Pharmaceutical composition containing pyrazolopyridine derivative having GLP-1 receptor agonist action

Abstract

To provide a pharmaceutical composition containing 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 noninvasively administered, and has improved activity, metabolic stability and bioavailability. The present invention also provides a method for preventing or treating non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity using the pharmaceutical composition.SOLUTION: The present invention provides a pharmaceutical composition which contains, as an active ingredient, a compound having a basic skeleton represented by formula (I) in which an indole ring and a pyrazolopyridine skeleton are bonded via a substituent, or a salt thereof, or a solvate thereof, and is used in the prevention or treatment of non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus) or obesity.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition containing as an active ingredient 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 a method for preventing or treating non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity using the pharmaceutical composition. [Background technology]

[0002] Glucagon-like peptide-1 (GLP-1) is a hormone that stimulates the body to absorb nutrients. GLP-1 is an incretin secreted from L cells in the small intestine when it passes through the gastrointestinal tract, and is known to exhibit a variety of actions via the GLP-1 receptor, including promoting glucose-dependent insulin secretion, suppressing glucagon secretion, delaying gastric emptying, and suppressing appetite. GLP-1 analogs have already been put to practical use as diabetes treatments, and are considered to be one of the most effective diabetes treatments due to their potent HbA1c-lowering and weight-reducing effects. However, all of these require invasive subcutaneous administration. Therefore, there is a need to develop GLP-1 receptor agonists that can be administered non-invasively. For example, the absorption enhancer sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC) Attempts have been made to improve the oral bioavailability of the GLP-1 analogue semaglutide using α-glucan (Patent Document 1) and to create small molecule GLP-1 receptor agonists (Patent Documents 2 and 3), but further improvements in pharmaceutical properties, including activity, metabolic stability, and bioavailability, are still required.

[0003] 2-[(2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl)carbonyl]-1H-indol is the compound listed below for the chemical library. Things are known.

[0004] [ka]

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

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

[0007] [Patent Document 1] International Publication No. 2012 / 080471 [Patent Document 2] International Publication No. 2009 / 111700 [Patent Document 3] International Publication No. 2010 / 114824 [Patent Document 4] International Publication No. 2016 / 038045 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 pharmaceutical composition containing a compound or a salt thereof, or a solvate of either, which has an action as a GLP-1 receptor agonist similar to that of a GLP-1 peptide, can be administered non-invasively, and has improved activity, metabolic stability, and bioavailability; and to provide a method for preventing or treating non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity using the pharmaceutical composition. [Means for solving the problem]

[0009] The present inventors have conducted extensive 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 the same activity as a GLP-1 receptor agonist as 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):

[0011] [ka]

[0012] [Wherein 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, wherein C 6-10 Aryl and 5-10 membered heteroaryl are substituted with halogen atoms, C 1-6 Alkyl (where C 1-6 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, wherein 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 1-6Alkoxy, and -NR Qa R Qb and further, each of the alkyl groups may be substituted with 1 to 3 substituents independently selected from two C 1-6 Alkyl groups together with the carbon atoms to which they are attached form C 3-8 may form a carbocyclic ring; R Qa and R Qb are independently hydrogen atoms, 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, where R 7 and R 8 Together they form C 3-15 The cycloalkane ring contains 1 to 3 C 1-6 and optionally substituted with alkyl, where C 1-6 Alkyl is a halogen atom, hydroxy, -NR 7a R 7b , C 1-6and R 7a and R 7b are independently hydrogen atoms, 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):

[0013] [ka]

[0014] -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 optionally substituted with one or more halogen atoms 1-6 represents alkyl, and R 9f is a hydrogen atom or C 1-6 represents alkyl, and 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, and R 9i is C 1-6 represents alkyl; Z 1are represented by formulas (IIIa), (IIIb), (IIIc), (IIId), and (IIIe):

[0015] [ka]

[0016] 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, n5 and n6 independently represent an integer of 0 to 10 (* represents a bonding site to the pyrazolopyridine skeleton, ** represents a bonding site to the Z 2 and binding sites, respectively); 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- 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 are each independently a hydrogen atom, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl, wherein C 1-6 Alkyl is a group containing 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 zfand R zg are each independently a hydrogen atom, C 1-6 Alkyl, and (C 1-6 alkyl)carbonyl, wherein C 1-6 Alkyl is a group containing 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 between 0 and 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, hydroxy, -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 a group consisting of one or more (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, wherein R zk and R zl are independently hydrogen atoms, 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 pharmaceutical composition comprising a compound represented by the formula (I):

[0017] [2]Q 1 is phenyl or pyridyl, wherein phenyl and pyridyl are 1-6 The pharmaceutical composition according to [1], wherein the compound is substituted with 1 to 4 substituents independently selected from alkyl.

[0018] [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 R 7 and R 8 Together they form C 3-8 The cycloalkane ring contains 1-2 C 1-6 and optionally substituted with alkyl, where C1-6 Alkyl is hydroxy, C 1-6 The pharmaceutical composition according to [1] or [2], which is optionally substituted with one or more substituents independently selected from alkoxy and 3- to 12-membered heterocyclyl.

[0019] [4]Z 2 But C 1-6 Alkyl, C 3-15 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein C 3-15 Cycloalkyl, 3-12 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 hydrogen atoms, C 1-6 Alkyl, and (C 1-6 alkyl)carbonyl, wherein 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 between 0 and 2, and 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, wherein R zi and R zj are independently a hydrogen atom or C 1-6 alkyl, and 3-12 membered heterocyclyl is hydroxy, C 1-6optionally 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 and optionally substituted with one or more substituents independently selected from zk1 and R zl1 are independently hydrogen atoms and C 1-6 selected from alkyl, The pharmaceutical composition according to any one of [1] to [3], which is optionally substituted with 1 to 4 substituents independently selected from:

[0020] [5] The pharmaceutical composition according to any one of [1] to [4], wherein Y is —C(═O)—. [6]R 1 The pharmaceutical composition according to any one of [1] to [5], wherein is a hydrogen atom. [7] The pharmaceutical composition according to any one of [1] to [6], wherein n1 and n2 are both 0.

[0021] [8]R 9 is represented by formula (IIb):

[0022] [ka]

[0023] is a group represented by R 9b is a hydrogen atom, C 1-6 Alkyl (where C 1-6 Alkyl is a halogen atom and C 1-6alkoxy), and (C 1-6 The pharmaceutical composition according to any one of [1] to [7], wherein the aryl group is selected from alkyl)carbonyl.

[0024] [9] The pharmaceutical composition according to any one of [1] to [8], wherein X is -N=, -CH=, or -CF=.

[10] Z 1 is of formula (IIIa):

[0025] [ka]

[0026] The pharmaceutical composition according to any one of [1] to [9], wherein * represents a bonding site to the pyrazolopyridine skeleton, and ** represents Z 2 and the binding sites for , respectively).

[11] The pharmaceutical composition according to any one of [1] to

[10] , which contains 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, or a salt thereof.

[0027]

[12] The pharmaceutical composition according to any one of [1] to

[11] , which contains the compound represented by formula (I) or a salt thereof as a hydrate.

[13] The pharmaceutical composition according to any one of [1] to

[12] for use in 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, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, Parkinson's disease, or dementia, where dementia includes, for example, Alzheimer's disease.

[0028]

[14] The pharmaceutical composition according to

[12] for use in the prevention or treatment of non-insulin dependent diabetes mellitus (type 2 diabetes) or obesity.

[15] 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 the pharmaceutical composition according to any one of [1] to

[12] to a subject. Examples of dementia include Alzheimer's disease.

[0029]

[16] A method for preventing or treating non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity, which comprises administering the pharmaceutical composition according to any one of [1] to

[12] to a subject. [Effects of the Invention]

[0030] The compound represented by formula (I), a salt thereof, or a solvate thereof, which is contained in the pharmaceutical composition of the present invention, has an activity 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 explanation of the drawings]

[0031] [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 (°). [Figure 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 (°). [Figure 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 (°). [Figure 5] 1 shows the results of powder X-ray diffraction measurement of calcium salt hydrate crystals (sample 162a) of Example Compound 67 obtained in Example 163. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 6] 1 shows the results of powder X-ray diffraction measurement of calcium salt hydrate crystals (sample 162b) of Example Compound 67 obtained in Example 163. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 7]

[0039] Figure 1 shows the results of thermogravimetry and differential thermal analysis of the sodium salt hydrate crystals of Compound 1 obtained in Example 164. The horizontal axis represents temperature (°C), and the right vertical axis represents the weight change (%) of the sample in thermogravimetry. The left vertical axis represents the heat flow observed in 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 below. The horizontal axis represents temperature (°C), and the right vertical axis represents the weight change (%) of the sample in thermogravimetry. The left vertical axis represents the heat flow observed in differential thermal analysis. [Figure 9] Effects of Example Compound 67 and exenatide on insulin secretion after intravenous administration of glucose in 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, and ** indicates P < 0.005, indicating significance compared to 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, and ** indicates P < 0.005, indicating significance compared to the vehicle group (Williams test). Each drug concentration indicates the mean value of the measured plasma drug concentration. [Figure 11] Effects of Example Compound 67 and exenatide on food intake in male cynomolgus monkeys. Food intake is shown as mean ± standard deviation (n = 6). Each drug was administered in a crossover manner. * indicates P < 0.025, and ** indicates P < 0.005, indicating significance compared to the vehicle group (Williams test). [Figure 12] Changes in plasma drug concentration after oral administration of this substance to cynomolgus monkeys. Plasma concentrations and each dose are shown as average values ​​of n=2. DETAILED DESCRIPTION OF THE INVENTION

[0032] 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, when X in formula (I) is -CR a = R a In the present invention, when a halogen atom is a substituent such as alkyl (for example, Q in formula (I)), preferred halogen atoms 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 a halogen atom, the halogen atom may be a fluorine atom or a chlorine atom. 1-6 Specific examples of alkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, pentafluoroethyl, 2-fluoromethyl, and the like. bromoethyl, 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, 6,6,6-trifluorohexyl, and the like.

[0033] 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.

[0034] In the present invention, "C 1-6 "Alkoxy" means C 1-6 means an alkyl-O- group, where C 1-6 Alkyl is as defined above, 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, and 2-ethylbutoxy.

[0035] In the present invention, "(C 1-6 "(C alkyl)carbonyl" means 1-6 alkyl)-C(O)- group, where C 1-6Alkyl is as defined above. Examples thereof include 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, and 2-ethylbutylcarbonyl.

[0036] In the present invention, "C 6-10 "Aryl" means an aromatic carbocyclic group, which may contain non-aromatic portions in addition to the aromatic portion. The ring may be 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, etc. Of these, phenyl is preferred.

[0037] In the present invention, "heteroaryl" refers to an aromatic 5- to 10-membered cyclic group containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur atoms in the atoms constituting the ring, and may have a non-aromatic portion in addition to the aromatic portion. The ring may be monocyclic, or a bicyclic heteroaryl fused with a benzene ring or a monocyclic heteroaryl ring. Examples thereof include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyridyl, benzisoxazolyl, and benzisothiazolyl.

