) can also be obtained by changing the order of the steps, for example, by sequentially applying compound d to steps A1-5, C-1, and A1-4, and by sequentially applying compound ba to steps B-2, B-3, B-4, B-5, C-1, and B-1.

[0084] Furthermore, salts of the compound represented by formula (I) can be obtained by contacting or reacting it with an acid or base usable in the manufacture of pharmaceuticals. The salt only needs to be pharmaceutically acceptable, and such salts include, for example, inorganic salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.), sulfonates (methanesulfonate, ethanesulfonic acid, benzenesulfonate, toluenesulfonate, etc.), carboxylates (formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, mandelate, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, glucon Examples include thalates, adipines, nicotinates, etc., alkali metal salts (lithium salts, sodium salts, potassium salts, cesium salts, rubidium salts, etc.), alkaline earth metal salts (magnesium salts, calcium salts, etc.), ammonium salts (ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, tetraalkylammonium salts, etc.), and basic amino acid salts (lysine salts, arginine salts, etc.). Alkali metal salts and alkaline earth metal salts are preferred, and sodium salts and calcium salts are even more preferred.

[0085] For example, the sodium salt of the compound represented by formula (I) can be obtained by suspending or dissolving the free form of the compound represented by formula (I) in an alcohol such as methanol or ethanol, acetonitrile, acetone, or dimethyl sulfoxide, and then adding a basic aqueous solution containing sodium ions such as sodium hydroxide, a methanol solution containing sodium methoxide, or an ethanol solution containing sodium ethoxide. The reaction temperature is, for example, 0°C to 80°C, preferably 20°C to 60°C.

[0086] The compound represented by formula (1) or its salt may be a solvate or a non-solvate. The solvent in the solvate may be water or an organic solvent. Suitable organic solvents include alcohols (e.g., methanol, ethanol, n-propanol), dimethylformamide, acetonitrile, acetone, and dimethyl sulfoxide. The compound represented by formula (I) and its salt may be used in hydrate form, and also in non-solvate form. The ratio of solvent molecules (preferably water molecules) to one molecule of the compound represented by formula (I) or its salt is, for example, 0.1 to 10, and more preferably 0.5 to 6. This ratio may vary depending on humidity, manufacturing method, manufacturing time, etc.

[0087] The solvates of the compound represented by formula (I) or its salts can be obtained, for example, by conventional methods such as precipitating the compound represented by formula (I) or its salts from a solvent. The hydrates can also be obtained by precipitating the compound represented by formula (I) or its salts from an aqueous organic solvent.

[0088] The solvates of the compound represented by formula (I) or its salts can be converted to the compound represented by formula (I) or its salts by conventional methods, such as heating under reduced pressure.

[0089] The compounds used as pharmaceuticals are preferably the compound itself (free form) represented by formula (I), the hydrate of the free form, the salt of the free form, and the hydrate of the salt, and more preferably the free form, the hydrate of the free form, the sodium salt of the free form, the hydrate of the sodium salt, the calcium salt of the free form, and the hydrate of the calcium salt.

[0090] In the present invention, the compound represented by formula (I), its salt, or its solvate may be used in a crystalline state or in an amorphous state.

[0091] The present invention includes all stereoisomers of the compound represented by formula (I) (e.g., enantiomers, diastereomers (including cis and trans geometric isomers)), racemates of the isomers, and other mixtures. For example, the compounds of the present invention may have one or more chiral centers, and the present invention includes racemic mixtures, diastereomer mixtures, and enantiomers of such compounds.

[0092] The present invention includes compounds in which the atoms constituting the compound molecule represented by formula (I) are isotopes, and includes compounds in which at least one atom is substituted with an atom having the same atomic number (number of protons) but a different mass number (sum of the number of protons and neutrons). Examples of isotopes included in the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine atoms, respectively. 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 It includes Cl, etc. In particular, 3 H 14Radioactive isotopes that decay by emitting radiation, such as 13C, are useful in tests for the distribution of pharmaceuticals or compounds within the body's tissues. Stable isotopes do not decay, their abundance remains almost unchanged, and they are not radioactive, making them safe to use. Compounds in which the atoms constituting the molecule of the present invention are isotopes can be converted according to conventional methods by replacing the reagents used in synthesis with reagents containing the corresponding isotopes.

[0093] The compounds of the present invention, their salts, or solvates thereof have GLP1 receptor agonist activity and blood glucose-lowering activity, and can be used to prevent or treat non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus), hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus (type 1 diabetes mellitus), diabetic complications, obesity, hypertension, dyslipidemia, arteriosclerosis, myocardial infarction, coronary heart disease, cerebral infarction, non-alcoholic fatty liver disease, Parkinson's disease, or dementia by administering a pharmaceutically effective amount thereof to a patient in its natural state or in the form of a pharmaceutical composition using an appropriate administration method.

[0094] In this invention, "diabetes" means a disease or condition in which the body is unable to maintain appropriate blood glucose levels, resulting in abnormalities in the metabolism of glucose production and utilization, and includes insulin-dependent diabetes mellitus (type 1 diabetes mellitus) and insulin-independent diabetes mellitus (type 2 diabetes mellitus).

[0095] "Hyperglycemia" refers to a condition in which plasma glucose levels, both in a fasting state and after glucose administration, are higher than normal (for example, 80-110 mg / dL in humans in a fasting state), and is one of the typical symptoms of diabetes.

[0096] "Imperfect glucose tolerance" includes insulin-resistant impaired glucose tolerance and insulin secretion deficiency.

[0097] "Diabetic complications" refer to complications resulting from diabetes or hyperglycemia, and can be either acute or chronic. Examples of "acute complications" include ketoacidosis and infections (e.g., skin infections, soft tissue infections, biliary tract infections, respiratory infections, urinary tract infections), while examples of "chronic complications" include microangiopathy (e.g., nephropathy, retinopathy), neuropathy (e.g., sensory neuropathy, motor neuropathy, autonomic neuropathy), and foot necrosis. Major diabetic complications include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

[0098] "Coronary heart disease" includes conditions such as myocardial infarction and angina pectoris.

[0099] Examples of "dementia" include Alzheimer's disease, vascular dementia, and diabetic dementia.

[0100] The method of administration may be any of the following: systemic administration such as oral, rectal, intravenous, intramuscular, subcutaneous, vaginal, intraperitoneal, intravesical, or inhalation; or local administration using ointments, gels, creams, etc.

[0101] When the compounds of the present invention, their salts, or solvates thereof are used in the form of a pharmaceutical composition, they are usually formulated into a specific dosage form. Examples of such formulations include tablets, capsules, granules, powders, fine granules, pills, aqueous or non-aqueous solutions, or suspensions. The compounds of the present invention, their salts, or solvates may also be used in the form of various controlled-release formulations. Examples of such controlled-release formulations include those implanted in the body, and those applied to the oral or nasal mucosa. The solutions or suspensions can be stored in containers suitable for portioning into individual doses.

[0102] The various formulations described above can be produced by known methods by mixing the compounds of the present invention or their salts, or solvates thereof, with pharmaceutically acceptable additives. Examples of such additives include excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring and deodorizing agents, bases, dispersants, diluents, surfactants, and emulsifiers.

[0103] Examples of excipients include starch (such as starch, potato starch, and corn starch), lactose, crystalline cellulose, and calcium hydrogen phosphate. Examples of lubricants (coating agents) include ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, shellac, talc, carnauba wax, and paraffin. Examples of binders include polyvinylpyrrolidone, macrogol, and compounds similar to those used as excipients. Examples of disintegrants include chemically modified starches such as croscarmellose sodium, carboxymethyl starch sodium, and cross-linked polyvinylpyrrolidone, as well as celluloses and compounds similar to those used as excipients. Examples of stabilizers include para-hydroxybenzoic acid esters such as methylparaben and propylparaben; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid. Examples of flavoring and odor-modifying agents include commonly used sweeteners, acidulants, and flavorings. Examples of base materials include fats such as lard; vegetable oils such as olive oil and sesame oil; higher alcohols such as stearyl alcohol and cetanol; animal oils; lanolin; petrolatum; paraffin; bentonite; glycerin; and glycol oil. Examples of dispersants include cellulose derivatives (such as gum arabic, tragacanth, and methylcellulose), polyester stearates, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbates, and sorbitan fatty acid esters. Examples of solvents or diluents used in liquid formulations include phenol, chlorocresol, purified water, and distilled water. Examples of surfactants or emulsifiers include polysorbate 80, polyoxyl stearate 40, and lauromacrogol.

[0104] The content of the compound of the present invention, its salt, or its solvates in the formulation varies depending on the dosage form, but is generally 0.01 to 100% by weight.

[0105] The formulation may contain only one of the compounds of the present invention, a salt thereof, or a solvate thereof, or it may contain two or more.

[0106] When the compounds of the present invention, their salts, or solvates thereof are used as preventive or therapeutic agents for non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus) or obesity, the dosage can be appropriately determined according to the severity of symptoms, age, weight, relative health status, presence or absence of concomitant drugs, and method of administration. For example, when the target of administration is a warm-blooded animal, particularly a human, the daily dosage for oral administration is, for example, 0.01 to 10,000 mg, preferably 0.1 to 1,000 mg. For parenteral administration, the daily dosage is, for example, 0.001 to 3,000 mg, preferably 0.01 to 300 mg. The above dosage may be administered once every day to several weeks, or divided into two or more doses per day.

[0107] The effective amount of the compound of the present invention, its salt, or any solvate thereof means a therapeutically effective amount or a preventive effective amount, which can be appropriately determined depending on the severity of symptoms, age, weight, relative health status, presence or absence of concomitant drugs, method of administration, etc. [Examples]

[0108] The present invention will be further explained by the following examples and reference examples. All starting materials and reagents were obtained from commercial suppliers or synthesized using known methods. Room temperature (rt) refers to 5 to 35°C. For silica gel, SHOKO Scientific Purif-Pack® SI 60μm (manufactured by Shoko Scientific), Biotage® SNAP Ultra Silica Cartridge (manufactured by Biotage), or SNAP KP-Sil Cartridge (manufactured by Biotage) were used. For reversed-phase silica gel, Wakosil® 25C18 (manufactured by Wako Pure Chemical Industries) or Biotage® SNAP Ultra C18 Cartridge (manufactured by Biotage) were used. HPLC purification of compounds was performed using an AutoPurification HPLC / MS System (manufactured by Waters) or a Preprative HPLC system with injection / fractionation function (manufactured by Gilson). 1¹H-NMR spectra were measured using ECP-400 (JEOL), Agilent400-MR (Agilent Technologies), AVANCE3 300MHz (Bruker), or AVANCE3 600MHz Cryo-TCI (Bruker), with or without Me4Si as an internal standard (s=singlet, brs=broad singlet, d=doublet, t=triplet, q=quartet, dd=double doublet, ddd=double doublet, m=multiplet). Chemical shifts in NMR data were expressed in ppm (parts per million, δ) relative to Me4Si or the deuterated solvent, and the coupling constant (J) was expressed in Hz (Hertz). LC / MS was performed using the instruments and analytical conditions shown in Table 1 for retention time measurement and mass spectrometry. Microwave irradiation was performed using Initiator™ (Biotage). Mass spectrometry in LC / MS was performed using the following mass spectrometers: SQD (Waters), SQD2 (Waters), 2020 (Shimadzu), or 2010EV (Shimadzu). [Table 1] TIFF2026048784000018.tif237153 TIFF2026048784000019.tif236153

[0109] <Example 1> Synthesis of 3-[(1S,2S)-1-[2-[2-(3,5-dimethylphenyl)-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-ethyl-3-methylpyridine-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (Compound 1) [ka]

[0110] (Process 1-1) [(5-cyano-1,2,3,6-tetrahydropyridine-4-yl)amino]potassium (compound 1b) To a solution of 3-(2-cyanoethylamino)propanenitrile (compound 1a, 22.0 g, 179 mmol) in tetrahydrofuran (THF) (179 mL), a solution of 1 M potassium tert-butoxide in THF (179 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, washed with THF (50 mL), and then dried under reduced pressure to obtain the title compound 1b (23.8 g, yield 83%) as a light brown solid. LC / MS mass spectrometry: m / z124([M+H] + ). LC / MS retention time: 0.14 min (Analysis conditions: SMD-FA05-1). 1 H-NMR (400MHz, MeOH-d4) δ:3.33(2H,t,J=1.3Hz),2.90(2H,t,J=5.9Hz),2.21(2H,tt,J=5.9,1.3Hz).

[0111] (Step 1-2) 3-amino-2-(3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 1d) To a solution of 3,5-dimethylphenylhydrazine hydrochloride (compound 1c, 5.00 g, 29.0 mmol) and compound 1b obtained in step 1-1 (4.67 g, 29.0 mmol) in ethanol (57.9 mL), 2N hydrochloric acid (23.2 mL, 46.3 mmol) was added and the mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to 0°C, and 5M aqueous sodium hydroxide (9.27 mL, 46.3 mmol) and di-tert-butyl dicarbonate (6.64 g, 30.4 mmol) were added and the mixture was stirred at 0°C for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0:1 to 1:1) to obtain the title compound 1d (7.82 g, yield 79%) as a pale yellow solid. LC / MS mass spectrometry: m / z343([M+H] + ). LC / MS retention time: 0.99 minutes (Analysis conditions: SMD-FA05-3).

[0112] (Step 1-3) 3-(2,2-dimethoxyethylcarbamoylamino)-2-(3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 1f) To a solution of compound 1d (2.53 g, 7.39 mmol) obtained in steps 1-2 in pyridine (7.39 mL), 2-isocyanato-1,1-dimethoxyethane (compound 1e, 1.94 g, 14.8 mmol) was added and the mixture was stirred at room temperature. After 3 hours and 15 minutes, diethylamine (1.08 g, 14.8 mmol) was added and the mixture was stirred at room temperature for 5 minutes, then water (50.6 mL) was added and the mixture was stirred at room temperature for 20 minutes. The resulting reaction suspension was filtered, and the filtered solid was washed with water (12.7 mL), dried under reduced pressure, and the title compound 1f (3.20 g, yield 91%) was obtained as a pale yellow solid. LC / MS mass spectrometry: m / z474([M+H] + ). LC / MS retention time: 0.78 min (Analysis conditions: SQD-FA05-1).

[0113] (Step 1-4) 3-[2-(3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]-1H-imidazole-2-one (compound 1g) To compound 1f (158 mg, 0.334 mmol) obtained in steps 1-3, formic acid (3.84 mL, 100 mmol) was added and the mixture was stirred at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure, and toluene was added and the solvent was removed under reduced pressure. Dichloromethane (1 mL) was added to the residue to dissolve it, and then hydrogen chloride (4 M dioxane solution, 0.835 mL, 3.34 mol) was added at room temperature. The reaction mixture was concentrated under reduced pressure, and toluene was added and the solvent was removed under reduced pressure to obtain 1 g of the crude product (176 mg) of the title compound. LC / MS mass spectrometry: m / z310([M+H] + ). LC / MS retention time: 0.39 min (Analysis conditions: SQD-FA05-3).

[0114] (Step 1-5) 4-Bromo-2-ethyl-3-methylpyridine (compound 1i) A solution of 4-bromo-2,3-dimethylpyridine (compound 1h, 7.05 g, 37.9 mmol) in THF (75.0 mL) was cooled to -78°C, and a 1.11 M lithium diisopropylamide n-hexane-THF solution (35.8 mL, 39.8 mmol) was slowly added. After stirring at -78°C for 5 minutes, iodomethane (2.84 mL, 45.5 mmol) was added. After stirring at -78°C for 5 minutes, the reaction solution was slowly raised to room temperature, stirred for 30 minutes, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate) to obtain the title compound 1i (6.98 g, 92% yield) as an orange oil. LC / MS mass spectrometry: m / z200([M+H] + ). LC / MS retention time: 0.38 min (Analysis conditions: SQD-FA05-3).

[0115] (Step 1-6) 5-Bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]indole-2-carboxylate ethyl (compound 1 liter) After degassing N,N'-dimethylpropylene urea (117 mL) solutions of 5-bromo-1-(cyanomethyl)indole-2-carboxylate ethyl (compound 1j, 3.60 g, 11.7 mmol) and (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (compound 1k, 4.86 g, 35.2 mmol) under reduced pressure, the mixture was purged with nitrogen and cooled to 0°C. Under a nitrogen atmosphere, a 1.0 M potassium bis(trimethylsilyl)amide THF solution (46.9 mL, 46.9 mmol) was slowly added dropwise. After stirring at 0°C for 2.5 hours, formic acid (5.30 mL, 141 mmol) was added, and the mixture was extracted with a hexane / ethyl acetate mixture (1:3). The organic layer was washed three times with water, twice with saturated sodium bicarbonate aqueous solution, and once with saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1:19 to 1:4) to obtain 1 liter (1.70 g, 42% yield) of the title compound as a white solid. LC / MS mass spectrometry: m / z347([M+H] + ). LC / MS retention time: 0.69 min (Analysis conditions: SQD-AA50-1).

[0116] (Step 1-7) 1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-5-(2-ethyl-3-methylpyridine-4-yl)indole-2-carboxylate ethyl (compound 1m) The dioxane (44 mL) suspension of the compounds obtained in steps 1-6 (1 L, 2.70 g, 7.78 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.17 g, 8.55 mmol), and potassium acetate (1.15 g, 11.7 mmol) was degassed under reduced pressure at room temperature and then purged with nitrogen. Under a nitrogen atmosphere, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.29 g, 1.56 mmol) was added and the mixture was stirred at 100°C for 3 hours. After cooling to room temperature, 4-bromo-2-ethyl-3-methylpyridine (compound 1i, 2.33 g, 11.7 mmol), sodium carbonate (2.47 g, 23.3 mmol), and water (7.4 mL) were added to the solution. After degassing under reduced pressure, the mixture was purged with nitrogen and stirred at 100°C for 2 hours. After cooling to room temperature, water (5.4 mL) and N-acetylcysteine ​​(0.635 g, 3.89 mmol) were added and the mixture was stirred for 0.5 hours. The reaction mixture was extracted with ethyl acetate, the organic layer was washed once with saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1:19 to 2:3) to obtain the pale yellow, gum-like title compound 1m (2.92 g, 97% yield). LC / MS mass spectrometry: m / z388([M+H] + ). LC / MS retention time: 1.06 minutes (Analysis conditions: SQD-AA05-2).

[0117] (Step 1-8) 5-(2-ethyl-3-methylpyridine-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]indole-2-carboxylate ethyl (compound 1n) To a solution of 1 m (0.225 g, 0.581 mmol) of the compound obtained in steps 1-7 in dimethyl sulfoxide (DMSO) (2.9 mL), 0.356 mL, 5.81 mmol of 50% hydroxyamine aqueous solution was added and the mixture was stirred at room temperature for 17 hours. Ethyl acetate (50 mL) was added, and the mixture was washed with water (10 mL) and saturated brine (10 mL), and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in DMSO (1.9 mL). Carbonyl diimidazole (188 mg, 1.16 mmol) and 1,8-diazabicycloundeca-7-ene (0.219 mL, 1.45 mmol) were added and the mixture was stirred at room temperature for 0.5 hours. Formic acid was added, and the mixture was purified by reverse-phase chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound 1n (169 mg, yield 65%) as a white powder. LC / MS mass spectrometry: m / z447([M+H] + ). LC / MS retention time: 0.80 min (Analysis conditions: SMD-FA05-3).

