Pyrazolopyridine derivative having GLP-1 receptor agonist effect

Abstract

To provide: a compound as a GLP-1 receptor agonist which has the same effect as GLP-1 peptide, may be non-invasively administered and is improved in activity, metabolic stability and bioavailability; and a preventive or therapeutic agent for non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity containing the compound as an active ingredient.SOLUTION: The present invention provides: a compound represented by Formula (I) in the figure, in which an indole ring or pyrrolo[2,3-b]pyridine ring and a pyrazolopyridine skeleton are bound to each other through a substituent; or a salt thereof; or a solvate of them.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a compound or a salt thereof, or a solvate thereof, which has an activity similar to that of GLP-1 as a GLP-1 receptor agonist, and also to an agent for preventing or treating non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity, which contains the compound or a salt thereof as an active ingredient. [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 have a variety of actions, such as glucose-dependent insulin secretion promotion, glucagon secretion inhibition, delayed gastric emptying, and food intake inhibition, via the GLP-1 receptor. GLP-1 analogs have already been put to practical use as diabetes treatment drugs, and are considered to be one of the most effective diabetes treatment drugs because of their strong HbA1c-lowering and weight-reducing effects, but all of them require invasive subcutaneous administration. Therefore, the creation of GLP-1 receptor agonists that can be administered non-invasively is expected. For example, attempts have been made to improve the bioavailability of the GLP-1 analogue Semaglutide when administered orally using an absorption enhancer (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, there is a demand for further improvements in pharmaceutical properties, including activity, metabolic stability, and bioavailability.

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

[0004] [ka]

[0005] Patent Document 4 describes the following pyrazolopyridine derivatives as compounds useful for preventing and treating sleeping sickness, leishmaniasis, and the like caused by parasitism of eukaryotic organisms: Trypanosomatidae, such as blastocrithidia.

[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 Summary of the Invention [Problem to be solved by the invention]

[0008] The problem to be solved by the present invention is to provide a compound or a salt thereof, or a solvate thereof, which has an action similar to that of a 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 an agent for preventing or treating non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity, which contains the compound or a salt thereof as an active ingredient. [Means for solving the problem]

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

[0010] That is, in one aspect of the present invention, the following invention is provided. [1] Formula (I): [ka]

[0033] In the formula, X is -N= or -CR a = R a is a hydrogen atom, a halogen atom, and C 1-6 alkyl; Y is selected from -C(=O)-, -CHR-, and -S(=O)-; R is a hydrogen atom or C 1-6 represents alkyl; Q 1 is C 6-10 aryl or 5-10 membered heteroaryl, where C 6-10 Aryl and 5-10 membered heteroaryl are halogen atoms, C 1-6 Alkyl (where C 1-6 The alkyl may be substituted with one or more halogen atoms, and C 1-6 optionally substituted with 1 to 5 substituents independently selected from alkoxy; 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 each independently selected from the group consisting of a halogen atom, C 1-6 Alkyl (where C 1-6 The alkyl may be substituted with one or more halogen atoms, C 1-6 Alkoxy, and -NR Qa R Qb and further comprising one to three substituents independently selected from two C 1-6 Alkyl groups together with the carbon atom to which they are attached form C3-8 may form a carbocyclic ring; R Qa and R Qb are independently a hydrogen atom, C 1-6 Alkyl, and (C 1-6 alkyl)carbonyl; R 1 , R 2 , and R 3 are each independently a hydrogen atom and C 1-6 Alkyl (where C 1-6 Alkyl is a halogen atom, C 1-6 alkoxy, and hydroxy; R 4 , R 5 , and R 6 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R 7 and R 8 are independently a hydrogen atom or C 1-6 Represents alkyl, where C 1-6 Alkyl is a halogen atom and C 3-15 cycloalkyl, or R 7 and R 8 together with the carbon atoms to which they are attached, C 3-15 may form a cycloalkane ring, or R 7 and R 8 Together they form C 3-15 The cycloalkane ring contains 1 to 3 C 1-6 Optionally substituted with alkyl, where C 1-6 Alkyl is a halogen atom, hydroxyl, -NR 7a R 7b , C 1-6 R is optionally substituted with one or more substituents independently selected from alkoxy, and 3- to 12-membered heterocyclyl; 7a and R 7b are independently a hydrogen atom, C 1-6 Alkyl, and (C 1-6alkyl)carbonyl; n1 represents an integer of 0 to 3; n2 represents an integer of 0 to 5; R 9 Formula (IIa), (IIb), (IIc), (IId): [ka] , -CO2R 9f , and -C(=O)-NR 9g R 9h R 9a , R 9b , R 9c , R 9d , and R 9g are each independently a hydrogen atom, C 1-6 Alkyl (where C 1-6 Alkyl is a halogen atom and C 1-6 alkoxy), and (C 1-6 alkyl)carbonyl; R 9e is a hydrogen atom or C which may be substituted with one or more halogen atoms. 1-6 represents alkyl, R 9f is a hydrogen atom or C 1-6 represents alkyl, R 9h is a hydrogen atom, C 1-6 Alkyl, (C 1-6 Alkyl)carbonyl, cyano, or -S(=O) n3 -R 9i n3 represents an integer of 0 to 2, R 9i is C 1-6 represents alkyl; Z 1 are represented by the formulae (IIIa), (IIIb), (IIIc), (IIId), and (IIIe): [ka] R za is a hydrogen atom, C 1-6 Alkyl, and (C 1-6 alkyl)carbonyl; Rzb and R zc are independently a hydrogen atom or C 1-6 n4 represents an integer of 1 to 3, and n5 and n6 each independently represent an integer of 0 to 10 (* represents a bonding site to the pyrazolopyridine skeleton, ** represents Z 2 and the binding sites for each; Z 2 is C 1-6 Alkyl, C 3-15 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein C 3-15 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl are in Group A: Group A: a) oxo, b) a halogen atom, c) cyano, d)-NR zd R ze ;where R zd and R ze are each independently a hydrogen atom, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl, where C 1-6 Alkyl is a group that is substituted with hydroxy, halogen atoms, and C 1-6 Optionally substituted with one or more substituents independently selected from alkoxy; e) -C(=O)-NR zf R zg ;where R zf and R zg are each independently a hydrogen atom, C 1-6 Alkyl, and (C 1-6 alkyl)carbonyl, where C 1-6 Alkyl is a group that is substituted with hydroxy, halogen atoms, and C 1-6 Optionally substituted with one or more substituents independently selected from alkoxy; f) -S(=O) n7 -R zh ; where n7 represents an integer from 0 to 2, and R zh is a hydrogen atom or C1-6 Represents alkyl, g) C 1-6 Alkyl; where C 1-6 Alkyl is a halogen atom, hydroxyl, -NR zi R zj , C 1-6 and 3- to 12-membered heterocyclyl, wherein R zi and R zj are independently a hydrogen atom or C 1-6 alkyl, and 3-12 membered heterocyclyl is hydroxy, C 1-6 optionally substituted with one or more substituents independently selected from alkyl and 3- to 12-membered heterocyclyl; h)C 1-6 Alkoxy; where C 1-6 Alkoxy is a group consisting of hydroxy, halogen atoms, and C 1-6 Optionally substituted with one or more substituents independently selected from alkoxy; i) 3- to 12-membered heterocyclyl; where 3- to 12-membered heterocyclyl is C 1-6 Alkyl and (C 1-6 Optionally substituted with one or more substituents independently selected from: j) C 6-10 Aryl; where C 6-10 Aryl is one or more (C 1-6 alkyl)carbonyl, and k) 5-10 membered heteroaryl; where 5-10 membered heteroaryl is C 1-6 Alkyl, C 1-6 Alkoxy, -NR zk R zl and 3- to 12-membered heterocyclyl, where R zk and R zl are independently a hydrogen atom, C 1-6 Alkyl, and (C 1-6 alkyl)carbonyl, and 3-12 membered heterocyclyl is selected from C 1-6 Alkyl and (C1-6 Optionally substituted with one or more substituents independently selected from: and optionally substituted with 1 to 5 substituents independently selected from A compound represented by the formula:

[0011] [2]Q 1 is phenyl or pyridyl, where phenyl and pyridyl are halogen atoms and 1-6 The compound according to [1], a salt thereof, or a solvate of either of the compound or salt thereof, each of which is 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 alkyl; R 7 is a hydrogen atom and R 8 C 1-6 alkyl; or R 7 and R 8 together with the carbon atoms to which they are attached, C 3-8 forming a cycloalkane ring, where the formed C 3-8 The cycloalkane ring contains 1-2 C 1-6 Optionally substituted with alkyl, where C 1-6 Alkyl is hydroxy, C 1-6 The compound according to [1] or [2], which may be substituted with one or more substituents independently selected from alkoxy and 3- to 12-membered heterocyclyl, a salt thereof, or a solvate of either of them.

[0013] [4] Z 2 But, C 1-6 Alkyl, C 3-15 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein C 3-15 Cycloalkyl, 3-12 membered heterocyclyl, C6-10 Aryl and 5-10 membered heteroaryl are group B: Group B: a) oxo, b) a halogen atom, c)-NR zd1 R ze1 ;where R zd1 and R ze1 are independently a hydrogen atom, C 1-6 Alkyl, and (C 1-6 alkyl)carbonyl, where C 1-6 Alkyl is C 1-6 Optionally substituted with one or more substituents independently selected from alkoxy; d) -S(=O) n7 -R zh1 ; where n7 represents an integer from 0 to 2, and R zh1 is C 1-6 Represents alkyl, e) C 1-6 Alkyl; where C 1-6 Alkyl is a halogen atom, hydroxyl, -NR zi R zj , C 1-6 and 3- to 12-membered heterocyclyl, wherein R zi and R zj are independently a hydrogen atom or C 1-6 alkyl, and 3-12 membered heterocyclyl is hydroxy, C 1-6 optionally substituted with one or more substituents independently selected from alkyl and 3- to 12-membered heterocyclyl; f) C 1-6 Alkoxy; where C 1-6 The alkoxy may be substituted with one or more hydroxy groups. g) 3- to 12-membered heterocyclyl; wherein the 3- to 12-membered heterocyclyl is one or more (C 1-6 alkyl)carbonyl, and h) 5-10 membered heteroaryl; where 5-10 membered heteroaryl is C 1-6 Alkyl, and -NR zk1 R zl1wherein R zk1 and R zl1 are independently a hydrogen atom and C 1-6 selected from alkyl, The compound according to any one of [1] to [3], a salt thereof, or a solvate of any of them, which may be substituted by 1 to 4 substituents independently selected from:

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

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

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

[0017] [8]R 9 is represented by formula (IIb): [ka] The compound according to any one of [1] to [7], a salt thereof, or a solvate thereof, represented by the following formula:

[0018] [9] The compound according to any one of [1] to [8], a salt thereof, or a solvate of any one of them, wherein X is -N=, -CH=, or -CF=.

[0019]

[10] Z 1 is represented by formula (IIIa): [ka] The compound according to any one of [1] to [9], a salt thereof, or a solvate of any one of them, represented by the formula: 2(The binding sites for

[0020]

[11] A pharmaceutical composition comprising the compound according to any one of [1] to

[10] , a salt thereof, or a solvate of either of them as an active ingredient.

[0021]

[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 steatohepatitis, Parkinson's disease, or dementia, comprising as an active ingredient the compound according to any one of [1] to

[10] , a salt thereof, or a solvate of either of them. Here, dementia can be, for example, Alzheimer's disease.

[0022]

[13] A preventive or therapeutic agent for non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity, comprising as an active ingredient the compound according to any one of [1] to

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

[0023]

[14] A method for preventing or treating non-insulin-dependent diabetes mellitus (type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus (type 1 diabetes), diabetic complications, obesity, hypertension, dyslipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, Parkinson's disease, or dementia, comprising administering to a subject an effective amount of the compound according to any one of [1] to

[10] , a salt thereof, or a solvate of any of them. Here, dementia includes, for example, Alzheimer's disease.

[0024]

[15] A method for preventing or treating non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity, comprising administering to a subject an effective amount of the compound according to any one of [1] to

[10] , a salt thereof, or a solvate of either of them. Effect of the Invention

[0025] The compound according to the present invention, a salt thereof, or a solvate thereof has an action as a GLP-1 receptor agonist similar to that of a GLP-1 peptide, and provides a non-peptide preventive or therapeutic agent for non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity, which is expected to have sufficient oral bioavailability. [Brief description of the drawings]

[0026] [Figure 1] 1 shows the results of powder X-ray diffraction measurement of the sodium salt hydrate crystals of Compound 1 (Sample 160a) obtained in Example 163. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Diagram 2] 1 shows the results of powder X-ray diffraction measurement of the sodium salt hydrate crystals of Compound 1 (Sample 160b) obtained in Example 163. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Diagram 3] 1 shows the results of powder X-ray diffraction measurement of the crystals (sample 161a) of Example Compound 66 obtained in Example 163. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 4] 1 shows the results of powder X-ray diffraction measurement of the crystals (sample 161b) of Example Compound 66 obtained in Example 163. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Diagram 5] The results of powder X-ray diffraction measurement of calcium salt hydrate crystals (sample 162a) of Example Compound 67 obtained in Example 163 are shown below. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 6] The results of powder X-ray diffraction measurement of calcium salt hydrate crystals (sample 162b) of Example Compound 67 obtained in Example 163 are shown below. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 7] The results of thermogravimetry and differential thermal analysis of the sodium salt hydrate crystals of Compound 1 obtained in Example 164 are shown. The horizontal axis is temperature (°C), and the right vertical axis is the weight change (%) of the sample in the thermogravimetry. The left vertical axis represents the heat flow observed in the differential thermal analysis. [Figure 8]The results of thermogravimetry and differential thermal analysis of calcium salt hydrate crystals of Example Compound 67 obtained in Example 164 are shown. The horizontal axis is temperature (°C), and the right vertical axis is the weight change (%) of the sample in the thermogravimetry. The left vertical axis represents the heat flow observed in the differential thermal analysis. [Figure 9] Effects of Example Compound 67 and Exenatide on insulin secretion after intravenous administration of glucose to male cynomolgus monkeys. The area under the insulin curve is shown as the mean ± standard error (n = 6). Each drug was administered in a crossover manner. * indicates P < 0.025, ** indicates P < 0.005, and indicates significance against the vehicle group (Williams test). Each drug concentration indicates the mean value of the measured plasma drug concentration. [Figure 10] Effects of Example Compound 67 and Exenatide on plasma glucose levels after intravenous administration of glucose to male cynomolgus monkeys. The area under the plasma glucose curve is shown as the mean ± standard error (n = 6). Each drug was administered in a crossover manner. * indicates P < 0.025, ** indicates P < 0.005, and indicates significance against the vehicle group (Williams test). Each drug concentration indicates the mean value of the measured plasma drug concentration. [Figure 11] The effect of Example Compound 67 and exenatide on the food intake of male cynomolgus monkeys. The food intake is shown as the mean ± standard deviation (n = 6). Each drug was administered in a crossover manner. * indicates P < 0.025, ** indicates P < 0.005, and indicates significance against the vehicle group (Williams test). [Figure 12] Changes in plasma drug concentration when this substance was orally administered to cynomolgus monkeys. Plasma concentration and each dose are shown as the average of n=2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] The present invention will now be described in further non-limiting terms. definition In the present invention, the term "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. In the present invention, when a halogen atom is a substituent of an aryl or the like (for example, X in formula (I) is -CR a = R a In the present invention, when a halogen atom is a substituent such as an alkyl group (for example, Q in formula (I)), preferred examples of the halogen atom include a fluorine atom and a chlorine atom. 1 C 6-10 Aryl or 5-10 membered heteroaryl is C 1-6 In the case where the alkyl group is substituted with an alkyl group, preferred halogen atoms include a fluorine atom and a chlorine atom. 1-6 Specific examples of alkyl 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 The term "alkyl" refers to a straight-chain or branched-chain alkyl group 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 "Alkoxy" means C 1-6 means an alkyl-O- group, where C 1-6Alkyl is as previously defined, and examples thereof include 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, and the like.

[0030] In the present invention, "(C 1-6 "C alkyl)carbonyl" means 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.