[0038] In the present invention, the term "heterocyclyl" refers to a non-aromatic cyclic group containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur atoms, and may be fully saturated or partially unsaturated. The ring may be 3 to 12-membered, preferably 3 to 10-membered, monocyclic, 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.

[0039] 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 a 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. Two groups together form C 3-15 When the group forms a cycloalkane ring, it 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.

[0040] 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-, or -CH2CH2CH2CH2CH2CH2-.

[0041] The cycloalkane ring, the carbon ring, and the cyclic hydrocarbon in the cycloalkyl may be a bridged ring. 3-15 Examples of the bridged ring in the 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., and C 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] 2,6 ]heptyl, tricyclo[4.3.1.1 2,5 ]undecyl, adamantyl, 2-adamantylidenyl, cubanyl, and the like.

[0042] The present invention provides a pharmaceutical composition comprising a compound represented by formula (I), a salt thereof, or a solvate of either of them.

[0043] [ka]

[0044] 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=.

[0045] 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, wherein C 6-10 Aryl and 5-10 membered heteroaryl are substituted with halogen atoms, C 1-6 Alkyl (where C 1-6 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, wherein phenyl or pyridyl is selected from the group consisting of halogen atoms and C 1-6More preferably, Q is substituted with 1 to 4 substituents independently selected from alkyl. 1 is a halogen atom and C 1-6 and phenyl substituted with 2 to 3 substituents independently selected from alkyl.

[0046] Q 2 represents a 3- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl, wherein 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, each of the alkyl groups may be substituted with 1 to 3 substituents independently selected from two C 1-6 Alkyl groups together with the carbon atoms to which they are attached form C 3-8 may form a carbocyclic ring; R Qa and R Qb are independently hydrogen atoms, C 1-6 Alkyl, and (C 1-6 Preferably, Q is selected from the group consisting of alkylcarbonyl. 2 represents i) 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 atoms 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 and R Qc and R Qd are independently hydrogen atoms and C 1-6 alkyl. Also preferably, Q 2represents a 5-6 membered heterocyclyl or heteroaryl, wherein the 5-6 membered heterocyclyl and the 5-6 membered heteroaryl are each selected from the group consisting of 1-3 C 1-6 It may be substituted with alkyl.

[0047] 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 these is a hydrogen atom; 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 alkyl.

[0048] 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 each preferably independently a hydrogen atom or a fluorine atom. 4 , R 5 , and R 6 The combination of R is a hydrogen atom; or R 4 is a hydrogen atom, R 5 is a hydrogen atom, R 6 is a fluorine atom.

[0049] R 7 and R 8 are independently a hydrogen atom or C1-6 represents alkyl, where C 1-6 Alkyl is a halogen atom and C 3-15 cycloalkyl, and further substituted with one or more substituents independently selected from R 7 and R 8 together with the carbon atoms to which they are attached, C 3-15 may form a cycloalkane ring, where R 7 and R 8 Together they form C 3-15 The cycloalkane ring contains 1 to 3 C 1-6 and optionally substituted with alkyl, where C 1-6 Alkyl is a halogen atom, hydroxy, -NR 7a R 7b , C 1-6 and R 7a and R 7b are independently hydrogen atoms, C 1-6 Alkyl, and (C 1-6 R is selected from the group consisting of alkyl and carbonyl. 7 and R 8 preferably taken together with the carbon atom to which they are attached, C 3-8 forming a cycloalkane ring, where R 7 and R 8 Together they form C 3-8 Cycloalkyl is one or more C 1-6 and 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 Preferably it is cycloalkyl. 3-6 Cycloalkyl includes, for example, cyclopentyl.

[0050] n1 represents an integer of 0 to 3, and n2 represents an integer of 0 to 5. n1 and n2 are each preferably 0 to 2, more preferably 0 or 1, and even more preferably 0. Furthermore, combinations of n1 and n2 are preferably 0 and 0, 0 and 1, 0 and 2, 1 and 0, 1 and 1, or 2 and 0, more preferably 0 and 0, 0 and 1, 1 and 0, 2 and 0, and even more preferably 0 and 0.

[0051] R 9 are represented by the formulas (IIa), (IIb), (IIc), and (IId):

[0052] [ka]

[0053] -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, and R 9f is a hydrogen atom or C 1-6 represents alkyl, and 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, and R 9i is C 1-6 Represents alkyl.

[0054] Z 1 are represented by formulas (IIIa), (IIIb), (IIIc), (IIId), and (IIIe):

[0055] [ka]

[0056] 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; n5 and n6 independently represent an integer of 0 to 10;

[0057] * indicates the bonding site with the pyrazolopyridine skeleton, ** indicates Z 2 and the binding sites of Z 2 is C 1-6 Alkyl, C 3-15 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5- to 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 group A.

[0058] 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, wherein C 1-6Alkyl is a group containing 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, wherein C 1-6 Alkyl is a group containing 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 between 0 and 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, hydroxy, -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 a group consisting of one or more (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, wherein R zk and R zl are independently hydrogen atoms, 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 and optionally substituted with one or more substituents independently selected from alkyl)carbonyl.

[0059] R zd , R ze , R zf and R zg C in 1-6 If the alkyl is substituted with hydroxy, C 1-6 Alkyl is preferably C 2-6 alkyl, more preferably C 2-4 It is alkyl.

[0060] C 1-6 When the alkoxy is substituted with one or more hydroxy groups, C 1-6 Alkyl is preferably C 2-6 alkyl, more preferably C 2-4 Preferably, Z is alkyl. 2 i) 1 or more -NR zd R ze C optionally substituted with 3-15 ii) cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from the C group; 6-10aryl, and iii) a 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from Group D.

[0061] More preferably, Z 2 i) C optionally substituted with 1 to 3 substituents independently selected from the C group 6-10 aryl, and ii) 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from Group D.

[0062] Group C: a) halogen atoms, b)-NR zd2 R ze2 ;where R zd2 and R ze2 are independently hydrogen atoms, 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; c)-S(=O) n7 -R zh1 where n7 represents an integer between 0 and 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; wherein the 5-10 membered heteroaryl is -NR zk1 R zl1 and optionally substituted with one or more substituents independently selected from zk1 and R zl1 are independently hydrogen atoms and C 1-6 alkyl.

[0063] Group D: a) oxo, b) a halogen atom, c)C 1-6Alkyl; where C 1-6 Alkyl is a group containing halogen atoms, hydroxy, 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.

[0064] In the present invention, the compound represented by formula (I) 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, form 1-3 C 1-6 Alkyl-substituted C 3-15 Form a cycloalkane ring, and the 1 to 3 C 1-6 Preferably, the alkyl is unsubstituted, and more preferably 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).

[0065] Next, examples of methods for producing the compound represented by formula (I), a salt thereof, or a solvate thereof will be described with reference to the following group of schemes. The compound represented by formula (I), its salt, or solvate thereof is produced via i) General Production Method A1 or General Production Method A2, ii) General Production Method B, and iii) General Production Method C. This production method 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 R9 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).

[0066] Also, R 7 and R 8 together with the carbon atoms to which they are attached, 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.

[0067] In addition, when the starting material or target product of a certain step undergoes an undesired chemical transformation under the reaction conditions of that step, the target product of that step can be obtained, for example, by protecting and deprotecting functional groups. Regarding the selection of protecting groups and the selection of protection and deprotection methods, reference can be made to, for example, T.W. Greene, P.G.M. Buts, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons, Inc., New York (2007). Some of the protection and deprotection of functional groups are also described in the following schemes.

[0068] <General method A1> Compound f can be synthesized by General Process A1 shown in the following scheme.

[0069] [ka]

[0070] During the ceremony, P 2 is a hydrogen atom or C 1-6 represents alkyl, and P 1a represents an amino protecting group, and P 3a and P 3b are independently, C 1-6 represents alkyl, or P3a 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.

[0071] 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.

[0072] Examples of the leaving group include a halogen atom, acetyloxy, trifluoroacetyloxy, methanesulfonyloxy, and paratoluenesulfonyloxy. Process A1-1a : Compound a1 can be obtained by reacting compound a with a base.

[0073] Examples of the base include metal hydrides such as sodium hydride, potassium hydride, and lithium hydride; and metal alkoxides such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-pentoxide, with potassium t-butoxide and other metal alkoxides being preferred.

[0074] Examples of the solvent include ether solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane, and THF is preferred. The reaction temperature is usually -30°C to 30°C, preferably -10°C to 10°C.

[0075] 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 commercially from Aldlab Chemicals, LLC, Tokyo Chemical Industry Co., Ltd., etc. Also, with reference to Bioorganic Medicinal Chemistry, 1999, 7, 795-809, CN 103086955, It can also be synthesized.

[0076] Compound a1 may be obtained as an alkali metal salt such as potassium salt by contacting with the base used in the reaction, and such salts can also be subjected to the next step. 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.

[0077] Examples of the acid include hydrochloric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like, and salts of strong acids with 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.

[0078] The reaction temperature is usually 40 to 200°C, preferably 60 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 from Alfa Aesar or the like as a salt with hydrogen chloride or the like. Compound a2, in which the hydrazine moiety is protected with t-butoxycarbonyl, can be used after deprotection with an acid such as methanesulfonic acid, as described in Synlett, 2011, 17, 2555-2558. Compound: Q, based on Medicinal Chemistry 2003, 46, 1546-1553 1 It can also be synthesized using -NH2 as a starting material.

[0079] Process A1-2 : Compound c can be obtained by reacting compound b with compound b1 or compound b2 in the presence of a base.

[0080] 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; and metal alkoxides such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-pentoxide. When compound b2 is used, metal alkoxides such as potassium t-butoxide are preferred.

[0081] Examples of solvents 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 DMA and other amide-based solvents being preferred.

[0082] 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. In addition, compound b1 can be synthesized 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 referring to WO99 / 50262. 3a )(OP 3b It can also be synthesized by reacting methyl methyl acrylate with a diisocyanate such as CDI.

[0083] Process A1-3 : Compound c can be reacted with an acid to give 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.).

[0084] 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 ester solvents (methyl acetate, ethyl acetate, isopropyl acetate, etc.), acetonitrile, and mixed solvents thereof, with ether solvents such as tetrahydrofuran being preferred.

[0085] The reaction temperature is usually 0 to 100°C, preferably 10 to 80°C. The reaction time is usually 10 minutes to 20 hours, preferably 30 minutes to 5 hours. 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.

[0086] 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.

[0087] 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.), and amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.), and preferably amide solvents such as N,N-dimethylacetamide.

[0088] The reaction temperature is usually 0 to 150°C, preferably 20 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 d can be reacted with compound d1 in the presence of a base, a copper catalyst, and a ligand to obtain compound e.

[0089] 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.

[0090] Examples of the copper catalyst include copper(I) iodide, copper(I) bromide, copper(I) chloride, copper(II) acetate, copper(II) oxide, and copper(I) trifluoromethanesulfonate, and copper(I) iodide is preferred.

[0091] 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.

[0092] 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, with N-methylpyrrolidone and other such amide solvents being preferred.

[0093] The reaction temperature is usually 30 to 200°C, preferably 60 to 160°C. The reaction time is usually 1 to 15 hours, preferably 3 to 9 hours. Process A1-5 : Compound f can be obtained by deprotecting compound e.