[0118] (Step 1-9) 5-(2-ethyl-3-methylpyridine-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 1o) To a DMSO (40 mL) solution of compound 1n (3.61 g, 8.08 mmol) obtained in steps 1-8, 10.1 mL of 2 M sodium hydroxide aqueous solution (20.2 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. Formic acid was added, and the mixture was purified by reverse-phase chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound 1o (3.38 g, 100% yield) as a white powder. LC / MS mass spectrometry: m / z419([M+H] + ). LC / MS retention time: 0.83 min (Analysis conditions: SQD-AA05-2).

[0119] (Step 1-10) 3-[(1S,2S)-1-[2-[2-(3,5-dimethylphenyl)-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-ethyl-3-methylpyridine-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 1p) To a solution of 1 g (1.25 g, 3.61 mmol) of the compound obtained in steps 1-4, compound 1o (1.59 g, 3.80 mmol) obtained in steps 1-9, and [dimethylamino(triazolo[4,5-b]pyridine-3-yloxy)methylidene]-dimethylazanium hexafluorophosphate (1.51 g, 3.98 mmol) in N,N'-dimethylformamide (DMF) (24.1 mL), diisopropylethylamine (3.15 mL, 18.1 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound 1p (2.44 g, 95% yield) as a light brown foam. LC / MS mass spectrometry: m / z710([M+H] + ). LC / MS retention time: 0.85 min (Analysis conditions: SMD-FA05-3).

[0120] (Step 1-11) 3-[(1S,2S)-1-[2-[2-(3,5-dimethylphenyl)-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-ethyl-3-methylpyridine-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 1) To a suspension of compound 1p (20 mg, 0.028 mmol) obtained in steps 1-10, 5-bromo-1-methylindazole (compound 1q, 11.9 mg, 0.056 mmol), (1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine (1.6 mg, 0.011 mmol), and potassium carbonate (11.7 mg, 0.085 mmol) in N-methylpyrrolidone (0.188 mL), copper(I) iodide (1.1 mg, 0.0056 mmol) was added at room temperature, and the mixture was stirred at 130 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was purified by reverse-phase silica gel chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound 1 (17.2 mg, yield 73%) as a light brown foam. LC / MS mass spectrometry: m / z840([M+H] + ). LC / MS retention time: 1.12 minutes (Analysis conditions: SMD-TFA05-3).

[0121] <Examples 2-50> Using the combinations of 2-oxoimidazole compounds shown in Table 2-2 and halogen compounds shown in Table 2-3, along with appropriate reagents, the same procedure as in step 1-11 of Example 1 was performed to obtain Example Compounds 2-50 shown in Table 2-1 by the following reactions. [ka] [Table 2-1] JPEG2026048784000023.jpg246162 JPEG2026048784000024.jpg246162 JPEG2026048784000025.jpg240162 JPEG2026048784000026.jpg246162 JPEG2026048784000027.jpg131162 JPEG2026048784000028.jpg129162 JPEG2026048784000029.jpg131162 JPEG2026048784000030.jpg136162 JPEG2026048784000031.jpg253162 JPEG2026048784000032.jpg131162 JPEG2026048784000033.jpg129162 JPEG2026048784000034.jpg124162 JPEG2026048784000035.jpg136162 JPEG2026048784000036.jpg246162 JPEG2026048784000037.jpg253162 JPEG2026048784000038.jpg131162 JPEG2026048784000039.jpg129162 JPEG2026048784000040.jpg124162 JPEG2026048784000041.jpg136162 JPEG2026048784000042.jpg131162 JPEG2026048784000043.jpg136162 JPEG2026048784000044.jpg131162 JPEG2026048784000045.jpg136162 JPEG2026048784000046.jpg137162 JPEG2026048784000047.jpg129162 JPEG2026048784000048.jpg137162 JPEG2026048784000049.jpg136162 JPEG2026048784000050.jpg142162 JPEG2026048784000051.jpg142162 JPEG2026048784000052.jpg131162 JPEG2026048784000053.jpg142162 JPEG2026048784000054.jpg131162 JPEG2026048784000055.jpg142162 JPEG2026048784000056.jpg131162 JPEG2026048784000057.jpg136162 JPEG2026048784000058.jpg124162 JPEG2026048784000059.jpg136162 JPEG2026048784000060.jpg124162 JPEG2026048784000061.jpg136162 JPEG2026048784000062.jpg253162 The compounds in Table 2-1 have rotational isomers, but for example, Compound 2 in Example 1 The 1H-NMR spectrum is as follows:

[0122] Rotational isomer A 1 H-NMR(600MHz, CDCl3) δ:11.29(1H,s),8.40(1H,d,J=5.2Hz),7.93(1H,s),7.74(1H,d,J=1.5Hz),7.70(1H,d,J=8.6Hz),7.56(1 H,s),7.45(1H,dd,J=9.0,1.5Hz),7.38(1H,d,J=9.0Hz),7.28(1H,m),7.14(1H,d,J=5.2Hz),7.04(2H,d,J HF =5.9Hz),6.82(1H,s),6.59(1H,d,J=3.0Hz),6.08(1H,d,J=3.0Hz),4.96(1H,d,J=1 6.0Hz),4.92(1H,d,J=16.0Hz),4.69(1H,ddd,J=13.1,4.4,4.4Hz),4.06(3H,s),3. 75(1H,ddd,J=13.1,9.5,5.0Hz),3.07(2H,m),2.97(2H,q,J=7.6Hz),2.26(3H,s),2 .25(6H,s),1.88(1H,s),1.51(2H,m),1.37(3H,t,J=7.6Hz),1.17(3H,d,J=5.6Hz).

[0123] Rotational isomer B 1 H-NMR(600MHz, CDCl3) δ:11.29(1H,s),8.44(1H,d,J=5.2Hz),8.04(1H,s),7.90(1H,d,J=1.4Hz),7.73(1H,d,J=8.8Hz),7.63(1 H,dd,J=9.0,1.4Hz),7.60(1H,s),7.51(1H,d,J=9.0Hz),7.30(1H,m),7.20(1H,d,J=5.2Hz),7.11(2H,d,J HF=6.0 Hz), 6.81 (1H, s), 6.71 (1H, d, J = 3.0 Hz), 6.22 (1H, d, J = 3.0 Hz), 5.24 (1H, d, J = 16.3 Hz), 4.64 (1H, d, J = 16.3 Hz), 4.45 (1H, ddd, J = 13.5, 4.6, 4.0 Hz), 4.12 (3H, s), 3.87 (1H, ddd, J = 13.5, 10.2, 3.8 Hz), 3.17 (1H, ddd, J = 15.5, 10.2, 4.6 Hz), 3.02 (1H, m), 3.00 (2H, q, J = 7.6 Hz), 2.30 (3H, s), 2.28 (6H, s), 1.96 (1H, dd, J = 6.0 Hz), 1.64 (1H, m), 1.58 (1H, dd, J = 9.4, 6.0 Hz), 1.39 (3H, t, J = 7.6 Hz), 1.19 (3H, d, J = 6.1 Hz).

Table 2-2

Table 2-3

[0124] The 2-oxoimidazole compound (3-[(1S,2S)-1-[5-(2-ethyl-3-methylpyridine-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, 2g of compound) used in the synthesis of Example Compounds 2-5 was synthesized as follows. [ka]

[0125] (Process 2-1) 4-Fluoro-3,5-dimethylaniline hydrochloride (compound 2b) 4-Fluoro-3,5-dimethylaniline (compound 2a, 3.97 g, 28.5 mmol) was added at room temperature to a mixture of concentrated hydrochloric acid (20 mL) and water (20 mL) while stirring. The mixture was stirred at the same temperature for 1 hour, and the solid from the reaction mixture was filtered and dried. Methoxycyclopentane (20 mL) was added to the obtained solid, and the mixture was stirred at 50 °C for 1 hour, followed by stirring at room temperature for 1.5 hours. The precipitated solid was filtered and washed with methoxycyclopentane (12 mL). The obtained solid was dried under reduced pressure to obtain the title compound 2b (4.88 g, 97% yield) as an off-white solid. This compound was used directly in the next step (step 2-2).

[0126] (Step 2-2) (4-Fluoro-3,5-dimethylphenyl)hydrazine hydrochloride (compound 2c) To compound 2b (1.00 g, 5.69 mmol) obtained in step 2-1, concentrated hydrochloric acid (10 mL) was added, and while vigorously stirring at 0°C, a solution of sodium nitrite (511 mg, 7.40 mmol) in aqueous solution (2.4 mL) was added over 1 minute, and the mixture was stirred at 0°C for 30 minutes. Next, a solution of tin(II) chloride (2.27 g, 12.0 mmol) in aqueous solution (2.4 mL) was added over 2 minutes. Further water (7 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solid from the reaction mixture was filtered, washed with water (2 mL), and dried to obtain the gray solid title compound 2c (1.75 g, yield 77%, content 48%). LC / MS mass spectrometry: m / z155([M+H] + ). LC / MS retention time: 0.54 min (Analysis conditions: SMD-FA05-1).

[0127] (Step 2-3) 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 2d) Compound 1b obtained in step 1-1 and compound 2c obtained in step 2-2 were used with appropriate reagents and the same procedure as in step 1-2 of Example 1. LC / MS mass spectrometry: m / z361([M+H] + ). LC / MS retention time: 1.04 min (Analysis conditions: SMD-FA05-3).

[0128] (Step 2-4) 3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 2e) Compound 2d obtained in step 2-3 was synthesized using appropriate reagents in the same manner as in step 1-3 of Example 1. LC / MS mass spectrometry: m / z492([M+H] + ). LC / MS retention time: 1.07 min (Analysis conditions: SMD-FA05-3).

[0129] (Step 2-5) 3-[2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]-1H-imidazole-2-one hydrochloride (compound 2f) Compound 2e obtained in step 2-4 was synthesized using appropriate reagents in the same manner as in step 1-4 of Example 1. LC / MS mass spectrometry: m / z328([M+H] + ). LC / MS retention time: 0.61 min (Analysis conditions: SMD-FA05-3).

[0130] (Step 2-6) 3-[(1S,2S)-1-[5-(2-ethyl-3-methylpyridine-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 2g) Compound 2f obtained in step 2-5 and compound 1o obtained in step 1-9 were synthesized using appropriate reagents in the same procedure as in step 1-10 of Example 1. The 2-oxoimidazole compound (3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridine-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, compound 6i) used in the synthesis of Example Compound 6 was synthesized as follows. [ka]

[0131] (Step 6-1) 5-Bromo-1-(cyanomethyl)-N-methyl-N-phenylindole-2-carboxamide (compound 6c) 5-bromo-1-(cyanomethyl)indole-2-carboxylic acid (compound 6a) and N-methylaniline (compound 6b) were synthesized using appropriate reagents in the same procedure as in steps 1-10 of Example 1. LC / MS mass spectrometry: m / z368([M+H] + ). LC / MS retention time: 1.25 minutes (Analysis conditions: SMD-FA05-3).

[0132] (Step 6-2) 5-Brom- 1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-N-methyl-N-phenylindole-2-carboxamide (compound 6d) Compound 6c obtained in step 6-1 was synthesized using appropriate reagents in the same manner as in step 1-6 of Example 1. LC / MS retention time: 1.37 minutes (Analysis conditions: SMD-FA05-1). 1 H-NMR (400MHz, DMSO-d6) δ:7.69(1H,s),7.65-7.25(7H,m),6.02(1H,brs),3.44(3H,s), 3.31(3H,d,J=9.5Hz),2.04-1.74(3H,m).

[0133] (Step 6-3) 5-Bromo-N-methyl-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]-N-phenylindole-2-carboxamide (compound 6e) Compound 6d obtained in step 6-2 was synthesized using appropriate reagents in the same manner as in step 1-8 of Example 1. LC / MS mass spectrometry: m / z467([M+H] + ). LC / MS retention time: 1.33 minutes (Analysis conditions: SMD-FA05-01).

[0134] (Step 6-4) 5-Bromo-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 6f) A mixed solution of compound 6e (9.70 g, 20.8 mmol) obtained in step 6-3, potassium hydroxide (11.7 g, 208 mmol), and methoxyethanol (41.5 mL) was stirred at 100°C for 4 hours. Under ice cooling, 6N hydrochloric acid (51.9 mL) was added, and the suspension was stirred at room temperature for 30 minutes. After filtering and washing with water (29.1 mL), the resulting solid was dried under reduced pressure to obtain the title compound 6f (7.42 g, yield 95%) as a light brown solid. LC / MS mass spectrometry: m / z376([MH] - ). LC / MS retention time: 1.10 minutes (Analysis conditions: SMD-FA05-2).

[0135] (Step 6-5) 5-(2-Methoxy-3-methylpyridine-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 6h) The DMSO (34.7 mL) suspension of compound 6f (3.00 g, 7.93 mmol), palladium(II) acetate (0.178 g, 0.793 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl) phosphane (0.756 g, 1.587 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.02 g, 11.9 mmol), and potassium phosphate (10.1 g, 47.6 mmol) obtained in step 6-4 was degassed under reduced pressure at room temperature and then purged with nitrogen. The mixture was stirred at 100°C for 0.5 hours under a nitrogen atmosphere and then cooled to room temperature. 4-iodo-2-methoxy-3-methylpyridine (compound 6 g, 1.98 g, 7.93 mmol) and water (4.96 mL) were added to the solution, degassed under reduced pressure, then purged with nitrogen and stirred at 100°C for 0.5 hours. After cooling to room temperature, water (12.4 mL) and formic acid (6 mL) were added, filtered, and the filtrate was purified directly by reverse-phase chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound 6h (1.83 g, yield 55%). LC / MS mass spectrometry: m / z421([M+H] + ). LC / MS retention time: 1.10 minutes (Analysis conditions: SMD-FA05-1).

[0136] (Step 6-6) 3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridine-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 6i) Compound 2f obtained in step 2-5 and compound 6h obtained in step 6-5 were synthesized using appropriate reagents in the same procedure as in step 1-10 of Example 1. The halogen compound (1-(5-bromoindazole-1-yl)-2-methylpropan-2-ol, compound 6l) used in the synthesis of Example Compound 6 was synthesized as follows.

[0137] (Step 6-7) 1-(5-bromoindazole-1-yl)-2-methylpropan-2-ol (compound 6k) [ka] 5-bromoindazole (compound 6j, 150 mg, 0.761 mmol) and 2,2-dimethyloxirane (compound 6k, 274 mg, 3.81 mmol) were dissolved in 1-methylpyrrolidine-2-one (NMP) (1.52 mL), and potassium carbonate (526 mg, 3.81 mmol) was added. The mixture was stirred under microwave at 180°C for 30 minutes. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was removed under reduced pressure. The compound was purified by silica gel column chromatography (ethyl acetate / hexane = 1:1) to obtain 6 L (115 mg, 56% yield) of the title compound. LC / MS mass spectrometry: m / z269([M+H] + ). LC / MS retention time: 1.00 min (Analysis conditions: SMD-FA05-2). The 2-oxoimidazole reagent (3-[(1S,2S)-1-[5-(2,2-dimethylmorpholine-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, compound 7c) used in the synthesis of Example Compound 7 was synthesized as follows. [ka]

[0138] (Step 7-1) 5-(2,2-dimethylmorpholine-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 7b) A 44 mL NMP suspension containing 2,2-dimethylmorpholine (compound 7a, 1.98 g, 17.2 mmol), tris(dibenzylideneacetone) dipalladium(0) (0.121 g, 0.132 mmol), 2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl (0.123 g, 0.264 mmol), and sodium tert-butoxide (5.08 g, 529 mmol) was degassed under reduced pressure at room temperature and then purged with nitrogen. Under a nitrogen atmosphere, compound 6f (5.0 g, 13.2 mmol) obtained in step 6-4 was added, and the mixture was stirred at 100 °C for 0.5 hours, then cooled to room temperature. Formic acid was added, and the mixture was purified by reverse-phase chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound 7b (5.26 g, 96% yield). LC / MS mass spectrometry: m / z413([M+H] + ). LC / MS retention time: 1.00 min (Analysis conditions: SMD-FA05-1).

[0139] (Step 7-2) 3-[(1S,2S)-1-[5-(2,2-dimethylmorpholine-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 7c) Compound 7b obtained in step 7-1 was synthesized using appropriate reagents in the same manner as in step 1-10 of Example 1. The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, compound 8c) used in the synthesis of example compounds 8 to 10 was synthesized as follows. [ka]

[0140] (Step 8-1) 1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]-5-(oxan-4-yl)indole-2-carboxylic acid (compound 8b) The suspension of compound 6f (0.30 g, 0.793 mmol) obtained in step 6-4, palladium(II) acetate (35.6 mg, 0.159 mmol), and 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (0.148 g, 0.317 mmol) in N,N-dimethylacetamide (DMA) (2.64 mL) was degassed under reduced pressure, then purged with nitrogen and stirred at room temperature for 15 minutes. Under a nitrogen atmosphere, a DMA solution of 1 M (tetrahydro-2H-pyran-4-yl)zinc(II) iodide (compound 8a) (7.9 mL, 7.93 mmol) was added, and the mixture was stirred at 80°C for 15 minutes, after which it was cooled to room temperature. Formic acid was added, and the mixture was purified by reverse-phase chromatography (methanol / water) to obtain the title compound 8b (0.19 g, yield 61%). LC / MS mass spectrometry: m / z382([MH] - ). LC / MS retention time: 1.00 min (Analysis conditions: SMD-FA05-2).

[0141] (Step 8-2) 3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 8c) Compound 8b obtained in step 8-1 was synthesized using appropriate reagents in the same manner as in step 1-10 of Example 1. The halogen compound (5-bromo-1-[(3R)-oxolan-3-yl]indazole, compound 8f) used in the synthesis of Example Compound 8 was synthesized as follows. [ka]

[0142] (Step 8-3) 4-Methylbenzenesulfonic acid [(3S)-oxolan-3-yl] (compound 8e) To a 3.78 mL solution of (3S)-oxolan-3-ol (compound 8d, 500 mg, 5.68 mmol) in dichloromethane, pyridine (1.28 mL, 15.9 mmol) and 4-methylbenzenesulfonyl chloride (1.51 g, 7.95 mmol) were added at 0°C. The mixture was stirred at room temperature, and after 15 hours, water and 1N hydrochloric acid were added to separate the organic layer. The organic layer was sequentially washed with saturated sodium bicarbonate aqueous solution and saturated brine. The solvent was removed under reduced pressure to obtain the title compound 8e (1.36 g, 99% yield). LC / MS retention time: 0.96 min (Analysis conditions: SMD-FA05-1). 1 H-NMR (400MHz, CDCl3) δ:7.79(2H,d,J=8Hz),7.35(2H,d,J=8Hz),5.12(1H,m),3.93-3.76(4H,m),2.46(3H,s),2.13-2.05(2H,m).

[0143] (Step 8-4) 5-Bromo-1-[(3R)-oxolan-3-yl]indazole (compound 8f) To a solution of 5-bromo-1H-indazole (compound 6j, 300 mg, 1.52 mmol) in DMF (3.8 mL), cesium carbonate (992 mg, 3.05 mmol) and compound 8e (369 mg, 1.52 mmol) obtained in step 8-3 were added, and the mixture was stirred at 100°C for 2 hours. After cooling to room temperature, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water, and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (ethyl acetate / hexane = 1:1) to obtain the title compound 8f (198 mg, yield 49%) as a colorless oil. LC / MS mass spectrometry: m / z267([M+H] + ). LC / MS retention time: 1.07 minutes (Analysis conditions: SMD-FA05-1). The halogen compound (N-(4-bromo-2-methoxyphenyl)-N-(3-methoxypropyl)acetamide, compound 9c) used in the synthesis of example compound 9 was synthesized as follows.