[0031] In the present invention, "C 6-10 "Aryl" means an aromatic carbocyclic group, which may have a non-aromatic portion in addition to the aromatic portion. The ring may be a monocyclic or a bicyclic aryl fused to a benzene ring or a monocyclic aryl ring. Examples include phenyl, 1-naphthyl, 2-naphthyl, azulenyl, isochromanyl, 2,4-dihydro-1H-isoquinolin-3-onyl, 1,3-dihydrobenzimidazol-2-onyl, and the like, preferably phenyl.

[0032] In the present invention, "heteroaryl" refers to 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 a monocyclic ring, or a bicyclic heteroaryl condensed with a benzene ring or a monocyclic heteroaryl ring. For example, 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, indolizinyl, imidazopyridyl, benzoisoxazolyl, and benzisothiazolyl.

[0033] In the present invention, "heterocyclyl" refers to 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 3-12 membered, preferably 3-10 membered, monocyclic, or bicyclic or spirocyclic. For example, oxetanyl, azetidinyl, 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 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, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrazolidinyl, thianyl, oxanyl, thioxanyl, indolinyl, isoindolinyl, tetrahydroindolinyl, quinuclidinyl, azepinyl, tropanyl, and the like.

[0034] In the present invention, "C 3-15 "Cycloalkyl" refers to a monovalent group derived from a cyclic saturated aliphatic hydrocarbon having 3 to 15 carbon atoms by removing any one hydrogen atom. 3-8 "Cycloalkyl" refers to cycloalkyl having 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-6 "Cycloalkyl" is a cycloalkyl containing 3 to 6 carbon atoms. When two groups are combined, they form a C 3-15 When the group forms a cycloalkane ring, the group becomes a divalent group, and examples thereof 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 together form C 3-8 When a carbocyclic 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-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2-. In addition, the cycloalkane ring, the carbocyclic ring, and the cyclic hydrocarbon in the cycloalkyl may be a bridged ring. 3-15 Examples of bridged rings in cycloalkyl include bicyclo[1.1.0]butane, bicyclo[3.2.1]octane, bicyclo[5.2.0]nonane, bicyclo[4.3.2]undecane, 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 ]Decan-2-ylidene (2-adamantylidene), pentacyclo[4.2.0.0 2,5 .0 3,8 .0 4,7 ]octane (cubane), etc., which are bridged rings.3-15 Examples of cycloalkyl include bicyclo[1.1.0]butyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, bicyclo[4.3.2]undecyl, tricyclo[2.2.1.0]butyl, and the like. 2,6 ]heptyl, tricyclo[4.3.1.1 2,5 ]undecyl, adamantyl, 2-adamantylidenyl, cubanyl, and the like.

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

[0037] X is -N= or -CR a = R a is a hydrogen atom, a halogen atom, and C 1-6 X is preferably -N=, -CH=, or -CF=, more preferably -CH=.

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

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

[0040] 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 each independently selected from the group consisting of a halogen atom, C 1-6 Alkyl (where C 1-6 The alkyl may be substituted with one or more halogen atoms, C 1-6 Alkoxy, and -NR Qa R Qb and further comprising one to three substituents independently selected from two C 1-6 Alkyl groups together with the carbon atom to which they are attached form C 3-8 may form a carbocyclic ring; R Qa and R Qb are independently a hydrogen atom, C 1-6 Alkyl, and (C 1-6 Preferably, Q is selected from the group consisting of alkyl, aryl ... 2 i) represents a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is selected from one or more C 1-6 may be substituted with alkyl, and may further comprise two C 1-6 Alkyl groups together with the carbon atom to which they are attached form C 3-8 or ii) represents a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is selected from the group consisting of a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, and -NR Qc R Qd R Qc and R Qd are independently a hydrogen atom and C 1-6 Also preferably, Q is selected from alkyl. 2 represents a 5-6 membered heterocyclyl or heteroaryl, where the 5-6 membered heterocyclyl and the 5-6 membered heteroaryl are each independently selected from 1 to 3 C 1-6It may be substituted with alkyl.

[0041] R 1 , R 2 , and R 3 are each independently a hydrogen atom and C 1-6 Alkyl (where C 1-6 Alkyl is a halogen atom, C 1-6 alkoxy, and hydroxy. 1 , R 2 , and R 3 The combination of 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 is selected from alkyl.

[0042] R 4 , R 5 , and R 6 are each independently a hydrogen atom, a halogen atom, or C 1-6 R is selected from alkyl. 4 , R 5 , and R 6 are preferably each independently a hydrogen atom or a fluorine atom. More preferably, R 4 , R 5 , and R 6 The combination of is hydrogen atom; or R 4 is a hydrogen atom, R 5 is a hydrogen atom, R 6 is a fluorine atom.

[0043] R 7 and R 8 are independently a hydrogen atom or C 1-6 Represents alkyl, where C 1-6 Alkyl is a halogen atom and C 3-15cycloalkyl; and R 7 and R 8 together with the carbon atoms to which they are attached, C 3-15 may form a cycloalkane ring, or R 7 and R 8 Together they form C 3-15 The cycloalkane ring contains 1 to 3 C 1-6 Optionally substituted with alkyl, where C 1-6 Alkyl is a halogen atom, hydroxyl, -NR 7a R 7b , C 1-6 R is optionally substituted with one or more substituents independently selected from alkoxy, and 3- to 12-membered heterocyclyl; 7a and R 7b are independently a hydrogen atom, C 1-6 Alkyl, and (C 1-6 R is selected from the group consisting of alkyl, carbonyl, and 7 and R 8 preferably taken together with the carbon atom to which they are attached, C 3-8 forming a cycloalkane ring, where the formed C 3-8 Cycloalkyl is one or more C 1-6 Optionally substituted with alkyl, where C 1-6 The alkyl may be substituted with one or more hydroxy groups. 3-8 Cycloalkyl is C 3-6 Cycloalkyl is preferred. 3-6 Cycloalkyl includes, for example, cyclopentyl.

[0044] n1 represents an integer of 0 to 3; n2 represents an integer of 0 to 5. Each of n1 and n2 is preferably 0 to 2, more preferably 0 to 1, and further preferably 0. Furthermore, the combinations of n1 and n2 are preferably 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 further preferably 0 and 0.

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

[0046] Z 1 are represented by the formulas (IIIa), (IIIb), (IIIc), (IIId), and (IIIe): [ka] R za is a hydrogen atom, C 1-6 Alkyl, and (C 1-6 alkyl)carbonyl; R zband R zc are independently a hydrogen atom or C 1-6 n4 represents an integer of 1 to 3; n5 and n6 each independently represents an integer of 0 to 10.

[0047] * indicates the bonding site with the pyrazolopyridine skeleton, ** indicates Z 2 and the binding sites for

[0048] Z 2 is C 1-6 Alkyl, C 3-15 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein C 3-15 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 The aryl and the 5- to 10-membered heteroaryl may be substituted with 1 to 5 substituents independently selected from the A group. Group A: a) oxo, b) a halogen atom, c) cyano, d)-NR zd R ze ;where R zd and R ze are each independently a hydrogen atom, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl, where C 1-6 Alkyl is a group that is substituted with hydroxy, halogen atoms, and C 1-6 Optionally substituted with one or more substituents independently selected from alkoxy; e) -C(=O)-NR zf R zg ;where R zf and R zg are each independently a hydrogen atom, C 1-6 Alkyl, and (C 1-6 alkyl)carbonyl, where C 1-6 Alkyl is a group that is substituted with hydroxy, halogen atoms, and C 1-6 Optionally substituted with one or more substituents independently selected from alkoxy; f) -S(=O) n7 -R zh ; where n7 represents an integer from 0 to 2, and R zh is a hydrogen atom or C 1-6 Represents alkyl, g) C 1-6 Alkyl; where C 1-6 Alkyl is a halogen atom, hydroxyl, -NR zi R zj , C 1-6 and 3- to 12-membered heterocyclyl, wherein R zi and R zj are independently a hydrogen atom or C 1-6 alkyl, and 3-12 membered heterocyclyl is hydroxy, C 1-6 optionally substituted with one or more substituents independently selected from alkyl and 3- to 12-membered heterocyclyl; h)C 1-6 Alkoxy; where C 1-6 Alkoxy is a group consisting of hydroxy, halogen atoms, and C 1-6 Optionally substituted with one or more substituents independently selected from alkoxy; i) 3- to 12-membered heterocyclyl; where 3- to 12-membered heterocyclyl is C 1-6 Alkyl and (C 1-6 Optionally substituted with one or more substituents independently selected from: j) C 6-10 Aryl; where C 6-10 Aryl is one or more (C 1-6 alkyl)carbonyl, and k) 5-10 membered heteroaryl; where 5-10 membered heteroaryl is C 1-6 Alkyl, C 1-6 Alkoxy, -NR zk R zl and 3- to 12-membered heterocyclyl, where R zk and R zl are independently a hydrogen atom, C 1-6Alkyl, and (C 1-6 alkyl)carbonyl, and 3-12 membered heterocyclyl is selected from C 1-6 Alkyl and (C 1-6 and optionally substituted with one or more substituents independently selected from alkyl)carbonyl.

[0049] R zd , R ze , R zf and R zg C in 1-6 When the alkyl is substituted with hydroxy, C 1-6 The alkyl is preferably C 2-6 alkyl, more preferably C 2-4 It is an alkyl.

[0050] C 1-6 When the alkoxy is substituted with one or more hydroxy groups, the C 1-6 The alkyl is preferably C 2-6 alkyl, more preferably C 2-4 It is an alkyl. Preferably, Z 2 i) 1 or more -NR zd R ze C which may be substituted with 3-15 ii) C optionally substituted with 1 to 3 substituents independently selected from the C group 6-10 aryl, and iii) a 5-10 membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from Group D. More preferably, Z 2 i) C optionally substituted with 1 to 3 substituents independently selected from the C group 6-10 aryl, and ii) a 5-10 membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from Group D. Group C: a) halogen atoms, b) -NR zd2 R ze2 ;where R zd2 and R ze2 are independently a hydrogen atom, C 1-6Alkyl, and (C 1-6 alkyl)carbonyl, where C 1-6 Alkyl is one or more C 1-6 optionally substituted with alkoxy; c) -S(=O) n7 -R zh1 ; where n7 represents an integer from 0 to 2, and R zh1 is C 1-6 Represents alkyl, d) C 1-6 Alkyl, e) C 1-6 Alkoxy; where C 1-6 The alkoxy may be substituted with one or more hydroxy groups. f) 5-10 membered heteroaryl; where 5-10 membered heteroaryl is -NR zk1 R zl1 wherein R zk1 and R zl1 are independently a hydrogen atom and C 1-6 is selected from alkyl. Group D: a) oxo, b) a halogen atom, c) C 1-6 Alkyl; where C 1-6 Alkyl is a halogen atom, hydroxyl, C 1-6 and 3- to 12-membered heterocyclyl, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from one or more C 1-6 optionally substituted with alkyl, and d) 3- to 12-membered heterocyclyl.

[0051] The compound represented by formula (I) of the present invention includes Z 1 is a group represented by formula (IIIa), Y is represented by -C(=O)-, and R 9 is a group represented by formula (IIb), and R 9b is a hydrogen atom, and R 7 and R 8 Together with the carbon atoms to which they are attached, they form 1-3 C 1-6Alkyl-substituted C 3-15 Form a cycloalkane ring, and the 1 to 3 C 1-6 Preferably, the alkyl is unsubstituted.

[0052] Next, examples of the method for producing the compound represented by formula (I), a salt thereof, or a solvate thereof will be described with reference to the following schemes.

[0053] The compound represented by formula (I), its salt, or solvate thereof is produced through i) General Process A1 or General Process A2, ii) General Process B, and iii) General Process C. This process is for producing a compound represented by formula (I) containing Z 1 is a group represented by formula (IIIa), Y is represented by -C(=O)-, and R 9 is a group represented by formula (IIb), and R 9b is a hydrogen atom, that is, this is an example of a preferred method for producing a compound represented by formula (Ia).

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

[0055] In addition, when the starting material or the target product of a certain process undergoes an undesired chemical transformation under the reaction conditions of the process, the target product of the process can be obtained, for example, by protecting and deprotecting a functional group. For the selection of a protecting group and the selection of a method of protection and deprotection, for example, TW Greene, PG M Huts, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons, Inc., New York (2007) can be referred to. Some of the protection and deprotection of functional groups are also described in the following scheme.

[0056] <General method A1> Compound f can be synthesized by General Process 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 an amino protecting group, P 3a and P 3b are independently 1-6 represents alkyl, or P 3a and P 3b may be joined together 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, and Y 1 is cyano or -CO-OP 2 represents Y 2 represents =O or =NH, and X 1 represents a leaving group. Examples of the amino protecting group include formyl, (C 1-6 Alkyl) carbonyl (acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.), carbamoyl, C 1-6 Examples of the alkoxycarbonyl include alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, etc.), substituted silyl (trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, etc.), aralkyloxycarbonyl (benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, etc.), allyl, and aralkyl. Examples of the leaving group include a halogen atom, acetyloxy, trifluoroacetyloxy, methanesulfonyloxy, and paratoluenesulfonyloxy.

[0057] Process A1-1a : Compound a1 can be obtained by reacting compound a with a base. Examples of the base 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 the like. Of these, metal alkoxides such as potassium t-butoxide are preferred. Examples of the solvent include ether solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane, and preferably THF. The reaction temperature is usually from -30°C to 30°C, preferably from -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 may be subjected to step A1-1b without isolation. Compound a can be purchased as a commercial product from Aldlab Chemicals, LLC, Tokyo Chemical Industry Co., Ltd., etc. Also, it can be synthesized with reference to Bioorganic Medicinal Chemistry, 1999, 7, 795-809, CN 103086955. Compound a1 may be obtained as an alkali metal salt such as a potassium salt upon contact with the base used in the reaction, and such salts may also be used in the next step.

[0058] Process A1-1b : Compound a1 can be reacted with compound a2 to obtain compound b. This reaction is preferably carried out in the presence of an acid. Examples of the acid include hydrochloric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like, and salts of strong acids and weak bases such as pyridine hydrochloride. Examples of the solvent include hydrocarbon solvents (hexane, heptane, benzene, toluene, xylene, etc.) and alcohol solvents (methanol, ethanol, etc.) Water may be present in the system. The reaction temperature is usually 40°C to 200°C, preferably 60°C to 150°C. The reaction time is usually 6 minutes to 30 hours, preferably 30 minutes to 3 hours. Compound a2 can be purchased commercially as a salt with hydrogen chloride or the like from Alfa Aesar or the like. Compound a2, in which the hydrazine moiety is protected with t-butoxycarbonyl, can be deprotected with an acid such as methanesulfonic acid before use, with reference to Synlett, 2011, 17, 2555-2558. Compound: Q 1 It can also be synthesized using -NH2 as the starting material.

[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 the base 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; metal alkoxides such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-pentoxide, etc. When compound b2 is used, it is preferably a metal alkoxide such as potassium t-butoxide. Examples of the solvent that can be used 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 usually from -50°C to 70°C, preferably from -30°C to 50°C. The reaction time is usually 15 minutes to 72 hours, preferably 1 hour to 30 hours. Compound b1 can be purchased commercially from Enamine Ltd., etc. Also, compound b1 can be obtained by referring to WO2006 / 048727: 3a )(OP 3b Compound b2 can also be synthesized by reacting OP with phosgene or triphosgene. Compound b2 can be purchased commercially from UkrOrgSyntez Ltd., etc. Also, compound b2 can be synthesized by reacting OP with phosgene or triphosgene with phosgene. 3a )(OP 3b It can also be synthesized by reacting 1,2-diisocyanate such as CDI with 1,2-diisocyanate such as ...

[0060] Process A1-3 : Compound c can be reacted with an acid to obtain compound d. 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.), 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 the solvent include ether solvents (ether, tetrahydrofuran, dioxane, dimethoxyethane, cyclopentyl methyl ether, etc.), aromatic hydrocarbon solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), aliphatic hydrocarbon solvents (pentane, hexane, heptane, octane, cyclohexane, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.), alcohol 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 solvents (methyl acetate, ethyl acetate, isopropyl acetate, etc.), acetonitrile, and mixed solvents thereof, and preferably ether solvents such as tetrahydrofuran. The reaction temperature is usually 0°C to 100°C, preferably 10°C to 80°C. The reaction time is usually 10 minutes to 20 hours, preferably 30 minutes to 5 hours.