[0094] 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.).

[0095] 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.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.), and halogen solvents (dichloromethane, chloroform, carbon tetrachloride, etc.), and preferably amide solvents such as N-methylpyrrolidone.

[0096] The reaction temperature is usually 0 to 200°C, preferably 10 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 can also be used in the next step.

[0097] <General manufacturing method A2> Z 2 But, -NR zd R ze C is replaced by 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.

[0098] [ka]

[0099] In the formula, Z2a is an unsubstituted C 3-15 It represents cycloalkyl or 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, C 1-6 represents alkyl, or R 10a and R 10b may 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.

[0100] 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.

[0101] Examples of the leaving group include a halogen atom, acetyloxy, trifluoroacetyloxy, methanesulfonyloxy, and paratoluenesulfonyloxy. Process A2-1 : Compound g can be reacted with azide in the presence of a base to give compound h.

[0102] Examples of the base include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.) Examples of the azide include metal azides such as sodium azide, trimethylsilyl azide, and diphenylphosphoryl azide, and diphenylphosphoryl azide is preferred.

[0103] 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 hydrocarbon solvents such as toluene are preferred.

[0104] 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. It is also available as a commercially available product from Enamine Ltd.

[0105] 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.

[0106] 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.).

[0107] 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. A base such as pyridine can also be used as the solvent.

[0108] The reaction temperature is usually 0 to 60°C, preferably 5 to 45°C. The reaction time is usually 30 minutes to 50 hours, preferably 2 hours to 10 hours. Process A2-3 : Compound j can be obtained by reacting compound i with compound i1 or compound i2 in the presence of a base.

[0109] 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.

[0110] 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 1,2-dichloro-1-ethoxyethane is preferred. Compound i1 can be purchased commercially from Tokyo Chemical Industry Co., Ltd., FCH Group, etc.

[0111] 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 commercially from Tokyo Chemical Industry Co., Ltd.

[0112] 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 DMA being preferred.

[0113] The reaction temperature is usually 0 to 60°C, preferably 20 to 45°C. The reaction time is usually 1 hour to 72 hours, preferably 12 minutes to 35 hours. Process A2-4 : Compound j can be reacted with an acid to give compound k.

[0114] 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 sulfonic acids such as methanesulfonic acid.

[0115] Examples of the solvent include ether solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane, and THF is preferred. The reaction temperature is usually 0 to 100°C, preferably 20 to 80°C.

[0116] The reaction time is usually 15 minutes to 6 hours, preferably 30 minutes to 3 hours. Process A2-5 : Compound l can be obtained by reacting compound k with compound k1 in the presence of a base.

[0117] Compound k1 may be, for example, a halogenated compound C such as methyl iodide. 1-6 Alkyl, acetyl chloride, etc. halogenated (C 1-6 alkyl)carbonyl. zd But (C 1-6 When the compound k1 is a ((C alkyl)carbonyl, 1-6 It is also preferable to use an acid anhydride represented by alkyl)carbonyl)2O, such as acetic anhydride.

[0118] Examples of the base include metal hydrides such as sodium hydride, potassium hydride, and lithium hydride; and metal alkoxides such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-pentoxide, with potassium pentoxide being preferred.

[0119] 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, with THF being preferred.

[0120] The reaction temperature is usually -50°C to 50°C, preferably -40°C to 40°C. The reaction time is usually 1 minute to 2 hours, preferably 3 minutes to 30 minutes. Process A2-6 : Compound m can be obtained by deprotecting compound l.

[0121] For deprotection, appropriate reagents and reaction conditions can be selected depending on the type of protecting group, but 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.

[0122] Examples of the solvent include ether solvents such as diethyl ether, THF, and dimethoxyethane; halogen-based solvents such as dichloromethane (CH2Cl2), chloroform, and carbon tetrachloride; N,N-dimethylformamide; and acetonitrile, with halogen-based solvents such as CH2Cl2 being preferred.

[0123] The reaction temperature is usually 0 to 60°C, preferably 10 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 can also be subjected to step A2-7.

[0124] 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.

[0125] 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.

[0126] 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.), and preferably tertiary amines such as triethylamine.

[0127] Examples of the solvent include ether solvents such as diethyl ether, THF, and dimethoxyethane; halogen-based solvents such as dichloromethane (CH2Cl2), chloroform, and carbon tetrachloride; N,N-dimethylformamide; and acetonitrile, with halogen-based solvents such as CH2Cl2 being preferred.

[0128] The reaction temperature is usually 0 to 60°C, preferably 15 to 40°C. The reaction time is usually 30 minutes to 20 hours, preferably 1 hour to 5 hours. Process A2-8 : Compound n can be reacted with compound n1 in the presence of a base to obtain compound o.

[0129] Compound n1 may be, for example, a halogenated compound C such as methyl iodide. 1-6 Alkyl, acetyl chloride, etc. halogenated (C 1-6 alkyl)carbonyl. ze C 1-6 If it is alkyl, C 1-6 The alkyl may be unsubstituted or C 1-6 It is preferably substituted with alkoxy.

[0130] 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. Process A2-9 : Compound p can be obtained by deprotecting compound o.

[0131] 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.

[0132] 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. <General manufacturing method B> Compound bf can be synthesized by General Process B shown in the following scheme.

[0133] [ka]

[0134] During the ceremony, P 21 is hydroxy, C 1-6 Alkoxy, or -NR 21a R 21b represents R 21a and R 21b are independently hydrogen atoms, 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.

[0135] Examples of the leaving group include a halogen atom, acetyloxy, trifluoroacetyloxy, methanesulfonyloxy, and paratoluenesulfonyloxy. Process B-1 : Compound bb can be obtained by reacting compound ba with compound ba1 in the presence of a palladium catalyst.

[0136] As a palladium catalyst, a complex formed in situ by adding a palladium compound and a ligand separately can be used. Alternatively, the complex prepared separately can be used as 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)] and tetrakis(triphenylphosphine)palladium(0).

[0137] Examples of palladium catalysts that can be used in this step include tris(dibenzylideneacetone)dipalladium(0), 5,10,15,20-tetraphenyl-21H,23H-porphine cobalt(II), palladium(II) acetate, bis(di-t-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane addition. Examples of suitable catalysts include dichlorobis(triphenylphosphine)palladium(II), palladium hydroxide, tetrakis(triphenylphosphine)palladium(0), and di-μ-chlorobis[(η-allyl)palladium(II)]. In step 11, 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 is preferably used as the catalyst.

[0138] 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.

[0139] Examples of reaction solvents 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 is also acceptable.

[0140] 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 esterifying or amidating a compound ba in which is —COOH.

[0141] X 21 Ga-Zn-X 21a Compound ba1 can be purchased commercially from Focus Synthesis LLC or the like. It can also be synthesized by referring to WO2014 / 201206 or the like.

[0142] Process B-2 : Compound bb can be reacted with compound bb1 in the presence of a base to obtain compound bc.

[0143] 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, with potassium hydroxide being preferred.

[0144] Examples of reaction solvents 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.

[0145] 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 is commercially available from Aquila Pharmatech LLC, etc. Compound bb can also be synthesized with reference to WO2013 / 010904, Organic Letters, 7(18), 3965-3968, 2005, US5998438, etc.

[0146] Process B-3 : Compound bc can be reacted with hydroxylamine (H2NOH) to give compound bd.

[0147] Examples of reaction solvents include aprotic polar solvents such as dimethyl sulfoxide (DMSO), dimethylformamide, dimethylacetamide, and 1-methyl-2-pyrrolidinone, and alcoholic solvents such as methanol and ethanol, with DMSO being preferred. DMSO may also be used as a mixed solvent with water.

[0148] 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.

[0149] 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.

[0150] Examples of the base include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, 1,8-diazabicycloundec-7-ene (DBU), DABCO, etc.) and metal hydroxides (sodium hydroxide, potassium hydroxide), and preferably tertiary amines such as DBU.

[0151] Examples of solvents include aprotic polar solvents such as dimethyl sulfoxide (DMSO), dimethylformamide, dimethylacetamide, and 1-methyl-2-pyrrolidinone, alcoholic solvents such as methanol and ethanol, and ether solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane, with DMSO being preferred.

[0152] 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. Process B-5 : P 21 Compound bf can be obtained by deprotecting compound be protected by using a base.

[0153] 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.

[0154] 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.

[0155] 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 reversed. For example, compound bc can be obtained by sequentially subjecting compound ba to step B-2 and step B-1. Compound bf can be obtained by sequentially subjecting compound ba to step B-2, step B-3, step B-4, step B-5, and step B-1. Compound bf can be obtained by sequentially subjecting compound ba to step B-2, step B-3, step B-4, step B-1, and step B-5.

[0156] Process B-Aa and Process 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 then be subjected to step B-2.

[0157] [ka]

[0158] In the formula, R Qc and R Qd are independently a hydrogen atom or C 1-6 represents alkyl, or R Qc and R Qd may be combined with the oxygen atom to which they are bonded and the boron atom to which the oxygen atom is bonded to form 1,3,2-dioxaborolanyl or 1,3,2-dioxaborinanyl.

[0159] Process B-Aa : The organic boron compound baa can be obtained by reacting the compound ba with the compound ba2 or Ba3 in the presence of a palladium catalyst. This step may be carried out in the presence of a base.

[0160] 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 compound ba2 include pinacolborane and 4,6,6-trimethyl-1,3,2-dioxaborinane. Examples of compound ba3 include diboronic acid, pinacoldiborane (4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)), bis(neopentylglycolato)diboron, and bis(hexyleneglycolato)diboron. These compounds can be purchased commercially from Tokyo Chemical Industry Co., Ltd., etc. (Journal of the American It can also be synthesized using i) pinacol and ii) diborane, BH3·THF complex, or BH3·dimethyl sulfide complex, with reference to Chemical Society, 131(45), 16346-16347, 2009 and Organic Synthesis, 77, 176-185, 2000.

[0161] The organoboron compound baa may be subjected to Step B-Ab without isolation. 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.

[0162] 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.

[0163] 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.

[0164] Process BB : Also, compound bb1 is X 21 -(CH2) n1 When the compound bca is represented by —CH—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 R 8 together with the carbon atoms to which they are attached, C 3-15 forming a cycloalkane ring, where R 7 and R 8 Together they form C 3-15 The cycloalkane ring contains 1 to 3 C 1-6 A compound bcb corresponding to the compound bc, which may be substituted with alkyl, can be obtained, and this may be subjected to step B-3.

[0165] [ka]

[0166] In the formula, R 7c , R7e and n8 is R 7d are each independently a hydrogen atom or C 1-6 represents alkyl, and n8 represents 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.

[0167] 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), with amide solvents such as DMPU being preferred.

[0168] 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 CGeneTech. Inc. or the like. It can also be synthesized with reference to Organic Letters, 12(17), 3938-3941, 2010.

[0169] <General manufacturing method C> Process C-1 :

[0170] [ka]

[0171] Compound (Ia) can be obtained by condensing compound f (or compound p) and compound bf using a condensing agent in the presence of a base. Examples of the condensing agent include BOP-based condensing 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); 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium; Examples thereof include tetrafluoroborate (TBTU), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium hexafluorophosphate (HATU), and ethyl(hydroxyimino)cyanoacetate (Oxyma), and preferably HATU.