[0144] (Step 9-1) [ka] To a solution of N-(4-bromo-2-methoxyphenyl)acetamide (compound 9a, 80 mg, 0.33 mmol) in DMF (0.8 mL), sodium hydride (50 wt% oil dispersion) (18.9 mg, 0.39 mmol) and 1-bromo-3-methoxypropane (75 mg, 0.49 mmol) were sequentially added, and the mixture was stirred at room temperature for 12 hours. Formic acid was added to the reaction mixture, and the mixture was purified by reverse-phase silica gel chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound 9c (103 mg, 99% yield), a colorless gum-like substance. LC / MS mass spectrometry: m / z316([M+H] + ). LC / MS retention time: 1.02 minutes (Analysis conditions: SMD-FA05-1). The halogen compound (5-bromo-1-(2,2,2-trifluoroethyl)indazole, compound 10b) used in the synthesis of example compound 10 was synthesized as follows.

[0145] (Step 10-1) [ka] The compounds were synthesized from 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (compound 10a) and 5-bromo-1H-indazole (compound 6j) using appropriate reagents, following the same procedure as in step 8-4 of Example 8. LC / MS mass spectrometry: m / z279([M+H] + ). LC / MS retention time: 1.17 minutes (Analysis conditions: SMD-FA05-1). The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridine-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, compound 11m) used in the synthesis of example compounds 11-13 was synthesized as follows. [ka]

[0146] (Step 11-1) N-(4-fluoro-3,5-dimethylphenyl)-N-[(2-methylpropan-2-yl)oxycarbonylamino]carbamate tert-butyl (compound 11b) 5-Bromo-2-fluoro-1,3-dimethylbenzene (compound 11a, 4.66 g, 22.6 mmol) was dissolved in THF (47.6 mL) and cooled to an ambient temperature of -70°C. 1.55Mn-butyllithium (13.1 mL, 20.4 mmol) was added dropwise at -70°C or below and stirred for 1 hour. A toluene solution of 20 wt% azodicarboxylic acid di-tert-butyl (25.0 g, 21.7 mmol) was added dropwise at an ambient temperature of -40°C or below and stirred for 30 minutes. The mixture was then heated to room temperature over 1 hour, and heptane (23.8 mL) and 20% aqueous ammonium chloride (47.6 mL) were added for extraction. The organic layer was concentrated, heptane (7.14 mL) was added, and it was heated to an ambient temperature of 70°C to dissolve. The mixture was cooled over 1 hour to precipitate crystals. The crystals were filtered and washed with heptane (2.38 mL). The crystals were dried to synthesize the crude product of the title compound 11b (3.53 g, yield 44%). 1 H-NMR (400MHz, DMSO-D6) δ:9.64-9.51(0.8H,m),9.24-9.07(0.2H,m),7.09-6.91(2H,m),2.29-2.09(6H,m),1.53-1.32(18H,m). LC / MS retention time: 1.40 minutes (Analysis conditions: SMD-FA05-3).

[0147] (Steps 11-2, 3, and 4) (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate tert-butyl (compound 11g) (3S)-3-aminobutanenitrile hydrochloride (compound 11c, 10.0 g, 82.9 mmol) was dissolved in ethanol (50.0 mL), and triethylamine (13.9 mL, 99.5 mmol) and ethyl acrylate (10.8 mL, 99.5 mmol) were added at room temperature. The solution was stirred at ambient temperature of 70°C for 3 hours and then cooled to room temperature to obtain a mixture containing ethyl 3-[[(2S)-1-cyanopropan-2-yl]amino]propanoate (compound 11e). Di-tert-butyl dicarbonate (21.7 mL, 99.5 mmol) was added to the reaction mixture at room temperature. The solution was stirred at room temperature for 14 hours, then N-methylpiperazine (2.76 mL, 24.9 mmol) was added and the mixture was stirred for 4 hours. 1N hydrochloric acid (50 mL) was added and the mixture was extracted with toluene (50 mL). The organic layer was washed with 15% aqueous sodium chloride solution (50.0 mL). The organic layer was concentrated under reduced pressure to obtain a mixture containing 3-[[(2S)-1-cyanopropan-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoate ethyl (compound 11f). THF (50.0 mL) was added to this mixture, and potassium tert-butoxide (10.2 g, 91.2 mmol) was added at an internal temperature of 30°C or below, and the mixture was stirred at room temperature for 1 hour. The internal temperature was reduced to 15°C, 2N hydrochloric acid (82.9 mL, 99.5 mmol) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 15% sodium chloride aqueous solution (50.0 mL) and then concentrated to obtain 11 g (15.8 g, yield 80%) of the title compound. LC / MS mass spectrometry: m / z237([MH] - ). LC / MS retention time: 0.92 minutes (Analysis conditions: SMD-FA05-1).

[0148] (Step 11-5) (4S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 11h) Compound 11b (2.13 g, 6.01 mmol) obtained in step 11-1 was dissolved in NMP (6.39 mL), methanesulfonic acid (1.30 g, 13.2 mmol) was added, and the mixture was stirred at an ambient temperature of 80°C for 7 hours. After cooling to room temperature, toluene (12.8 mL), potassium carbonate (0.914 g), and water (12.8 g) were added to the reaction mixture and the mixture was stirred at room temperature for 10 minutes. The aqueous layer was removed, and a solution of compound 11 g (1.43 g, 6.01 mmol) obtained in step 11-4 in toluene (6.3 mL), pyridine hydrochloride (71.0 mg, 0.60 mmol), and toluene (4.2 mL) were added, and the mixture was stirred at an ambient temperature of 90°C for 1 hour. The reaction mixture was cooled and washed with 1 M sodium hydroxide aqueous solution (12.6 mL). The organic layer was concentrated under reduced pressure to synthesize the title compound 11h (1.68 g, 75% yield). LC / MS mass spectrometry: m / z375([M+H] + ). LC / MS retention time: 1.08 minutes (Analysis conditions: SMD-FA05-1).

[0149] (Step 11-6) (4S)-3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 11j) To a solution of compound 11h (106 mg, 0.283 mmol) obtained in step 11-5 in DMA (0.53 mL), N-(2,2-dimethoxyethyl)imidazole-1-carboxamide (compound 11i, 62.0 mg, 0.311 mol) was added, and potassium tert-butoxide (95.0 mg, 0.849 mol) was added under a nitrogen atmosphere. The mixture was stirred at ambient temperature of 25°C for 4 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water, and the solvent was removed under reduced pressure. The compound was purified by silica gel column chromatography (ethyl acetate / hexane = 3:2) to obtain the title compound 11j (105 mg, yield 73%). LC / MS mass spectrometry: m / z506([M+H] + ). LC / MS retention time: 1.09 minutes (Analysis conditions: SMD-FA05-1).

[0150] (Step 11-7) (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 11k) Compound 11j (4.45 g, 8.79 mmol) obtained in step 11-6 was suspended in THF (44.5 mL), and methylsulfonic acid (0.676 g, 7.03 mmol) was added and the mixture was stirred at ambient temperature of 60°C for 2 hours. After cooling to room temperature, a solution of tripotassium phosphate (1.87 g, 8.79 mmol) in water (17.8 mL) was added, and di-tert-butyl dicarbonate (0.768 g, 3.52 mmol) was added and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried over magnesium sulfate. After filtration, the organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / hexane = 3:7) to obtain the title compound 11k (3.43 g, yield 88%). LC / MS mass spectrometry: m / z442([M+H] + ). LC / MS retention time: 1.09 minutes (Analysis conditions: SMD-FA05-1).

[0151] (Step 11-8) 3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]-1H-imidazole-2-one hydrochloride (compound 11l) To a solution of compound 11k (1.85 g, 4.19 mmol) obtained in step 11-7 in dichloromethane (8.38 ml), a 4 M hydrogen chloride dioxane solution (10.5 mL, 41.9 mmol) was added. After stirring this mixture at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to obtain a crude product (1.63 g) containing the title compound 11l as a brown solid. LC / MS mass spectrometry: m / z342([M+H] + ). LC / MS retention time: 0.63 min (Analysis conditions: SMD-FA05-1).

[0152] (Step 11-9) 3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridine-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 11m) Compound 11L obtained in step 11-8 and compound 6H obtained in step 6-5 were synthesized using appropriate reagents in the same procedure as in step 1-10 of Example 1. The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(3-fluoro-2-methylpyridine-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, compound 14d) used in the synthesis of Example Compound 14 was synthesized as follows. [ka]

[0153] (Step 14-1) 5-(2-chloro-3-fluoropyridine-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 14b) Compound 6f obtained in step 6-4 and 2-chloro-3-fluoro-4-iodopyridine (compound 14a) were synthesized using appropriate reagents in the same manner as in step 6-5 of Example 6. LC / MS mass spectrometry: m / z429([M+H] + ). LC / MS retention time: 1.14 minutes (Analysis conditions: SMD-TFA05-3).

[0154] (Step 14-2) 5-(3-fluoro-2-methylpyridine-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 14c) The mixed suspension of compound 14b (810 mg, 1.32 mmol) obtained in step 14-1, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (48 mg, 0.066 mmol), potassium carbonate (2.74 g, 19.8 mmol), and methylboronic acid (792 mg, 13.2 mmol) in DMSO / water in a 7:1 ratio (13.2 mL) was degassed under reduced pressure at room temperature and then purged with nitrogen. The mixture was stirred at 100 °C for 0.5 hours under a nitrogen atmosphere and then cooled to room temperature. Formic acid was added, and the mixture was purified by reverse-phase chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound 14c (124 mg, yield 23%) as a pale yellow solid. LC / MS mass spectrometry: m / z409([M+H] + ). LC / MS retention time: 0.85 min (Analysis conditions: SMD-FA05-3).

[0155] (Step 14-3) 3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(3-fluoro-2-methylpyridine-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 14d) Compound 11l obtained in step 11-8 and compound 14c obtained in step 14-2 were synthesized using appropriate reagents in the same procedure as in step 1-10 of Example 1. The 2-oxoimidazole reagent (3-[(1S,2S)-1-[5-[2-(dimethylamino)-3-methylpyridine-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, compound 15d) used in the synthesis of Example Compound 15 was synthesized as follows. [ka]

[0156] (Step 15-1) 4-iodo-N,N,3-trimethylpyridine-2-amine (compound 15b) A solution of 2-chloro-4-iodo-3-methylpyridine (compound 15a, 500 mg, 1.97 mmol), N-ethyl-N-propan-2-ylpropan-2-amine (0.515 mL, 2.96 mmol), and 2M dimethylamine in THF (2.96 mL, 5.92 mmol) was stirred in DMF (7.9 mL) at 130°C for 17 hours, then cooled to room temperature, and formic acid (0.4 mL) was added. The solution was purified by reverse-phase chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound 15b (258 mg, 50% yield) as a light brown liquid. LC / MS mass spectrometry: m / z263([M+H] + ). LC / MS retention time: 0.52 min (Analysis conditions: SQD-FA05-1).

[0157] (Step 15-2) 5-[2-(dimethylamino)-3-methylpyridine-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 15c) Compound 6f obtained in step 6-4 and compound 15b obtained in step 15-1 were synthesized using appropriate reagents in the same manner as in step 6-5 of Example 6. LC / MS mass spectrometry: m / z432([MH] - ). LC / MS retention time: 0.51 min (Analysis conditions: SQD-FA05-1).

[0158] (Step 15-3) 3-[(1S,2S)-1-[5-[2-(dimethylamino)-3-methylpyridine-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 15d) Compound 15c obtained in step 15-2 and compound 11l obtained in step 11-8 were synthesized using appropriate reagents in the same procedure as in step 1-10 of Example 1. The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, compound 16a) used in the synthesis of example compounds 16 to 30 was synthesized as follows. [ka]

[0159] (Step 16-1) 3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 16a) Compound 11l obtained in step 11-8 and compound 8b obtained in step 8-1 were synthesized using appropriate reagents in the same manner as in step 1-10 of Example 1. The halogen compound (5-bromo-1-[(3-methyloxetan-3-yl)methyl]indazole, compound 17b) used in the synthesis of example compound 17 was synthesized as follows.

[0160] (Step 17-1) [ka] 3-methyl-3-[(4-methylphenyl)sulfonylmethyl]oxetane (compound 17a) and 5-bromo-1H-indazole (compound 6j) were synthesized using appropriate reagents in the same procedure as in step 9-1 of Example 9. LC / MS mass spectrometry: m / z281([M+H] + ). LC / MS retention time: 1.10 minutes (Analysis conditions: SMD-FA05-2). The halogen compound (2-(4-bromo-2-methoxyphenoxy)-2-methylpropan-1-ol, compound 20b) used in the synthesis of example compound 20 was synthesized as follows.

[0161] (Step 20-1) 2-(4-bromo-2-methoxyphenoxy)-2-methylpropan-1-ol (compound 20b) [ka] Under a nitrogen atmosphere, a THF solution (1.38 mL) of 2-(4-bromo-2-methoxyphenoxy)-2-methylpropanecarboxylic acid (compound 20a, 400 mg, 1.38 mmol) was added dropwise to a THF solution (0.95 M, 4.37 mL, 4.15 mmol) of borane (compound 20a, 400 mg, 1.38 mmol) at 0°C, and the mixture was stirred for 24 hours. After adding a 1 M aqueous sodium hydroxide solution and stirring, the mixture was neutralized with 1 N hydrochloric acid. Ethyl acetate was added and the mixture was extracted. The organic layer was washed with water, and the solvent was removed under reduced pressure to obtain the title compound 20b (339 mg, yield 89%). LC / MS retention time: 1.04 min (Analysis conditions: SMD-FA05-3). 1 H-NMR (400MHz, CDCl3) δ:7.04-7.01(2H,m),6.90-6.86(1H,m),3.85(3H,s),3.44(2H,m),3.34(1H,m),1.28(6H,s). The halogen compound (5-bromo-1-[(3S)-oxolan-3-yl]indazole, compound 22c) used in the synthesis of example compound 22 was synthesized as follows. [ka]

[0162] (Step 22-1) 4-Methylbenzenesulfonic acid [(3R)-oxolan-3-yl] (compound 22b) (3R)-oxolan-3-ol was synthesized using appropriate reagents in the same manner as in step 8-3 of Example 8. LC / MS retention time: 0.95 minutes (Analysis conditions: SMD-FA05-3).

[0163] (Step 22-2) 5-Bromo-1-[(3S)-oxolan-3-yl]indazole (compound 22c) Compound 22b obtained in step 22-1 and 5-bromo-1H-indazole were synthesized using appropriate reagents in the same manner as in step 8-4 of Example 8. LC / MS mass spectrometry: m / z267([M+H] + ). LC / MS retention time: 1.06 minutes (Analysis conditions: SMD-FA05-3). The halogen compound (6-bromo-1,1-dimethyl-3,4-dihydroisochromene, compound 24d) used in the synthesis of example compound 24 was synthesized as follows. [ka]

[0164] (Step 24-1) Trifluoromethanesulfonic acid (1,1-dimethyl-3,4-dihydroisochromen-6-yl) (compound 24b) It was synthesized using 1,1-dimethyl-3,4-dihydroisochromen-6-ol (compound 24a) and trifluoromethylsulfonyl trifluoromethanesulfonic acid (triflate anhydride) with appropriate reagents, following the same procedure as in step 8-3 of Example 8. LC / MS retention time: 0.96 min (Analysis conditions: SQD-FA05-01).

[0165] (Step 24-2) 2-(1,1-dimethyl-3,4-dihydroisochromen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (compound 24c) The compound 24b (120 mg, 0.387 mmol) obtained in step 24-1, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (147 mg, 0.580 mmol), triethylamine (0.162 mL, 1.16 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.2 mg, 0.019 mmol) were degassed under reduced pressure in a 1,4-dioxane (2.58 mL) solution, then purged with nitrogen and stirred at 100 °C for 14 hours. After cooling to room temperature, formic acid was added, and the mixture was purified by reverse-phase chromatography (acetonitrile / water, 0.1% formic acid) to obtain a pale brown liquid mixture (134 mg) containing the title compound 24c. LC / MS mass spectrometry: m / z289([M+H] + ). LC / MS retention time: 1.03 minutes (Analysis conditions: SQD-FA05-1).

[0166] (Step 24-3) 6-Bromo-1,1-dimethyl-3,4-dihydroisochromene (compound 24d) To a methanol (1.9 mL) solution of compound 24c (111 mg, 0.385 mmol) obtained in step 24-2, an aqueous solution (1.9 mL) of copper(II) bromide (258 mg, 1.16 mmol) was added, and the mixture was stirred at 60°C for 6 hours. After cooling to room temperature, an aqueous solution of saturated ammonium chloride was added, and the mixture was extracted twice with dichloromethane. The organic layer was dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1:4) to obtain the title compound 24d (47.7 mg, yield 51%) as a colorless liquid. 1 H-NMR (400MHz, CDCl3) δ:7.29(1H,dd,J=2.0,8.4Hz), 7.24-7.22(1H,m), 6.97(1H,d,J=8.4Hz), 3.92(2H,t,J=5.6Hz), 2.80(2H,t,J=5.6Hz), 1.50(6H,s). LC / MS retention time: 0.96 min (Analysis conditions: SQD-FA05-1). The halogen compound (6-(4-bromo-2-methylphenyl)-N,N-dimethylpyrimidine-4-amine, compound 25b) used in the synthesis of example compound 25 was synthesized as follows. [ka]

[0167] (Step 25-1) 6-(4-bromo-2-methylphenyl)-N,N-dimethylpyrimidine-4-amine (compound 25b) To a methanol (0.2 mL) solution of 4-(4-bromo-2-methylphenyl)-6-chloropyrimidine (compound 25a, 12.9 mg, 0.045 mmol), 2M dimethylamine THF solution (0.227 mL, 0.455 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by reverse-phase silica gel column chromatography (acetonitrile / water, 0.1% formic acid) to synthesize the title compound 25b (9.2 mg, yield 69%) as an off-white solid. LC / MS mass spectrometry: m / z292([M+H] + ). LC / MS retention time: 0.67 min (Analysis conditions: SMD-FA05-3). The halogen compound (5-bromo-4-fluoro-1-(2,2,2-trifluoroethyl)indazole, compound 28b) used in the synthesis of example compound 28 was synthesized as follows. [ka]

[0168] (Step 28-1) 5-Bromo-4-fluoro-1-(2,2,2-trifluoroethyl)indazole (compound 28b) The compounds were synthesized using appropriate reagents from 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (compound 10a) and 5-bromo-4-fluoro-1H-indazole (compound 28a), following the same procedure as in step 8-4 of Example 8. LC / MS mass spectrometry: m / z297([M+H] + ). LC / MS retention time: 1.20 minutes (Analysis conditions: SMD-FA05-1). The halogen compound (5-bromo-4-fluoro-1-[(3-methyloxetan-3-yl)methyl]indazole, compound 29a) used in the synthesis of example compound 29 was synthesized as follows. [ka]

[0169] (Step 29-1) 5-Bromo-4-fluoro-1-[(3-methyloxetan-3-yl)methyl]indazole (compound 29a) 3-methyl-3-[(4-methylphenyl)sulfonylmethyl]oxetane (compound 17a) and 5-bromo-4-fluoro-1H-indazole (compound 28a) were synthesized using appropriate reagents in the same procedure as in step 8-4 of Example 8. LC / MS mass spectrometry: m / z299([M+H] + ). LC / MS retention time: 1.11 minutes (Analysis conditions: SMD-FA05-1). The halogen compound (1-(5-bromo-4-fluoroindazole-1-yl)-2-methylpropan-2-ol, compound 30a) used in the synthesis of example compound 30 was synthesized as follows. [ka]

[0170] (Step 30-1) 1-(5-bromo-4-fluoroindazole-1-yl)-2-methylpropan-2-ol (compound 30a) 5-bromo-4-fluoro-1H-indazole (compound 28a) and 2,2-dimethyloxirane (compound 6k) were synthesized using appropriate reagents in the same procedure as in steps 6-7 of Example 6. LC / MS mass spectrometry: m / z287([M+H] + ). LC / MS retention time: 1.01 min (Analysis conditions: SMD-FA05-1). The 2-oxoimidazole reagent (3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, compound 31l) used in the synthesis of example compounds 31 to 40 was synthesized as follows. [ka]

[0171] (Step 31-1) 5-(2,2-dimethyloxan-4-yl)-1H-indole-2-carboxylate ethyl (compound 31c) Zinc powder (1.95 g, 29.8 mmol) was suspended in DMF (6 mL) and nitrogen purged. Chlorotrimethylsilane (0.417 mL, 3.28 mmol) and 1,2-dibromoethane (0.284 mL, 3.28 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. A solution of 4-iodo-2,2-dimethyltetrahydropyran (5.37 g, 22.4 mmol) in DMF (9 mL) was added dropwise, and the mixture was stirred at room temperature for 20 minutes. To this solution, palladium(II) acetate (0.084 g, 0.373 mmol), 4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (0.198 g, 0.746 mol), and 5-bromoindole-2-carboxylate ethyl (2.0 g, 7.46 mmol) were added, and nitrogen purged. After stirring at an ambient temperature of 50°C for 1 hour, the ambient temperature was cooled to 0°C and the mixture was neutralized with 5N hydrochloric acid (6 mL). 30% sodium chloride aqueous solution (50 mL) and ethyl acetate (100 mL) were added, and insoluble matter was removed using Celite. The filtrate was extracted with ethyl acetate and washed with 30% sodium chloride aqueous solution. After drying with magnesium sulfate, the mixture was filtered, and the solvent was removed by reduced pressure distillation. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to synthesize the title compound 31c (1.86 g, yield 83%) as a pale pink solid. LC / MS mass spectrometry: m / z302([M+H] + ). LC / MS retention time: 0.90 min (Analysis conditions: SQD-FA05-4).