[0061] Process A1-4 : a)Z 2 But, C 1-6 Alkyl, C 3-15 In the case of cycloalkyl and 3- to 12-membered heterocyclyl, compound d can be reacted with compound d1 in the presence of a base to give compound e. Examples of the base 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 the solvent 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.), and preferably, amide-based solvents such as N,N-dimethylacetamide. The reaction temperature is usually 0°C to 150°C, preferably 20°C to 120°C. The reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 5 hours. b) Z 2 But, C 6-10 In the case of aryl and 5- to 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 the base include weakly basic inorganic salts (sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate, etc.) and organic bases (triethylamine, pyridine, tetrabutylammonium fluoride, etc.), and preferably weakly basic inorganic salts such as potassium carbonate. The copper catalyst includes copper(I) iodide, copper(I) bromide, copper(I) chloride, copper(II) acetate, copper(II) oxide, copper(I) trifluoromethanesulfonate, etc., and is preferably copper(I) iodide. Examples of the ligand include diamines such as phenanthroline, quinolin-8-ol, 2,2,6,6-tetramethylheptane-3,5-dione, N,N'-dimethylethane-1,2-diamine, trans-cyclohexane-1,2-diamine, and trans-N,N'-dimethylcyclohexane-1,2-diamine, and preferably trans-N,N'-dimethylcyclohexane-1,2-diamine. Examples of the solvent include ether solvents (ether, tetrahydrofuran, dioxane, dimethoxyethane, cyclopentyl methyl ether, etc.), aromatic hydrocarbon solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), aliphatic hydrocarbon solvents (pentane, hexane, heptane, octane, cyclohexane, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.), alcohol 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 solvents (methyl acetate, ethyl acetate, isopropyl acetate, etc.), and acetonitrile, and preferably N-methylpyrrolidone or other amide solvents. The reaction temperature is usually 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 In the case of an alkoxycarbonyl, deprotection is preferably carried out 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.), 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 the solvent 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.), and preferably, amide-based solvents such as N-methylpyrrolidone. The reaction temperature is usually from 0°C to 200°C, preferably from 10°C to 120°C. The reaction time is usually 30 minutes to 10 hours, preferably 1 hour to 6 hours. Compound f may be obtained as a salt with the acid used in the reaction, and such a salt may also be subjected to the next step.

[0063] <General manufacturing method A2> Z 2 But -NR zd R ze C replaced with 3-15 When the group is bulky, such as cycloalkyl, compound p corresponding to compound f can also be synthesized by General Process A2 shown in the following scheme. [ka] In the formula, Z 2a is unsubstituted C 3-15 It represents a cycloalkyl or a 3- to 12-membered heterocyclyl. P 1a and P 2a represents an amino protecting group, X 2 , X 3 , X 4 and X 5 each independently represents a leaving group, R 10a and R 10b are independently 1-6 represents alkyl, or R 10a and R 10bmay be bonded together 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 the amino protecting group include formyl, (C 1-6 Alkyl) carbonyl (acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.), carbamoyl, C 1-6 Examples of the alkoxycarbonyl include alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, etc.), substituted silyl (trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, etc.), aralkyloxycarbonyl (benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, etc.), allyl, and aralkyl. Examples of the leaving group include a halogen atom, acetyloxy, trifluoroacetyloxy, methanesulfonyloxy, and paratoluenesulfonyloxy.

[0064] Process A2-1 : Compound g can be reacted with azide in the presence of a base to give compound h. The base includes, for example, tertiary amines (such as triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, and DABCO). Examples of the azide include metal azides such as sodium azide, trimethylsilyl azide, and diphenylphosphoryl azide, and preferably diphenylphosphoryl azide. Examples of the solvent include ether solvents (tetrahydrofuran, methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, etc.), hydrocarbon solvents (hexane, heptane, benzene, toluene, etc.), and amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.), and preferably hydrocarbon solvents such as toluene. The reaction temperature is usually 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 in, for example, Journal of the American Chemical Society, 2016, 138, 1698-1708 and WO2009 / 152133. In addition, it is also available as a commercially available product from 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 the base include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.), and nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine, pyrazine, pyridazine, etc.). Examples of the solvent include ether solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane, and hydrocarbon solvents such as hexane, heptane, benzene, and toluene. In addition, a base such as pyridine can also be used as the solvent. The reaction temperature is usually 0°C to 60°C, preferably 5°C to 45°C. The reaction time is usually 30 minutes to 50 hours, preferably 2 hours 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 the base include weakly basic inorganic salts (sodium carbonate, potassium carbonate, cesium carbonate, etc.), metal hydrides (sodium hydride, potassium hydride, etc.), and preferably weakly basic inorganic salts such as cesium carbonate. 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, and preferably 1,2-dichloro-1-ethoxyethane. Compound i1 can be purchased as a commercial product from Tokyo Chemical Industry Co., Ltd., FCH Group, and the like. Examples of compound i2 include 2-chloro-1,1-dimethoxyethane, 2-chloro-1,1-diethoxyethane, 2-bromo-1,1-dimethoxyethane, 2-bromo-1,1-ethoxyethane, etc. Compound i2 can be purchased as a commercial product from Tokyo Chemical Industry Co., Ltd. Examples of the solvent 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 usually 0°C to 60°C, preferably 20°C to 45°C. The reaction time is usually 1 hour to 72 hours, preferably 12 minutes to 35 hours.

[0067] Process A2-4 : Compound j can be reacted with an acid to give compound k. Examples of the acid include inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acids (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.), 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.), and preferably sulfonic acids such as methanesulfonic acid. Examples of the solvent include ether solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane, and preferably THF. The reaction temperature is usually 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. Compound k1 may be, for example, a halogenated compound C such as methyl iodide. 1-6 Alkyl, acetyl chloride, and other halogenated 1-6 alkyl)carbonyl. zd But (C 1-6 When the compound k1 is a (alkyl)carbonyl, the compound k2 is replaced with ((C 1-6 It is also preferable to use an acid anhydride represented by the formula (alkyl)carbonyl)2O, for example, acetic anhydride. Examples of the base 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 preferably metal alkoxides such as potassium pentoxide. Examples of the solvent include ether solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane; and hydrocarbon solvents such as hexane, heptane, benzene, and toluene, and preferably THF. The reaction temperature is usually from -50°C to 50°C, preferably from -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. For deprotection, appropriate reagents and reaction conditions can be selected depending on the type of protecting group. When the protecting group is t-butoxycarbonyl, it is preferable to react with an acid. Examples of the acid 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.), and preferably carboxylic acids such as trifluoroacetic acid. Examples of the solvent 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 CH2Cl2 and other halogen-based solvents being preferred. The reaction temperature is usually 0°C to 60°C, preferably 10°C to 40°C. The reaction time is usually 30 minutes to 10 hours, preferably 1 hour to 5 hours. Compound m may be obtained as a salt with the acid used in the reaction, and such a salt may also be subjected to step A2-7.

[0070] Process A2-7 : Compound n can be obtained by protecting one of the amino groups in compound m. For protection, appropriate reagents and reaction conditions can be selected depending on the type of protecting group. 1-6 In the case of an alkoxycarbonyl, it is preferable to react it with a base. 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, preferably di-t-butyl dicarbonate. Examples of the base include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.), nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine, pyrazine, pyridazine, etc.), and preferably tertiary amines such as triethylamine. Examples of the solvent 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 CH2Cl2 and other halogen-based solvents being preferred. The reaction temperature is usually 0°C to 60°C, preferably 15°C to 40°C. The reaction time is usually 30 minutes to 20 hours, preferably 1 hour 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. Compound n1 may be, for example, a halogenated C such as methyl iodide. 1-6 Alkyl, acetyl chloride, and other halogenated 1-6 alkyl)carbonyl. ze C 1-6 If it is an alkyl group, it is C 1-6 The alkyl is unsubstituted or 1-6 It is preferably substituted with alkoxy. This step is carried out in the same manner as in 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. For deprotection, appropriate reagents and reaction conditions can be selected depending on the type of protecting group. 1a C such as t-butoxycarbonyl 1-6 In the case of an alkoxycarbonyl, deprotection is preferably carried out using an acid. This step is carried out in the same manner as in step A1-5, and the acid, solvent, reaction temperature, and reaction time used in the reaction are also the same as in step A1-5.

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

[0074] Process B-1 : Compound bb can be obtained by reacting compound ba with compound ba1 in the presence of a palladium catalyst. As the palladium catalyst, a complex formed in the system by adding a palladium compound and a ligand separately can be used. The complex prepared separately can also be used as it is. Examples of the ligand 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 the palladium compound to be combined with the ligand include di-μ-chlorobis[(η-allyl)palladium(II)], tetrakis(triphenylphosphine)palladium(0), and the like. Examples of the palladium catalyst that can be used in this step include tris(dibenzylideneacetone)dipalladium(0), 5,10,15,20-tetraphenyl-21H,23H-porphinecobalt(II), palladium(II) acetate, 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(0), and di-μ-chlorobis[(η-allyl)palladium(II)]. In step 11, it is preferable to use, as a catalyst, a complex formed by using di-μ-chlorobis[(η-allyl)palladium(II)] as the palladium compound and 2-(di-t-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl as the ligand. This step may 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.), metal alkoxides (potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, etc.), and the like. Examples of the reaction solvent include ether solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane, 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 usually 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 with reference to Synthetic Communications, 39(14), 2506-2515, 2009. -COP 21 It can also be obtained by esterification or amidation of compound ba, in which is -COOH. X 21 Ga-Zn-X 21a Compound ba1 can be purchased commercially from Focus Synthesis LLC, etc. It can also be synthesized with reference to WO2014 / 201206, etc.

[0075] Process B-2 : Compound bb can be reacted with compound bb1 in the presence of a base to obtain compound bc. Examples of the base 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, and preferably potassium hydroxide. Examples of the reaction solvent include amide solvents such as N,N-dimethylacetamide (DMA), N,N-dimethylimidazolidinone (DMI), and DMF, and preferably DMI. A mixed solvent with water may also be used. The reaction temperature is usually from -10°C to 100°C, preferably from 0°C to 45°C. The reaction time is usually 30 minutes to 10 hours, preferably 1 hour to 5 hours. Compound bb can be commercially purchased from Aquila Pharmatech LLC, etc. It can also be synthesized with reference 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 hydroxylamine (H2NOH). Examples of the reaction solvent include aprotic polar solvents such as dimethylsulfoxide (DMSO), dimethylformamide, dimethylacetamide, and 1-methyl-2-pyrrolidinone, and alcoholic solvents such as methanol and ethanol, and preferably DMSO. Also, it may be a mixed solvent with water. The reaction temperature is usually from -10°C to 100°C, preferably from 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 bd can be reacted with triphosgene, a chlorocarbonate (methyl chlorocarbonate, ethyl chlorocarbonate, isopropyl chlorocarbonate, etc.), carbonyldiimidazole, etc., preferably carbonyldiimidazole, in the presence of a base to obtain compound be. Examples of the base include tertiary amines (such as triethylamine, N-methylmorpholine, diisopropylethylamine, 1,8-diazabicycloundec-7-ene (DBU), and DABCO) and metal hydroxides (sodium hydroxide and potassium hydroxide), and preferably tertiary amines such as DBU. Examples of the solvent include aprotic polar solvents such as dimethyl sulfoxide (DMSO), dimethylformamide, dimethylacetamide, and 1-methyl-2-pyrrolidinone, alcohol solvents such as methanol and ethanol, and ether solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane, and preferably DMSO. The reaction temperature is usually from -10°C to 100°C, preferably from 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 be protected by the formula (I) can be deprotected using a base to obtain compound bf. Examples of the base 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. Examples of the solvent include alcohol solvents such as methanol, ethanol, methoxyethanol, and t-butyl alcohol, ether 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 usually from -20°C to 120°C, preferably from 20°C to 100°C. The reaction time is usually 20 minutes to 10 hours, preferably 30 minutes to 5 hours. The order of steps B-1, B-2, B-3, B-4 and B-5 can be changed. For example, compound ba can be obtained by sequentially subjecting compound ba to steps B-2 and B-1. Compound bf can be obtained by sequentially subjecting compound ba to steps B-2, B-3, B-4, B-5 ​​and B-1. Compound bf can be obtained by sequentially subjecting compound ba to steps B-2, B-3, B-4, B-1 and B-5.

[0079] Steps B-Aa and B-Ab : Also, X 21 When is a halogen atom, compound ba can also be subjected to the following steps B-Aa and B-Ab to obtain compound bb, which may be subjected to step B-2. [ka] In the formula, R Qc and R Qd are independently a hydrogen atom or C 1-6 represents an alkyl group, or R Qc and R Qd may be combined with the oxygen atom to which they are bonded and the boron atom to which they are bonded to form 1,3,2-dioxaborolanyl or 1,3,2-dioxaborinanyl.

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

[0081] Process B-Ab : The organic boron compound baa is reacted with the compound ba1 in the presence of a base to obtain the compound bb. Examples of the base include weakly basic inorganic salts (sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), and preferably sodium carbonate. The solvent, reaction temperature and reaction time used in the reaction are the same as those in Step B-1. Compound bb can also be obtained by converting compound ba1 to an organoboron compound in the same manner as in the conversion of compound ba to compound baa, and then reacting this with compound ba.

[0082] Process BB : Also, compound bb1 is X 21 -(CH2) n1 When the compound bca is represented by —CH2—CN, the compound bca corresponding to the compound bc obtained in step B-2 is subjected to the following step BB, that is, reacted with the compound bc1 in the presence of a base to obtain R 7 and R8 together with the carbon atoms to which they are attached, C 3-15 It forms a cycloalkane ring, and R 7 and R 8 Together they form C 3-15 The cycloalkane ring contains 1 to 3 C 1-6 Compound bcb, which corresponds to compound bc, which may be substituted with alkyl, can be obtained, and this may be subjected to step B-3. [ka] In the formula, R 7c , R 7e and n8 is R 7d are each independently a hydrogen atom or C 1-6 alkyl, and n8 is an integer of 0 to 3. Examples of the base include metal hydrides such as sodium hydride, potassium hydride, lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), and lithium 2,2,6,6-tetramethylpyrrolidide, and preferably KHMDS. Examples of the solvent include ether solvents such as THF, diethyl ether, and dioxane, and amide solvents such as N,N-dimethylacetamide (DMA), N,N-dimethylimidazolidinone (DMI), DMF, and N,N'-dimethylpropyleneurea (DMPU), and preferably amide solvents such as DMPU. 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 hour to 4 hours. Compound bc1 can be purchased commercially from CGenTech. Inc., etc. It can also be synthesized with reference to Organic Letters, 12(17), 3938-3941, 2010.

[0083] <General manufacturing method C> Process C-1 : [ka] Compound f (or compound p) and compound bf are condensed using a condensing agent in the presence of a base to obtain compound (Ia). Examples of the condensation agent include BOP-based condensation agents such as benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP (registered trademark)), PyAOP, BroP, PyCloP, PyBroP (registered trademark), and DEPBT; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM), and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium Examples of the compound include tetrafluoroborate (TBTU), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium hexafluorophosphate (HATU), and ethyl (hydroxyimino)cyanoacetate (Oxyma), and preferably HATU. Examples of the base include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.), nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine, pyrazine, pyridazine, etc.), and preferably tertiary amines such as diisopropylethylamine. Examples of the solvent include ether 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, and preferably an aprotic polar solvent such as DMF. 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. Compound (Ia) can also be obtained by changing the order of the steps, for example, by subjecting compound d to step A1-5, step C-1, and step A1-4 in that order, or by subjecting compound ba to step B-2, step B-3, step B-4, step B-5, step C-1, and step B-1 in that order.

[0084] The compound represented by formula (I) can be contacted or reacted with an acid or base that can be used in the manufacture of pharmaceuticals to obtain a salt thereof. The salt may be any pharma- ceutically acceptable salt, and examples of such salts include inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.), sulfonate salts (methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, etc.), carboxylate salts (formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, mandelate, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, glutamate, carboxylate ... Examples of the salt include 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.). Among these, alkali metal salts and alkaline earth metal salts are preferred, and sodium salts and calcium salts are 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, dimethyl sulfoxide, or the like, and 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 contained in the solvate may be either water or an organic solvent. As the organic solvent, alcohol (e.g., methanol, ethanol, n-propanol), dimethylformamide, acetonitrile, acetone, dimethyl sulfoxide, etc. can be used. The compound represented by formula (I) and its salt are preferably used in the form of a hydrate, and also preferably used in the form of a non-solvate. 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, more preferably 0.5 to 6. This ratio may vary depending on humidity, production method, production time, etc.