[0172] 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.), and preferably tertiary amines such as diisopropylethylamine.

[0173] 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 aprotic polar solvents such as DMF.

[0174] 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. The compound represented by formula (I) can be contacted with or reacted with an acid or base that can be used in the production of pharmaceuticals to obtain a salt thereof. The salt may be any pharmaceutically acceptable salt, and examples of such salts include inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.), sulfonates (methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, etc.), carboxylates (formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, mandelate, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, glutam ... Examples of suitable salts include talates, adipates, nicotinates, etc.), alkali metal salts (lithium salts, sodium salts, potassium salts, cesium salts, rubidium salts, etc.), alkaline earth metal salts (magnesium salts, calcium salts, etc.), ammonium salts (ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, tetraalkylammonium salts, etc.), and basic amino acid salts (lysine salts, arginine salts, etc.). Alkali metal salts and alkaline earth metal salts are preferred, and sodium salts and calcium salts are more preferred. For example, the free form of the compound represented by formula (I) can be suspended or dissolved in alcohol such as methanol or ethanol, acetonitrile, acetone, dimethyl sulfoxide, or the like, and then a basic aqueous solution containing sodium ions such as sodium hydroxide, a methanol solution containing sodium methoxide, or an ethanol solution containing sodium ethoxide can be added to obtain the sodium salt of the compound represented by formula (I). The reaction temperature is, for example, 0°C to 80°C, preferably 20°C to 60°C.

[0175] The compound represented by formula (1) or a salt thereof may be a solvate or a non-solvate. The solvent contained in the solvate may be either water or an organic solvent. Examples of organic solvents that can be used include alcohols (e.g., methanol, ethanol, n-propanol), dimethylformamide, acetonitrile, acetone, and dimethyl sulfoxide. The compound represented by formula (I) and a salt thereof are preferably used in the form of a hydrate, and are 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 a salt thereof is, for example, 0.1 to 10, and more preferably 0.5 to 6. This ratio may vary depending on humidity, the production method, the production time, and the like.

[0176] The solvate of the compound represented by formula (I) or its salt can be obtained by a conventional method, for example, by precipitating the compound represented by formula (I) or its salt from a solvent. The hydrate can also be obtained by precipitating the compound represented by formula (I) or its salt from a water-containing organic solvent.

[0177] A solvate of the compound of formula (I) or a salt thereof can be converted to the compound of formula (I) or a salt thereof by a conventional method, for example, by heating under reduced pressure. As the solvate of the compound represented by formula (I) or a salt thereof, 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.

[0178] 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.

[0179] The present invention includes all stereoisomers of the compound represented by formula (I) (e.g., enantiomers, diastereomers (including cis and trans geometric isomers)), racemates of such isomers, and other mixtures thereof. For example, the compound represented by formula (I) may have one or more asymmetric centers, and the present invention includes racemic mixtures, diastereomeric mixtures, and enantiomers of such compounds.

[0180] In the present invention, the atoms constituting the compound molecule represented by formula (I) may be isotopes, and include those in which at least one atom has been replaced with an atom having the same atomic number (number of protons) but a different mass number (sum of the number of protons and neutrons). Examples of isotopes contained in the compound represented by formula (I) 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 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 14 Radioactive isotopes such as C, which decay by emitting radiation, are useful in testing the tissue distribution of pharmaceuticals or compounds in the body. Stable isotopes do not decay, their abundance remains almost constant, and they are not radioactive, so they can be used safely. If the atoms constituting the compound molecule represented by formula (I) are isotopes, they can be converted in the usual way by replacing the reagents used in synthesis with reagents containing the corresponding isotope. The pharmaceutical composition of the present invention has a GLP1 receptor agonist effect and a blood glucose lowering effect, and by administering a pharmaceutically effective amount thereof to a patient by an appropriate administration method, it 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.

[0181] 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).

[0182] "Hyperglycemia" refers to a condition in which plasma glucose levels are higher than normal (e.g., 80-110 mg / dL in humans when fasting) either during fasting or after glucose administration, and is one of the typical symptoms of diabetes.

[0183] "Impaired glucose tolerance" includes insulin-resistant impaired glucose tolerance and insulin secretion disorders. "Diabetic complications" refer to complications resulting from diabetes or hyperglycemia, and may be either acute or chronic. Examples of "acute complications" include ketoacidosis and infections (e.g., skin infections, soft tissue infections, biliary tract infections, respiratory infections, and urinary tract infections), while examples of "chronic complications" include microangiopathy (e.g., nephropathy and retinopathy), neuropathy (e.g., sensory neuropathy, motor neuropathy, and autonomic neuropathy), and foot gangrene. Major diabetic complications include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. "Coronary heart disease" includes myocardial infarction, angina pectoris, and the like.

[0184] "Dementia" includes, for example, Alzheimer's disease, vascular dementia, and diabetic dementia. The pharmaceutical composition of the present invention may be administered by 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 an ointment, gel, cream, or the like.

[0185] The pharmaceutical composition of the present invention is usually formulated into a certain preparation (dosage form) for use. Such preparations include, for example, tablets, capsules, granules, powders, fine granules, pills, aqueous or non-aqueous solutions or suspensions, etc. The pharmaceutical composition of the present invention can also be used in the form of various controlled-release preparations. Examples of such controlled-release preparations include those that are implanted into the body and those that are applied to the oral or nasal mucosa. The solution or suspension can be filled and stored in a container suitable for dividing into individual dosage amounts.

[0186] The above-mentioned various formulations can be produced by a known method by mixing the compound represented by formula (I) or a salt thereof, or a solvate thereof with pharmaceutically acceptable additives, such as excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, bases, dispersants, diluents, surfactants, emulsifiers, etc.

[0187] 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, hydroxypropylmethyl cellulose, shellac, talc, carnauba wax, and paraffin.

[0188] Examples of binders include polyvinylpyrrolidone, macrogol, and compounds similar to the above-mentioned excipients. Examples of disintegrants include chemically modified starches such as croscarmellose sodium, sodium carboxymethyl starch, and cross-linked polyvinylpyrrolidone, celluloses, and the same compounds as the above-mentioned excipients.

[0189] Examples of stabilizers include paraoxybenzoic acid esters such as methylparaben and propylparaben; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; sorbic acid; and the like.

[0190] Examples of flavoring agents 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; glycolic oil; and the like.

[0191] 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.

[0192] Examples of solvents or diluents for liquid preparations include phenol, chlorocresol, purified water, and distilled water. Examples of surfactants or emulsifiers include polysorbate 80, polyoxyl 40 stearate, and lauromacrogol.

[0193] The content of the compound represented by formula (I) 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. The formulation may contain only one kind of the compound represented by formula (I) or a salt thereof, or a solvate thereof, or may contain two or more kinds of them.

[0194] When the pharmaceutical composition of the present invention is used as a preventive or therapeutic agent for non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity, the dosage as the amount of the active ingredient can be appropriately determined depending on the severity of symptoms, age, body weight, relative health condition, presence or absence of concomitant medications, administration method, etc. For example, when the subject is a warm-blooded animal, particularly a human, the daily dosage as the amount of the active ingredient is, for example, 0.01 to 10,000 mg, preferably 0.1 to 1,000 mg, for oral administration. For parenteral administration, the dosage is, for example, 0.001 to 3,000 mg, preferably 0.01 to 300 mg. The dosage may be administered once per day to every few weeks, or in two or more divided doses per day.

[0195] In the present invention, the term "effective amount" means a therapeutically effective amount or a prophylactically effective amount of the compound represented by formula (I), a salt thereof, or a solvate of either of them, which is an active ingredient, and can be determined appropriately depending on the severity of symptoms, age, body weight, relative health condition, the presence or absence of concomitant drugs, the administration method, etc. [Example]

[0196] The present invention is further illustrated by the following examples and reference examples. All starting materials and reagents were obtained from commercial suppliers or synthesized using known methods. Room temperature (rt) refers to 5 to 35°C. Silica gel used was SHOKO Scientific Purif-Pack® SI 60 μm (Shoko Scientific), Biotage® SNAP Ultra Silica Cartridge (Biotage), or SNAP KP-Sil Cartridge (Biotage). Reverse-phase silica gel used was Wakosil® 25C18 (Wako Pure Chemical Industries, Ltd.) or Biotage® SNAP Ultra C18 Cartridge (Biotage). HPLC purification of compounds was performed using an AutoPurification HPLC / MS System (Waters) or a Preprative HPLC system with injection / fractionation function (Gilson). 1 H-NMR spectra were measured with or without Me4Si as an internal standard using an ECP-400 (JEOL), an Agilent400-MR (Agilent Technologies), an AVANCE3 300MHz (Bruker), or an AVANCE3 600MHz Cryo-TCI (Bruker). (s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, ddd = double double doublet, m = multiplet.) Chemical shifts for NMR data are expressed in ppm (parts per million, δ) relative to Me4Si or deuterated solvent, and coupling constants (J) are expressed in Hz. The values ​​are shown in Hertz. LC / MS was performed using the equipment and analytical conditions shown in Table 1 to measure retention times and perform mass analysis. Microwave irradiation was performed using an Initiator™ (Biotage). Mass analysis in LC / MS was performed using a mass spectrometer: SQD (Waters), SQD2 (Waters), 2020 (Shimadzu), or 2010EV (Shimadzu).

[0197] [Table 1-1]

[0198] [Table 1-2]

[0199] 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)

[0200] [ka]

[0201] (Process 1-1) [(5-cyano-1,2,3,6-tetrahydropyridin-4-yl)amino]potassium (Compound 1b) To a solution of 3-(2-cyanoethylamino)propanenitrile (compound 1a, 22.0 g, 179 mmol) in tetrahydrofuran (THF) (179 mL), a 1 M solution of potassium tert-butoxide in THF (179 mL) was added 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 give the title compound 1b (23.8 g, 83% yield) as a light brown solid.

[0202] 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).

[0203] (Step 1-2) tert-Butyl 3-amino-2-(3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Compound 1d) To a solution of 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 in ethanol (57.9 mL), 2N hydrochloric acid (23.2 mL, 46.3 mmol) was added and stirred at 50 °C for 1 h. The reaction mixture was cooled to 0 °C, and 5 M aqueous sodium hydroxide (9.27 mL, 46.3 mmol) and di-tert-butyl dicarbonate (6.64 g, 30.4 mmol) were added, followed by stirring at 0 °C for 1 h. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0:1 to 1:1) to give the title compound 1d (7.82 g, 79% yield) as a pale yellow solid.

[0204] LC / MS mass spectrometry: m / z343([M+H] + ). LC / MS retention time: 0.99 minutes (Analysis conditions: SMD-FA05-3). (Step 1-3) tert-Butyl 3-(2,2-dimethoxyethylcarbamoylamino)-2-(3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Compound 1f) To a solution of compound 1d (2.53 g, 7.39 mmol) obtained in step 1-2 in pyridine (7.39 mL), 2-isocyanato-1,1-dimethoxyethane (compound 1e, 1.94 g, 14.8 mmol) was added and stirred at room temperature. After 3 hours and 15 minutes, diethylamine (1.08 g, 14.8 mmol) was added and stirred at room temperature for 5 minutes. Water (50.6 mL) was then added and stirred at room temperature for 20 minutes. The reaction mixture, which became a suspension, was filtered, and the collected solid was washed with water (12.7 mL) and dried under reduced pressure to obtain the title compound 1f (3.20 g, 91% yield) as a pale yellow solid.