[0172] (Step 31-2) 5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indole-2-carboxylate ethyl (compound 31d) The stereoisomers contained in compound 31c (900 mg) obtained in step 31-1 were separated by supercritical fluid chromatography to obtain the title compound 31d (423 mg, yield 47%). Partitioning conditions Equipment: SFC15 (Waters) Column: CHIRALPAK-IE / SFC, 10×250mm, 5μm (Daicel) Column temperature: 40℃ Solvent: Supercritical carbon dioxide / methanol:ethyl acetate (1:1) = 60 / 40 (homogeneous system) Flow rate: 15mL / min, 140bar Analysis conditions Equipment: Nexera (Shimadzu) Column: CHIRALPAK-IE, 4.6 × 250 mm, 5 μm (Daicel) Column temperature: 25℃ Solvent: Hexane / Ethanol = 30 / 70 (homogeneous system) Flow rate: 1mL / min, room temperature Retention time of title compound: 9.98 minutes, retention time of isomer: 6.86 minutes Furthermore, the fact that the title compound is the S-isomer was determined by X-ray crystal structure analysis of compound 31j.

[0173] (Step 31-3) 5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indole-2-carboxylic acid (compound 31e) Compound 31d (993 mg, 3.29 mmol) obtained in step 31-2 was dissolved in methanol (14.9 mL), and 2 M sodium hydroxide aqueous solution (3.62 mL, 7.25 mmol) was added dropwise, and the mixture was stirred at an ambient temperature of 65°C for 1 hour. The reaction mixture was cooled to an ambient temperature of 15°C, and 5N hydrochloric acid (1.52 mL, 7.58 mmol) was added dropwise. Water (7.45 mL) was added dropwise, and the precipitated solid was filtered off. The obtained solid was washed with water (5.0 mL) and dried under reduced pressure to obtain the title compound 31e (827 mg, yield 96%). LC / MS mass spectrometry: m / z274([M+H] + ). LC / MS retention time: 0.65 min (Analysis conditions: SQD-FA05-4).

[0174] (Step 31-4) 5-[(4S)-2,2-dimethyloxan-4-yl]-N-methyl-N-phenyl-1H-indole-2-carboxamide (compound 31f) Compound 31e (805 mg, 2.95 mmol) obtained in step 31-3 was dissolved in DMA (8.0 mL), and thionyl chloride (0.256 mL, 3.53 mmol) was added dropwise at an internal temperature of 10°C or below. After stirring for 1 hour, N-methylaniline (0.384 mL, 3.53 mmol) and triethylamine (0.985 mL, 7.07 mmol) were added dropwise at 10°C or below, and the mixture was stirred at room temperature for 1 hour. Water (4.0 mL) was added dropwise, and the precipitated solid was filtered off. The obtained solid was washed with water (8.0 mL) and dried under reduced pressure to obtain the title compound 31f (995 mg, yield 93%). LC / MS mass spectrometry: m / z363([M+H] + ). LC / MS retention time: 1.20 minutes (Analysis conditions: SMD-FA05-1).

[0175] (Step 31-5) 1-(cyanomethyl)-5-[(4S)-2,2-dimethyloxan-4-yl]-N-methyl-N-phenylindole-2-carboxamide (compound 31h) Compound 31f (101 mg, 0.276 mmol) obtained in step 31-4 was dissolved in 1,3-dimethyl-2-imidazolidinone (DMI) (1.0 mL) at room temperature, and 8 M potassium hydroxide aqueous solution (0.103 mL, 0.828 mmol) and water (0.10 mL) were added. 2-chloroacetonitrile (0.026 mL, 0.414 mmol) was added to the resulting solution at ambient temperature of 10°C, and the mixture was stirred for 2.5 hours. 5N hydrochloric acid (0.193 mL), water (0.10 mL), and cyclopentyl methyl ether (1.0 mL) were added to the reaction solution for extraction, and the aqueous layer was extracted again with cyclopentyl methyl ether (1.0 mL). The combined organic layer was washed with 15% sodium chloride aqueous solution (1.0 mL), and then concentrated under reduced pressure at ambient temperature of 40°C to obtain the title compound 31h, a light brown oily substance, which was used in the next step 31-6 without purification. LC / MS mass spectrometry: m / z402([M+H]+ ). LC / MS retention time: 0.93 minutes (Analysis conditions: SMD-FA05-1).

[0176] (Step 31-6) 1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-5-[(4S)-2,2-dimethyloxan-4-yl]-N-methyl-N-phenylindole-2-carboxamide (compound 31i) Compound 31h obtained in step 31-5 was synthesized using appropriate reagents in the same manner as in step 1-6 of Example 1. LC / MS mass spectrometry: m / z442([M+H] + ). LC / MS retention time: 0.95 min (Analysis conditions: SQD-FA05-1).

[0177] (Step 31-7) 5-[(4S)-2,2-dimethyloxan-4-yl]-N-methyl-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]-N-phenylindole-2-carboxamide (compound 31j) Compound 31i obtained in step 31-6 was synthesized using appropriate reagents in the same manner as in step 1-6 of Example 1. LC / MS mass spectrometry: m / z501([M+H] + ). LC / MS retention time: 0.99 min (Analysis conditions: SQD-FA05-1).

[0178] (Step 31-8) 5-[(4S)-2,2-dimethyloxan-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 31k) Compound 31j obtained in step 31-7 was synthesized using appropriate reagents in the same manner as in step 6-4 of Example 6. LC / MS mass spectrometry: m / z401([MH] - ). LC / MS retention time: 1.05 minutes (Analysis conditions: SMD-FA05-1).

[0179] (Step 31-9) 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 31l) Compound 11l obtained in step 11-8 and compound 31k obtained in step 31-8 were synthesized using appropriate reagents in the same procedure as in step 1-10 of Example 1. The halogen compound 5-bromo-1-(2-methoxyethyl)-3-methylbenzimidazole-2-one (compound 33b), used in the synthesis of example compound 33, was synthesized as follows.

[0180] (Step 33-1) [ka] 5-bromo-3-methyl-1H-benzimidazole-2-one (compound 33a) was synthesized using appropriate reagents in the same manner as in step 8-4 of Example 8. LC / MS mass spectrometry: m / z285([M+H] + ). LC / MS retention time: 0.95 min (Analysis conditions: SMD-FA05-1). The halogen compound (5-bromo-4-fluoro-1-(2-methoxyethyl)indazole, compound 36a) used in the synthesis of example compound 36 was synthesized as follows.

[0181] (Step 36-1) [ka] It was synthesized from 5-bromo-4-fluoro-1H-indazole (compound 28a) using appropriate reagents and the same procedure as in step 8-4 of Example 8. LC / MS mass spectrometry: m / z273([M+H] + ). LC / MS retention time: 1.10 minutes (Analysis conditions: SMD-FA05-1). The halogen compound (5-bromo-4-fluoro-1-[(3S)-oxolan-3-yl]indazole, compound 40a) used in the synthesis of example compound 40 was synthesized as follows.

[0182] (Step 40-1) [ka] 5-bromo-4-fluoro-1H-indazole (compound 28a) and 4-methylbenzenesulfonic acid [(3R)-oxolan-3-yl] (compound 22b) were synthesized using appropriate reagents in the same procedure as in step 8-4 of Example 8. LC / MS mass spectrometry: m / z285([M+H] + ). LC / MS retention time: 1.10 minutes (Analysis conditions: SMD-FA05-1). The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(2S,4S)-2-methyloxan-4-yl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, compound 41f) used in the synthesis of example compound 41 was synthesized as follows. [ka]

[0183] (Steps 41-1 and 41-2) 1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-N-methyl-5-[(2S,4S)-2-methyloxan-4-yl]-N-phenylindole-2-carboxamide (compound 41c) A suspension of zinc (29 mg, 0.44 mmol) in DMA (0.12 mL) was degassed under reduced pressure at room temperature and then purged with nitrogen. Under a nitrogen atmosphere, a 7:5 mixed solution of chlorotrimethylsilane / 1,2-dibromoethane (0.0083 mL, 0.039 mmol of chlorotrimethylsilane) was added and stirred for 15 minutes. Then, (2S)-4-iodo-2-methyltetrahydro-2H-pyran (80 mg, 0.35 mmol) was added dropwise at room temperature and stirred for 30 minutes to obtain a mixture containing iodo-[(2S)-2-methyloxan-4-yl]zinc (compound 41b). Palladium(II) acetate (6.4 mg, 0.028 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (26 mg, 0.057 mmol), 5-bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-N-methyl-N-phenylindole-2-carboxamide (58 mg, 0.14 mmol), and DMA (0.123 mL) were added. After degassing under reduced pressure, the mixture was purged with nitrogen and stirred at 80°C for 1 hour. The mixture was cooled to room temperature, ethyl acetate and 1N hydrochloric acid were added, and after filtration, the filtrate was extracted with ethyl acetate. The organic layer was washed once with saturated brine, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1:1) to obtain the title compound 41c (31 mg, yield 51%). LC / MS mass spectrometry: m / z428([M+H] + ). LC / MS retention time: 1.01 min (Analysis conditions: SQD-AA05-1).

[0184] (Step 41-3) N-methyl-5-[(2S,4S)-2-methyloxan-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]-N-phenylindole-2-carboxamide (compound 41d) Compound 41c obtained in step 41-2 was synthesized using appropriate reagents in the same manner as in step 1-8 of Example 1. LC / MS mass spectrometry: m / z487([M+H] + ). LC / MS retention time: 1.30 minutes (Analysis conditions: SMD-FA05-1).

[0185] (Step 41-4) 5-[(2S,4S)-2-methyloxan-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 41e) Compound 41d obtained in step 41-3 was synthesized using appropriate reagents in the same manner as in step 6-4 of Example 6. LC / MS mass spectrometry: m / z396([MH] - ). LC / MS retention time: 1.02 minutes (Analysis conditions: SMD-FA05-1).

[0186] (Step 41-5) 3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(2S,4S)-2-methyloxan-4-yl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 41f) Compound 41e obtained in step 41-4 was synthesized using appropriate reagents in the same manner as in step 1-10 of Example 1. The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, compound 42g) used in the synthesis of example compounds 42 and 43 was synthesized as follows. [ka]

[0187] (Process 42-1, 2) (4S)-3-amino-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 42c) From 4-chloro-3,5-dimethylaniline (compound 42a), (4-chloro-3,5-dimethylphenyl)hydrazine hydrochloride (compound 42b) was obtained using appropriate reagents in the same procedure as in step 2-2 of Example 2. Then, compound 42c was synthesized using 11 g of the compound obtained in step 11-4 and appropriate reagents in the same procedure as in step 1-2 of Example 1. LC / MS mass spectrometry: m / z391([M+H] + ). LC / MS retention time: 1.22 minutes (Analysis conditions: SMD-FA10-4).

[0188] (Step 42-3) (4S)-2-(4-chloro-3,5-dimethylphenyl)-3-(2,2-dimethoxyethylcarbamoylamino)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 42d) Compound 42c obtained in step 42-2 was synthesized using appropriate reagents in the same manner as in step 1-3 of Example 1. LC / MS mass spectrometry: m / z522([M+H] + ). LC / MS retention time: 1.55 minutes (Analysis conditions: SMD-TFA05-5).

[0189] (Step 42-4) (4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 42e) Compound 42d obtained in step 42-3 was synthesized using appropriate reagents in the same manner as in step 11-8 of Example 11. LC / MS mass spectrometry: m / z458([M+H] + ). LC / MS retention time: 1.16 minutes (Analysis conditions: SMD-FA05-1).

[0190] (Step 42-5) 3-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]-1H-imidazole-2-one hydrochloride (compound 42f) Compound 42e obtained in step 42-4 was synthesized using appropriate reagents in the same manner as in step 111-8 of Example 11. LC / MS mass spectrometry: m / z358([M+H] + ). LC / MS retention time: 0.69 min (Analysis conditions: SMD-FA05-1).

[0191] (Step 42-6) 3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 42g) Compound 42f obtained in step 42-5 and compound 31k obtained in step 31-8 were synthesized using appropriate reagents in the same procedure as in step 1-10 of Example 1. The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, compound 44a) used in the synthesis of example compounds 44 and 45 was synthesized as follows. [ka]

[0192] (Step 44-1) 3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 44a) Compound 42f obtained in step 42-5 and compound 8b obtained in step 8-1 were synthesized using appropriate reagents in the same manner as in step 1-10 of Example 1. The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, compound 46f) used in the synthesis of example compounds 46 and 47 was synthesized as follows. [ka]

[0193] (Step 46-1) (4S)-3-amino-2-(4-fluoro-3-methylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 46b) (4-fluoro-3-methylphenyl)hydrazine hydrochloride (compound 46a) and 11 g of the compound obtained in step 11-4 were used with appropriate reagents and synthesized in the same manner as in step 1-2 of Example 1. LC / MS mass spectrometry: m / z361([M+H] + ). LC / MS retention time: 1.02 minutes (Analysis conditions: SMD-FA05-1).

[0194] (Step 46-2) (4S)-3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3-methylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 46c) Compound 46b obtained in step 46-1 was synthesized using appropriate reagents in the same manner as in step 1-3 of Example 1. LC / MS mass spectrometry: m / z492([M+H] + ). LC / MS retention time: 1.03 minutes (Analysis conditions: SMD-FA05-1).

[0195] (Step 46-3) (4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 46d) Compound 46c obtained in step 46-2 was synthesized using appropriate reagents in the same manner as in step 11-7 of Example 11. LC / MS mass spectrometry: m / z428([M+H] + ). LC / MS retention time: 2.11 minutes (Analysis conditions: SMD-FA05-long).

[0196] (Step 46-4) 3-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]-1H-imidazole-2-one hydrochloride (compound 46e) Compound 46d obtained in step 46-3 was synthesized using appropriate reagents in the same manner as in step 11-8 of Example 11. LC / MS mass spectrometry: m / z328([M+H] + ). LC / MS retention time: 0.59 min (Analysis conditions: SMD-FA05-3).

[0197] (Step 46-5) 3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 46f) Compound 46e obtained in step 46-4 and compound 8b obtained in step 8-1 were synthesized using appropriate reagents in the same manner as in step 1-10 of Example 1. The 2-oxoimidazole reagent (3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, compound 48a) used in the synthesis of example compounds 48-50 was synthesized as follows. [ka]

[0198] (Step 48-1) 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 48a) Compound 46e obtained in step 46-5 and compound 31k obtained in step 31-8 were synthesized using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0199] <Examples 51-53> Using 3-[(1S,2S)-1-[5-bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 51d) and substituted morpholine, along with appropriate reagents, the same procedure as in step 7-1 of Example 7 was carried out to obtain Example compounds 51-53 shown in Table 2-4 by the following reaction. [ka] [Table 2-4] JPEG2026048784000105.jpg173153 JPEG2026048784000106.jpg162153 Compound 51d was synthesized as follows. [ka]

[0200] (Step 51-1) 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 51a) To a suspension of compound 2f (0.611 g, 1.68 mmol) obtained in step 2-5 in dichloromethane (16.8 mL), triethylamine (0.936 mL, 6.72 mmol) and di-t-butyl dicarbonate (0.425 mL, 1.85 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After adding water (20.0 mL) and 5% potassium bisulfate aqueous solution (20.0 mL) to the reaction mixture, it was extracted with dichloromethane and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0:1 to 1:0) to obtain the title compound 51a (0.360 g, yield 50%). LC / MS mass spectrometry: m / z428([M+H] + ). LC / MS retention time: 1.06 minutes (Analysis conditions: SMD-FA05-3).

[0201] (Step 51-2) 2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 51b) Compound 51a obtained in step 51-1 and 5-bromo-1-methylindazole were synthesized using appropriate reagents in the same manner as in step 1-11 of Example 1. LC / MS mass spectrometry: m / z558([M+H] + ). LC / MS retention time: 1.25 minutes (Analysis conditions: SMD-FA05-1).

[0202] (Step 51-3) 1-[2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]-3-(1-methylindazole-5-yl)imidazole-2-one hydrochloride (compound 51c) Compound 51b obtained in step 51-2 was synthesized using appropriate reagents in the same manner as in step 11-9 of Example 11. LC / MS mass spectrometry: m / z458([M+H] +). LC / MS retention time: 0.78 min (Analysis conditions: SMD-FA05-1).

[0203] (Step 51-4) 3-[(1S,2S)-1-[5-bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 51d) Compound 51c obtained in step 51-3 and compound 6f obtained in step 6-4 were synthesized using appropriate reagents in the same manner as in step 1-10 of Example 1. LC / MS mass spectrometry: m / z817([M+H] + ). LC / MS retention time: 1.41 minutes (Analysis conditions: SMD-FA05-1).