[0087] The solvate of the compound represented by formula (I) or its salt can be obtained by a conventional method, such as precipitating the compound represented by formula (I) or its salt from a solvent, etc. The hydrate can also be obtained by precipitating the compound represented by formula (I) or its salt from a water-containing organic solvent.

[0088] The solvate of the compound represented by formula (I) or a salt thereof can be converted to the compound represented by formula (I) or a salt thereof by conventional methods, such as, for example, heating under reduced pressure.

[0089] As a compound used as a pharmaceutical, the compound represented by formula (I) itself (free form), a hydrate of the free form, a salt of the free form, or a hydrate of the salt is preferred, and the free form, a hydrate of the free form, a sodium salt of the free form, a hydrate of the sodium salt, a calcium salt of the free form, or a hydrate of the calcium salt is more preferred.

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

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

[0092] The present invention also includes compounds in which the atoms constituting the compound molecule of the present invention represented by formula (I) are isotopes, and includes compounds in which at least one atom is replaced with an atom having the same atomic number (proton number) but a different mass number (sum of the number of protons and neutrons). Examples of isotopes contained in the compound of the present invention include a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom, and a chlorine atom, each of which is represented by the following: 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, etc. In particular, 3 H and 14Radioisotopes such as C that decay by emitting radiation are useful in tests of the distribution of pharmaceuticals or compounds in the body tissues. Stable isotopes do not decay, their abundance hardly changes, and they are not radioactive, so they can be used safely. When the atoms constituting the compound molecule of the present invention are isotopes, they can be converted in the usual manner by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0093] The compound of the present invention or a salt thereof, or a solvate thereof has a GLP1 receptor agonist effect and a blood glucose lowering effect, and can be used for the prevention or treatment of non-insulin-dependent diabetes mellitus (type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus (type 1 diabetes), diabetic complications, obesity, hypertension, dyslipidemia, arteriosclerosis, myocardial infarction, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, Parkinson's disease, or dementia, by administering a pharmacologic effective amount thereof to a patient by an appropriate administration method, either as is or in the form of a pharmaceutical composition.

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

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

[0096] "Impaired glucose tolerance" includes insulin-resistant impaired glucose tolerance and insulin secretion disorders.

[0097] "Diabetic complications" refers to complications resulting from diabetes or hyperglycemia, and may be either acute or chronic. "Acute complications" include, for example, ketoacidosis, infections (e.g., skin infections, soft tissue infections, biliary infections, respiratory infections, urinary tract infections), and "chronic complications" include, for example, microangiopathy (e.g., nephropathy, retinopathy), neuropathy (e.g., sensory neuropathy, motor neuropathy, autonomic neuropathy), and foot gangrene. Major diabetic complications include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

[0098] "Coronary heart disease" includes myocardial infarction, angina pectoris, and the like.

[0099] "Dementia" includes, for example, Alzheimer's disease, vascular dementia, and diabetic dementia.

[0100] The administration method may be any of systemic administration such as oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intravaginal administration, intraperitoneal administration, intravesical administration, and inhalation administration, and local administration using ointments, gels, creams, etc.

[0101] When the compound of the present invention or its salt, or its solvate is used in the form of a pharmaceutical composition, it is usually formulated into a certain preparation (dosage form). Such preparations include, for example, tablets, capsules, granules, powders, fine granules, pills, aqueous or non-aqueous solutions or suspensions. The compound of the present invention or its salt, or its solvate can also be used in the form of various controlled release preparations. Such controlled release preparations include, for example, those that are implanted in the body and used, and those that are applied to the oral mucosa or nasal mucosa. The solution or suspension can be filled and stored in a container suitable for dividing into individual doses.

[0102] The above-mentioned various preparations can be produced by mixing the compound of the present invention or its salt, or a solvate thereof with pharma- ceutically acceptable additives in a known manner. Examples of such additives include excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, bases, dispersants, diluents, surfactants, emulsifiers, etc.

[0103] Examples of excipients include starch (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, calcium hydrogen phosphate, and the like. Examples of lubricants (coating agents) include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, and paraffin. Examples of the binder include polyvinylpyrrolidone, macrogol, and the same compounds as the above-mentioned excipients. Examples of disintegrants include chemically modified starches such as croscarmellose sodium, sodium carboxymethyl starch, and cross-linked polyvinylpyrrolidone, as well as celluloses and compounds similar to the above-mentioned excipients. Examples of the stabilizer include paraoxybenzoic acid esters such as methylparaben and propylparaben; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid. Examples of the flavoring agent include commonly used sweeteners, acidulants, and fragrances. Examples of bases 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 glycolic oil. Examples of dispersants include cellulose derivatives (gum arabic, tragacanth, methylcellulose, etc.), stearic acid polyesters, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbates, and sorbitan fatty acid esters. Examples of the solvent or diluent in the liquid preparation include phenol, chlorocresol, purified water, and distilled water. Examples of surfactants or emulsifiers include polysorbate 80, polyoxyl 40 stearate, and lauromacrogol.

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

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

[0106] When the compound of the present invention or a salt thereof, or a solvate thereof is used as a preventive or therapeutic agent for non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity, the dosage can be appropriately determined depending on the severity of symptoms, age, body weight, relative health condition, the presence or absence of concomitant drugs, administration method, etc. For example, when the subject of administration is a warm-blooded animal, particularly a human, the daily dosage is, for example, 0.01 to 10,000 mg, preferably 0.1 to 1,000 mg, in oral administration. In addition, the daily dosage is, for example, 0.001 to 3,000 mg, preferably 0.01 to 300 mg, in parenteral administration. The dosage may be administered once per day to several weeks, or may be administered in two or more divided doses per day.

[0107] The effective amount of the compound of the present invention, a salt thereof, or a solvate of either of them means a therapeutically effective amount or a prophylactically effective amount, and can be appropriately determined depending on the severity of symptoms, age, body weight, relative health condition, the presence or absence of concomitant drugs, the administration method, etc. EXAMPLES

[0108] The contents of the present invention are further described in 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. Silica gel used was SHOKO Scientific Purif-Pack (registered trademark) SI 60 μm (manufactured by Shoko Scientific), Biotage (registered trademark) SNAP Ultra Silica Cartridge (manufactured by Biotage), or SNAP KP-Sil Cartridge (manufactured by Biotage), and reverse phase silica gel was Wakosil (registered trademark) 25C18 (Wako Pure Chemical Industries, Ltd.) or Biotage (registered trademark) SNAP Ultra C18 Cartridge (manufactured by Biotage). HPLC purification of the compounds was performed using AutoPurification HPLC / MS System (manufactured by Waters) or Preprative HPLC system with injection / fractionation function (manufactured by Gilson). 1H-NMR spectra were measured with or without Me4Si as an internal standard using an ECP-400 (JEOL), Agilent400-MR (Agilent Technologies), AVANCE3 300MHz (Bruker) or AVANCE3 600MHz Cryo-TCI (Bruker) (s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, ddd = double doublet, m = multiplet). Chemical shifts of NMR data are expressed in ppm (parts per million, δ) based on Me4Si or deuterated solvent, and coupling constants (J) are expressed in Hz (Hertz). LC / MS was performed to measure retention times and mass analysis using the equipment and analytical conditions in Table 1. Microwave irradiation was performed using an InitiatorTM (Biotage). Mass spectrometry in LC / MS was measured using a mass spectrometer: SQD (manufactured by Waters), SQD2 (manufactured by Waters), 2020 (manufactured by Shimadzu), or 2010EV (manufactured by Shimadzu). [Table 1] TIFF2025032241000018.tif237155 TIFF2025032241000019.tif236155

[0109] <Example 1> Synthesis of 3-[(1S,2S)-1-[2-[2-(3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-ethyl-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (Compound 1) [ka]

[0110] (Process 1-1) [(5-cyano-1,2,3,6-tetrahydropyridin-4-yl)amino]potassium (compound 1b) A 1M solution of potassium tert-butoxide in THF (179 mL) was added to a solution of 3-(2-cyanoethylamino)propanenitrile (compound 1a, 22.0 g, 179 mmol) in tetrahydrofuran (THF) (179 mL) and 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, 83% yield) 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) 3,5-Dimethylphenylhydrazine hydrochloride (compound 1c, 5.00 g, 29.0 mmol) and compound 1b (4.67 g, 29.0 mmol) obtained in step 1-1 were added to an ethanol (57.9 mL) solution of 2N hydrochloric acid (23.2 mL, 46.3 mmol) and stirred at 50 ° C for 1 hour. The reaction mixture was cooled to 0 ° C, and 5M aqueous sodium hydroxide solution (9.27 mL, 46.3 mmol) and di-tert-butyl dicarbonate (6.64 g, 30.4 mmol) were added and stirred at 0 ° C for 1 hour. Water was added to the reaction mixture, and it was extracted with ethyl acetate, and the organic layer was washed with saturated saline 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) 2-isocyanato-1,1-dimethoxyethane (compound 1e, 1.94 g, 14.8 mmol) was added to a pyridine (7.39 mL) solution of compound 1d (2.53 g, 7.39 mmol) obtained in step 1-2, 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, and then water (50.6 mL) was added and the mixture was stirred at room temperature for 20 minutes. The reaction mixture that became a suspension was filtered, and the solid collected by filtration was washed with water (12.7 mL) and then dried under reduced pressure to obtain the title compound 1f (3.20 g, 91% yield) 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]pyridin-3-yl]-1H-imidazol-2-one (compound 1g) To the compound 1f (158 mg, 0.334 mmol) obtained in step 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 to the mixture, and the solvent was distilled off under reduced pressure. The residue was dissolved by adding dichloromethane (1 mL), 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 to the mixture, and the solvent was distilled off under reduced pressure to obtain the crude product (176 mg) of the title compound 1g. 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 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 warmed to room temperature, stirred for 30 minutes, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate) to obtain the title compound 1i (6.98 g, yield 92%) 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) Ethyl 5-bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]indole-2-carboxylate (Compound 1l) A solution of ethyl 5-bromo-1-(cyanomethyl)indole-2-carboxylate (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) in N,N'-dimethylpropylene urea (117 mL) was degassed under reduced pressure, substituted with nitrogen, and cooled to 0 ° C. Under a nitrogen atmosphere, a 1.0 M solution of potassium bis(trimethylsilyl)amide in THF (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 extracted with a mixed solution of hexane / ethyl acetate (1:3). The organic layer was washed three times with water, twice with a saturated aqueous sodium bicarbonate solution, and once with saturated saline, 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 the title compound 1l (1.70 g, yield 42%) 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-methylpyridin-4-yl)indole-2-carboxylate ethyl (Compound 1m) A suspension of compound 1l (2.70 g, 7.78 mmol) obtained in step 1-6, 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) in dioxane (44 mL) was degassed under reduced pressure at room temperature and then replaced 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 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, and the mixture was degassed under reduced pressure, substituted 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 stirred for 0.5 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed once with saturated saline 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 title compound 1m (2.92 g, yield 97%) as a pale yellow gum. LC / MS mass spectrometry: m / z388([M+H] + ). LC / MS retention time: 1.06 min (Analysis conditions: SQD-AA05-2).

[0117] (Step 1-8) Ethyl 5-(2-ethyl-3-methylpyridin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylate (Compound 1n) To a solution of compound 1m (0.225 g, 0.581 mmol) obtained in step 1-7 in dimethyl sulfoxide (DMSO) (2.9 mL), 50% aqueous hydroxylamine solution (0.356 mL, 5.81 mmol) was added and stirred at room temperature for 17 hours. Ethyl acetate (50 mL) was added, washed with water (10 mL) and saturated saline (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), and carbonyldiimidazole (188 mg, 1.16 mmol) and 1,8-diazabicycloundec-7-ene (0.219 mL, 1.45 mmol) were added and 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, 65% yield) 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-methylpyridin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-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 step 1-8, 2 M aqueous sodium hydroxide solution (10.1 mL, 20.2 mmol) was added and stirred at room temperature for 1.5 hours. Formic acid was added and the mixture was purified directly 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-ethyl-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 1p) Compound 1g (1.25g, 3.61mmol) obtained in step 1-4, compound 1o (1.59g, 3.80mmol) obtained in step 1-9, and [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium hexafluorophosphate (1.51g, 3.98mmol) were added to a solution of N,N'-dimethylformamide (DMF) (24.1mL) and stirred at room temperature for 30 minutes. The reaction mixture was purified directly by reverse phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound 1p (2.44g, 95% yield) in the form of 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-ethyl-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 1) Compound 1p (20 mg, 0.028 mmol) obtained in step 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) were added to a suspension in N-methylpyrrolidone (0.188 mL) and copper iodide (I) (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 reversed-phase silica gel chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound 1 (17.2 mg, 73% yield) 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 to 50> The same operations as in steps 1-11 of Example 1 were carried out using the combinations of 2-oxoimidazole compounds shown in Table 2-2 and halogen compounds shown in Table 2-3 below, as well as appropriate reagents, to obtain Example Compounds 2 to 50 shown in Table 2-1 by the following reactions. [ka] [Table 2-1] JPEG2025032241000023.jpg246162 JPEG2025032241000024.jpg246162 JPEG2025032241000025.jpg240162 JPEG2025032241000026.jpg246162 JPEG2025032241000027.jpg131162 JPEG2025032241000028.jpg129162 JPEG2025032241000029.jpg131162 JPEG2025032241000030.jpg136162 JPEG2025032241000031.jpg253162 JPEG2025032241000032.jpg131162 JPEG2025032241000033.jpg129162 JPEG2025032241000034.jpg124162 JPEG2025032241000035.jpg136162 JPEG2025032241000036.jpg246162 JPEG2025032241000037.jpg253162 JPEG2025032241000038.jpg131162 JPEG2025032241000039.jpg129162 JPEG2025032241000040.jpg124162 JPEG2025032241000041.jpg136162 JPEG2025032241000042.jpg131162 JPEG2025032241000043.jpg136162 JPEG2025032241000044.jpg131162 JPEG2025032241000045.jpg136162 JPEG2025032241000046.jpg137162 JPEG2025032241000047.jpg129162 JPEG2025032241000048.jpg137162 JPEG2025032241000049.jpg136162 JPEG2025032241000050.jpg142162 JPEG2025032241000051.jpg142162 JPEG2025032241000052.jpg131162 JPEG2025032241000053.jpg142162 JPEG2025032241000054.jpg131162 JPEG2025032241000055.jpg142162 JPEG2025032241000056.jpg131162 JPEG2025032241000057.jpg136162 JPEG2025032241000058.jpg124162 JPEG2025032241000059.jpg136162 JPEG2025032241000060.jpg124162 JPEG2025032241000061.jpg136162 JPEG2025032241000062.jpg253162 The compounds in Table 2-1 have rotational isomers. For example, Example Compound 2 1 H-NMR is as follows:

[0122] Rotamer 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] Rotamer 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=6.0Hz), 6.81(1H, s), 6.71(1H, d, J = 3.0Hz), 6.22(1H, d, J = 3.0Hz), 5.24(1H, d, J = 16.3Hz), 4.64(1H, d, J = 16.3Hz), 4.45(1H, ddd, J = 13.5, 4.6, 4.0Hz), 4.12(3H, s), 3.87(1H, ddd, J = 13.5, 10.2, 3.8Hz), 3.17(1H, ddd, J = 15.5, 10.2, 4.6Hz), 3.02(1H, m), 3.00(2H, q, J = 7.6Hz), 2.30(3H, s), 2.28(6H, s), 1.96(1H, dd, J = 6.0Hz), 1.64(1H, m), 1.58(1H, dd, J = 9.4, 6.0Hz), 1.39(3H, t, J = 7.6Hz), 1.19(3H, d, J = 6.1Hz).