[0205] LC / MS mass spectrometry: m / z474([M+H] + ). LC / MS retention time: 0.78 min (Analysis conditions: SQD-FA05-1). (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 compound 1f (158 mg, 0.334 mmol) obtained in step 1-3, formic acid (3.84 mL, 100 mmol) was added and stirred at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure, toluene was added, and the solvent was evaporated under reduced pressure. Dichloromethane (1 mL) was added to the residue to dissolve it, and then hydrogen chloride (4 M dioxane solution, 0.835 mL, 3.34 mol) was added at room temperature. The reaction mixture was concentrated under reduced pressure, toluene was added, and the solvent was evaporated under reduced pressure to obtain the crude product of the title compound 1g (176 mg).

[0206] LC / MS mass spectrometry: m / z310([M+H] + ). LC / MS retention time: 0.39 min (Analysis conditions: SQD-FA05-3). (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 and stirred for 30 minutes. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate) to afford the title compound 1i (6.98 g, 92% yield) as an orange oil.

[0207] LC / MS mass spectrometry: m / z200([M+H] + ). LC / MS retention time: 0.38 min (Analysis conditions: SQD-FA05-3). (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, purged 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 the mixture was extracted with a 1:3 mixture of hexane and ethyl acetate. The organic layer was washed three times with water, twice with saturated aqueous sodium bicarbonate, and once with saturated brine, and then 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 give the title compound 1l (1.70 g, yield 42%) as a white solid.

[0208] LC / MS mass spectrometry: m / z347([M+H] + ). LC / MS retention time: 0.69 min (Analysis conditions: SQD-AA50-1). (Step 1-7) Ethyl 1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-5-(2-ethyl-3-methylpyridin-4-yl)indole-2-carboxylate (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 purged with nitrogen. Under a nitrogen atmosphere, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.29 g, 1.56 mmol) was added and 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. The mixture was degassed under reduced pressure, purged with nitrogen, and stirred at 100 °C for 2 hours. After cooling to room temperature, water (5.4 mL) and N-acetylcysteine ​​(0.635 g, 3.89 mmol) were added and stirred for 0.5 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed once with saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1:19 to 2:3) to give the title compound 1m (2.92 g, 97% yield) as a pale yellow gum.

[0209] LC / MS mass spectrometry: m / z388([M+H] + ). LC / MS retention time: 1.06 min (Analysis conditions: SQD-AA05-2). (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, and the mixture was washed with water (10 mL) and saturated brine (10 mL) and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. 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. The mixture was stirred at room temperature for 0.5 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 1n (169 mg, 65% yield) as a white powder.

[0210] LC / MS mass spectrometry: m / z447([M+H] + ). LC / MS retention time: 0.80 min (Analysis conditions: SMD-FA05-3). (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 solution of compound 1n (3.61 g, 8.08 mmol) obtained in step 1-8 in DMSO (40 mL), 2 M aqueous sodium hydroxide (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 give the title compound 1o (3.38 g, 100% yield) as a white powder.

[0211] LC / MS mass spectrometry: m / z419([M+H] + ). LC / MS retention time: 0.83 min (Analysis conditions: SQD-AA05-2). (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 (1.25 g, 3.61 mmol) obtained in step 1-4, compound 1o (1.59 g, 3.80 mmol) obtained in step 1-9, and [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium hexafluorophosphate (1.51 g, 3.98 mmol) were added to a solution of N,N'-dimethylformamide (DMF) (24.1 mL) and diisopropylethylamine (3.15 mL, 18.1 mmol) was added and stirred at room temperature for 30 minutes. The reaction mixture was directly purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound 1p (2.44 g, 95% yield) as a light brown foam.

[0212] LC / MS mass spectrometry: m / z710([M+H] + ). LC / MS retention time: 0.85 min (Analysis conditions: SMD-FA05-3). (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) To a suspension of 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) in N-methylpyrrolidone (0.188 mL), copper(I) iodide (1.1 mg, 0.0056 mmol) was added at room temperature, and the mixture was stirred at 130 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was purified by reverse-phase silica gel chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound 1 (17.2 mg, 73% yield) as a pale brown foam.

[0213] LC / MS mass spectrometry: m / z840([M+H] + ). LC / MS retention time: 1.12 minutes (Analysis conditions: SMD-TFA05-3). <Examples 2 to 50> Using the combinations of 2-oxoimidazole compounds shown in Table 2-2 below and halogen compounds shown in Table 2-3 below, and appropriate reagents, the same operations as in Steps 1-11 of Example 1 were carried out to obtain Example Compounds 2 to 50 shown in Table 2-1 by the following reactions.

[0214] [ka]

[0215] [Table 2-1]

[0216] [Table 2-2]

[0217] [Table 2-3]

[0218] [Table 2-4]

[0219] [Table 2-5]

[0220] [Table 2-6]

[0221] [Table 2-7]

[0222] [Table 2-8]

[0223] [Table 2-9]

[0224] [Table 2-10]

[0225] [Table 2-11]

[0226] [Table 2-12]

[0227] [Table 2-13]

[0228] [Table 2-14]

[0229] The compounds in Table 2-1 have rotational isomers. For example, Example Compound 2 1 H-NMR is as follows: 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=5.9 Hz), 6.82 (1H, s), 6.59 (1H, d, J = 3.0 Hz), 6.08 (1H, d, J = 3.0 Hz), 4.96 (1H, d, J = 16.0 Hz), 4.92 (1H, d, J = 16.0 Hz), 4.69 (1H, ddd, J = 13.1, 4.4, 4.4 Hz), 4.06 (3H, s), 3.75 (1H, ddd, J = 13.1, 9.5, 5.0 Hz), 3.07 (2H, m), 2.97 (2H, q, J = 7.6 Hz), 2.26 (3H, s), 2.25 (6H, s), 1.88 (1H, s), 1.51 (2H, m), 1.37 (3H, t, J = 7.6 Hz), 1.17 (3H, d, J = 5.6 Hz).

[0230] Rotational isomer B 1 1H-NMR (600 MHz, CDCl3) δ: 11.29 (1H, s), 8.44 (1H, d, J = 5.2 Hz), 8.04 (1H, s), 7.90 (1H, d, J = 1.4 Hz), 7.73 (1H, d, J = 8.8 Hz), 7.63 (1H, dd, J = 9.0, 1.4 Hz), 7.60 (1H, s), 7.51 (1H, d, J = 9.0 Hz), 7.30 (1H, m), 7.20 (1H, d, J = 5.2 Hz), 7.11 (2H, d, J HF =6.0 Hz), 6.81 (1H, s), 6.71 (1H, d, J = 3.0 Hz), 6.22 (1H, d, J = 3.0 Hz), 5.24 (1H, d, J = 16.3 Hz), 4.64 (1H, d, J = 16.3 Hz), 4.45 (1H, ddd, J = 13.5, 4.6, 4.0 Hz), 4.12 (3H, s), 3.87 (1H, ddd, J = 13.5, 10.2, 3.8 Hz), 3.17 (1H, ddd, J = 15.5, 10.2, 4.6 Hz), 3.02 (1H, m), 3.00 (2H, q, J = 7.6 Hz), 2.30 (3H, s), 2.28 (6H, s), 1.96 (1H, dd, J = 6.0 Hz), 1.64 (1H, m), 1.58 (1H, dd, J = 9.4, 6.0 Hz), 1.39 (3H, t, J = 7.6 Hz), 1.19 (3H, d, J = 6.1 Hz).

[0231]

Table 表2-15

[0232] [Table 2-16]

[0233] [Table 2-17]

[0234] [Table 2-18]

[0235] [Table 2-19]

[0236] [Table 2-20]

[0237] 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.

[0238] [ka]

[0239] (Step 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 a stirred mixture of concentrated hydrochloric acid (20 mL) and water (20 mL) at room temperature. The mixture was stirred at that temperature for 1 hour, and the solid in the reaction mixture was collected by filtration and dried. Methoxycyclopentane (20 mL) was further added to the resulting 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 collected by filtration and washed with methoxycyclopentane (12 mL). The resulting solid was dried under reduced pressure to give the title compound 2b (4.88 g, 97% yield) as an off-white solid.

[0240] This compound was used directly in the next step (Step 2-2). (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, followed by stirring at 0°C for 30 minutes. Next, a solution of tin(II) chloride (2.27 g, 12.0 mmol) in water (2.4 mL) was added over 2 minutes. Further water (7 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solid in the reaction mixture was collected by filtration, washed with water (2 mL), and dried to obtain the title compound 2c (1.75 g, 77% yield, 48% content) as a gray solid.

[0241] LC / MS mass spectrometry: m / z155([M+H] + ). LC / MS retention time: 0.54 min (Analysis conditions: SMD-FA05-1). (Step 2-3) tert-Butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 2d) This compound was obtained from compound 1b obtained in step 1-1 and compound 2c obtained in step 2-2 by the same procedure as in step 1-2 of Example 1 using appropriate reagents.

[0242] LC / MS mass spectrometry: m / z361([M+H] + ). LC / MS retention time: 1.04 min (Analysis conditions: SMD-FA05-3). (Step 2-4) tert-Butyl 3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Compound 2e) Compound 2d obtained in step 2-3 was synthesized using appropriate reagents in the same manner as in step 1-3 of Example 1. LC / MS mass spectrometry: m / z492([M+H] + ). LC / MS retention time: 1.07 min (Analysis conditions: SMD-FA05-3).

[0243] (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 using appropriate reagents in the same manner as in step 1-4 of Example 1.

[0244] LC / MS mass spectrometry: m / z328([M+H] + ). LC / MS retention time: 0.61 min (Analysis conditions: SMD-FA05-3). (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 using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0245] 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.

[0246] [ka]

[0247] (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 appropriate reagents in the same manner as in steps 1-10 of Example 1.

[0248] LC / MS mass spectrometry: m / z368([M+H] + ). LC / MS retention time: 1.25 minutes (Analysis conditions: SMD-FA05-3). (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 synthesized using appropriate reagents in the same manner as in steps 1-6 of Example 1.

[0249] 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).

[0250] (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 using appropriate reagents in the same manner as in step 1-8 of Example 1.

[0251] LC / MS mass spectrometry: m / z467([M+H] + ). LC / MS retention time: 1.33 minutes (Analysis conditions: SMD-FA05-01). (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. Under ice-cooling, 6N hydrochloric acid (51.9 mL) was added, and the suspension was stirred at room temperature for 30 minutes. After filtering and washing with water (29.1 mL), the resulting solid was dried under reduced pressure to give the title compound 6f (7.42 g, 95% yield) as a light brown solid.