[0204] <Examples 54-73> Using amine derivatives and carboxylic acid derivatives, the same procedure as in steps 1-10 of Example 1 was carried out, and the following reactions yielded Example Compounds 54-72 and Example Compound 73 shown in Table 2-5. [ka] [Table 2-5] JPEG2026048784000110.jpg205162 JPEG2026048784000111.jpg225162 JPEG2026048784000112.jpg244162 JPEG2026048784000113.jpg225162 JPEG2026048784000114.jpg225162 JPEG2026048784000115.jpg218162 JPEG2026048784000116.jpg237162 JPEG2026048784000117.jpg244162 JPEG2026048784000118.jpg237162 JPEG2026048784000119.jpg244162 JPEG2026048784000120.jpg244162 JPEG2026048784000121.jpg237162 JPEG2026048784000122.jpg244162 JPEG2026048784000123.jpg244162 JPEG2026048784000124.jpg237162 JPEG2026048784000125.jpg244162 JPEG2026048784000126.jpg251162 JPEG2026048784000127.jpg220162 Note that rotational isomers exist for the compounds in Table 2-5, for example, compounds 66 and 67 in Example 1 The 1H-NMR spectrum is as follows:

[0205] <Example Compound 66> Principal rotational isomer 1 H-NMR(600MHz, CDCl3) δ:11.32(1H,s),8.04(1H,d,J=0.4Hz),7.86(1H,d,J=1.4Hz),7.61(1H,m) ,7.59(1H,m),7.52(1H,s),7.50(H,d,J=9.0Hz),7.27(1H,m),7.15(2H,d,J HF =6.0Hz),6.74(1H,d,J=3.1Hz),6.70(1H,s),6.32(1H,d,J=3.1Hz),5.79(1H,q,J=6.6Hz),4.47(1H,dd,J=13.6,5.0Hz),4.12(3H ,s),3.89-3.81(2H,m),3.60(1H,ddd,J=13.6,13.1,3.6Hz),3.15(1H,ddd,J=16.0,13.1,5.0Hz),3.09-2.98(2H,m),2.27(6H,d,J HF=1.4Hz),1.91(1H,dd,J=6.0Hz),1.82-1.60(4H,m),1.60-1.50(2H,m),1.55(3H,d,J=6.6Hz),1.34(3H,s),1.28(3H,s),1.19(3H,d,J=5.9Hz). Vice-reverse heterosexual body 1 H-NMR (600MHz, CDCl3) δ:11.26(1H,s),7.93(1H,s),7.65(1H,s),7.57(1H,d,J=8.6Hz),7.49(1H,m),7.34(2H,s),7.25(1H,m),7.05(2H,d,J HF =6.0Hz),6.69(1H,s),6.59(1H,d,J=3.1Hz),6.09(1H,d,J=3.1Hz),5.26(1H,q,J=6.6Hz),4.87(1H,dd,J=12.8,5.1Hz),4.07(3H,s),3.90-3.78( 2H,m),3.40(1H,ddd,J=12.8,12.6,4.5Hz),3.10-2.98(3H,m),2.23(6H, s),1.82-1.37(10H,m),1.33(3H,s),1.25(3H,s),1.06(3H,d,J=6.2Hz).

[0206] <Example Compound 67> main body of the opposite sex 1 H-NMR(600MHz, CDCl3) δ:11.32(1H,s),8.13(1H,d,J HF =0.7Hz),7.59(1H,d,J=8.6Hz),7.52(1H,s),7.48(1H,dd,J=8.9Hz,J HF =6.9Hz),7.28(1H,d,J=8.9Hz),7.26(1H,dd,J=8.6,1.7Hz),7.16(2H,d,J HF =6.1Hz),6.70(1H,s),6.61(1H,dd,J=3.0Hz,J HF=1.1Hz),6.31(1H,d,J=3.0Hz),5.79(1H,q,J=6.7Hz),4.47(1H,dd,J=13.5,5.2Hz),4.12(3H,s),3.88(1H,m),3.83(1 H,m),3.60(1H,ddd,J=13.5,12.9,3.6Hz),3.15(1H,ddd,J=15.8,12.9,5.2Hz),3.04(1H,m),3.00(1H,m),2.29(6H,d,J HF =1.1Hz),1.91(1H,dd,J=6.1,5.8Hz),1.79-1.76(2H,m),1.74(1H,m),1.65(1H,m),1.57(3H,d,J=6.7 Hz),1.60-1.55(1H,m),1.52(1H,dd,J=9.5,5.8Hz),1.34(3H,s),1.28(3H,s),1.20(3H,d,J=6.0Hz). Vice-reverse heterosexual body 1 H-NMR (600MHz, CDCl3) δ:11.27(1H,s),8.04(1H,s),7.55(1H,d,J=8.7Hz),7.52(1H,s),7.25-7.22(2H,m),7.12(1H,d,J=8.8Hz),7.06(2H,d,J HF =6.0Hz),6.71(1H,s),6.47(1H,m),6.08(1H,d,J=3.0Hz),5.26(1H,q,J=6.6Hz),4. 87(1H,dd,J=13.1,4.8Hz),4.07(3H,s),3.90-3.80(2H,m),3.39(1H,ddd,J=13.1,1 2.2,4.6Hz),3.08-2.97(3H,m),2.25(6H,s),1.79-1.73(3H,m),1.67(3H,d,J=6.6H z),1.64(1H,m),1.45-1.37(2H,m),1.34(3H,s),1.28(3H,s),1.06(3H,d,J=6.0Hz).

[0207] For the synthesis of Example Compound 55, the compound 55e was synthesized using the following method.

change

[0208] Compound 56c, used in the synthesis of Example Compound 56, was synthesized as follows. [ka] (Step 56-1) 2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1-(2-methoxyethyl)indazole-5-yl]-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 56b) Compound 51a obtained in step 51-1 and 5-bromo-1-(2-methoxyethyl)indazole (compound 56a) were synthesized using appropriate reagents in the same procedure as in step 1-11 of Example 1. LC / MS mass spectrometry: m / z602([M+H] + ). LC / MS retention time: 1.30 minutes (Analysis conditions: SMD-FA05-2). (Step 56-2) 1-[2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[1-(2-methoxyethyl)indazole-5-yl]imidazole-2-one hydrochloride (compound 56c) Compound 56b obtained in step 56-1 was synthesized using appropriate reagents in the same manner as in step 11-8 of Example 11. LC / MS mass spectrometry: m / z502([M+H] + ). LC / MS retention time: 0.54 min (Analysis conditions: SQD-FA05-1).

[0209] The amine derivative (compound 57j) used in the synthesis of example compound 57 was synthesized as follows. [ka] (Step 57-1) N-(4-isocyanatocuban-1-yl)carbamate tert-butyl (compound 57b) To a solution of 4-[(2-methylpropan-2-yl)oxycarbonylamino]cubane-1-carboxylic acid (compound 57a, 111 mg, 0.423 mmol) in toluene (2.1 mL), triethylamine (0.0676 mL, 0.487 mmol) and diphenyl phosphoryl azide (0.10 mL, 0.465 mmol) were added at room temperature and stirred at room temperature for 100 minutes, followed by stirring at 85°C for 3.5 hours. The reaction mixture was removed under reduced pressure to obtain the title compound 57b as the crude product. 1 H-NMR (400MHz, CDCl3) δ: 12.3 (1H, brs), 3.95 (6H, brs), 1.45 (9H, s). (Step 57-2) (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[[4-[(2-methylpropan-2-yl)oxycarbonylamino]cubane-1-yl]carbamoylamino]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl(compound 57c) Compound 57b obtained in step 57-1 and compound 11h obtained in step 11-5 were synthesized using appropriate reagents in the same manner as in step 1-3 of Example 1. LC / MS mass spectrometry: m / z636([M+H] + ). LC / MS retention time: 0.93 minutes (Analysis conditions: SQD-FA05-1). (Step 57-3) (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[5-hydroxy-3-[4-[(2-methylpropan-2-yl)oxycarbonylamino]cubane-1-yl]-2-oxoimidazolidine-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 57d) To a DMA (0.25 mL) suspension of compound 57c (31.6 mg, 0.050 mmol) obtained in step 57-2 and cesium carbonate (82.8 mg, 0.254 mmol), 1,2-dichloro-1-ethoxyethane (0.0155 mL, 0.127 mmol) was added at room temperature and the mixture was stirred at room temperature for 170 minutes. Cesium carbonate (104 mg, 0.32 mmol) and then 1,2-dichloro-1-ethoxyethane (0.0184 mL, 0.162 mmol) were added to the reaction mixture at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and water, and 1N hydrochloric acid (0.54 mL) was added to adjust the pH to 7, after which it was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, and after solvent removal under reduced pressure, toluene was added and the solvent was removed under reduced pressure to obtain the title compound 57d as the crude product. LC / MS mass spectrometry: m / z678([M+H] + ). LC / MS retention time: 0.98 min (Analysis conditions: SQD-FA05-1). (Step 57-4) (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-[4-[(2-methylpropan-2-yl)oxycarbonylamino]cubane-1-yl]-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 57e) To a solution of compound 57d (115 mg, 0.17 mmol) obtained in step 57-3 in THF (1.1 mL), methylsulfonic acid (0.011 mL, 0.17 mmol) was added at room temperature, and the mixture was stirred at 60°C for 90 minutes. Potassium phosphate (36.5 mg, 0.172 mmol), water (0.45 mL), and (2-methylpropan-2-yl)oxycarbonyl tert-butyl carbonate (0.012 mL, 0.052 mmol) were added to the reaction mixture, and the mixture was stirred for 1 hour. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried on magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1:2 to 1:1) to obtain the title compound 57e (48.5 mg, yield 43%). LC / MS mass spectrometry: m / z660([M+H] + ). LC / MS retention time: 1.04 min (Analysis conditions: SQD-FA05-1). (Step 57-5) (4S)-3-[3-[4-[Acetyl-[(2-methylpropane-2-yl)oxycarbonyl]amino]cubane-1-yl]-2-oxoimidazole-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 57f) To a solution of compound 57e (16.1 mg, 0.024 mmol) obtained in step 57-4 in THF (0.22 mL), 1.7 M potassium pentoxide toluene solution (0.024 mL, 0.041 mmol) was added at -26 °C, and the mixture was stirred at -30 °C for 3 minutes. Acetic anhydride (8 μL, 0.085 mmol) was added to the reaction mixture at -30 °C, and the mixture was stirred from -30 °C to -25 °C for 5 minutes, and from -25 °C to room temperature for 3 minutes. Water (0.5 mL) was added to the reaction mixture, then diluted with ethyl acetate, and water was added again for extraction with ethyl acetate. The organic layer was dried on magnesium sulfate, the solvent was removed under reduced pressure, and the compound was purified by silica gel column chromatography (ethyl acetate / hexane = 1:3 to 2:3) to obtain the title compound 57f (9.2 mg, yield 54%). LC / MS mass spectrometry: m / z701([M+H] + ). LC / MS retention time: 1.12 minutes (Analysis conditions: SQD-FA05-1). (Step 57-6) N-[4-[3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]-2-oxoimidazole-1-yl]cubane-1-yl]acetamide 2,2,2-trifluoroacetate (compound 57g) To a solution of compound 57f (8.5 mg, 0.012 mmol) obtained in step 57-5 in dichloromethane (0.097 mL), TFA (0.019 mL) was added at room temperature and the mixture was stirred at room temperature for 3 hours. After removing the solvent from the reaction mixture under reduced pressure, toluene was added and the solvent was removed, and then hexane-dichloromethane was added and the solvent was removed to obtain 57 g (9.4 mg) of the title compound as the crude product. LC / MS mass spectrometry: m / z501([M+H] + ). LC / MS retention time: 0.49 min (Analysis conditions: SQD-FA05-1). (Step 57-7) (4S)-3-[3-(4-acetamidocuban-1-yl)-2-oxoimidazole-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 57h) From 57 g of the compound obtained in step 57-6, the compound was synthesized using appropriate reagents in the same manner as in step 51-1 of Example 51. LC / MS mass spectrometry: m / z602([M+H] + ). LC / MS retention time: 0.85 min (Analysis conditions: SQD-FA05-1). (Step 57-8) (4S)-3-[3-[4-[Acetyl(2-methoxyethyl)amino]cuban-1-yl]-2-oxoimidazole-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 57i) Compound 57h obtained in step 57-7 was synthesized using appropriate reagents in the same manner as in step 57-5 of Example 57. LC / MS mass spectrometry: m / z660([M+H] + ). LC / MS retention time: 0.93 minutes (Analysis conditions: SQD-FA05-1). (Step 57-9) N-[4-[3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]-2-oxoimidazole-1-yl]cubane-1-yl]-N-(2-methoxyethyl)acetamide hydrochloride (compound 57j) Compound 57i obtained in step 57-8 was synthesized using appropriate reagents in the same manner as in step 11-8 of Example 11. LC / MS mass spectrometry: m / z560([M+H] + ). LC / MS retention time: 0.53 min (Analysis conditions: SQD-FA05-1).

[0210] Compound 58e, used in the synthesis of Example Compound 58, was synthesized as follows. [ka] (Step 58-1) 3-amino-2-(4-fluoro-3-methylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 58a) Compound 1b obtained in step 1-1 and compound 46a obtained in step 46-1 were synthesized using appropriate reagents in the same manner as in step 1-2 of Example 1. LC / MS mass spectrometry: m / z347([M+H] + ). LC / MS retention time: 0.98 min (Analysis conditions: SMD-FA05-3). (Step 58-2) 3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3-methylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 58b) Compound 58a obtained in step 58-1 was synthesized using appropriate reagents in the same manner as in step 1-3 of Example 1. LC / MS mass spectrometry: m / z478([M+H] + ). LC / MS retention time: 1.03 minutes (Analysis conditions: SMD-FA05-3). (Step 58-3) 2-(4-fluoro-3-methylphenyl)-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 58c) Compound 58b obtained in step 58-2 was synthesized using appropriate reagents in the same manner as in step 11-7 of Example 11. LC / MS mass spectrometry: m / z414([M+H] + ). LC / MS retention time: 0.72 min (Analysis conditions: SQD-FA05-1). (Step 58-4) 2-(4-fluoro-3-methylphenyl)-3-[3-[1-(2-methoxyethyl)indazole-5-yl]-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 58d) Compound 58c obtained in step 58-3 and 5-bromo-1-(2-methoxyethyl)indazole (compound 56a) were synthesized using appropriate reagents in the same procedure as in step 1-11 of Example 1. LC / MS mass spectrometry: m / z588([M+H] + ). LC / MS retention time: 0.88 min (Analysis conditions: SQD-FA05-1). (Step 58-5) 1-[2-(4-fluoro-3-methylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[1-(2-methoxyethyl)indazole-5-yl]imidazole-2-one hydrochloride (compound 58e) Compound 58d obtained in step 58-4 was synthesized using appropriate reagents in the same manner as in step 11-9 of Example 11. LC / MS mass spectrometry: m / z488([M+H] + ). LC / MS retention time: 0.50 min (Analysis conditions: SQD-FA05-1).

[0211] Compound 60c, used in the synthesis of Example Compound 60, was synthesized as follows. [ka] (Step 60-1) 2-(3,5-dimethylphenyl)-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 60a) From 1 g of the compound obtained in steps 1-4, the compound was synthesized using appropriate reagents in the same manner as in step 51-1 of Example 51. LC / MS mass spectrometry: m / z410([M+H] + ). LC / MS retention time: 0.77 min (Analysis conditions: SQD-FA05-1). (Step 60-2) 2-(3,5-dimethylphenyl)-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 60b) Compound 60a obtained in step 60-1 and 5-bromo-1-methylindazole (compound 1q) were synthesized using appropriate reagents in the same manner as in step 1-11 of Example 1. LC / MS mass spectrometry: m / z540([M+H] + ). LC / MS retention time: 1.24 minutes (Analysis conditions: SMD-FA05-3). (Step 60-3) 1-[2-(3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]-3-(1-methylindazole-5-yl)imidazole-2-one hydrochloride (compound 60c) Compound 60b obtained in step 60-2 was synthesized using appropriate reagents in the same manner as in step 11-8 of Example 11. LC / MS mass spectrometry: m / z440([M+H] + ). LC / MS retention time: 0.74 min (Analysis conditions: SMD-FA05-2).

[0212] Compound 61b, used in the synthesis of Example Compound 61, was synthesized as follows. [ka] (Step 61-1) (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 61a) Compound 11k obtained in step 11-7 and 5-bromo-1-methylindazole (compound 1q) were synthesized using appropriate reagents in the same procedure as in step 1-11 of Example 1. LC / MS mass spectrometry: m / z572([M+H] + ). LC / MS retention time: 1.30 minutes (Analysis conditions: SMD-FA05-1). (Step 61-2) 1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1-methylindazole-5-yl)imidazole-2-one hydrochloride (compound 61b) Compound 61a obtained in step 61-1 was synthesized using appropriate reagents in the same manner as in step 11-8 of Example 11. LC / MS mass spectrometry: m / z472([M+H] + ). LC / MS retention time: 0.79 min (Analysis conditions: SMD-FA05-1).

[0213] Compound 62b, used in the synthesis of Example Compound 62, was synthesized as follows. [ka] (Step 62-1) (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1-(2-methoxyethyl)indazole-5-yl]-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 62a) Compound 11k obtained in step 11-7 and 5-bromo-1-(2-methoxyethyl)indazole (compound 56a) were synthesized using appropriate reagents in the same procedure as in step 1-11 of Example 1. LC / MS mass spectrometry: m / z616([M+H] + ). LC / MS retention time: 1.29 minutes (Analysis conditions: SMD-FA05-1). (Step 62-2) 1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[1-(2-methoxyethyl)indazole-5-yl]imidazole-2-one hydrochloride (compound 62b) Compound 62a obtained in step 62-1 was synthesized using appropriate reagents in the same manner as in step 11-8 of Example 11. LC / MS mass spectrometry: m / z516([M+H] + ). LC / MS retention time: 0.76 min (Analysis conditions: SMD-FA05-1).

[0214] Compound 63g used in the synthesis of Example Compound 63 was synthesized as follows. [ka] (Step 63-1) 5-Bromo-7-fluoro-N-methyl-N-phenyl-1H-indole-2-carboxamide (compound 63b) It was synthesized from 5-bromo-7-fluoro-1H-indole-2-carboxylic acid (compound 63a) using appropriate reagents and following the same procedure as in steps 1-10 of Example 1. (Step 63-2) 5-Bromo-1-(cyanomethyl)-7-fluoro-N-methyl-N-phenylindole-2-carboxamide (compound 63c) Compound 63b obtained in step 63-1 was synthesized using appropriate reagents in the same manner as in step 9-1 of Example 9. LC / MS mass spectrometry: m / z386([M+H] + ). LC / MS retention time: 3.17 minutes (Analysis conditions: SMD-FA10-long). (Step 63-3) 5-Bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-7-fluoro-N-methyl-N-phenylindole-2-carboxamide (compound 63d) Compound 63c obtained in step 63-2 was synthesized using appropriate reagents in the same manner as in step 1-6 of Example 1. LC / MS mass spectrometry: m / z426([M+H] + ). LC / MS retention time: 1.36 minutes (Analysis conditions: SMD-FA05-1). 1 H-NMR (300MHz, CDCl3) δ:7.75(1H,s),7.43-7.30(6H,m),6.08(1H,brs),3.44(3H,s),2.11-1.69(3H,m),1.40-1.35(3H,m). (Step 63-4) 1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-7-fluoro-N-methyl-5-(oxan-4-yl)-N-phenylindole-2-carboxamide (compound 63e) Compound 63d obtained in step 63-3 and (tetrahydro-2H-pyran-4-yl)zinc(II) iodide (compound 8a) were synthesized using appropriate reagents in the same procedure as in step 8-1 of Example 8. LC / MS mass spectrometry: m / z432([M+H] + ). LC / MS retention time: 1.22 minutes (Analysis conditions: SMD-FA05-1). (Step 63-5) 7-Fluoro-N-methyl-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]-5-(oxan-4-yl)-N-phenylindole-2-carboxamide (compound 63f) Compound 63e obtained in step 63-4 was synthesized using appropriate reagents in the same manner as in step 1-8 of Example 1. LC / MS mass spectrometry: m / z491([M+H] + ). LC / MS retention time: 1.21 minutes (Analysis conditions: SQD-FA05-01). (Step 63-6) 7-Fluoro-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]-5-(oxan-4-yl)indole-2-carboxylic acid (compound 63g) Compound 63f obtained in step 63-5 was synthesized using appropriate reagents in the same manner as in step 6-4 of Example 6. LC / MS mass spectrometry: m / z402([M+H] + ). LC / MS retention time: 0.97 min (Analysis conditions: SMD-FA05-1).