Table 2-2

Table 2-3

[0124] The 2-oxoimidazole compound (3-[(1S,2S)-1-[5-(2-ethyl-3-methylpyridin-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 2g) used in the synthesis of Example Compounds 2 to 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 to concentrated hydrochloric acid (20 mL) and water (20 mL) at room temperature while stirring. The mixture was stirred at the same temperature for 1 hour, and the solid in the reaction mixture was filtered and dried. Methoxycyclopentane (20 mL) was further added to the obtained solid, and the mixture was stirred at 50° C. for 1 hour and then 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) Concentrated hydrochloric acid (10 mL) was added to compound 2b (1.00 g, 5.69 mmol) obtained in step 2-1, and while vigorously stirring at 0° C., a solution of sodium nitrite (511 mg, 7.40 mmol) in water (2.4 mL) was added over 1 minute, and the mixture was stirred at 0° C. for 30 minutes. Then, a solution of tin(II) chloride (2.27 g, 12.0 mmol) in water (2.4 mL) was added over 2 minutes. Water (7 mL) was further added, and the mixture was stirred at room temperature for 1 hour. The solid in the reaction mixture was filtered, washed with water (2 mL), and then dried to obtain the title compound 2c (1.75 g, 77% yield, 48% content) as a gray solid. 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 prepared by the same procedure as in step 1-2 of Example 1 using appropriate reagents. 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) From compound 2d obtained in step 2-3, the compound was synthesized by the same procedure as in step 1-3 of Example 1 using an appropriate reagent. 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]pyridin-3-yl]-1H-imidazol-2-one hydrochloride (compound 2f) Compound 2e obtained in step 2-4 was synthesized by the same procedure as in step 1-4 of Example 1 using appropriate reagents. 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-methylpyridin-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 2g) The compound 2f obtained in step 2-5 and the compound 1o obtained in step 1-9 were synthesized by the same procedure as in step 1-10 of Example 1 using appropriate reagents. The 2-oxoimidazole compound (3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-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) The compound was synthesized from 5-bromo-1-(cyanomethyl)indole-2-carboxylic acid (compound 6a) and N-methylaniline (compound 6b) using an appropriate reagent in the same manner 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-Bromo- 1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-N-methyl-N-phenylindole-2-carboxamide (compound 6d) Compound 6c obtained in step 6-1 was used to synthesize the compound according to the same procedures as in steps 1-6 of Example 1 using appropriate reagents. 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-oxadiazol-3-yl)cyclopropyl]-N-phenylindole-2-carboxamide (compound 6e) Compound 6d obtained in step 6-2 was synthesized by the same procedure as in step 1-8 of Example 1 using appropriate reagents. 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-oxadiazol-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. 6N hydrochloric acid (51.9 mL) was added under ice cooling, and the suspension was stirred at room temperature for 30 minutes. After filtering and washing with water (29.1 mL), the obtained solid was dried under reduced pressure to obtain the title compound 6f (7.42 g, 95% yield) 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-methylpyridin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 6h) A suspension of compound 6f (3.00 g, 7.93 mmol) obtained in step 6-4, 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) in DMSO (34.7 mL) was degassed under reduced pressure at room temperature, and then replaced 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 6g, 1.98 g, 7.93 mmol) and water (4.96 mL) were added to the solution, which was then degassed under reduced pressure, replaced 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, and the mixture was filtered. The filtrate was purified directly by reverse phase chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound 6h (1.83 g, 55% yield). 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 6i) The compound 2f obtained in step 2-5 and the compound 6h obtained in step 6-5 were synthesized by the same procedure as in step 1-10 of Example 1 using appropriate reagents. The halogen compound (1-(5-bromoindazol-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-Bromoindazol-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-methylpyrrolidin-2-one (NMP) (1.52 mL), and potassium carbonate (526 mg, 3.81 mmol) was added. The mixture was stirred at 180° C. for 30 minutes under microwave. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was distilled off under reduced pressure. The product was purified by silica gel column chromatography (ethyl acetate / hexane=1:1) to obtain the title compound 6l (115 mg, 56% yield). 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-dimethylmorpholin-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 7c) used in the synthesis of Example Compound 7 was synthesized as follows. [ka]

[0138] (Step 7-1) 5-(2,2-Dimethylmorpholin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 7b) A suspension of 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) in NMP (44 mL) was degassed under reduced pressure at room temperature, and then substituted with nitrogen. Compound 6f (5.0 g, 13.2 mmol) obtained in step 6-4 was added under a nitrogen atmosphere, and the mixture was stirred at 100 ° C. for 0.5 hours, 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) as it was, 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-dimethylmorpholin-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 7c) Compound 7b obtained in step 7-1 was synthesized by the same procedure as in step 1-10 of Example 1 using appropriate reagents. The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-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-oxadiazol-3-yl)cyclopropyl]-5-(oxan-4-yl)indole-2-carboxylic acid (compound 8b) Compound 6f (0.30 g, 0.793 mmol) obtained in step 6-4, palladium (II) acetate (35.6 mg, 0.159 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (0.148 g, 0.317 mmol) in N,N-dimethylacetamide (DMA) (2.64 mL) was degassed under reduced pressure, replaced with nitrogen, and stirred at room temperature for 15 minutes. Under a nitrogen atmosphere, 1M (tetrahydro-2H-pyran-4-yl) zinc (II) iodide (compound 8a) in DMA solution (7.9 mL, 7.93 mmol) was added, stirred at 80 ° C. for 15 minutes, and then 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, 61% yield). 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 8c) Compound 8b obtained in step 8-1 was synthesized by the same procedure as in steps 1-10 of Example 1 using appropriate reagents. 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 dichloromethane solution (3.78 mL) of (3S)-oxolan-3-ol (compound 8d, 500 mg, 5.68 mmol), 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 for 15 hours, and then water and 1N hydrochloric acid were added to separate the organic layer. The organic layer was washed successively with a saturated aqueous solution of sodium bicarbonate and saturated saline. 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) Cesium carbonate (992 mg, 3.05 mmol) and compound 8e (369 mg, 1.52 mmol) obtained in step 8-3 were added to a solution of 5-bromo-1H-indazole (compound 6j, 300 mg, 1.52 mmol) in DMF (3.8 mL), and the mixture was stirred at 100° C. for 2 hours. After cooling to room temperature, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was distilled off under reduced pressure. The product was purified by silica gel column chromatography (ethyl acetate / hexane=1:1) to obtain the title compound 8f (198 mg, 49% yield) 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 added in sequence and stirred at room temperature for 12 hours. Formic acid was added to the reaction solution, and the mixture was purified by reversed-phase silica gel chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound 9c (103 mg, 99% yield) as a colorless gum. 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 compound was synthesized from 2,2,2-trifluoroethyl trifluoromethanesulfonate (Compound 10a) and 5-bromo-1H-indazole (Compound 6j) using an appropriate reagent in the same manner 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 11m) used in the synthesis of Example Compounds 11 to 13 was synthesized as follows. [ka]

[0146] (Step 11-1) N-(4-fluoro-3,5-dimethylphenyl)-N-[(2-methylpropan-2-yl)oxycarbonylamino]carbamic acid 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 external temperature of -70 ° C. 1.55 M n-butyl lithium (13.1 mL, 20.4 mmol) was added dropwise at -70 ° C or lower and stirred for 1 hour. A toluene solution of 20 wt% di-tert-butyl azodicarboxylate (25.0 g, 21.7 mmol) was added dropwise at an internal temperature of -40 ° C or lower and stirred for 30 minutes, then the temperature was raised to room temperature over 1 hour, and heptane (23.8 mL) and 20% aqueous ammonium chloride solution (47.6 mL) were added for extraction. The organic layer was concentrated, heptane (7.14 mL) was added, and the mixture was heated to an external temperature of 70 ° C to dissolve, and cooled over 1 hour to precipitate crystals. The crystals were collected by filtration and washed with heptane (2.38 mL). The crystals were dried to obtain 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 an external temperature of 70°C for 3 hours and 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 solution at room temperature. The solution was stirred at room temperature for 14 hours, 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 ethyl 3-[[(2S)-1-cyanopropan-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoate (Compound 11f). To this mixture was added THF (50.0 mL), potassium tert-butoxide (10.2 g, 91.2 mmol) at an internal temperature of 30° C. or less, and the mixture was stirred at room temperature for 1 hour. The internal temperature was adjusted 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% aqueous sodium chloride solution (50.0 mL) and then concentrated to obtain the title compound 11g (15.8 g, 80% yield). 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 external 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 solution, and the mixture was stirred at room temperature for 10 minutes. The aqueous layer was removed, and a solution of compound 11g (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 external temperature of 90 ° C. for 1 hour. The reaction solution was cooled and washed with 1M aqueous sodium hydroxide solution (12.6 mL). The organic layer was concentrated under reduced pressure to give the title compound 11h (1.68 g, yield 75%). 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, and the mixture was stirred at an external temperature of 25° C. for 4 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was distilled off under reduced pressure. The product was purified by silica gel column chromatography (ethyl acetate / hexane=3:2) to obtain the title compound 11j (105 mg, 73% yield). 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-imidazol-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 added to THF (44.5 mL) to suspend, methylsulfonic acid (0.676 g, 7.03 mmol) was added, and the mixture was stirred at an external 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 solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride 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]pyridin-3-yl]-1H-imidazol-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), 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 11m) The compound was synthesized from compound 11l obtained in step 11-8 and compound 6h obtained in step 6-5 by the same procedure as in step 1-10 of Example 1 using appropriate reagents. The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(3-fluoro-2-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-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-fluoropyridin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 14b) The compound 6f obtained in step 6-4 and 2-chloro-3-fluoro-4-iodopyridine (compound 14a) were synthesized by the same procedure as in step 6-5 of Example 6 using an appropriate reagent. 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-methylpyridin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 14c) A 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 7:1 (13.2 mL) was degassed under reduced pressure at room temperature, and then substituted with nitrogen. After stirring at 100°C for 0.5 hours under a nitrogen atmosphere, it was 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, 23% yield) 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(3-fluoro-2-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 14d) The compound was synthesized from compound 11l obtained in step 11-8 and compound 14c obtained in step 14-2 by the same procedure as in step 1-10 of Example 1 using appropriate reagents. The 2-oxoimidazole reagent (3-[(1S,2S)-1-[5-[2-(dimethylamino)-3-methylpyridin-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-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-trimethylpyridin-2-amine (compound 15b) 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), 2M dimethylamine in THF (2.96 mL, 5.92 mmol) in DMF (7.9 mL) was stirred at 130 ° C for 17 hours, cooled to room temperature, and formic acid (0.4 mL) was added. Purification by reverse phase chromatography (acetonitrile / water, 0.1% formic acid) gave 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-methylpyridin-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 15c) The compound 6f obtained in step 6-4 and the compound 15b obtained in step 15-1 were synthesized by the same procedure as in step 6-5 of Example 6 using appropriate reagents. 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-methylpyridin-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 15d) The compound 15c obtained in step 15-2 and the compound 11l obtained in step 11-8 were synthesized by the same procedure as in step 1-10 of Example 1 using appropriate reagents. The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 16a) The compound was synthesized from compound 11l obtained in step 11-8 and compound 8b obtained in step 8-1 by the same procedure as in step 1-10 of Example 1 using appropriate reagents. 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] The compound was synthesized from 3-methyl-3-[(4-methylphenyl)sulfonylmethyl]oxetane (Compound 17a) and 5-bromo-1H-indazole (Compound 6j) using an appropriate reagent in the same manner 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 of borane (0.95M, 4.37mL, 4.15mmol) was added dropwise to a THF solution (1.38mL) of 2-(4-bromo-2-methoxyphenoxy)-2-methylpropanecarboxylic acid (compound 20a, 400mg, 1.38mmol) at 0°C, and the mixture was stirred for 24 hours. After adding a 1M aqueous solution of sodium hydroxide and stirring, the mixture was neutralized by adding 1N hydrochloric acid. Ethyl acetate was added for extraction. The organic layer was washed with water, and the solvent was distilled off under reduced pressure to obtain the title compound 20b (339mg, 89% yield). 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) The compound was synthesized by the same procedure as in step 8-3 of Example 8 using (3R)-oxolan-3-ol and an appropriate reagent. 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) The compound 22b obtained in step 22-1 and 5-bromo-1H-indazole were synthesized by the same procedure as in step 8-4 of Example 8 using an appropriate reagent. 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) The compound was synthesized from 1,1-dimethyl-3,4-dihydroisochromen-6-ol (compound 24a) and trifluoromethylsulfonyl trifluoromethanesulfonate (triflate anhydride) using an appropriate reagent in the same manner 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) 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-dioxaborolane (147 mg, 0.580 mmol), triethylamine (0.162 mL, 1.16 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.2 mg, 0.019 mmol) in 1,4-dioxane (2.58 mL) was degassed under reduced pressure, substituted 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 mixture (134 mg) containing the title compound 24c as a light brown liquid. 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) A solution of copper(II) bromide (258 mg, 1.16 mmol) in water (1.9 mL) was added to a solution of compound 24c (111 mg, 0.385 mmol) obtained in step 24-2 in methanol (1.9 mL), and the mixture was stirred at 60° C. for 6 hours. After cooling to room temperature, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted twice with dichloromethane, and 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, 51% yield) 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-dimethylpyrimidin-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-dimethylpyrimidin-4-amine (compound 25b) 4-(4-bromo-2-methylphenyl)-6-chloropyrimidine (compound 25a, 12.9 mg, 0.045 mmol) was added to a methanol (0.2 mL) solution of 2M dimethylamine THF solution (0.227 mL, 0.455 mmol) and stirred at room temperature for 3 hours. The reaction mixture was purified by reversed-phase silica gel column chromatography (acetonitrile / water, 0.1% formic acid) to synthesize the title compound 25b (9.2 mg, 69% yield) 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 compound was synthesized from 2,2,2-trifluoroethyl trifluoromethanesulfonate (compound 10a) and 5-bromo-4-fluoro-1H-indazole (compound 28a) using an appropriate reagent in the same manner 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) The compound was synthesized from 3-methyl-3-[(4-methylphenyl)sulfonylmethyl]oxetane (compound 17a) and 5-bromo-4-fluoro-1H-indazole (compound 28a) using an appropriate reagent in the same manner 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-fluoroindazol-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-fluoroindazol-1-yl)-2-methylpropan-2-ol (compound 30a) The compound was synthesized from 5-bromo-4-fluoro-1H-indazole (compound 28a) and 2,2-dimethyloxirane (compound 6k) using an appropriate reagent in the same manner 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 31l) used in the synthesis of Example compounds 31 to 40 was synthesized as follows. [ka]

[0171] (Step 31-1) Ethyl 5-(2,2-dimethyloxan-4-yl)-1H-indole-2-carboxylate (compound 31c) Zinc dust (1.95g, 29.8mmol) was suspended in DMF (6mL) and purged with nitrogen. Chlorotrimethylsilane (0.417mL, 3.28mmol) and 1,2-dibromoethane (0.284mL, 3.28mmol) were added and stirred at room temperature for 5 minutes. A solution of 4-iodo-2,2-dimethyltetrahydropyran (5.37g, 22.4mmol) in DMF (9mL) was added dropwise and stirred at room temperature for 20 minutes. Palladium(II) acetate (0.084g, 0.373mmol), 4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (0.198g, 0.746mol), and ethyl 5-bromoindole-2-carboxylate (2.0g, 7.46mmol) were added to this solution and purged with nitrogen. After stirring at an external temperature of 50°C for 1 hour, the external temperature was cooled to 0°C and neutralized with 5N hydrochloric acid (6mL). 30% aqueous sodium chloride solution (50mL) and ethyl acetate (100mL) were added, and insoluble matter was removed using Celite. The filtrate was extracted with ethyl acetate and washed with 30% aqueous sodium chloride solution. After drying over magnesium sulfate and filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to synthesize the title compound 31c (1.86g, 83% yield) 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 the 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%). Fractionation 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 x 250 mm, 5 μm (Daicel) Column temperature: 25℃ Solvent: hexane / ethanol = 30 / 70 (homogeneous system) Flow rate: 1mL / min, room temperature Title compound retention time: 9.98 min, isomer retention time: 6.86 min The title compound was identified as the S-configuration 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), 2M aqueous sodium hydroxide solution (3.62 mL, 7.25 mmol) was added dropwise, and the mixture was stirred at an external temperature of 65° C. for 1 hour. The reaction solution was cooled to an external 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 collected by filtration. 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 less. 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 less, and the mixture was stirred at room temperature for 1 hour. Water (4.0 mL) was added dropwise, and the precipitated solid was collected by filtration. 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 obtained solution at an external temperature of 10 ° C. and 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 a 15% sodium chloride aqueous solution (1.0 mL), and then concentrated under reduced pressure at an external temperature of 40 ° C. to obtain the title compound 31h as a light brown oil, 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 min (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) The compound 31h obtained in step 31-5 was synthesized by the same procedure as in steps 1-6 of Example 1 using appropriate reagents. 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-oxadiazol-3-yl)cyclopropyl]-N-phenylindole-2-carboxamide (compound 31j) The compound 31i obtained in step 31-6 was synthesized by the same procedures as in steps 1-6 of Example 1 using appropriate reagents. 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-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 31k) The compound 31j obtained in step 31-7 was synthesized by the same procedure as in step 6-4 of Example 6 using an appropriate reagent. 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 31l) The compound was synthesized from compound 11l obtained in step 11-8 and compound 31k obtained in step 31-8 by the same procedure as in step 1-10 of Example 1 using appropriate reagents. The halogen compound 5-bromo-1-(2-methoxyethyl)-3-methylbenzimidazol-2-one (compound 33b) used in the synthesis of Example compound 33 was synthesized as follows.