[0252] LC / MS mass spectrometry: m / z376([MH] - ). LC / MS retention time: 1.10 minutes (Analysis conditions: SMD-FA05-2). (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 purged with nitrogen. The mixture was stirred under a nitrogen atmosphere at 100 °C for 0.5 h 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, purged with nitrogen, and stirred at 100°C for 0.5 hours. After cooling to room temperature, water (12.4 mL) and formic acid (6 mL) were added, filtered, and the filtrate was purified directly by reverse-phase chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound 6h (1.83 g, 55% yield).

[0253] LC / MS mass spectrometry: m / z421([M+H] + ). LC / MS retention time: 1.10 minutes (Analysis conditions: SMD-FA05-1). (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 was synthesized from compound 2f obtained in step 2-5 and compound 6h obtained in step 6-5 using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0254] 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.

[0255] (Step 6-7) 1-(5-Bromoindazol-1-yl)-2-methylpropan-2-ol (compound 6k)

[0256] [ka]

[0257] 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 irradiation. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1:1) to give the title compound 6l (115 mg, 56% yield).

[0258] 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.

[0259] [ka]

[0260] (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 purged with nitrogen. Compound 6f (5.0 g, 13.2 mmol) obtained in step 6-4 was added under a nitrogen atmosphere, stirred at 100 °C for 0.5 h, and then cooled to room temperature. Formic acid was added, and the mixture was purified directly by reverse-phase chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound 7b (5.26 g, 96% yield).

[0261] LC / MS mass spectrometry: m / z413([M+H] + ). LC / MS retention time: 1.00 min (Analysis conditions: SMD-FA05-1). (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 using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0262] 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.

[0263] [ka]

[0264] (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) A suspension of compound 6f (0.30 g, 0.793 mmol) obtained in step 6-4, palladium(II) acetate (35.6 mg, 0.159 mmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (0.148 g, 0.317 mmol) in N,N-dimethylacetamide (DMA) (2.64 mL) was degassed under reduced pressure, purged with nitrogen, and stirred at room temperature for 15 minutes. Under a nitrogen atmosphere, a 1 M solution of (tetrahydro-2H-pyran-4-yl)zinc(II) iodide (compound 8a) in DMA (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 directly by reverse-phase chromatography (methanol / water) to give the title compound 8b (0.19 g, 61% yield).

[0265] LC / MS mass spectrometry: m / z382([MH] - ). LC / MS retention time: 1.00 min (Analysis conditions: SMD-FA05-2). (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 using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0266] 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.

[0267] [ka]

[0268] (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, and the organic layer was separated. The organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated brine. The solvent was evaporated under reduced pressure to give the title compound 8e (1.36 g, 99% yield).

[0269] 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).

[0270] (Step 8-4) 5-Bromo-1-[(3R)-oxolan-3-yl]indazole (compound 8f)To a solution of 5-bromo-1H-indazole (compound 6j, 300 mg, 1.52 mmol) in DMF (3.8 mL), cesium carbonate (992 mg, 3.05 mmol) and compound 8e (369 mg, 1.52 mmol) obtained in step 8-3 were added, and the mixture was stirred at 100°C for 2 hours. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (ethyl acetate / hexane = 1:1) afforded the title compound 8f (198 mg, 49% yield) as a colorless oil.

[0271] LC / MS mass spectrometry: m / z267([M+H] + ). LC / MS retention time: 1.07 min (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.

[0272] (Step 9-1)

[0273] [ka]

[0274] 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 sequentially and stirred at room temperature for 12 hours. Formic acid was added to the reaction mixture, and the mixture was purified by reverse-phase silica gel chromatography (acetonitrile / water, 0.1% formic acid) to afford the title compound 9c (103 mg, 99% yield) as a colorless gum.

[0275] 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.

[0276] (Step 10-1)

[0277] [ka]

[0278] 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.

[0279] 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.

[0280] [ka]

[0281] (Step 11-1) tert-Butyl N-(4-fluoro-3,5-dimethylphenyl)-N-[(2-methylpropan-2-yl)oxycarbonylamino]carbamate (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-butyllithium (13.1 mL, 20.4 mmol) was added dropwise at an internal temperature of -70°C or below, and the mixture was stirred for 1 hour. A 20 wt% solution of di-tert-butyl azodicarboxylate in toluene (25.0 g, 21.7 mmol) was added dropwise at an internal temperature of -40°C or below, and the mixture was stirred for 30 minutes. The mixture was then warmed to room temperature over 1 hour, and extracted with heptane (23.8 mL) and 20% aqueous ammonium chloride solution (47.6 mL). The organic layer was concentrated, and heptane (7.14 mL) was added. The mixture was heated to an external temperature of 70°C to dissolve the solid. The mixture was then cooled for 1 hour to precipitate crystals. The crystals were collected by filtration and washed with heptane (2.38 mL). The crystals were dried to synthesize the crude product of the title compound 11b (3.53 g, yield 44%).

[0282] 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).

[0283] LC / MS retention time: 1.40 minutes (Analysis conditions: SMD-FA05-3). (Steps 11-2, 3, and 4) (2S)-tert-Butyl 3-cyano-2-methyl-4-oxopiperidine-1-carboxylate (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 then cooled to room temperature to obtain a mixture containing ethyl 3-[[(2S)-1-cyanopropan-2-yl]amino]propanoate (Compound 11e).

[0284] Di-tert-butyl dicarbonate (21.7 mL, 99.5 mmol) was added to the reaction mixture at room temperature. The solution was stirred at room temperature for 14 hours, and N-methylpiperazine (2.76 mL, 24.9 mmol) was added and 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 give a mixture containing ethyl 3-[[(2S)-1-cyanopropan-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoate (Compound 11f).

[0285] To this mixture was added THF (50.0 mL), and potassium tert-butoxide (10.2 g, 91.2 mmol) was added at an internal temperature of 30°C or less, followed by stirring at room temperature for 1 hour. The internal temperature was then increased to 15°C, and 2N hydrochloric acid (82.9 mL, 99.5 mmol) was added, followed by extraction with ethyl acetate. The organic layer was washed twice with 15% aqueous sodium chloride solution (50.0 mL) and then concentrated to give the title compound 11g (15.8 g, 80% yield).

[0286] LC / MS mass spectrometry: m / z237([MH] - ). LC / MS retention time: 0.92 minutes (Analysis conditions: SMD-FA05-1). (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 ester (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. The organic layer was washed with 1 M aqueous sodium hydroxide solution (12.6 mL) and concentrated under reduced pressure to give the title compound 11h (1.68 g, yield 75%).

[0287] LC / MS mass spectrometry: m / z375([M+H] + ). LC / MS retention time: 1.08 minutes (Analysis conditions: SMD-FA05-1). (Step 11-6) (4S)-tert-Butyl 3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (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, followed by stirring 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 residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3:2) to give the title compound 11j (105 mg, 73% yield).

[0288] LC / MS mass spectrometry: m / z506([M+H] + ). LC / MS retention time: 1.09 minutes (Analysis conditions: SMD-FA05-1). (Step 11-7) (4S)-tert-Butyl 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 (Compound 11k) Compound 11j (4.45 g, 8.79 mmol) obtained in step 11-6 was suspended in THF (44.5 mL), 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 saturated aqueous sodium chloride 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, 88% yield).

[0289] LC / MS mass spectrometry: m / z442([M+H] + ). LC / MS retention time: 1.09 minutes (Analysis conditions: SMD-FA05-1). (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) was added 4 M hydrogen chloride dioxane solution (10.5 mL, 41.9 mmol). After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to give a crude product (1.63 g) containing the title compound 11l as a brown solid.

[0290] LC / MS mass spectrometry: m / z342([M+H] + ). LC / MS retention time: 0.63 min (Analysis conditions: SMD-FA05-1). (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 using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0291] 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.

[0292] [ka]

[0293] (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 using an appropriate reagent in the same manner as in step 6-5 of Example 6.

[0294] LC / MS mass spectrometry: m / z429([M+H] + ). LC / MS retention time: 1.14 minutes (Analysis conditions: SMD-TFA05-3). (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 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 (7:1:1) (13.2 mL) was degassed under reduced pressure at room temperature and then purged with nitrogen. The mixture was stirred at 100°C under a nitrogen atmosphere for 0.5 hours and then cooled to room temperature. Formic acid was added, and the mixture was purified directly by reverse-phase chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound 14c (124 mg, 23% yield) as a pale yellow solid.

[0295] LC / MS mass spectrometry: m / z409([M+H] + ). LC / MS retention time: 0.85 min (Analysis conditions: SMD-FA05-3). (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 using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0296] 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.

[0297] [ka]

[0298] (Step 15-1) 4-Iodo-N,N,3-trimethylpyridin-2-amine (Compound 15b) A solution of 2-chloro-4-iodo-3-methylpyridine (Compound 15a, 500 mg, 1.97 mmol), N-ethyl-N-propan-2-ylpropan-2-amine (0.515 mL, 2.96 mmol), and 2 M dimethylamine in THF (2.96 mL, 5.92 mmol) in DMF (7.9 mL) was stirred at 130° C. for 17 hours and then cooled to room temperature. Formic acid (0.4 mL) was added, and the mixture was purified by reverse phase chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound 15b (258 mg, 50% yield) as a pale brown liquid.

[0299] LC / MS mass spectrometry: m / z263([M+H] + ). LC / MS retention time: 0.52 min (Analysis conditions: SQD-FA05-1). (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 was synthesized from compound 6f obtained in step 6-4 and compound 15b obtained in step 15-1 using appropriate reagents in the same manner as in step 6-5 of Example 6.

[0300] LC / MS mass spectrometry: m / z432([MH] - ). LC / MS retention time: 0.51 min (Analysis conditions: SQD-FA05-1). (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 using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0301] 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.

[0302] [ka]

[0303] (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 11l obtained in step 11-8 and the compound 8b obtained in step 8-1 were synthesized using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0304] 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. (Step 17-1)

[0305] [ka]

[0306] The compound was synthesized from 3-methyl-3-[(4-methylphenyl)sulfonylmethyl]oxetane (Compound 17a) and 5-bromo-1H-indazole (Compound 6j) using appropriate reagents in the same manner as in Step 9-1 of Example 9.

[0307] 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.

[0308] (Step 20-1) 2-(4-Bromo-2-methoxyphenoxy)-2-methylpropan-1-ol (compound 20b)

[0309] [ka]

[0310] Under a nitrogen atmosphere, a borane THF solution (0.95 M, 4.37 mL, 4.15 mmol) was added dropwise to a THF solution (1.38 mL) of 2-(4-bromo-2-methoxyphenoxy)-2-methylpropanecarboxylic acid (compound 20a, 400 mg, 1.38 mmol) at 0°C, followed by stirring for 24 hours. After adding 1 M aqueous sodium hydroxide and stirring, the mixture was neutralized with 1 N hydrochloric acid. Ethyl acetate was added for extraction. The organic layer was washed with water, and the solvent was evaporated under reduced pressure to give the title compound 20b (339 mg, 89% yield).

[0311] 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).

[0312] 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.

[0313] [ka]

[0314] (Step 22-1) 4-Methylbenzenesulfonic acid [(3R)-oxolan-3-yl] (compound 22b) The compound was synthesized using (3R)-oxolan-3-ol and an appropriate reagent in the same manner as in Step 8-3 of Example 8.