[0215] Compound 64b, used in the synthesis of Example Compound 64, was synthesized as follows. [ka] (Step 64-1) (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[2-oxo-3-[1-[(3R)-oxolan-3-yl]indazole-5-yl]imidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 64a) Compound 11k obtained in step 11-7 and compound 8f obtained in step 8-4 were synthesized using appropriate reagents in the same manner as in step 1-11 of Example 1. LC / MS mass spectrometry: m / z628([M+H] + ). LC / MS retention time: 1.32 minutes (Analysis conditions: SMD-FA05-1). (Step 64-2) 1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]-3-[1-[(3R)-oxolan-3-yl]indazole-5-yl]imidazole-2-one hydrochloride (compound 64b) Compound 64a obtained in step 64-1 was synthesized using appropriate reagents in the same manner as in step 11-8 of Example 11. LC / MS mass spectrometry: m / z528([M+H] + ). LC / MS retention time: 0.78 min (Analysis conditions: SMD-FA05-1).

[0216] Compound 65c, used in the synthesis of Example Compound 65, was synthesized as follows. [ka] (Step 65-1) (4S)-2-(4-chloro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 65b) Compound 42e obtained in step 42-4 and 5-bromo-4-fluoro-1-methylindazole (compound 65a) were synthesized using appropriate reagents in the same manner as in step 1-11 of Example 1. LC / MS mass spectrometry: m / z606([M+H] + ). LC / MS retention time: 1.38 minutes (Analysis conditions: SMD-FA05-1). (Step 65-2) 1-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]-3-(4-fluoro-1-methylindazole-5-yl)imidazole-2-one hydrochloride (compound 65c) Compound 65b obtained in step 65-1 was synthesized using appropriate reagents in the same manner as in step 11-8 of Example 11. LC / MS mass spectrometry: m / z506([M+H] + ). LC / MS retention time: 0.86 min (Analysis conditions: SMD-FA05-1).

[0217] Compound 67b, used in the synthesis of Example Compound 67, was synthesized as follows. [ka] (Step 67-1) (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 67a) Compound 11k obtained in step 11-7 and 5-bromo-4-fluoro-1-methylindazole (compound 65a) were synthesized using appropriate reagents in the same procedure as in step 1-11 of Example 1. LC / MS mass spectrometry: m / z590([M+H] + ). LC / MS retention time: 1.31 minutes (Analysis conditions: SMD-FA05-1). (Step 67-2) 1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(4-fluoro-1-methylindazole-5-yl)imidazole-2-one hydrochloride (compound 67b) Compound 67a obtained in step 67-1 was synthesized using appropriate reagents in the same manner as in step 11-8 of Example 11. LC / MS mass spectrometry: m / z490([M+H] + ). LC / MS retention time: 0.80 min (Analysis conditions: SMD-FA05-1).

[0218] Compound 68c, used in the synthesis of Example Compound 68, was synthesized as follows. [ka] (Step 68-1) (4S)-3-[3-(4-chloro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 68b) Compound 11k obtained in step 11-7 and 5-bromo-4-chloro-1-methylindazole (compound 68a) were synthesized using appropriate reagents in the same procedure as in step 1-11 of Example 1. LC / MS mass spectrometry: m / z606([M+H] + ). LC / MS retention time: 1.34 minutes (Analysis conditions: SMD-FA05-1). (Step 68-2) 1-(4-chloro-1-methylindazole-5-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]imidazole-2-one hydrochloride (compound 68c) Compound 68b obtained in step 68-1 was synthesized using appropriate reagents in the same manner as in step 11-8 of Example 11. LC / MS mass spectrometry: m / z506([M+H] + ). LC / MS retention time: 0.83 minutes (Analysis conditions: SMD-FA05-1).

[0219] Compound 69b, used in the synthesis of Example Compound 69, was synthesized as follows. [ka] (Step 69-1) ( 4S)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-2-(4-fluoro-3-methylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 69a) Compound 46d obtained in step 46-3 and 5-bromo-4-fluoro-1-methylindazole (compound 65a) were synthesized using appropriate reagents in the same manner as in step 1-11 of Example 1. LC / MS mass spectrometry: m / z576([M+H] + ). LC / MS retention time: 1.25 minutes (Analysis conditions: SMD-FA05-1). (Step 69-2) 1-(4-fluoro-1-methylindazole-5-yl)-3-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]imidazole-2-one hydrochloride (compound 69b) Compound 69a obtained in step 69-1 was synthesized using appropriate reagents in the same manner as in step 11-8 of Example 11. LC / MS mass spectrometry: m / z476([M+H] + ). LC / MS retention time: 0.77 min (Analysis conditions: SMD-FA05-1).

[0220] Compound 70c, used in the synthesis of Example Compound 70, was synthesized as follows. [ka] (Step 70-1) (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(6-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 70b) Compound 11k obtained in step 11-7 and 5-bromo-6-fluoro-1-methylindazole (compound 70a) were synthesized using appropriate reagents in the same procedure as in step 1-11 of Example 1. LC / MS mass spectrometry: m / z590([M+H] + ). LC / MS retention time: 1.28 minutes (Analysis conditions: SMD-FA05-1). (Step 70-2) 1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(6-fluoro-1-methylindazole-5-yl)imidazole-2-one hydrochloride (compound 70c) Compound 70b obtained in step 70-1 was synthesized using appropriate reagents in the same manner as in step 11-8 of Example 11. LC / MS mass spectrometry: m / z490([M+H] + ). LC / MS retention time: 0.81 min (Analysis conditions: SMD-FA05-1).

[0221] Compound 71b, used in the synthesis of Example Compound 71, was synthesized as follows. [ka] (Step 71-1) 5-Bromo-6-fluoro-1-(2-methoxyethyl)indazole (compound 71b) It was synthesized from 5-bromo-6-fluoro-1H-indazole (compound 71a) using appropriate reagents and the same procedure as in step 8-4 of Example 8. LC / MS mass spectrometry: m / z273([M+H] + ). LC / MS retention time: 1.06 minutes (Analysis conditions: SMD-FA05-1). (Step 71-2) (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[6-fluoro-1-(2-methoxyethyl)indazole-5-yl]-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 71c) Compound 11k obtained in step 11-7 and compound 71b obtained in step 71-1 were synthesized using appropriate reagents in the same manner as in step 1-11 of Example 1. LC / MS mass spectrometry: m / z634([M+H] + ). LC / MS retention time: 1.30 minutes (Analysis conditions: SMD-FA05-1). (Step 71-3) 1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]-3-[6-fluoro-1-(2-methoxyethyl)indazole-5-yl]imidazole-2-one hydrochloride (compound 71d) Compound 71c obtained in step 71-2 was synthesized using appropriate reagents in the same manner as in step 11-8 of Example 11. LC / MS mass spectrometry: m / z534([M+H] + ). LC / MS retention time: 0.83 minutes (Analysis conditions: SMD-FA05-1).

[0222] <Example 73> Synthesis of 3-[(1S,2S)-1-[5-(2-ethyl-3-methylpyridine-4-yl)-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (Compound 73) (Step 73-1) [ka] A racemic mixture (compound 73a, 29.6 mg, 0.058 mmol) synthesized in the same manner as the compound obtained in step 61-2, and compound 1o (26.8 mg, 0.064 mmol) obtained in step 1-9 were dissolved in DMF (1.5 mL). HATU (26.6 mg, 0.070 mmol) and N,N-diisopropylethylamine (18.1 mg, 0.14 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with distilled water. The organic layer was concentrated under reduced pressure to obtain a residue, which was a mixture of stereoisomers. The stereoisomers were separated by reverse-phase HPLC to obtain Entity A (14.5 mg, yield 29%) and Entity B (15.5 mg, yield 31%), which is the title compound 73, a white solid. Partitioning conditions Column: YMC Actus ODS-A, 20×100mm, 5μm Solvent: 0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution = 40 / 60 (homogeneous system) Flow rate: 20mL / min, room temperature Entity A LC / MS mass spectrometry: m / z872([M+H] + ). LC / MS retention time: 0.99 minutes (Analysis conditions: SMD-FA05-3). Entity B (Compound 73) LC / MS mass spectrometry: m / z872([M+H] + ). LC / MS retention time: 1.01 min (Analysis conditions: SMD-FA05-3).

[0223] <Example 74> Synthesis of 3-[(1S,2S)-1-[6-fluoro-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridine-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (Compound 74) [ka] (Step 74-1) 5-Bromo-6-fluoro-N-methyl-N-phenyl-1H-indole-2-carboxamide (compound 74b) It was synthesized from 5-bromo-6-fluoro-1H-indole-2-carboxylic acid (compound 74a) using appropriate reagents and the same procedure as in steps 1-10 of Example 1. LC / MS mass spectrometry: m / z347([M+H] + ). LC / MS retention time: 1.06 minutes (Analysis conditions: SMD-TFA05-4). (Step 74-2) 5-Bromo-1-(cyanomethyl)-6-fluoro-N-methyl-N-phenylindole-2-carboxamide (compound 74c) Compound 74b obtained in step 74-1 was synthesized using appropriate reagents in the same manner as in step 9-1 of Example 9. LC / MS mass spectrometry: m / z386([M+H] + ). LC / MS retention time: 1.06 min (Analysis conditions: SMD-TFA50-4). (Step 74-3) 5-Bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-6-fluoro-N-methyl-N-phenylindole-2-carboxamide (compound 74d) Compound 74c obtained in step 74-2 and (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (compound 1k) were synthesized using appropriate reagents in the same procedure as in step 1-6 of Example 1. LC / MS mass spectrometry: m / z426([M+H] + ). LC / MS retention time: 1.04 minutes (Analysis conditions: SMD-FA10-5). (Step 74-4) 5-Bromo-6-fluoro-N-methyl-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]-N-phenylindole-2-carboxamide (compound 74e) Compound 74d obtained in step 74-3 was synthesized using appropriate reagents in the same manner as in step 1-8 of Example 1. LC / MS mass spectrometry: m / z485([M+H] + ). LC / MS retention time: 1.33 minutes (Analysis conditions: SMD-FA05-1). (Step 74-5) 5-Bromo-6-fluoro-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 74f) Compound 74e obtained in step 74-4 was synthesized using appropriate reagents in the same manner as in step 6-4 of Example 6. LC / MS mass spectrometry: m / z396([M+H] + ). LC / MS retention time: 0.80 min (Analysis conditions: SQD-FA05-1). (Step 74-6) 3-[(1S,2S)-1-[5-bromo-6-fluoro-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 74g) Compound 74f obtained in step 74-5 and compound 61b obtained in step 61-2 were synthesized using appropriate reagents in the same manner as in step 1-10 of Example 1. LC / MS mass spectrometry: m / z849([M+H] + ). LC / MS retention time: 1.42 minutes (Analysis conditions: SMD-FA05-1). (Step 74-7) 3-[(1S,2S)-1-[6-fluoro-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridine-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 74) Using 74 g of the compound obtained in step 74-6 and 6 g of 4-iodo-2-methoxy-3-methylpyridine (compound), along with appropriate reagents, the compound was synthesized by the same procedure as in step 6-5 of Example 6. LC / MS mass spectrometry: m / z892([M+H] + ). LC / MS retention time: 1.48 minutes (Analysis conditions: SMD-TFA05-1).

[0224] <Examples 75-77> Using an indole bromide compound, an iodo(oxan-4-yl) zinc derivative, and appropriate reagents, the same procedure as in step 8-1 of Example 8 was carried out, and the example compounds 75-77 shown in Table 2-6 were obtained by the following reaction. [ka] [Table 2-6] JPEG2026048784000147.jpg134155 JPEG2026048784000148.jpg133155

[0225] Compound 75b, used in the synthesis of Example Compound 75, was synthesized as follows. (Step 75-1) Iodo(6-oxaspiro[4.5]decane-9-yl)zinc(compound 75b) [ka] It was synthesized from 9-iodo-6-oxaspiro[4.5]decane (compound 75a) using appropriate reagents and the same procedure as in step 41-1 of Example 41. This compound was used directly in the next step.

[0226] Compound 76a, used in the synthesis of Example Compound 76, was synthesized as follows. [ka] (Step 76-1) 3-[(1S,2S)-1-[5-bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1-(2-methoxyethyl)indazole-5-yl]-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 76a) Compound 56b obtained in step 56-1 and compound 6f obtained in step 6-4 were synthesized using appropriate reagents in the same manner as in step 1-10 of Example 1. LC / MS mass spectrometry: m / z861([M+H] + ). LC / MS retention time: 1.45 minutes (Analysis conditions: SMD-FA05-2).

[0227] <Example 77> [ka] (Step 77-1) 2-Ethyl-4-iodooxane (compound 77b) To a solution of 0.588 mL, 6.93 mmol of buta-3-en-1-ol in 2.48 mL of acetic acid, propionaldehyde (0.650 mL, 9.01 mmol) and lithium iodide (2.78 g, 20.8 mmol) were sequentially added, and the mixture was stirred at 60°C for 1 hour. Water was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure (with a lower limit of 150 hPa), and the residue was purified by silica gel chromatography (ethyl acetate / hexane = 0:1 to 1:9) to obtain the title compound 77b, a pale yellow oily substance, as a diastereomer mixture (1.12 g, yield 67%, syn:anti = 1.00:0.45). 1 H-NMR (400 MHz, CDCl3): syn δ:4.31-4.23(1H,m),3.90-3.82(1H,m),3.44-3.37(1H,m),3.21-3.15(1H,m),2.37-1.38(6H,m),0.92(3H,t,J=7.4Hz). anti δ:4.87-4.84(1H,m),3.90-3.82(2H,m),3.70-3.64(1H,m),2.37-1.38(6H,m),0.94(3H,t,J=7.6Hz). (Step 77-2) (2-ethyloxan-4-yl)-iodozinc (compound 77c) To a DMA (0.25 mL) solution of zinc (102 mg, 1.56 mmol), a mixture of chloro(trimethyl)silane (0.017 mL, 0.137 mmol) and 1,2-dibromoethane (0.012 mL, 0.137 mmol) was slowly added dropwise under a nitrogen atmosphere, maintaining a temperature below 65°C, and the mixture was stirred at room temperature for 15 minutes. Subsequently, a DMA (0.625 mL) solution of compound 77b (300 mg, 1.25 mmol) obtained in step 77-1 was slowly added dropwise, maintaining a temperature below 65°C, and the mixture was stirred under a nitrogen atmosphere at room temperature for 30 minutes to obtain a DMA solution (0.86 M) of the diastereomer mixture of the title compound 77c. (Step 77-3) 3-[(1S,2S)-1-[5-(2-ethyloxan-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 77) To a DMA (0.163 mL) solution of compound 51d (40.0 mg, 0.049 mmol) obtained in step 51-4, palladium(II) acetate (2.20 mg, 0.00978 mmol) and 2-(2-dicyclohexylphosphanylphenyl)-1-N,1-N,3-N,3-N-tetramethylbenzene-1,3-diamine (8.54 mg, 0.020 mmol) were added, the mixture was degassed under reduced pressure, then nitrogen was purged, and the mixture was stirred at room temperature for 5 minutes. Subsequently, a DMA (0.86 M, 0.398 mL, 0.342 mmol) solution of compound 77c obtained in step 77-2 was added, and the mixture was stirred at room temperature for 1.5 hours. Formic acid was added to the reaction mixture, and the mixture was purified by reverse-phase silica gel chromatography (acetonitrile / water, 0.1% formic acid) to obtain a syn diastereomer mixture. The syn-diastereomer mixture was separated into stereoisomers by reverse-phase HPLC to obtain Entity A (17.4 mg, 41% yield) and Entity B (14.9 mg, 37% yield), which is the title compound 77, both of which are white amorphous materials. Partitioning conditions Column: CHIRALCEL OD-RH 5μm, 4.6mm × 150mm (Daicel) Solvent: 0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution = 20 / 80 (homogeneous system) Flow rate: 1.0mL / min, room temperature Entity A LC / MS mass spectrometry: m / z 851([M+H] + ). HPLC retention time: 4.99 minutes (preparative conditions). LC / MS retention time: 1.46 minutes (Analysis conditions: SMD-FA05-1). Entity B (Compound 77) LC / MS mass spectrometry: m / z 851([M+H] + ). HPLC retention time: 6.64 minutes (preparative conditions). LC / MS retention time: 1.46 minutes (Analysis conditions: SMD-FA05-1).

[0228] <Example 78> Synthesis of 3-[(1S,2S)-2-ethyl-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]cyclopropyl]-4H-1,2,4-oxadiazole-5-one (Compound 78) [ka] (Step 78-1) 2-[5-bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]acetonitrile (compound 78a) Compound 51c obtained in step 51-3 and 5-bromo-1-(cyanomethyl)indole-2-carboxylic acid (compound 6a) were synthesized using appropriate reagents in the same procedure as in step 1-10 of Example 1. LC / MS mass spectrometry: m / z718([M+H] + ). LC / MS retention time: 1.30 minutes (Analysis conditions: SMD-FA05-1). (Step 78-2) 2-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]acetonitrile (compound 78b) Compound 78a obtained in step 78-1 and (tetrahydro-2H-pyran-4-yl)zinc(II) iodide (compound 8a) were synthesized using appropriate reagents in the same procedure as in step 8-1 of Example 8. LC / MS mass spectrometry: m / z724([M+H] + ). LC / MS retention time: 1.21 minutes (Analysis conditions: SMD-FA05-1). (Step 78-3) (1S,2S)-2-ethyl-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]cyclopropane-1-carbonitrile (compound 78d) Compound 78b obtained in step 78-2 was synthesized using appropriate reagents in the same manner as in step 1-6 of Example 1. LC / MS mass spectrometry: m / z778([M+H] + ). LC / MS retention time: 1.27 minutes (Analysis conditions: SMD-FA05-RP). (Step 78-4) 3-[(1S,2S)-2-ethyl-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]cyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 78) Compound 78d obtained in step 78-2 was synthesized using appropriate reagents in the same manner as in step 1-8 of Example 1. LC / MS mass spectrometry: m / z837([M+H] + ). LC / MS retention time: 1.39 minutes (Analysis conditions: SMD-TFA05-2).