[0180] (Step 33-1) [ka] The compound was synthesized from 5-bromo-3-methyl-1H-benzimidazol-2-one (compound 33a) using an appropriate reagent 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] Synthesis was performed from 5-bromo-4-fluoro-1H-indazole (Compound 28a) using an appropriate reagent in the same manner 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] The compound was synthesized from 5-bromo-4-fluoro-1H-indazole (compound 28a) and 4-methylbenzenesulfonic acid [(3R)-oxolan-3-yl] (compound 22b) using an appropriate reagent in the same manner 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(2S,4S)-2-methyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 41f) used in the synthesis of Example Compound 41 was synthesized as follows. [ka]

[0183] (Steps 41-1 and 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 replaced with nitrogen. Under a nitrogen atmosphere, a 7:5 mixed solution of chlorotrimethylsilane / 1,2-dibromoethane (0.0083 mL, chlorotrimethylsilane was 0.039 mmol) was added and stirred for 15 minutes, after which (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 (6.4mg, 0.028mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (26mg, 0.057mmol), 5-bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-N-methyl-N-phenylindole-2-carboxamide (58mg, 0.14mmol), and DMA (0.123mL) were added, degassed under reduced pressure, substituted 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 the mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed once with saturated saline and 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 (31mg, 51% yield). 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-oxadiazol-3-yl)cyclopropyl]-N-phenylindole-2-carboxamide (compound 41d) The compound 41c obtained in step 41-2 was synthesized by the same procedure as in steps 1-8 of Example 1 using appropriate reagents. 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-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 41e) The compound 41d obtained in step 41-3 was synthesized by the same procedure as in step 6-4 of Example 6 using an appropriate reagent. 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(2S,4S)-2-methyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 41f) The compound 41e obtained in step 41-4 was synthesized by the same procedure as in step 1-10 of Example 1 using an appropriate reagent. The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-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), a procedure similar to that in step 2-2 of Example 2 was used with an appropriate reagent to obtain (4-chloro-3,5-dimethylphenyl)hydrazine hydrochloride (compound 42b). Then, using compound 11g obtained in step 11-4 and an appropriate reagent, compound 42c was synthesized by a procedure similar to that 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) The compound 42c obtained in step 42-2 was synthesized by the same procedure as in step 1-3 of Example 1 using an appropriate reagent. 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 42e) The compound 42d obtained in step 42-3 was synthesized by the same procedure as in step 11-8 of Example 11 using an appropriate reagent. 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]pyridin-3-yl]-1H-imidazol-2-one hydrochloride (compound 42f) The compound 42e obtained in step 42-4 was synthesized by the same procedure as in step 111-8 of Example 11 using an appropriate reagent. 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 42g) The compound 42f obtained in step 42-5 and the compound 31k obtained in step 31-8 were synthesized by the same procedure as in step 1-10 of Example 1 using appropriate reagents. The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 44a) The compound 42f obtained in step 42-5 and the compound 8b obtained in step 8-1 were synthesized by the same procedure as in step 1-10 of Example 1 using appropriate reagents. The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-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) The compound was synthesized from (4-fluoro-3-methylphenyl)hydrazine hydrochloride (compound 46a) and compound 11g obtained in step 11-4 by the same procedure as in step 1-2 of Example 1 using an appropriate reagent. 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 by the same procedure as in step 1-3 of Example 1 using an appropriate reagent. 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 46d) The compound 46c obtained in step 46-2 was synthesized by the same procedure as in step 11-7 of Example 11 using an appropriate reagent. 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]pyridin-3-yl]-1H-imidazol-2-one hydrochloride (compound 46e) The compound 46d obtained in step 46-3 was synthesized by the same procedure as in step 11-8 of Example 11 using an appropriate reagent. 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 46f) The compound 46e obtained in step 46-4 and the compound 8b obtained in step 8-1 were synthesized by the same procedure as in step 1-10 of Example 1 using appropriate reagents. 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 48a) used in the synthesis of Example compounds 48 to 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 48a) The compound was synthesized from compound 46e obtained in step 46-5 and compound 31k obtained in step 31-8 by the same procedure as in step 1-10 of Example 1 using appropriate reagents.

[0199] <Examples 51 to 53> Using 3-[(1S,2S)-1-[5-bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 51d) and substituted morpholine, and an appropriate reagent, the same operation as in step 7-1 of Example 7 was carried out, and the example compounds 51 to 53 shown in Table 2-4 were obtained by the following reaction. [ka] [Table 2-4] JPEG2025032241000105.jpg173153 JPEG2025032241000106.jpg162153 Compound 51d was synthesized as follows. [ka]

[0200] (Step 51-1) 2-(4-Fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-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. Water (20.0 mL) and a 5% aqueous potassium hydrogen sulfate solution (20.0 mL) were added to the reaction solution, which was then 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, 50% yield). 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 51b) The compound 51a obtained in step 51-1 and 5-bromo-1-methylindazole were synthesized by the same procedure as in step 1-11 of Example 1 using an appropriate reagent. 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]pyridin-3-yl]-3-(1-methylindazol-5-yl)imidazol-2-one hydrochloride (compound 51c) The compound 51b obtained in step 51-2 was synthesized by the same procedure as in step 11-9 of Example 11 using an appropriate reagent. 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 51d) The compound was synthesized from compound 51c obtained in step 51-3 and compound 6f obtained in step 6-4 by the same procedure as in step 1-10 of Example 1 using appropriate reagents. LC / MS mass spectrometry: m / z817([M+H] + ). LC / MS retention time: 1.41 minutes (Analysis conditions: SMD-FA05-1).

[0204] <Examples 54 to 73> Using amine derivatives and carboxylic acid derivatives, the same procedures as in steps 1-10 of Example 1 were carried out by the following reactions to obtain Example compounds 54 to 72 and Example compound 73 shown in Table 2-5. [ka] [Table 2-5] JPEG2025032241000110.jpg205162 JPEG2025032241000111.jpg225162 JPEG2025032241000112.jpg244162 JPEG2025032241000113.jpg225162 JPEG2025032241000114.jpg225162 JPEG2025032241000115.jpg218162 JPEG2025032241000116.jpg237162 JPEG2025032241000117.jpg244162 JPEG2025032241000118.jpg237162 JPEG2025032241000119.jpg244162 JPEG2025032241000120.jpg244162 JPEG2025032241000121.jpg237162 JPEG2025032241000122.jpg244162 JPEG2025032241000123.jpg244162 JPEG2025032241000124.jpg237162 JPEG2025032241000125.jpg244162 JPEG2025032241000126.jpg251162 JPEG2025032241000127.jpg220162 The compounds in Tables 2-5 have rotational isomers. For example, the compounds of Examples 66 and 67 1 H-NMR is as follows:

[0205] <Example Compound 66> Main Rotamer 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)indazol-5-yl]-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 56b) The compound was synthesized from compound 51a obtained in step 51-1 and 5-bromo-1-(2-methoxyethyl)indazole (compound 56a) by the same procedure as in step 1-11 of Example 1 using an appropriate reagent. 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)indazol-5-yl]imidazol-2-one hydrochloride (compound 56c) The compound 56b obtained in step 56-1 was synthesized by the same procedure as in step 11-8 of Example 11 using an appropriate reagent. 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) tert-Butyl N-(4-isocyanatocuban-1-yl)carbamate (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 diphenylphosphoryl azide (0.10 mL, 0.465 mmol) were added at room temperature, and the mixture was stirred at room temperature for 100 minutes and then at 85° C. for 3.5 hours. The solvent in the reaction mixture was distilled off under reduced pressure to obtain the title compound 57b as a 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]cuban-1-yl]carbamoylamino]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl ester (compound 57c) The compound was synthesized from compound 57b obtained in step 57-1 and compound 11h obtained in step 11-5 by the same procedure as in step 1-3 of Example 1 using appropriate reagents. LC / MS mass spectrometry: m / z636([M+H] + ). LC / MS retention time: 0.93 min (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]cuban-1-yl]-2-oxoimidazolidin-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl ester (compound 57d) 1,2-dichloro-1-ethoxyethane (0.0155mL, 0.127mmol) was added to a suspension of compound 57c (31.6mg, 0.050mmol) obtained in step 57-2 and cesium carbonate (82.8mg, 0.254mmol) in DMA (0.25mL) at room temperature and stirred at room temperature for 170 minutes. Cesium carbonate (104mg, 0.32mmol) and then 1,2-dichloro-1-ethoxyethane (0.0184mL, 0.162mmol) were added to the reaction mixture at room temperature and stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and water, and 1N hydrochloric acid (0.54mL) was added to adjust the pH to 7, and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, toluene was added, and the solvent was evaporated under reduced pressure to obtain the title compound 57d as a 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]cuban-1-yl]-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl ester (compound 57e) Methylsulfonic acid (0.011mL, 0.17mmol) was added to a solution of compound 57d (115mg, 0.17mmol) obtained in step 57-3 in THF (1.1mL) at room temperature, and the mixture was stirred at 60°C for 90 minutes. Potassium phosphate (36.5mg, 0.172mmol), water (0.45mL) and (2-methylpropan-2-yl)oxycarbonyl tert-butyl carbonate (0.012mL, 0.052mmol) were added to the reaction mixture and stirred for 1 hour. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over magnesium sulfate and the solvent was distilled off 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 (48.5mg, 43% yield). 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-methylpropan-2-yl)oxycarbonyl]amino]cuban-1-yl]-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl ester (compound 57f) To a solution of compound 57e (16.1 mg, 0.024 mmol) obtained in step 57-4 in THF (0.22 mL) was added 1.7 M potassium pentoxide toluene solution (0.024 mL, 0.041 mmol) 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 stirred at -30 ° C. to -25 ° C. for 5 minutes, and at -25 ° C. to room temperature for 3 minutes. Water (0.5 mL) was added to the reaction mixture, and the mixture was diluted with ethyl acetate, and further water was added and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was removed under reduced pressure, and the mixture 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]pyridin-3-yl]-2-oxoimidazol-1-yl]cuban-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 the solvent was removed from the reaction mixture under reduced pressure, toluene was added and the solvent was removed, and hexane-dichloromethane was added and the solvent was removed, to obtain the title compound 57g (9.4 mg) as a 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-oxoimidazol-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 compound 57g obtained in step 57-6, the compound was synthesized by the same procedure as in step 51-1 of Example 51 using an appropriate reagent. 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]cubane-1-yl]-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl ester (compound 57i) The compound 57h obtained in step 57-7 was synthesized by the same procedure as in step 57-5 of Example 57 using an appropriate reagent. LC / MS mass spectrometry: m / z660([M+H] + ). LC / MS retention time: 0.93 min (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]pyridin-3-yl]-2-oxoimidazol-1-yl]cuban-1-yl]-N-(2-methoxyethyl)acetamide hydrochloride (compound 57j) The compound 57i obtained in step 57-8 was synthesized by the same procedure as in step 11-8 of Example 11 using an appropriate reagent. 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) The compound was synthesized from compound 1b obtained in step 1-1 and compound 46a obtained in step 46-1 by the same procedure as in step 1-2 of Example 1 using appropriate reagents. 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) The compound 58a obtained in step 58-1 was synthesized by the same procedure as in step 1-3 of Example 1 using an appropriate reagent. 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 58c) The compound 58b obtained in step 58-2 was synthesized by the same procedure as in step 11-7 of Example 11 using an appropriate reagent. 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)indazol-5-yl]-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 58d) The compound 58c obtained in step 58-3 and 5-bromo-1-(2-methoxyethyl)indazole (compound 56a) were synthesized by the same procedure as in step 1-11 of Example 1 using an appropriate reagent. 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)indazol-5-yl]imidazol-2-one hydrochloride (compound 58e) The compound 58d obtained in step 58-4 was synthesized by the same procedure as in step 11-9 of Example 11 using an appropriate reagent. 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 60a) The compound 1g obtained in step 1-4 was synthesized by the same procedure as in step 51-1 of Example 51 using appropriate reagents. 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl ester (compound 60b) The compound 60a obtained in step 60-1 and 5-bromo-1-methylindazole (compound 1q) were synthesized by the same procedure as in step 1-11 of Example 1 using an appropriate reagent. 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]pyridin-3-yl]-3-(1-methylindazol-5-yl)imidazol-2-one hydrochloride (compound 60c) The compound 60b obtained in step 60-2 was synthesized by the same procedure as in step 11-8 of Example 11 using an appropriate reagent. 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl ester (compound 61a) The compound was synthesized from compound 11k obtained in step 11-7 and 5-bromo-1-methylindazole (compound 1q) using an appropriate reagent in the same manner 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-methylindazol-5-yl)imidazol-2-one hydrochloride (compound 61b) The compound 61a obtained in step 61-1 was synthesized by the same procedure as in step 11-8 of Example 11 using an appropriate reagent. 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)indazol-5-yl]-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl ester (compound 62a) The compound was synthesized from compound 11k obtained in step 11-7 and 5-bromo-1-(2-methoxyethyl)indazole (compound 56a) by the same procedure as in step 1-11 of Example 1 using an appropriate reagent. 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)indazol-5-yl]imidazol-2-one hydrochloride (compound 62b) The compound 62a obtained in step 62-1 was synthesized by the same procedure as in step 11-8 of Example 11 using an appropriate reagent. 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) The compound was synthesized from 5-bromo-7-fluoro-1H-indole-2-carboxylic acid (compound 63a) using an appropriate reagent in the same manner 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) The compound 63b obtained in step 63-1 was synthesized by the same procedure as in step 9-1 of Example 9 using an appropriate reagent. 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) The compound 63c obtained in step 63-2 was synthesized by the same procedure as in steps 1-6 of Example 1 using appropriate reagents. 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) The compound was synthesized from compound 63d obtained in step 63-3 and (tetrahydro-2H-pyran-4-yl)zinc(II) iodide (compound 8a) by the same procedure as in step 8-1 of Example 8 using an appropriate reagent. 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-oxadiazol-3-yl)cyclopropyl]-5-(oxan-4-yl)-N-phenylindole-2-carboxamide (compound 63f) The compound 63e obtained in step 63-4 was synthesized by the same procedure as in steps 1-8 of Example 1 using appropriate reagents. 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-oxadiazol-3-yl)cyclopropyl]-5-(oxan-4-yl)indole-2-carboxylic acid (compound 63g) The compound 63f obtained in step 63-5 was synthesized by the same procedure as in step 6-4 of Example 6 using an appropriate reagent. 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]indazol-5-yl]imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 64a) The compound was synthesized from compound 11k obtained in step 11-7 and compound 8f obtained in step 8-4 by the same procedure as in step 1-11 of Example 1 using appropriate reagents. 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]pyridin-3-yl]-3-[1-[(3R)-oxolan-3-yl]indazol-5-yl]imidazol-2-one hydrochloride (compound 64b) The compound 64a obtained in step 64-1 was synthesized by the same procedure as in step 11-8 of Example 11 using an appropriate reagent. 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl ester (compound 65b) The compound 65a was synthesized from compound 42e obtained in step 42-4 and 5-bromo-4-fluoro-1-methylindazole (compound 65a) by the same procedure as in step 1-11 of Example 1 using an appropriate reagent. 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]pyridin-3-yl]-3-(4-fluoro-1-methylindazol-5-yl)imidazol-2-one hydrochloride (compound 65c) The compound 65b obtained in step 65-1 was synthesized by the same procedure as in step 11-8 of Example 11 using an appropriate reagent. 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl ester (compound 67a) The compound was synthesized from compound 11k obtained in step 11-7 and 5-bromo-4-fluoro-1-methylindazole (compound 65a) by the same procedure as in step 1-11 of Example 1 using an appropriate reagent. 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-methylindazol-5-yl)imidazol-2-one hydrochloride (compound 67b) The compound 67a obtained in step 67-1 was synthesized by the same procedure as in step 11-8 of Example 11 using an appropriate reagent. 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-methylindazol-5-yl)-2-oxoimidazol-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) The compound was synthesized from compound 11k obtained in step 11-7 and 5-bromo-4-chloro-1-methylindazole (compound 68a) by the same procedure as in step 1-11 of Example 1 using an appropriate reagent. 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-methylindazol-5-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one hydrochloride (compound 68c) The compound 68b obtained in step 68-1 was synthesized by the same procedure as in step 11-8 of Example 11 using an appropriate reagent. 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-2-(4-fluoro-3-methylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 69a) The compound 46d obtained in step 46-3 and 5-bromo-4-fluoro-1-methylindazole (compound 65a) were synthesized by the same procedure as in step 1-11 of Example 1 using an appropriate reagent. 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-methylindazol-5-yl)-3-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one hydrochloride (compound 69b) The compound 69a obtained in step 69-1 was synthesized by the same procedure as in step 11-8 of Example 11 using appropriate reagents. 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl ester (compound 70b) The compound was synthesized from compound 11k obtained in step 11-7 and 5-bromo-6-fluoro-1-methylindazole (compound 70a) by the same procedure as in step 1-11 of Example 1 using an appropriate reagent. 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-methylindazol-5-yl)imidazol-2-one hydrochloride (compound 70c) The compound 70b obtained in step 70-1 was synthesized by the same procedure as in step 11-8 of Example 11 using appropriate reagents. 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) The compound was synthesized from 5-bromo-6-fluoro-1H-indazole (Compound 71a) using an appropriate reagent in the same manner 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)indazol-5-yl]-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl ester (compound 71c) The compound was synthesized from compound 11k obtained in step 11-7 and compound 71b obtained in step 71-1 by the same procedure as in step 1-11 of Example 1 using appropriate reagents. 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]pyridin-3-yl]-3-[6-fluoro-1-(2-methoxyethyl)indazol-5-yl]imidazol-2-one hydrochloride (compound 71d) The compound 71c obtained in step 71-2 was synthesized by the same procedure as in step 11-8 of Example 11 using an appropriate reagent. 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-methylpyridin-4-yl)-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-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 added to a DMF (1.5 mL) solution of HATU (26.6 mg, 0.070 mmol) and N,N-diisopropylethylamine (18.1 mg, 0.14 mmol) and stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and washed with distilled water. The organic layer was concentrated under reduced pressure to obtain a residue that was a mixture of stereoisomers. The stereoisomers were separated by reverse phase HPLC to obtain Entity A (14.5 mg, 29% yield) and Entity B (15.5 mg, 31% yield), which is the title compound 73 as a white solid. Fractionation conditions Column: YMC Actus ODS-A, 20 x 100 mm, 5 μm 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (Compound 74) [ka] (Step 74-1) 5-Bromo-6-fluoro-N-methyl-N-phenyl-1H-indole-2-carboxamide (compound 74b) Synthesis was performed in the same manner as in Steps 1-10 of Example 1 using 5-bromo-6-fluoro-1H-indole-2-carboxylic acid (Compound 74a) and appropriate reagents. LC / MS mass spectrometry: m / z347([M+H] + ). LC / MS retention time: 1.06 min (Analysis conditions: SMD-TFA05-4). (Step 74-2) 5-Bromo-1-(cyanomethyl)-6-fluoro-N-methyl-N-phenylindole-2-carboxamide (compound 74c) From compound 74b obtained in step 74-1, the compound was synthesized by the same procedure as in step 9-1 of Example 9 using an appropriate reagent. LC / MS mass spectrometry: m / z386([M+H] + ). LC / MS retention time: 1.06 minutes (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) The compound 74c obtained in step 74-2 and (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (compound 1k) were synthesized by the same procedure as in step 1-6 of Example 1 using an appropriate reagent. 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-oxadiazol-3-yl)cyclopropyl]-N-phenylindole-2-carboxamide (compound 74e) The compound 74d obtained in step 74-3 was synthesized by the same procedure as in steps 1-8 of Example 1 using appropriate reagents. 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-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 74f) The compound 74e obtained in step 74-4 was synthesized by the same procedure as in step 6-4 of Example 6 using an appropriate reagent. 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 74g) The compound 74f obtained in step 74-5 and the compound 61b obtained in step 61-2 were synthesized by the same procedure as in step 1-10 of Example 1 using appropriate reagents. 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 74) The compound was synthesized in the same manner as in step 6-5 of Example 6 using compound 74g obtained in step 74-6, 4-iodo-2-methoxy-3-methylpyridine (compound 6g), and an appropriate reagent. LC / MS mass spectrometry: m / z892([M+H] + ). LC / MS retention time: 1.48 minutes (Analysis conditions: SMD-TFA05-1).