[0315] LC / MS retention time: 0.95 minutes (Analysis conditions: SMD-FA05-3). (Step 22-2) 5-Bromo-1-[(3S)-oxolan-3-yl]indazole (compound 22c) Compound 22b obtained in step 22-1 and 5-bromo-1H-indazole were synthesized using an appropriate reagent in the same manner as in step 8-4 of Example 8.

[0316] 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.

[0317] [ka]

[0318] (Step 24-1) 1,1-dimethyl-3,4-dihydroisochromen-6-yl trifluoromethanesulfonate (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.

[0319] LC / MS retention time: 0.96 min (Analysis conditions: SQD-FA05-01). (Step 24-2) 2-(1,1-dimethyl-3,4-dihydroisochromen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (compound 24c) A solution of 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), and [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, purged with nitrogen, and stirred at 100 °C for 14 hours. After cooling to room temperature, formic acid was added, and the mixture was purified by reverse-phase chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound 24c (134 mg) as a pale brown liquid.

[0320] LC / MS mass spectrometry: m / z289([M+H] + ). LC / MS retention time: 1.03 minutes (Analysis conditions: SQD-FA05-1). (Step 24-3) 6-Bromo-1,1-dimethyl-3,4-dihydroisochromene (compound 24d) To a solution of compound 24c (111 mg, 0.385 mmol) obtained in step 24-2 in methanol (1.9 mL), an aqueous solution (1.9 mL) of copper(II) bromide (258 mg, 1.16 mmol) was added and stirred at 60 °C for 6 hours. After cooling to room temperature, saturated aqueous ammonium chloride was added, and the mixture was extracted twice with dichloromethane. The organic layer was dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1:4) to give the title compound 24d (47.7 mg, 51% yield) as a colorless liquid.

[0321] 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).

[0322] 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.

[0323] [ka]

[0324] (Step 25-1) 6-(4-Bromo-2-methylphenyl)-N,N-dimethylpyrimidin-4-amine (Compound 25b) 4-(4-bromo-2-methylphenyl)-6-chloropyrimidine (compound 25a, 1 To a solution of 25b (2.9 mg, 0.045 mmol) in methanol (0.2 mL), 2 M dimethylamine in THF (0.227 mL, 0.455 mmol) was added and stirred at room temperature for 3 hours. The reaction mixture was purified by reverse-phase silica gel column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound 25b (9.2 mg, 69% yield) as an off-white solid.

[0325] 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.

[0326] [ka]

[0327] (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.

[0328] 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.

[0329] [ka]

[0330] (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 appropriate reagents in the same manner as in step 8-4 of Example 8.

[0331] 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.

[0332] [ka]

[0333] (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 appropriate reagents in the same manner as in Steps 6-7 of Example 6.

[0334] 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 311), used in the synthesis of example compounds 31 to 40, was synthesized as follows.

[0335] [ka]

[0336] (Step 31-1) Ethyl 5-(2,2-dimethyloxan-4-yl)-1H-indole-2-carboxylate (Compound 31c) Zinc dust (1.95 g, 29.8 mmol) was suspended in DMF (6 mL) and the atmosphere was purged with nitrogen. Chlorotrimethylsilane (0.417 mL, 3.28 mmol) and 1,2-dibromoethane (0.284 mL, 3.28 mmol) were added and stirred at room temperature for 5 minutes. A solution of 4-iodo-2,2-dimethyltetrahydropyran (5.37 g, 22.4 mmol) in DMF (9 mL) was added dropwise and stirred at room temperature for 20 minutes. Palladium(II) acetate (0.084 g, 0.373 mmol), 4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (0.198 g, 0.746 mol), and ethyl 5-bromoindole-2-carboxylate (2.0 g, 7.46 mmol) were added to the solution and the atmosphere was 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 (6 mL). 30% aqueous sodium chloride solution (50 mL) and ethyl acetate (100 mL) were added, and insoluble matter was removed using Celite. The filtrate was extracted with ethyl acetate and washed with 30% aqueous sodium chloride solution. After drying over magnesium sulfate and filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound 31c (1.86 g, 83% yield) as a pale pink solid.

[0337] LC / MS mass spectrometry: m / z302([M+H] + ). LC / MS retention time: 0.90 min (Analysis conditions: SQD-FA05-4). (Step 31-2) Ethyl 5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indole-2-carboxylate (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%).

[0338] 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 Retention time of title compound: 9.98 min, retention time of isomer: 6.86 min The title compound was determined to be the S-configuration by X-ray crystal structure analysis of compound 31j.

[0339] (Step 31-3) 5-[(4S)-2,2-Dimethyloxan-4-yl]-1H-indole-2-carboxylic acid (compound 31e) Compound 31d (993 mg, 3.29 mmol) obtained in step 31-2 was dissolved in methanol (14.9 mL), and 2 M aqueous sodium hydroxide solution (3.62 mL, 7.25 mmol) was added dropwise thereto, followed by stirring at an external temperature of 65°C for 1 hour. The reaction solution was cooled to an external temperature of 15°C, and 5 N hydrochloric acid (1.52 mL, 7.58 mmol) was added dropwise thereto. 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%).

[0340] LC / MS mass spectrometry: m / z274([M+H] + ). LC / MS retention time: 0.65 min (Analysis conditions: SQD-FA05-4). (Step 31-4) 5-[(4S)-2,2-Dimethyloxan-4-yl]-N-methyl-N-phenyl-1H-indole-2-carboxamide (Compound 31f) Compound 31e (805 mg, 2.95 mmol) obtained in step 31-3 was dissolved in DMA (8.0 mL), and thionyl chloride (0.256 mL, 3.53 mmol) was added dropwise at an internal temperature of 10°C or below. After stirring for 1 hour, N-methylaniline (0.384 mL, 3.53 mmol) and triethylamine (0.985 mL, 7.07 mmol) were added dropwise at 10°C or below, and the mixture was stirred at room temperature for 1 hour. Water (4.0 mL) was added dropwise, and the precipitated solid was collected by filtration. The obtained solid was washed with water (8.0 mL) and dried under reduced pressure to give the title compound 31f (995 mg, 93% yield).

[0341] LC / MS mass spectrometry: m / z363([M+H] + ). LC / MS retention time: 1.20 minutes (Analysis conditions: SMD-FA05-1). (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 aqueous potassium hydroxide (0.103 mL, 0.828 mmol) and water (0.10 mL) were added. 2-Chloroacetonitrile (0.026 mL, 0.414 mmol) was added to the resulting solution at an external temperature of 10 °C, and the mixture was stirred for 2.5 hours. The reaction solution was extracted with 5 N hydrochloric acid (0.193 mL), water (0.10 mL), and cyclopentyl methyl ether (1.0 mL). The aqueous layer was extracted again with cyclopentyl methyl ether (1.0 mL). The combined organic layers were washed with 15% aqueous sodium chloride (1.0 mL) and then concentrated under reduced pressure at an external temperature of 40 °C. The title compound 31h was obtained as a light brown oil and used in the next step 31-6 without further purification.

[0342] LC / MS mass spectrometry: m / z402([M+H] + ). LC / MS retention time: 0.93 minutes (Analysis conditions: SMD-FA05-1). (Step 31-6) 1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-5-[(4S)-2,2-dimethyloxan-4-yl]-N-methyl-N-phenylindole-2-carboxamide (compound 31i) Compound 31h obtained in step 31-5 was synthesized using appropriate reagents in the same manner as in steps 1-6 of Example 1.

[0343] LC / MS mass spectrometry: m / z442([M+H] + ). LC / MS retention time: 0.95 min (Analysis conditions: SQD-FA05-1). (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) Compound 31i obtained in step 31-6 was synthesized using appropriate reagents in the same manner as in steps 1-6 of Example 1.

[0344] LC / MS mass spectrometry: m / z501([M+H] + ). LC / MS retention time: 0.99 min (Analysis conditions: SQD-FA05-1). (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 using an appropriate reagent in the same manner as in step 6-4 of Example 6.

[0345] LC / MS mass spectrometry: m / z401([MH] - ). LC / MS retention time: 1.05 minutes (Analysis conditions: SMD-FA05-1). (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 using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0346] 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.

[0347] (Step 33-1)

[0348] [ka]

[0349] Synthesis was carried out 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] + ).

[0350] 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.

[0351] (Step 36-1)

[0352] [ka]

[0353] Synthesis was carried out from 5-bromo-4-fluoro-1H-indazole (Compound 28a) using appropriate reagents in the same manner as in Step 8-4 of Example 8. LC / MS mass spectrometry: m / z273([M+H] + ).

[0354] 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.

[0355] (Step 40-1)

[0356] [ka]

[0357] 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.

[0358] 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.

[0359] [ka]

[0360] (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 purged with nitrogen. Under a nitrogen atmosphere, a 7:5 mixture of chlorotrimethylsilane and 1,2-dibromoethane (0.0083 mL, 0.039 mmol of chlorotrimethylsilane) was added and stirred for 15 minutes. Then, (2S)-4-iodo-2-methyltetrahydro-2H-pyran (80 mg, 0.35 mmol) was added dropwise at room temperature and stirred for 30 minutes to give a mixture containing iodo-[(2S)-2-methyloxan-4-yl]zinc (Compound 41b). Palladium(II) acetate (6.4 mg, 0.028 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (26 mg, 0.057 mmol), 5-bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-N-methyl-N-phenylindole-2-carboxamide (58 mg, 0.14 mmol), and DMA (0.123 mL) were added. The mixture was degassed under reduced pressure, purged with nitrogen, and stirred at 80 °C for 1 h. The mixture was cooled to room temperature, and ethyl acetate and 1N hydrochloric acid were added. After filtration, the filtrate was extracted with ethyl acetate. The organic layer was washed once with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1:1) to give the title compound 41c (31 mg, 51% yield).

[0361] LC / MS mass spectrometry: m / z428([M+H] + ). LC / MS retention time: 1.01 min (Analysis conditions: SQD-AA05-1). (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) Compound 41c obtained in step 41-2 was synthesized using an appropriate reagent in the same manner as in step 1-8 of Example 1.

[0362] LC / MS mass spectrometry: m / z487([M+H] + ). LC / MS retention time: 1.30 minutes (Analysis conditions: SMD-FA05-1). (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.

[0363] LC / MS mass spectrometry: m / z396([MH] - ). LC / MS retention time: 1.02 minutes (Analysis conditions: SMD-FA05-1). (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 appropriate reagents.

[0364] 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.

[0365] [ka]

[0366] (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 ester (Compound 42c) (4-Chloro-3,5-dimethylphenyl)hydrazine hydrochloride (compound 42b) was obtained from 4-chloro-3,5-dimethylaniline (compound 42a) using an appropriate reagent in the same manner as in step 2-2 of Example 2, and then compound 42c was synthesized using compound 11g obtained in step 11-4 and an appropriate reagent in the same manner as in step 1-2 of Example 1.

[0367] LC / MS mass spectrometry: m / z391([M+H] + ). LC / MS retention time: 1.22 minutes (Analysis conditions: SMD-FA10-4). (Step 42-3) (4S)-tert-Butyl 2-(4-chloro-3,5-dimethylphenyl)-3-(2,2-dimethoxyethylcarbamoylamino)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Compound 42d) Compound 42c obtained in step 42-2 was synthesized using an appropriate reagent in the same manner as in step 1-3 of Example 1.