[0229] <Example 79> Synthesis of 3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]-2-(hydroxymethyl)cyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 79) [ka] (Step 79-1) 5-Bromo-1-[(1S,2S)-1-cyano-2-(phenylmethoxymethyl)cyclopropyl]-N-methyl-N-phenylindole-2-carboxamide (compound 79b) Compound 6c obtained in step 6-1 and (4R)-4-(phenylmethoxymethyl)-1,3,2-dioxathiolane 2,2-dioxide (compound 79a) were synthesized using appropriate reagents in the same procedure as in step 1-6 of Example 1. LC / MS mass spectrometry: m / z514([M+H] + ). LC / MS retention time: 1.48 minutes (Analysis conditions: SMD-FA05-1). (Step 79-2) 1-[(1S,2S)-1-cyano-2-(phenylmethoxymethyl)cyclopropyl]-N-methyl-5-(oxan-4-yl)-N-phenylindole-2-carboxamide (compound 79c) Compound 79b obtained in step 79-1 and (tetrahydro-2H-pyran-4-yl)zinc(II) iodide (compound 8a) were synthesized using appropriate reagents in the same procedure as in step 8-1 of Example 8. LC / MS mass spectrometry: m / z520([M+H] + ). LC / MS retention time: 1.37 minutes (Analysis conditions: SMD-FA05-1). (Step 79-3) N-methyl-5-(oxan-4-yl)-1-[(1S,2S)-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)-2-(phenylmethoxymethyl)cyclopropyl]-N-phenylindole-2-carboxamide (79d) Compound 79c obtained in step 79-2 was synthesized using appropriate reagents in the same manner as in step 1-8 of Example 1. LC / MS mass spectrometry: m / z579([M+H] + ). LC / MS retention time: 1.37 minutes (Analysis conditions: SMD-FA05-1). (Step 79-4) 5-(oxan-4-yl)-1-[(1S,2S)-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)-2-(phenylmethoxymethyl)cyclopropyl]indole-2-carboxylic acid (79e) Compound 79d obtained in step 79-3 was synthesized using appropriate reagents in the same manner as in step 6-4 of Example 6. LC / MS mass spectrometry: m / z490([M+H] + ). LC / MS retention time: 1.12 minutes (Analysis conditions: SMD-FA05-1). (Step 79-5) 3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]-2-(phenylmethoxymethyl)cyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 79f) Compound 79e obtained in step 79-4 and compound 51c obtained in step 51-3 were synthesized using appropriate reagents in the same manner as in step 1-10 of Example 1. LC / MS mass spectrometry: m / z929([M+H] + ). LC / MS retention time: 1.41 minutes (Analysis conditions: SMD-FA05-1). (Step 79-6) 3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]-2-(hydroxymethyl)cyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 79) A solution of compound 79f (35.4 mg, 0.0381 mmol) obtained in step 79-5 was cooled to 0°C in dichloromethane (0.762 mL), and a hexane solution of 1 M boron trichloride (0.191 mL, 0.191 mmol) was slowly added. The reaction solution was heated to room temperature and stirred for 105 minutes. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (18.5 mg, yield 50%). LC / MS mass spectrometry: m / z839([M+H] + ). LC / MS retention time: 1.20 minutes (Analysis conditions: SMD-TFA05-1).

[0230] <Example 80> Synthesis of 3-[(1S,2S)-1-[2-[(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 80) [ka] (Step 80-1) (E)-3-[[(2S)-1-cyanopropan-2-yl]amino]buta-2-enoate ethyl (compound 80c) (3S)-3-aminobutanenitrile (compound 80b, 7.0 g, 83.2 mmol) and iodine (2.12 g, 8.35 mmol) were dissolved in acetonitrile (50 mL), to which ethyl 3-oxobutanoate (compound 80a, 13 g, 99.9 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and after the solvent was removed by distillation, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:2) to obtain the title compound 80c (9.5 g, yield 58%) as a yellow oily substance. LC / MS mass spectrometry: m / z197([M+H] + ). LC / MS retention time: 0.86 min (Analysis conditions: SMD-FA10-1). (Step 80-2) 3-[[(2S)-1-cyanopropan-2-yl]amino]ethyl butanoate (compound 80d) Compound 80c (10 g, 51.0 mmol) obtained in step 80-1 and sodium triacetoxyborohydride (43.3 g, 204 mmol) were dissolved in dichloromethane (200 mL), to which acetic acid (3 mL) was added and the mixture was stirred at room temperature for 16 hours. Water and acetic acid were added to the reaction mixture to adjust the pH to 5, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 1:4) to obtain the title compound 80d (5.5 g, yield 54%) as a yellow oily substance. LC / MS retention time: 0.83 min (Analysis conditions: SMD-FA10-4). (Step 80-3) (6S)-1-formyl-4-hydroxy-2,6-dimethyl-3,6-dihydro-2H-pyridine-5-carbonitrile (compound 80e) To a toluene (10 mL) solution of potassium tert butoxide (680 mg, 6.06 mmol), a toluene (5 mL) solution of compound 80d (1.0 g, 5.04 mmol) obtained in step 80-2 was slowly added dropwise at 80°C. After stirring at 80°C for 1 hour, the mixture was cooled to room temperature to obtain a toluene solution of (6S)-4-hydroxy-2,6-dimethyl-1,2,3,6-tetrahydropyridine-5-carbonitride. At 0°C, a solution of acetic anhydride (12.1 g, 118 mmol) in toluene (5 mL) was slowly added dropwise to formic acid (7.26 g). After stirring at 0°C for 30 minutes, the prepared solution of (6S)-4-hydroxy-2,6-dimethyl-1,2,3,6-tetrahydropyridine-5-carbonitride in toluene was slowly added dropwise. After stirring at 110°C for 16 hours, the mixture was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the solvent was removed by distillation to obtain a mixture (1.3 g) containing the title compound 80e as an oily substance. (Step 80-4) (4S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbaldehyde (compound 80f) A solution of compound 80e (1.30 g, 7.21 mmol) obtained in step 80-3 and (4-fluoro-3,5-dimethylphenyl)hydrazine hydrochloride (compound 2c, 690 mg, 3.62 mmol) in ethanol (30 mL) was heated to 75°C and stirred for 16 hours. The mixture was cooled to room temperature and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1:0 to 9:1) to obtain the title compound 80f (two steps from step 80-3, 800 mg, yield 35%) as a yellow solid. LC / MS mass spectrometry: m / z317([M+H] + ). LC / MS retention time: 0.79 min (Analysis conditions: SMD-FA10-3). (Step 80-5) 1-(2,2-dimethoxyethyl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-5-formyl-4,6-dimethyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3-yl]urea (compound 80g) To a DMA (50 mL) solution of N,N'-carbodimidazole (1.63 g, 10.1 mmol), 2,2-dimethoxyethane-1-amine (1.14 g, 10.8 mmol) was added at 0°C and the mixture was stirred for 30 minutes. Potassium tert-butoxide (5.62 g, 50.1 mmol) and compound 80f (2.64 g, 8.34 mmol) obtained in step 80-4 were sequentially added to the solution. After stirring at room temperature for 6 hours, water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 80 g (2.80 g, yield 75%) of the title compound as a brown oily substance. LC / MS mass spectrometry: m / z448([M+H] + ). LC / MS retention time: 0.84 min (Analysis conditions: SMD-FA10-2). (Step 80-6) (4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbaldehyde (compound 80h) A solution of 80 g (2.50 g, 5.59 mmol) of the compound obtained in step 80-5 and 4-methylbenzenesulfonic acid (1.06 g, 6.16 mmol) in DMF (30 mL) was heated to 80°C and stirred for 2 hours. After cooling to room temperature, water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain a diastereochemical mixture (480 mg) containing the title compound (compound 80h) as a white solid. LC / MS mass spectrometry: m / z384([M+H] + ). LC / MS retention time: 1.64 minutes (Analysis conditions: SMD-TFA05-6). A diastereochemical mixture (480 mg, 5.59 mmol) containing the title compound (compound 80h: (4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbaldehyde) was separated into stereoisomers by SFC, yielding Entity A (155 mg, yield 7.0%) and Entity B (270 mg, yield 12%), which are the title compound 80h. SFC preparative conditions Column: CHIRALPAK AD-H, 50×500mm, 3μm (Daicel) Solvent: Supercritical carbon dioxide / ethanol = 70:30 (homogeneous system) Flow rate: 150mL / min, 35℃ Detection wavelength: 254nm Entity A (compound 80h) SFC retention time: 4.07 minutes. LC / MS mass spectrometry: m / z384([M+H] + ). LC / MS retention time: 2.15 minutes (Analysis conditions: SMD-FA1060-1). 1 H-NMR(300MHz,DMSO-D6) δ:10.35(1H,s),8.24(1H,s),7.11(2H,d,J=6.3Hz),6.60-6.58(2H,m),5.21-5.14(1H,m) ,4.46-4.21(1H,m),2.96-2.89(1H,m),2.74-2.68(1H,m),2.20(6H,s),1.27-1.13(6H,m). Furthermore, the 6R isomer of compound 80h was confirmed by 2D-NOESY analysis, which determined that its stereochemistry is cis. Entity B SFC retention time: 5.60 minutes. LC / MS mass spectrometry: m / z384([M+H] + ). LC / MS retention time: 2.16 minutes (Analysis conditions: SMD-FA1060-1). 1H-NMR(300MHz,DMSO-D6) δ:10.35(1H,s),8.31(1H,s),7.08(2H,d,J=6.3Hz),6.61-6.54(2H,m),5.39(1H,q,J=6.9Hz),3.89-3.84(1H,m),2 .90(1H,dd,J=3.3,15.6Hz),2.59-2.51(1H,m),2.20(6H,d,J=2.1Hz),1.55(3H,d,J=6.6Hz),1.18(3H,d,J=6.6Hz). (Step 80-7) 3-[(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]-1H-imidazole-2-one (compound 80i) To a solution of compound 80h (100 mg, 0.261 mmol) obtained in step 80-6 in ethanol (1.0 mL), 5 M sodium hydroxide aqueous solution (0.261 mL) was added and the mixture was stirred at 80°C for 10 hours. After cooling to room temperature and stirring for 60 hours, saturated ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate to synthesize the title compound 80i (79%, 73 mg) as a white solid. LC / MS mass spectrometry: m / z356([M+H] + ). LC / MS retention time: 0.44 min (Analysis conditions: SQD-FA05-2). (Step 80-8) 1-[(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1-methylindazole-5-yl)imidazole-2-one (compound 80j) To a suspension of compound 80i (15 mg, 0.042 mmol) obtained in step 80-7, 5-bromo-1-methylindazole (compound 1q, 10.7 mg, 0.051 mmol), (1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine (6.00 mg, 0.042 mmol), and potassium carbonate (17.5 mg, 0.127 mmol) in N-methylpiperazine (0.188 mL), copper(I) iodide (4.02 mg, 0.021 mmol) was added at room temperature, and the mixture was stirred at 130°C for 90 minutes under a nitrogen atmosphere. The reaction mixture was purified by reverse-phase silica gel chromatography (acetonitrile / water, 0.1% formic acid) and concentrated under reduced pressure. The residue was mixed with a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was then concentrated under reduced pressure to obtain the title compound 80j (17.4 mg, yield 85%). LC / MS mass spectrometry: m / z486([M+H] +). LC / MS retention time: 0.51 min (Analysis conditions: SQD-FA05-2). (Step 80-9) 5-(oxan-4-yl)-1-[(1S,2S)-2-[5-oxo-4-(2-trimethylsilylethoxymethyl)-1,2,4-oxadiazole-3-yl]-2-methylcyclopropyl]indole-2-carboxylic acid 2-trimethylsilylethoxymethyl (compound 80k) To a solution of compound 8b (100 mg, 0.261 mmol) obtained in step 8-1 in DMF (2.6 mL), 55 wt% sodium hydride (34.1 mg, 0.782 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.116 mL, 0.652 mmol) were added and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. After concentration, the resulting residue was purified by normal-phase column chromatography (ethyl acetate / hexane) to obtain the title compound 80k (147 mg, yield 88%), a yellow gum-like substance. LC / MS retention time: 1.21 minutes (Analysis conditions: SQD-FA05-2) (Step 80-10) 5-(oxan-4-yl)-1-[(1S,2S)-1-[5-oxo-4-(2-trimethylsilylethoxymethyl)-1,2,4-oxadiazole-3-yl]-2-methylcyclopropyl]indole-2-carboxylic acid (80l) To a solution of compound 80k (147 mg, 0.228 mmol) obtained in step 80-9 in dichloromethane (2.3 mL), magnesium bromide diethyl ether complex (295 mg, 1.14 mmol) was added and the mixture was stirred at 0°C for 6.5 hours. After raising the temperature to room temperature and stirring for 30 minutes, saturated ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate. After concentration, the residue was diluted with DMSO and water, and purified by reverse-phase chromatography (acetonitrile / water, 0.1% formic acid) to synthesize the title compound 80l (60 mg, yield 51%). LC / MS mass spectrometry: m / z512([MH] - ). LC / MS retention time: 1.03 minutes (Analysis conditions: SQD-FA05-2). (Step 80-11) 5-(oxan-4-yl)-1-[(1S,2S)-2-[5-oxo-4-(2-trimethylsilylethoxymethyl)-1,2,4-oxadiazole-3-yl]-2-methylcyclopropyl]indole-2-carbonyl chloride (compound 80m) To a solution of 80 L (18 mg, 0.036 mmol) of the compound obtained in step 80-10 in acetonitrile (0.36 mL), 1-chloro-N,N,2-trimethylpropa-1-ene-1-amine (0.0057 mL, 0.043 mmol) was added, and after stirring at room temperature for 2 hours, the solution was concentrated to obtain the crude product of the title compound 80 m. This compound was used directly in the next step. (Step 80-12) 3-[(1S,2S)-2-[2-[(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]-2-methylcyclopropyl]-4-(2-trimethylsilylethoxymethyl)-1,2,4-oxadiazole-5-one (compound 80n) Compound 80m obtained in step 80-11 was dissolved in THF (0.717 mL), compound 80j obtained in step 80-8 (19.1 mg, 0.036 mmol) and N,N-diisopropylethylamine (0.0188 mL, 0.108 mmol) were added, and the mixture was stirred at room temperature for 22 hours, after which methanol and formic acid were added. The mixture was concentrated, the residue was diluted with DMSO and water, and purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to synthesize the title compound 80n (32 mg, yield 91%). LC / MS mass spectrometry: m / z982([M+H] + ). LC / MS retention time: 1.12 minutes (Analysis conditions: SQD-FA50-1). (Step 80-13) 3-[(1S,2S)-1-[2-[(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 80) To a solution of compound 80n (32 mg, 0.033 mmol) obtained in step 80-12 in THF (0.326 mL), acetic acid (0.0019 mL, 0.033 mmol) and a THF solution of 1 M tetrabutylammonium fluoride (0.065 mL, 0.065 mmol) were added and the mixture was stirred at 80°C for 66 hours. Acetic acid (0.0019 mL, 0.033 mmol) and a THF solution of 1 M tetrabutylammonium fluoride (0.065 mL, 0.065 mmol) were added and the mixture was stirred for 23.5 hours. A further THF solution of 1 M tetrabutylammonium fluoride (0.065 mL, 0.065 mmol) was added and the mixture was stirred for 7 hours, after which formic acid was added. After concentration, the mixture was diluted with DMSO and water and purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to synthesize the title compound 80 (18 mg, yield 65%). LC / MS mass spectrometry: m / z851([M+H] + ). LC / MS retention time: 1.42 minutes (Analysis conditions: SMD-TFA05-1).

[0231] Furthermore, in the same manner as in Examples 1 to 80, example compounds 101 to 159, shown in Table 2-7 below, were obtained.

Table 2-7

[0232] <Example 160> Preparation of monosodium salt hydrate crystals of compound 1 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (compound 1, 1005.5 mg) obtained in Example 1 was dissolved in acetonitrile (3.02 mL) at room temperature. To this solution, 5M aqueous sodium hydroxide (0.495 mL) and a seed crystal of the sodium salt hydrate of compound 1 were added and the mixture was stirred at room temperature for 2 hours. Further addition of tert-butyl methyl ether (3.02 mL) and stirring at room temperature for 1 hour, followed by the addition of tert-butyl methyl ether (9.05 mL) and stirring at room temperature for 2 hours, yielded 1007.0 mg of the sodium salt hydrate crystal of the title compound in powder form (Sample 160a). Seed crystals were obtained by the following method. Compound 1 (26.9 mg) was mixed with DMSO (0.244 mL) and 2M sodium hydroxide aqueous solution (0.032 mL). This solution (0.030 mL) was freeze-dried at -20°C for 2 days. Acetonitrile (0.015 mL) was added to the freeze-dried product, and the mixture was shaken at room temperature for 2 days. Then, tert-butyl methyl ether (0.015 mL) was added, and the mixture was shaken at room temperature for 12 days to obtain powdered hydrate crystals of the sodium salt of Compound 1 (Sample 160b).

[0233] <Example 161> Crystal preparation of Example Compound 66 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (Example Compound 66, 400.3 mg) was suspended in ethanol (8.00 mL), a seed crystal of Example Compound 66 was added, and the mixture was stirred at 70°C for 5 minutes. After stirring this suspension at 50°C for 1 hour, the mixture was stirred at room temperature for 17 hours to obtain crystals of Example Compound 66 (381.1 mg) in powder form (Sample 161a). The seed crystal was obtained by the following method. Example compound 66 (31.8 mg) was suspended in ethanol (0.636 mL) and stirred at 80°C. This suspension was stirred at 40°C for 1 hour, and then stirred at room temperature for 22 hours to obtain crystalline example compound 66 (24.2 mg) in powder form (Sample 161b).

[0234] <Example 162> Preparation of 1 / 2 calcium salt hydrate crystals of compound 67 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one (Example Compound 67, 1120 mg) was dissolved in ethanol (5.60 mL) and 2M sodium hydroxide aqueous solution (0.75 mL) at room temperature. To this solution, 0.68 mL of 1.26 M aqueous calcium acetate solution, a seed crystal of the calcium salt hydrate of Example Compound 67, and 0.68 mL of water were added and the mixture was stirred at room temperature for 3 hours. Further, 1.2 mL of water was added and the mixture was stirred at room temperature for 1 hour, then 2.3 mL of water was added and the mixture was stirred at room temperature for 1 hour to obtain 973.0 mg of calcium salt hydrate crystals of Example Compound 67 in powder form (Sample 162a). The seed crystal was obtained by the following method. Example compound 67 (69.0 mg) was dissolved in DMSO (0.229 mL), and 1.06 M calcium methoxyethoxide (0.147 mL) was added. This solution (0.015 mL) was freeze-dried at -20°C for 2 days. A water-acetonitrile mixture (3:1, 0.015 mL) was added to the freeze-dried product, and the mixture was shaken at room temperature for 7 days to obtain powdered hydrate crystals of the calcium salt of Example compound 67 (Sample 162b).

[0235] <Example 163> Powder X-ray diffraction measurement The sodium salt hydrate crystals of compound 1 obtained in Example 160 (samples 160a and 160b), the crystals of example compound 66 obtained in Example 161 (samples 161a and 161b), and the calcium salt hydrate crystals of example compound 67 obtained in Example 162 (samples 162a and 162b) were subjected to powder X-ray diffraction measurements using the following methods. The results are shown in Figures 1 to 6. Measurement device: D8 Discover with GADDS CS diffractometer (manufactured by Bruker AXS) Cathode: Cu Tube voltage: 40kV Tube current: 40mA Scanning range: 5~25.3° Sampling width: 0.02°

[0236] <Example 164> Thermogravimetric Analysis and Differential Thermal Analysis The sodium salt hydrate crystals of compound 1 (sample 160a) and the calcium salt hydrate crystals of example compound 67 (sample 162a) were subjected to thermogravimetric and differential thermal analysis using the following methods. The results are shown in Figures 7 and 8. Sample 160a dehydrated to approximately 110°C and did not exhibit a clear melting point. Similarly, sample 162a dehydrated to approximately 240°C and did not exhibit a clear melting point. Measuring device: EXSTAR TG / DTA6200R (manufactured by Seiko Instruments (now Hitachi High-Tech Science)) Measurement range: 30~350℃ Heating rate: 10°C / min Atmosphere: Nitrogen

[0237] <Example 165> Karl Fischer moisture measurement The water content in the sodium salt hydrate crystals of compound 1 (sample 160a) and the calcium salt hydrate crystals of example compound 67 (sample 162a) was measured using a coulometric Karl Fischer moisture meter (Metrohm 756 KF Coulometer). The results were 7.4% for sample 160a and 6.2% for sample 162a. The results from Examples 164 and 165 confirmed that the water contained in the sodium salt hydrate crystals of Compound 1 and the calcium salt hydrate crystals of Example Compound 67 is mainly crystal water.