[0224] <Examples 75 to 77> Using an indole bromide compound, an iodo(oxan-4-yl)zinc derivative, and an appropriate reagent, the same procedure as in step 8-1 of Example 8 was carried out to obtain Example Compounds 75 to 77 shown in Table 2-6 by the following reaction. [ka] [Table 2-6] JPEG2025032241000147.jpg134155 JPEG2025032241000148.jpg133155

[0225] Compound 75b used in the synthesis of Example Compound 75 was synthesized as follows. (Step 75-1) Iodo(6-oxaspiro[4.5]decan-9-yl)zinc (compound 75b) [ka] The compound 75a was synthesized from 9-iodo-6-oxaspiro[4.5]decane (compound 75a) using an appropriate reagent in the same manner 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)indazol-5-yl]-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 76a) The compound 56b obtained in step 56-1 and the compound 6f obtained in step 6-4 were synthesized by the same procedure as in step 1-10 of Example 1 using appropriate reagents. 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) Propionaldehyde (0.650mL, 9.01mmol) and lithium iodide (2.78g, 20.8mmol) were added in sequence to a solution of but-3-en-1-ol (0.588mL, 6.93mmol) in acetic acid (2.48mL), and the mixture was stirred at 60°C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with 10% aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure (150hPa was set as the lower limit), and the residue was purified by silica gel chromatography (ethyl acetate / hexane = 0:1 to 1:9) to obtain the title compound 77b as a pale yellow oily product as a diastereomeric mixture (1.12g, 67% yield, syn:anti = 1.00:0.45). 1 H-NMR (400MHz, 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) A mixture of chloro(trimethyl)silane (0.017mL, 0.137mmol) and 1,2-dibromoethane (0.012mL, 0.137mmol) was slowly added dropwise to a solution of zinc (102mg, 1.56mmol) in DMA (0.25mL) under a nitrogen atmosphere so as to maintain the temperature below 65°C, and the mixture was stirred at room temperature for 15 minutes. Subsequently, a solution of compound 77b (300mg, 1.25mmol) obtained in step 77-1 in DMA (0.625mL) was slowly added dropwise to maintain the temperature below 65°C, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere to obtain a DMA solution (0.86M) of the diastereomeric 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 77) To a solution of compound 51d (40.0 mg, 0.049 mmol) obtained in step 51-4 in DMA (0.163 mL), 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, and the mixture was degassed under reduced pressure, substituted with nitrogen, and stirred at room temperature for 5 minutes. Subsequently, a solution of compound 77c obtained in step 77-2 in DMA (0.86 M, 0.398 mL, 0.342 mmol) 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 reversed-phase silica gel chromatography (acetonitrile / water, 0.1% formic acid) to obtain a syn-form diastereomeric mixture. The syn diastereomeric mixture was separated into stereoisomers by reverse phase HPLC to give Entity A (17.4 mg, 41% yield) as a white amorphous substance and Entity B (14.9 mg, 37% yield), which is the title compound 77, as a white amorphous substance. Fractionation 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one (Compound 78) [ka] (Step 78-1) 2-[5-bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]acetonitrile (compound 78a) The compound was synthesized from compound 51c obtained in step 51-3 and 5-bromo-1-(cyanomethyl)indole-2-carboxylic acid (compound 6a) by the same procedure as in step 1-10 of Example 1 using an appropriate reagent. 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]acetonitrile (compound 78b) The compound was synthesized from compound 78a obtained in step 78-1 and (tetrahydro-2H-pyran-4-yl)zinc(II) iodide (compound 8a) by the same procedure as in step 8-1 of Example 8 using an appropriate reagent. 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]cyclopropane-1-carbonitrile (compound 78d) From compound 78b obtained in step 78-2, the compound was synthesized by the same procedure as in steps 1-6 of Example 1 using appropriate reagents. 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 78) The compound 78d obtained in step 78-2 was synthesized by the same procedure as in steps 1-8 of Example 1 using an appropriate reagent. 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-(hydroxymethyl)cyclopropyl]-4H-1,2,4-oxadiazol-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) The compound 6c obtained in step 6-1 and (4R)-4-(phenylmethoxymethyl)-1,3,2-dioxathiolane 2,2-dioxide (compound 79a) were synthesized by the same procedure as in step 1-6 of Example 1 using an appropriate reagent. 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) The compound was synthesized from compound 79b obtained in step 79-1 and (tetrahydro-2H-pyran-4-yl)zinc(II) iodide (compound 8a) by the same procedure as in step 8-1 of Example 8 using an appropriate reagent. 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-oxadiazol-3-yl)-2-(phenylmethoxymethyl)cyclopropyl]-N-phenylindole-2-carboxamide (79d) The compound 79c obtained in step 79-2 was synthesized by the same procedure as in steps 1-8 of Example 1 using appropriate reagents. 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-oxadiazol-3-yl)-2-(phenylmethoxymethyl)cyclopropyl]indole-2-carboxylic acid (79e) The compound 79d obtained in step 79-3 was synthesized by the same procedure as in step 6-4 of Example 6 using an appropriate reagent. 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-(phenylmethoxymethyl)cyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 79f) The compound was synthesized from compound 79e obtained in step 79-4 and compound 51c obtained in step 51-3 by the same procedure as in step 1-10 of Example 1 using appropriate reagents. 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-(hydroxymethyl)cyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 79) A solution of compound 79f (35.4 mg, 0.0381 mmol) obtained in step 79-5 in dichloromethane (0.762 mL) was cooled to 0° C., and a 1M solution of boron trichloride in hexane (0.191 mL, 0.191 mmol) was slowly added. The reaction solution was warmed to room temperature and stirred for 105 minutes, after which a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated saline 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (Compound 80) [ka] (Step 80-1) (E)-3-[[(2S)-1-cyanopropan-2-yl]amino]but-2-enoic acid ethyl ester (compound 80c) Ethyl 3-oxobutanoate (compound 80a, 13 g, 99.9 mmol) was added to a solution of (3S)-3-aminobutanenitrile (compound 80b, 7.0 g, 83.2 mmol) and iodine (2.12 g, 8.35 mmol) in acetonitrile (50 mL), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and 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, 58% yield) 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) Ethyl 3-[[(2S)-1-cyanopropan-2-yl]amino]butanoate (compound 80d) Acetic acid (3 mL) was added to a dichloromethane (200 mL) solution of compound 80c (10 g, 51.0 mmol) obtained in step 80-1 and sodium triacetoxyborohydride (43.3 g, 204 mmol), and the mixture was stirred at room temperature for 16 hours. Water and acetic acid were added to the reaction solution to adjust the pH to 5, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline 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, 54% yield) 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 solution of potassium tert-butoxide (680 mg, 6.06 mmol) in toluene (10 mL), a solution of compound 80d (1.0 g, 5.04 mmol) obtained in step 80-2 in toluene (5 mL) 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-carbonitrile. A solution of acetic anhydride (12.1 g, 118 mmol) in toluene (5 mL) was slowly added dropwise to formic acid (7.26 g) at 0° C., and the mixture was stirred at 0° C. for 30 minutes, and then the toluene solution of (6S)-4-hydroxy-2,6-dimethyl-1,2,3,6-tetrahydropyridine-5-carbonitrile prepared above was slowly added dropwise. After stirring at 110° C. for 16 hours, the mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure, and the solvent was distilled off 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 reaction solution was cooled to room temperature and 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]pyridin-3-yl]urea (compound 80g) 2,2-Dimethoxyethane-1-amine (1.14g, 10.8mmol) was added to a solution of N,N'-carbodiimidazole (1.63g, 10.1mmol) in DMA (50mL) at 0°C and stirred for 30 minutes. To the solution, potassium tert-butoxide (5.62g, 50.1mmol) and compound 80f (2.64g, 8.34mmol) obtained in step 80-4 were added in sequence. 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 saline, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 80g (2.80g, 75% yield) 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-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbaldehyde (compound 80h) A solution of compound 80g (2.50 g, 5.59 mmol) 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 saline, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain a diastereomeric 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). The title compound (compound 80h: (4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbaldehyde) was separated into stereoisomers by SFC to obtain the title compound 80h, Entity A (155 mg, 7.0% yield) and Entity B (270 mg, 12% yield). 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: 254 nm 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). The fact that compound 80h is a 6R form was confirmed by 2D-NOESY that the configuration 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]pyridin-3-yl]-1H-imidazol-2-one (compound 80i) A 5M aqueous sodium hydroxide solution (0.261 mL) was added to a solution of the compound 80h (100 mg, 0.261 mmol) obtained in step 80-6 in ethanol (1.0 mL), and the mixture was stirred at 80° C. for 10 hours. After cooling to room temperature and stirring for 60 hours, a saturated aqueous ammonium chloride 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-methylindazol-5-yl)imidazol-2-one (compound 80j) 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) were added to a suspension of N-methylpiperazine (0.188 mL) with copper(I) iodide (4.02 mg, 0.021 mmol) at room temperature, and the mixture was stirred at 130° C. for 90 minutes under a nitrogen atmosphere. The reaction mixture was purified by reversed-phase silica gel chromatography (acetonitrile / water, 0.1% formic acid) and concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue, which was then extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to give 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-oxadiazol-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 stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate and concentrated. The resulting residue was purified by normal phase column chromatography (ethyl acetate / hexane) to obtain the title compound 80k (147 mg, 88% yield) as a yellow gum. 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-oxadiazol-3-yl]-2-methylcyclopropyl]indole-2-carboxylic acid (80l) To a dichloromethane (2.3 mL) solution of compound 80k (147 mg, 0.228 mmol) obtained in step 80-9, magnesium bromide·diethyl ether complex (295 mg, 1.14 mmol) was added and stirred at 0° C. for 6.5 hours. After warming to room temperature and stirring for 30 minutes, a saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, concentrated, and 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, 51% yield). 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-oxadiazol-3-yl]-2-methylcyclopropyl]indole-2-carbonyl chloride (compound 80m) To a solution of compound 80l (18 mg, 0.036 mmol) obtained in step 80-10 in acetonitrile (0.36 mL), 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.0057 mL, 0.043 mmol) was added, and the mixture was stirred at room temperature for 2 hours and then concentrated to obtain a crude product of the title compound 80m. 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4-(2-trimethylsilylethoxymethyl)-1,2,4-oxadiazol-5-one (compound 80n) Compound 80m obtained in step 80-11 was dissolved in THF (0.717 mL), compound 80j (19.1 mg, 0.036 mmol) obtained in step 80-8 and N,N-diisopropylethylamine (0.0188 mL, 0.108 mmol) were added, and the mixture was stirred at room temperature for 22 hours, followed by addition of methanol and formic acid. The mixture was concentrated, and 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, 91% yield). 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 80) Acetic acid (0.0019mL, 0.033mmol) and 1M tetrabutylammonium fluoride in THF solution (0.065mL, 0.065mmol) were added to the compound 80n (32mg, 0.033mmol) obtained in step 80-12 in THF (0.326mL) and stirred at 80°C for 66 hours. Acetic acid (0.0019mL, 0.033mmol) and 1M tetrabutylammonium fluoride in THF solution (0.065mL, 0.065mmol) were added and stirred for 23.5 hours, and 1M tetrabutylammonium fluoride in THF solution (0.065mL, 0.065mmol) was added and stirred for 7 hours, and formic acid was added. After concentration, it 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 (18mg, 65% yield). LC / MS mass spectrometry: m / z851([M+H] + ). LC / MS retention time: 1.42 minutes (Analysis conditions: SMD-TFA05-1).