[0238] <Test Example 1> Measurement of in vitro cAMP signaling activation of compounds in human GLP1R (peptide) Human GLP-1(7-37) was purchased from the Peptide Institute, dissolved in phosphate-buffered saline to a concentration of 200 μM, and stored in a -80°C freezer. (cell culture) A human GLP1R stable expression cell line (hGLP1R-HEK293) was used in the experiment. The cells were cultured at 37°C in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (Sigma-Aldrich), 100 units / mL penicillin G, 100 μg / mL streptomycin sulfate (Gibco), and 500 μg / mL Geneticin (Gibco), under a humidified atmosphere containing 5% CO2. (cAMP assay) hGLP1R-HEK293 2.0 × 10⁻¹ per well 4 Cells were seeded individually in a 96-well plate and incubated overnight. The following day, the cell culture medium was replaced with 50 μL of medium A (DMEM, 20 mM HEPES, 0.05% BSA, 0.5 mM 3-isobutyl-1-methylxanthine) and incubated at 37°C for 30 minutes. Subsequently, 50 μL of medium B (DMEM, 20 mM HEPES, 0.05% BSA, 0.5 mM 3-isobutyl-1-methylxanthine) containing GLP-1 or a compound was added, and incubated for another 30 minutes at 37°C. After that, 100 μL of Assay lysis buffer (Applied Bioscience) was added, and incubated at 37°C for 30 minutes. The cAMP concentration was quantified using the cAMP HiRange kit (Cisbio Bioassays). (EC 50 (Calculation of) The cAMP concentration in each well was converted to the reaction rate (%), with the cAMP concentration when human GLP-1 (7-37) was treated at a concentration of 1 nM set as 100%. Dose-response curves for each example compound were created using 4-parameter logistic regression analysis with XLfit (ver5.4.0.8), and the 50% effective concentration (EC) was calculated. 50 The result was calculated. The results are shown in Table 3. [Table 3]

[0239] <Test Example 2>: Insulin secretion promoting effect and blood glucose lowering effect Under anesthesia, male cynomolgus monkeys were continuously administered intravenously for 40 minutes with a solution of Example Compound 67 (solvent: PEG400 (10 vol%): propylene glycol (10 vol%): 100 mM Glycine-NaOH buffer, pH 9.0 (80 vol%)) to achieve steady-state plasma drug concentrations of 0.94, 1.6, or 4.8 nmol / L. Similarly, the control drug, exenatide solution (solvent: Tween 0.05% / PBS(-)), was administered to achieve steady-state plasma drug concentrations of 9.2 or 23.9 pmol / L. The solvent group received the solvent from the Example Compound 67 solution. Next, a 50% glucose solution was administered intravenously to a glucose concentration of 0.5 g / kg, and blood samples were collected at 5 or 10-minute intervals to measure plasma insulin and glucose concentrations. The area under the curve was calculated from the time course of each parameter after drug administration to evaluate insulin secretion-promoting and blood glucose-lowering effects. In the group administered with compound 67, a drug concentration-dependent increase in the area under the insulin curve (Figure 9) and a decrease in the area under the plasma glucose curve were observed at steady-state plasma concentrations of 0.94–4.8 nmol / L (Figure 10). In the control group administered with cexenatide, a similar increase in the area under the insulin curve (Figure 9) and a decrease in the area under the plasma glucose curve were observed at steady-state plasma concentrations of 9.2–23.9 pmol / L with continuous intravenous administration (Figure 10). Furthermore, the exenatide concentration of 9.2 pmol / L (38.5 pg / mL) was close to the lower limit of the therapeutic concentration range (50-350 pg / mL) for exenatide in human diabetic patients (Drug Interview Form, Byetta Subcutaneous Injection 5 μg Pen 300, Byetta Subcutaneous Injection 10 μg Pen 300, September 2016 (9th revised edition)). From the above, it was shown that example compound 67 exhibits insulin secretion-promoting and blood glucose-lowering effects equivalent to exenatide at plasma concentrations of 1.6 nmol / L or higher.

[0240] <Test Example 3>: Feeding suppression effect Male cynomolgus monkeys were orally administered example compound 67 for five consecutive days, and the effect on food intake from 3 hours after administration to 90 minutes later each day was examined. In addition, the control drug, exenatide, was subcutaneously administered for five consecutive days, and the effect on food intake from 30 minutes after administration to 90 minutes later was examined. The solvent group consisted of both the oral administration solvent for example compound 67 (DMSO (10 vol%): Cremophor EL (10 vol%): PEG400 (15 vol%): 100 mM Glycine-NaOH buffer pH 10 (65 vol%), 1 mL / kg) and the subcutaneous administration solvent for exenatide (0.05 w / v% Tween / PBS (-), 0.1 mL / kg). In addition, a subcutaneous solvent was administered to the 67 compound dose group (administered drug concentration, 0.05 or 0.1 mg / mL), and an oral solvent was administered to the exenatide dose group (administered drug concentration, 3 or 6 μg / mL). Example compound 67 suppressed food intake in a dose-dependent manner (Figure 11A). The degree of suppression was almost equivalent to that of the control drug exenatide (Figure 11B). Plasma drug concentrations (mean ± standard error) immediately after measuring food intake in each group were 8.0 ± 1.0 nM (0.05 mg / kg group) and 16.3 ± 2.3 nM (0.1 mg / kg group) in the Example compound 67 administration group, and 91 ± 8.5 pM (0.3 μg / kg group) and 199 ± 13.1 pM (0.6 μg / kg group) in the exenatide administration group.

[0241] <Test Example 4> Pharmacokinetics of Compounds Suspensions of calcium salt hydrate crystals of Example Compound 67 obtained in Example 162 (Sample 162a) (doses: 0.05, 0.15, 0.45, and 1.35 mg / kg) were orally administered (forced intragastric administration via gastric catheter) to male cynomolgus monkeys (n=2 for each dose). Blood was then collected venously at time points to obtain plasma. The drug concentration in the plasma was quantified by liquid chromatography-tandem mass spectrometry. The lower limit of quantification was 0.3 ng / mL. Figure 12 shows the plasma drug concentration profile and the time to reach the peak plasma drug concentration (T). max ), maximum plasma drug concentration (C max ) and the area under the plasma drug concentration-time curve (AUC) up to 24 hours after administration. 0-24h ) are shown in Table 4. Plasma drug concentrations after oral administration were C25 at 2 hours after administration for all doses. max After reaching a certain level, it declined in a similar progression pattern. The increase in plasma drug exposure at doses of 0.05, 0.15, 0.45, and 1.35 mg / kg (dose ratio: 1:3:9:27) was approximately proportional to the increase in dose (C max Ratio: 1.0:4.3:6.7:31, AUC 0-24h (Ratio: 1.0:5.7:8.8:44). This substance was shown to be absorbed and eliminated from the gastrointestinal tract in a dose-dependent manner. [Table 4]

Claims

1. Equation (I): 【Chemistry 1】 [In the formula, X is -N = or -CR ａ Represents =; R ａ These are hydrogen atoms, halogen atoms, and C １－６ Selected from alkyl groups; Y is -C(=O)-, -CHR-, and -S(=O) ２ - is selected from; R is a hydrogen atom or C １－６ Represents alkyl; Q １ represents aryl or 5- to 10-membered heteroaryl, where [[MASK_C]] ６－１０ aryl and 5- to 10-membered heteroaryl are each independently substituted from 1 to 5 substituents selected from halogen atoms, [[MASK_C]] ６－１０ alkyl (where [[MASK_C]] １－６ alkyl may be substituted with one or more halogen atoms), and [[MASK_C]] １－６ alkoxy; １－６ and may be substituted with 1 to 5 substituents independently selected therefrom. It should be noted that in the original text, the repeated "C" seems to be a placeholder that might need to be replaced with the actual relevant content in a more complete context. Here, I just translated it as "[[MASK_C]]" for the purpose of following the translation rules. Q ２ represents a 3- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl, where the 3- to 12-membered heterocyclyl and the 5- to 10-membered heteroaryl are halogen atoms, C １－６ Alkyl (where C) １－６ The alkyl group may be substituted with one or more halogen atoms), C １－６ Alkoxy and -NR Ｑａ R Ｑｂ It may be substituted with 1 to 3 substituents independently selected from the above, and furthermore, 2 C １－６ Alkyl groups, together with the carbon atoms to which they are bonded, C ３－８ It may also form a carbon ring; R Ｑａ and R Ｑｂ These are, independently, hydrogen atoms and C １－６ Alkyl, and (C １－６ Selected from alkyl)carbonyl; R １ , R ２ , and R ３ These are, independently, hydrogen atoms and C １－６ Alkyl (where C) １－６ Alkyl is a halogen atom, C １－６ Selected from (may be substituted with one or more substituents independently selected from alkoxy and hydroxyl); R ４ , R ５ , and R ６ These are, independently, a hydrogen atom, a halogen atom, and C １－６ Selected from alkyl groups; R ７ and R ８ These are, independently, hydrogen atoms or C １－６ This represents alkyl, where C １－６ Alkyls are halogen atoms and C ３－１５ It may be substituted with one or more substituents independently selected from cycloalkyl, or R ７ and R ８ They come together with the carbon atoms to which they bond, C ３－１５ A cycloalkane ring may be formed, or R ７ and R ８ C formed by these together ３－１５ A cycloalkane ring consists of 1 to 3 carbon atoms. １－６ It may be substituted with alkyl, where C １－６ Alkyl is a halogen atom, hydroxyl, -NR ７ａ R ７ｂ , C １－６ R may be substituted with one or more substituents independently selected from alkoxys and 3- to 12-membered heterocyclines, ７ａ and R ７ｂ These are, independently, hydrogen atoms and C １－６ Alkyl, and (C １－６ Selected from alkyl)carbonyl; n1 represents an integer from 0 to 3; n2 represents an integer from 0 to 5; R ９ These are equations (IIa), (IIb), (IIc), (IId): 【Chemistry 2】 , -CO ２ R ９ｆ , and -C(=O)-NR ９ｇ R ９ｈ Selected from the groups represented by; R ９ａ , R ９ｂ , R ９ｃ , R ９ｄ , and R ９ｇ These are, independently, hydrogen atoms and C １－６ Alkyl (where C) １－６ Alkyls are halogen atoms and C １－６ (May be substituted with one or more substituents independently selected from the alkoxy), and (C １－６ Selected from alkyl)carbonyl, R ９ｅ C may be substituted with a hydrogen atom or one or more halogen atoms. １－６ R represents alkyl, ９ｆ is a hydrogen atom or C １－６ R represents alkyl, ９ｈ C is a hydrogen atom. １－６ Alkyl, (C １－６ Alkyl)carbonyl, cyano, or -S (=O) ｎ３ -R ９ｉ This represents; n3 represents an integer from 0 to 2, and R ９ｉ C １－６ Represents alkyl; Z １ These are equations (IIIa), (IIIb), (IIIc), (IIId), and (IIIe): 【Transformation 3】 Selected from the groups represented by; R ｚａ C is a hydrogen atom. １－６ Alkyl, and (C １－６ Selected from alkyl)carbonyl, R ｚｂ and R ｚｃ These are, independently, hydrogen atoms or C １－６ The characters represent alkyl, n4 represents an integer from 1 to 3, and n5 and n6 independently represent integers from 0 to 10 (* indicates the binding site to the pyrazolopyridine skeleton, ** indicates Z ２ (These represent the connection points with each other.) Z ２ is selected from C １－６ alkyl, C ３－１５ cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, where C ３－１５ cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are Group A: Group A: a) Oxo, b) Halogen atom, c) Cyano, d) -NR ｚｄ R ｚｅ ; wherein R ｚｄ and R ｚｅ are each independently selected from a hydrogen atom, C １－６ alkyl and (C １－６ alkyl)carbonyl, wherein C １－６ alkyl may be substituted with one or more substituents independently selected from hydroxy, a halogen atom, and C １－６ alkoxy. e)-C(=O)-NR ｚｆ R ｚｇ ; Here R ｚｆ and R ｚｇ These are, independently, hydrogen atoms and C １－６ Alkyl, and (C １－６ Selected from alkyl)carbonyl, where C １－６ Alkyls are composed of hydroxyl, halogen, and C atoms. １－６ It may be substituted with one or more substituents independently selected from the alkoxy. f) - S (= O) ｎ７ -R ｚｈ Here, n7 represents an integer from 0 to 2, R ｚｈ is a hydrogen atom or C １－６ Representing alkyl, g) C １－６ alkyl; here, C １－６ Alkyl is a halogen atom, hydroxyl, -NR ｚｉ R ｚｊ , C １－６ It may be substituted with one or more substituents independently selected from alkoxys and 3- to 12-membered heterocyclyls, where R ｚｉ and R ｚｊ These are, independently, hydrogen atoms or C １－６ Alkyl is represented, and heterocyclyls with 3 to 12 members are hydroxy, C １－６ It may be substituted with one or more substituents independently selected from alkyl groups and 3- to 12-membered heterocyclines. h) C １－６ Alkoxy; here C １－６ Alkoxy compounds consist of hydroxyl, halogen, and C atoms. １－６ It may be substituted with one or more substituents independently selected from the alkoxy. i) 3- to 12-membered heterocyclines; where 3- to 12-membered heterocyclines are C １－６ Alkyl and (C １－６ It may be substituted with one or more substituents independently selected from the alkyl)carbonyl. j) C ６－１０ Ariel; here C ６－１０ Ayl is one or more (C １－６ It may be substituted with an alkyl carbonyl, and k) A 5- to 10-membered heteroaryl; where a 5- to 10-membered heteroaryl is C １－６ Alkyl, C １－６ Alkoxy, -NR ｚｋ R ｚｌ , and may be substituted with one or more substituents independently selected from 3- to 12-membered heterocyclines, where R ｚｋ and R ｚｌ These are, independently, hydrogen atoms and C １－６ Alkyl, and (C １－６ Selected from alkyl)carbonyl, 3- to 12-membered heterocyclines are C １－６ Alkyl and (C １－６ It may be substituted with one or more substituents independently selected from the alkyl)carbonyl. [May be substituted with 1 to 5 substituents independently selected from the above.] A compound represented by , a salt thereof, or a solvate thereof.

2. Q １ However, it is phenyl or pyridyl, where phenyl and pyridyl are halogen atoms and C １－６ The compound according to claim 1, a salt thereof, or a solvate thereof, which is substituted with one to four substituents independently selected from alkyl.

3. R ７ and R ８ Are both hydrogen atoms?; R ７ and R ８ Both are C １－６ Is it alkyl?; R ７ is a hydrogen atom and R ８ C １－６ It is alkyl; or R ７ and R ８ They come together with the carbon atoms to which they bond, C ３－８ It forms a cycloalkane ring, and here the formed C ３－８ Cycloalkyl groups consist of 1-2 carbon atoms. １－６ It may be substituted with alkyl, where C １－６ Alkyl is hydroxy, C １－６ The compound according to claim 1 or 2, a salt thereof, or a solvate thereof, which may be substituted with one or more substituents independently selected from alkoxys and 3- to 12-membered heterocyclines.

4. Z ２ However, C １－６ Alkyl, C ３－１５ Cycloalkyl, 3-12 membered heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, where C ３－１５ Cycloalkyl, 3-12 membered heterocyclyl, C ６－１０ Aryls, and 5- to 10-membered heteroaryls, belong to group B: Group B: a) Oxo, b) Halogen atom, c) -NR ｚｄ１ R ｚｅ１ ; Here R ｚｄ１ and R ｚｅ１ These are, independently, hydrogen atoms and C １－６ Alkyl, and (C １－６ Selected from alkyl)carbonyl, where C １－６ Alkyl is a group of 1 or more C １－６ It may be substituted with an alkoxy. d) - S (= O) ｎ７ -R ｚｈ１ Here, n7 represents an integer from 0 to 2, R ｚｈ１ C １－６ Representing alkyl, e) C １－６ alkyl; here, C １－６ Alkyl is a halogen atom, hydroxyl, -NR ｚｉ R ｚｊ , C １－６ It may be substituted with one or more substituents independently selected from alkoxys and 3- to 12-membered heterocyclyls, where R ｚｉ and R ｚｊ These are, independently, hydrogen atoms or C １－６ Alkyl is represented, and 3- to 12-membered heterocyclyls are hydroxy, C １－６ It may be substituted with one or more substituents independently selected from alkyl groups and 3- to 12-membered heterocyclines. f) C １－６ Alkoxy; here C １－６ The alkoxy may be substituted with one or more hydroxyls. g) A heterocyclyl with 3 to 12 members; where a heterocyclyl with 3 to 12 members has 1 or more (C １－６ It may be substituted with an alkyl carbonyl, and h) 5-10 member heteroaryls; where a 5-10 member heteroaryl is C １－６ Alkyl and -NR ｚｋ１ R ｚｌ１ It may be substituted with one or more substituents independently selected from R, where R ｚｋ１ and R ｚｌ１ These are, independently, hydrogen atoms and C １－６ Selected from alkyl groups, A compound according to any one of claims 1 to 3, a salt thereof, or a solvate thereof, which may be substituted with one to four substituents independently selected from the above.

5. A compound according to any one of claims 1 to 4, a salt thereof, or a solvate thereof, wherein Y is -C(=O)-.

6. R １ The compound, salt thereof, or solvate thereof, according to any one of claims 1 to 5, wherein the compound is a hydrogen atom.

7. A compound according to any one of claims 1 to 6, a salt thereof, or a solvate thereof, wherein both n1 and n2 are 0.

8. R ９ However, equation (IIb): 【Chemistry 4】 A compound according to any one of claims 1 to 7, a salt thereof, or a solvate thereof, represented by [formula].

9. A compound according to any one of claims 1 to 8, a salt thereof, or a solvate thereof, wherein X is -N=, -CH=, or -CF=.

10. Z １ However, equation (IIIa): 【Transformation 5】 A compound according to any one of claims 1 to 9, a salt thereof, or a solvate thereof (where * indicates the binding site with the pyrazolopyridine skeleton, and ** indicates Z ２ (These represent the connection points with each other.)

11. A pharmaceutical composition containing, as an active ingredient, a compound according to any one of claims 1 to 10, a salt thereof, or a solvate thereof.

12. A preventive or therapeutic agent for non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus), hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus (type 1 diabetes mellitus), diabetic complications, obesity, hypertension, dyslipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, non-alcoholic fatty liver disease, Parkinson's disease, or dementia, comprising a compound according to any one of claims 1 to 10, a salt thereof, or a solvate thereof as an active ingredient.

13. A preventive or therapeutic agent for non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus) or obesity, comprising as an active ingredient a compound according to any one of claims 1 to 10, a salt thereof, or a solvate thereof.

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