[0231] Moreover, in the same manner as in Examples 1 to 80, Example Compounds 101 to 159 shown in the following Table 2-7 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 1, 1005.5 mg) obtained in Example 1 was added with acetonitrile (3.02 mL) and dissolved at room temperature. 5M aqueous sodium hydroxide solution (0.495 mL) and seed crystals of sodium salt hydrate of compound 1 were added to this solution and stirred at room temperature for 2 hours. Further, tert-butyl methyl ether (3.02 mL) was added, and the mixture was stirred at room temperature for 1 hour, and then tert-butyl methyl ether (9.05 mL) was added, and the mixture was stirred at room temperature for 2 hours to obtain the title compound sodium salt hydrate crystals (1007.0 mg) as powder crystals (Sample 160a). Note that the seed crystals were obtained by the following method. Compound 1 (26.9 mg) was added with DMSO (0.244 mL) and 2 M aqueous sodium hydroxide 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 and stirred at room temperature for 2 days. Then, tert-butyl methyl ether (0.015 mL) was added and the mixture was shaken and stirred at room temperature for 12 days to obtain a powdered crystal of the sodium salt hydrate of compound 1 (sample 160b).

[0233] <Example 161> Preparation of crystals 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (Example compound 66, 400.3 mg) was suspended in ethanol (8.00 mL), seed crystals of Example compound 66 were added, and the mixture was stirred at 70 ° C. for 5 minutes. The suspension was stirred at 50 ° C. for 1 hour, and then stirred at room temperature for 17 hours to obtain crystals of Example compound 66 (381.1 mg) as powder crystals (Sample 161a). The seed crystals were 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 crystals of Example compound 66 (24.2 mg) as powder crystals (Sample 161b).

[0234] <Example 162> Preparation of 1 / 2 calcium salt hydrate crystals of Example 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (Example compound 67, 1120 mg) was added with ethanol (5.60 mL) and 2M aqueous sodium hydroxide solution (0.75 mL) and dissolved at room temperature. To this solution, 1.26M calcium acetate aqueous solution (0.68mL), seed crystals of calcium salt hydrate of Example Compound 67, and water (0.68mL) were added, and the mixture was stirred at room temperature for 3 hours. Water (1.2mL) was further added, and the mixture was stirred at room temperature for 1 hour, and then water (2.3mL) was added, and the mixture was stirred at room temperature for 1 hour to obtain calcium salt hydrate crystals of Example Compound 67 (973.0mg) as powder crystals (Sample 162a). The seed crystals were 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 shaken and stirred at room temperature for 7 days to obtain calcium salt hydrate crystals of Example compound 67 as powder crystals (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 each subjected to powder X-ray diffraction measurement by the following measurement method. The results are shown in Figures 1 to 6. Measurement equipment: D8 Discover with GADDS CS diffractometer (manufactured by Bruker AXS) Anticathode: Cu Tube voltage: 40kV Tube current: 40mA Scanning range: 5~25.3° Sampling width: 0.02°

[0236] <Example 164> Thermogravimetry 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 thermogravimetry and differential thermal analysis by the following measurement method. The results are shown in Figures 7 and 8. Sample 160a was dehydrated by about 110°C and did not show a clear melting point. Sample 162a was dehydrated by about 240°C and did not show a clear melting point. Measurement equipment: EXSTAR TG / DTA6200R (manufactured by Seiko Instruments (currently Hitachi High-Tech Science)) Measurement range: 30~350℃ Heating rate: 10℃ / min Atmosphere: Nitrogen

[0237] Example 165 Karl Fischer moisture content measurement The moisture content of 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. From the results of Example 164 and Example 165, it was confirmed that the water contained in the sodium salt hydrate crystals of Compound 1 and the calcium salt hydrate crystals of Example Compound 67 was mainly water of crystallization.

[0238] <Test Example 1> In vitro cAMP signal activation measurement of compounds in human GLP1R (peptide) Human GLP-1 (7-37) was purchased from Peptide Institute, dissolved in phosphate buffered saline to a concentration of 200 μM, and stored in a −80° C. freezer. (cell culture) Human GLP1R stable expressing cell line (hGLP1R-HEK293) was used for the experiment. The cells were cultured in Dulbecco's modified Eagle's 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) at 37°C in a humidified atmosphere containing 5% CO2. (cAMP assay) 2.0 × 10 hGLP1R-HEK293 per well 4 The cells were seeded in a 96-well plate at 100 μL each and cultured overnight. The next 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. Next, 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 at 37°C for 30 minutes. Then, 100 μL of Assay lysis buffer (Applied Bioscience) was added and incubated at 37°C for 30 minutes. The cAMP concentration was quantified using a cAMP HiRange kit (Cisbio Bioassays). (EC 50 (Calculation of The cAMP concentration in each well was converted into a response rate (%), with the cAMP concentration when human GLP-1 (7-37) was applied at a concentration of 1 nM being taken as 100%. A dose-response curve for each example compound was created using four-parameter logistic regression analysis with XLfit (ver5.4.0.8), and the 50% effective concentration (EC 50 The results are shown in Table 3. [Table 3]

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

[0240] <Test Example 3>: Food intake suppression effect Example compound 67 was orally administered to male cynomolgus monkeys for 5 consecutive days, and the effect on food intake for 90 minutes from 3 hours after administration was examined on each day. In addition, a control drug, exenatide, was subcutaneously administered for 5 consecutive days, and the effect on food intake for 90 minutes from 30 minutes after administration was examined. The vehicle group was administered both the vehicle for oral administration of 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 vehicle for subcutaneous administration of exenatide (0.05 w / v% Tween / PBS (-), 0.1 mL / kg). In accordance with this, a subcutaneous administration solvent was additionally administered to the Example Compound 67 administration group (administration drug concentration, 0.05 or 0.1 mg / mL), and an oral administration solvent was additionally administered to the exenatide administration group (administration 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). The plasma drug concentrations (mean ± standard error) immediately after the food intake measurement 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 group, and 91 ± 8.5 pM (0.3 μg / kg group) and 199 ± 13.1 pM (0.6 μg / kg group) in the exenatide group.

[0241] <Test Example 4> Pharmacokinetics of the compound Suspensions (doses: 0.05, 0.15, 0.45 and 1.35 mg / kg) of calcium salt hydrate crystals of Example Compound 67 (Sample 162a) obtained in Example 162 were orally administered (forced intragastric administration via a gastric catheter) to male cynomolgus monkeys (n=2 for each dose), and then blood was collected from a vein over time and plasma was separated. The drug concentration in the plasma was quantified by liquid chromatography tandem mass spectrometry. The lower limit of quantification was 0.3 ng / mL. The time course of the drug concentration in plasma is shown in Figure 12, and the time to reach the maximum plasma drug concentration (T max ), maximum plasma drug concentration (C max ) and the area under the plasma drug concentration-time curve up to 24 hours after administration (AUC 0-24h ) are shown in Table 4. After oral administration, plasma drug concentrations were C at 2 hours after administration for all doses. max After reaching 1.35 mg / kg, plasma exposure increased approximately proportionally to the 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. Formula (I): 【Chemistry 1】 [Wherein, X is -N= or -CR ａ =; R ａ is a hydrogen atom, a halogen atom, and C １－６ alkyl; Y is -C(=O)-, -CHR-, or -S(=O) ２ -; R is selected from a hydrogen atom or C １－６ represents alkyl; Q １ is C ６－１０ aryl or 5-10 membered heteroaryl, where C ６－１０ Aryl and 5- to 10-membered heteroaryl are each independently selected from the group consisting of halogen atoms, C １－６ Alkyl (where C １－６ The alkyl may be substituted with one or more halogen atoms, and C １－６ optionally substituted with 1 to 5 substituents independently selected from alkoxy; 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 selected from the group consisting of a halogen atom, C １－６ Alkyl (where C １－６ The alkyl may be substituted with one or more halogen atoms. １－６ Alkoxy, and -NR Ｑａ R Ｑｂ and further comprising one to three substituents independently selected from two C １－６ Alkyl groups taken together with the carbon atom to which they are attached form C ３－８ may form a carbocyclic ring; R Ｑａ and R Ｑｂ are independently a hydrogen atom, C １－６ Alkyl, and (C １－６ alkyl)carbonyl; R １ , R ２ , and R ３ each independently represents a hydrogen atom and C １－６ Alkyl (where C １－６ Alkyl is a halogen atom, C １－６ alkoxy, and hydroxy; R ４ , R ５ , and R ６ are each independently a hydrogen atom, a halogen atom, or C １－６ alkyl; R ７ and R ８ are independently a hydrogen atom or C １－６ Represents alkyl, where C １－６ Alkyl is a halogen atom and C ３－１５ cycloalkyl; or R ７ and R ８ together with the carbon atom to which they are attached, C ３－１５ may form a cycloalkane ring, or R ７ and R ８ Together they form C ３－１５ The cycloalkane ring is a ring having 1 to 3 C １－６ Optionally substituted with alkyl, where C １－６ Alkyl is a halogen atom, hydroxy, -NR ７ａ R ７ｂ , C １－６ alkoxy, and 3- to 12-membered heterocyclyl; R ７ａ and R ７ｂ are independently a hydrogen atom, C １－６ Alkyl, and (C １－６ alkyl)carbonyl; n1 represents an integer of 0 to 3; n2 represents an integer of 0 to 5; R ９ are represented by the formulas (IIa), (IIb), (IIc), and (IId): 【Chemistry 2】 , -CO ２ R ９ｆ and -C(=O)-NR ９ｇ R ９ｈ R ９ａ , R ９ｂ , R ９ｃ , R ９ｄ , and R ９ｇ Each independently represents a hydrogen atom, C １－６ Alkyl (where C １－６ Alkyl is a halogen atom and C １－６ alkoxy), and １－６ alkyl)carbonyl; R ９ｅ is a hydrogen atom or C optionally substituted with one or more halogen atoms. １－６ represents alkyl, R ９ｆ is a hydrogen atom or C １－６ represents alkyl, R ９ｈ is a hydrogen atom, C １－６ Alkyl, (C １－６ alkyl)carbonyl, cyano, or -S(=O) ｎ３ -R ９ｉ n3 represents an integer of 0 to 2; R ９ｉ is C １－６ represents alkyl; Z １ are represented by the formulas (IIIa), (IIIb), (IIIc), (IIId), and (IIIe): 【Chemistry 3】 R ｚａ is a hydrogen atom, C １－６ Alkyl, and (C １－６ alkyl)carbonyl; R ｚｂ and R ｚｃ are independently a hydrogen atom or C １－６ n4 represents an integer of 1 to 3, and n5 and n6 each independently represent an integer of 0 to 10 (* represents a bonding site to the pyrazolopyridine skeleton, ** represents Z ２ Each represents a binding site for Z ２ is C １－６ Alkyl, C ３－１５ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１０ aryl, and 5-10 membered heteroaryl, wherein C ３－１５ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１０ Aryl and 5- to 10-membered heteroaryl are in 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 represents a hydrogen atom, C １－６ Alkyl and (C １－６ alkyl)carbonyl, wherein C １－６ Alkyl is hydroxy, halogen atoms, and C １－６ Optionally substituted with one or more substituents independently selected from alkoxy; e)-C(=O)-NR ｚｆ R ｚｇ ; where R ｚｆ and R ｚｇ Each independently represents a hydrogen atom, C １－６ Alkyl, and (C １－６ alkyl)carbonyl, wherein C １－６ Alkyl is hydroxy, halogen atoms, and C １－６ Optionally substituted with one or more substituents independently selected from alkoxy; f) -S(=O) ｎ７ -R ｚｈ where n7 represents an integer from 0 to 2, R ｚｈ is a hydrogen atom or C １－６ Represents alkyl, g) C １－６ Alkyl; where C １－６ Alkyl is a halogen atom, hydroxy, -NR ｚｉ R ｚｊ , C １－６ and 3- to 12-membered heterocyclyl, where R ｚｉ and R ｚｊ are independently a hydrogen atom or C １－６ alkyl, and 3- to 12-membered heterocyclyl is hydroxy, C １－６ optionally substituted with one or more substituents independently selected from alkyl, and 3- to 12-membered heterocyclyl; h) C １－６ Alkoxy; where C １－６ Alkoxy is a group consisting of hydroxy, halogen atoms, and C １－６ Optionally substituted with one or more substituents independently selected from alkoxy; i) 3- to 12-membered heterocyclyl; wherein 3- to 12-membered heterocyclyl is C １－６ Alkyl and (C １－６ Optionally substituted with one or more substituents independently selected from: j) C ６－１０ Aryl; where C ６－１０ Aryl is one or more of (C １－６ Optionally substituted with alkyl)carbonyl, and k) 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl is C １－６ Alkyl, C １－６ Alkoxy, -NR ｚｋ R ｚｌ and 3- to 12-membered heterocyclyl, where R ｚｋ and R ｚｌ are independently a hydrogen atom, C １－６ Alkyl, and (C １－６ alkyl)carbonyl, and 3- to 12-membered heterocyclyl is selected from C １－６ Alkyl and (C １－６ Optionally substituted with one or more substituents independently selected from: and optionally substituted with 1 to 5 substituents independently selected from A compound represented by the formula:

2. Q １ is phenyl or pyridyl, where phenyl and pyridyl are selected from the group consisting of halogen atoms and C １－６ The compound according to claim 1, which is substituted with 1 to 4 substituents independently selected from alkyl, a salt thereof, or a solvate of either of them.

3. R ７ and R ８ are both hydrogen atoms; R ７ and R ８ Both are C １－６ Is alkyl; R ７ is a hydrogen atom and R ８ C １－６ alkyl; or R ７ and R ８ together with the carbon atom to which they are attached, C ３－８ forming a cycloalkane ring, wherein the formed C ３－８ Cycloalkyl is 1 to 2 C １－６ Optionally substituted with alkyl, where C １－６ Alkyl is hydroxy, C １－６ The compound according to claim 1 or 2, optionally substituted with one or more substituents independently selected from alkoxy and 3- to 12-membered heterocyclyl, a salt thereof, or a solvate of either of them.

4. Z ２ But, C １－６ Alkyl, C ３－１５ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１０ aryl, and 5-10 membered heteroaryl, wherein C ３－１５ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１０ Aryl and 5- to 10-membered heteroaryl are in Group B: Group B: a) oxo, b) a halogen atom, c) -NR ｚｄ１ R ｚｅ１ ; where R ｚｄ１ and R ｚｅ１ are independently a hydrogen atom, C １－６ Alkyl, and (C １－６ alkyl)carbonyl, wherein C １－６ Alkyl is one or more C １－６ optionally substituted with alkoxy; d) -S(=O) ｎ７ -R ｚｈ１ where n7 represents an integer from 0 to 2, R ｚｈ１ is C １－６ Represents alkyl, e) C １－６ Alkyl; where C １－６ Alkyl is a halogen atom, hydroxy, -NR ｚｉ R ｚｊ , C １－６ and 3- to 12-membered heterocyclyl, where R ｚｉ and R ｚｊ are independently a hydrogen atom or C １－６ alkyl, and 3- to 12-membered heterocyclyl is hydroxy, C １－６ optionally substituted with one or more substituents independently selected from alkyl, and 3- to 12-membered heterocyclyl; f) C １－６ Alkoxy; where C １－６ The alkoxy may be substituted with one or more hydroxy groups. g) 3- to 12-membered heterocyclyl; wherein the 3- to 12-membered heterocyclyl is one or more (C １－６ Optionally substituted with alkyl)carbonyl, and h) 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl is C １－６ Alkyl, and -NR ｚｋ１ R ｚｌ１ wherein R ｚｋ１ and R ｚｌ１ are independently a hydrogen atom and C １－６ selected from alkyl, The compound according to any one of claims 1 to 3, a salt thereof, or a solvate of either of them, which is optionally substituted with 1 to 4 substituents independently selected from:

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

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

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

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

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

10. Z １ is represented by formula (IIIa): 【Chemistry 5】 The compound according to any one of claims 1 to 9, a salt thereof, or a solvate thereof, wherein * represents a bonding site to the pyrazolopyridine skeleton, ** represents Z ２ (each represents a binding site for

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

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 the compound according to any one of claims 1 to 10, a salt thereof, or a solvate of either of them as an active ingredient.

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

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