[0368] LC / MS mass spectrometry: m / z522([M+H] + ). LC / MS retention time: 1.55 minutes (Analysis conditions: SMD-TFA05-5). (Step 42-4) (4S)-tert-Butyl 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 (Compound 42e) Compound 42d obtained in step 42-3 was synthesized using an appropriate reagent in the same manner as in step 11-8 of Example 11.

[0369] LC / MS mass spectrometry: m / z458([M+H] + ). LC / MS retention time: 1.16 minutes (Analysis conditions: SMD-FA05-1). (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) This was synthesized from compound 42e obtained in step 42-4 using an appropriate reagent in the same manner as in step 111-8 of Example 11.

[0370] LC / MS mass spectrometry: m / z358([M+H] + ). LC / MS retention time: 0.69 min (Analysis conditions: SMD-FA05-1). (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 using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0371] 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.

[0372] [ka]

[0373] (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) Compound 42f obtained in step 42-5 and compound 8b obtained in step 8-1 were synthesized using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0374] 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.

[0375] [ka]

[0376] (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 ester (compound 46b) This was synthesized from (4-fluoro-3-methylphenyl)hydrazine hydrochloride (Compound 46a) and Compound 11g obtained in Step 11-4 using appropriate reagents in the same manner as in Step 1-2 of Example 1.

[0377] LC / MS mass spectrometry: m / z361([M+H] + ). LC / MS retention time: 1.02 minutes (Analysis conditions: SMD-FA05-1). (Step 46-2) (4S)-tert-Butyl 3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3-methylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Compound 46c) Compound 46b obtained in step 46-1 was synthesized using an appropriate reagent in the same manner as in steps 1-3 of Example 1.

[0378] LC / MS mass spectrometry: m / z492([M+H] + ). LC / MS retention time: 1.03 minutes (Analysis conditions: SMD-FA05-1). (Step 46-3) (4S)-tert-Butyl 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 (compound 46d) Compound 46c obtained in step 46-2 was synthesized using an appropriate reagent in the same manner as in step 11-7 of Example 11.

[0379] LC / MS mass spectrometry: m / z428([M+H] + ). LC / MS retention time: 2.11 minutes (Analysis conditions: SMD-FA05-long). (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) Compound 46d obtained in step 46-3 was synthesized using an appropriate reagent in the same manner as in step 11-8 of Example 11.

[0380] LC / MS mass spectrometry: m / z328([M+H] + ). LC / MS retention time: 0.59 min (Analysis conditions: SMD-FA05-3). (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 using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0381] 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.

[0382] [ka]

[0383] (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 using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0384] <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), substituted morpholine, and an appropriate reagent, the same procedure as in step 7-1 of Example 7 was carried out, and example compounds 51 to 53 shown in Table 2-4 were obtained by the following reaction.

[0385] [ka]

[0386] [Table 2-21]

[0387] Compound 51d was synthesized as follows.

[0388] [ka]

[0389] (Step 51-1) tert-Butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (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 mL) and 5% aqueous potassium hydrogen sulfate solution (20 mL) were added to the reaction mixture, 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 give the title compound 51a (0.360 g, 50% yield).

[0390] LC / MS mass spectrometry: m / z428([M+H] + ). LC / MS retention time: 1.06 minutes (Analysis conditions: SMD-FA05-3). (Step 51-2) tert-Butyl 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 (Compound 51b) From the compound 51a obtained in step 51-1 and 5-bromo-1-methylindazole, The compound was synthesized using appropriate reagents in the same manner as in Steps 1-11 of Example 1.

[0391] LC / MS mass spectrometry: m / z558([M+H] + ). LC / MS retention time: 1.25 minutes (Analysis conditions: SMD-FA05-1). (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 using an appropriate reagent in the same manner as in step 11-9 of Example 11.

[0392] LC / MS mass spectrometry: m / z458([M+H] + ). LC / MS retention time: 0.78 min (Analysis conditions: SMD-FA05-1). (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 using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0393] LC / MS mass spectrometry: m / z817([M+H] + ). LC / MS retention time: 1.41 minutes (Analysis conditions: SMD-FA05-1). <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.

[0394] [ka]

[0395] [Table 2-22]

[0396] [Table 2-23]

[0397] [Table 2-24]

[0398] [Table 2-25]

[0399] [Table 2-26]

[0400] [Table 2-27]

[0401] [Table 2-28]

[0402] The compounds in Table 2-5 have rotational isomers. For example, the compounds of Example 66 and 67 1 H-NMR is as follows: 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).

[0403] 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).

[0404] <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).

[0405] 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).

[0406] For the synthesis of Example Compound 55, the compound 55e was synthesized using the following method.

[0407]

change

[0408] (Step 55-1) tert-Butyl 3-amino-2-(4-chloro-3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 55a) The compound 42a obtained in step 42-1 and the compound 1b obtained in step 1-1 were synthesized using appropriate reagents in the same manner as in step 1-2 of Example 1.

[0409] LC / MS mass spectrometry: m / z377([M+H] + ). LC / MS retention time: 0.87 min (Analysis conditions: SQD-FA05-1). (Step 55-2) tert-Butyl 2-(4-chloro-3,5-dimethylphenyl)-3-(2,2-dimethoxyethylcarbamoylamino)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Compound 55b) Compound 55a obtained in step 55-1 was synthesized using an appropriate reagent in the same manner as in steps 1-3 of Example 1.

[0410] LC / MS mass spectrometry: m / z508([M+H] + ). LC / MS retention time: 0.83 min (Analysis conditions: SQD-FA05-1). (Step 55-3) tert-Butyl 2-(4-chloro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Compound 55c) A suspension of compound 55b (903 mg, 1.78 mmol) obtained in step 55-2 and p-toluenesulfonic acid monohydrate (338 mg, 1.78 mmol) in DMF (7.11 mL) was stirred at 80 °C for 1 h. After cooling to room temperature, potassium phosphate (377 mg, 1.78 mmol), water (3.5 mL), and di-tert-butyl dicarbonate (388 mg, 1.78 mmol) were added and stirred at room temperature for 1 h. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1:4 to 1:0) to give the title compound 55c (799 mg, 100% yield) as a pale yellow foam.

[0411] LC / MS mass spectrometry: m / z444([M+H] + ). LC / MS retention time: 0.82 minutes (Analysis conditions: SQD-FA05-1). (Step 55-4) tert-Butyl 2-(4-chloro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Compound 55d) The compound was synthesized from compound 55c obtained in step 55-3 and 5-bromo-1-methylindazole (compound 1q) using an appropriate reagent in the same manner as in step 1-11 of Example 1.

[0412] LC / MS mass spectrometry: m / z574([M+H] + ). LC / MS retention time: 1.34 minutes (Analysis conditions: SMD-FA05-1). (Step 55-5) 1-[2-(4-chloro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1-methylindazol-5-yl)imidazol-2-one hydrochloride (Compound 55e) The compound 55d obtained in step 55-4 was synthesized by the same procedure as in step 11-8 of Example 11 using an appropriate reagent.

[0413] LC / MS mass spectrometry: m / z474([M+H] + ). LC / MS retention time: 0.81 min (Analysis conditions: SMD-FA05-1). Compound 56c used in the synthesis of Example Compound 56 was synthesized as follows.

[0414] [ka]

[0415] (Step 56-1) tert-Butyl 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 (Compound 56b) The compound was synthesized from compound 51a obtained in step 51-1 and 5-bromo-1-(2-methoxyethyl)indazole (compound 56a) using an appropriate reagent in the same manner as in step 1-11 of Example 1.

[0416] 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) Compound 56b obtained in step 56-1 was synthesized using an appropriate reagent in the same manner as in step 11-8 of Example 11.

[0417] LC / MS mass spectrometry: m / z502([M+H] + ). LC / MS retention time: 0.54 min (Analysis conditions: SQD-FA05-1). The amine derivative (compound 57j) used in the synthesis of example compound 57 was synthesized as follows.

[0418] [ka]

[0419] (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 evaporated under reduced pressure to give the title compound 57b as a crude product.

[0420] 1 H-NMR (400MHz, CDCl3) δ: 12.3 (1H, brs), 3.95 (6H, brs), 1.45 (9H, s). (Step 57-2) (4S)-tert-Butyl 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 (Compound 57c) The compound was synthesized from compound 57b obtained in step 57-1 and compound 11h obtained in step 11-5 using appropriate reagents in the same manner as in step 1-3 of Example 1.

[0421] LC / MS mass spectrometry: m / z636([M+H] + ). LC / MS retention time: 0.93 min (Analysis conditions: SQD-FA05-1). (Step 57-3) (4S)-tert-Butyl 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 (Compound 57d) To a suspension of compound 57c (31.6 mg, 0.050 mmol) obtained in step 57-2 and cesium carbonate (82.8 mg, 0.254 mmol) in DMA (0.25 mL), 1,2-dichloro-1-ethoxyethane (0.0155 mL, 0.127 mmol) was added at room temperature and stirred at room temperature for 170 minutes. Cesium carbonate (104 mg, 0.32 mmol) and then 1,2-dichloro-1-ethoxyethane (0.0184 mL, 0.162 mmol) were added to the reaction mixture at room temperature and stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and water, adjusted to pH 7 with 1N hydrochloric acid (0.54 mL), and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Toluene was added and the solvent was evaporated under reduced pressure to give the title compound 57d as a crude product.

[0422] LC / MS mass spectrometry: m / z678([M+H] + ). LC / MS retention time: 0.98 min (Analysis conditions: SQD-FA05-1). (Step 57-4) (4S)-tert-Butyl 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 (Compound 57e) To a solution of compound 57d (115 mg, 0.17 mmol) obtained in step 57-3 in THF (1.1 mL) was added methylsulfonic acid (0.011 mL, 0.17 mmol) at room temperature, followed by stirring at 60 °C for 90 minutes. Potassium phosphate (36.5 mg, 0.172 mmol), water (0.45 mL), and tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate (0.012 mL, 0.052 mmol) were added to the reaction mixture, followed by stirring 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 evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1:2 to 1:1) to give the title compound 57e (48.5 mg, 43% yield).

[0423] LC / MS mass spectrometry: m / z660([M+H] + ). LC / MS retention time: 1.04 min (Analysis conditions: SQD-FA05-1). (Step 57-5) (4S)-tert-Butyl 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 (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 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, which was then diluted with ethyl acetate. Further water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the product was purified by silica gel column chromatography (ethyl acetate / hexane = 1:3 to 2:3) to give the title compound 57f (9.2 mg, 54% yield).

[0424] 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) was added TFA (0.019 mL) at room temperature, and the mixture was stirred at room temperature for 3 hours. After the solvent was evaporated under reduced pressure, toluene was added and the solvent was evaporated, and hexane-dichloromethane was added and the solvent was evaporated to give the title compound 57g (9.4 mg) as a crude product.

[0425] LC / MS mass spectrometry: m / z501([M+H] + ). LC / MS retention time: 0.49 min (Analysis conditions: SQD-FA05-1). (Step 57-7) (4S)-tert-Butyl 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 (Compound 57h) From compound 57g obtained in step 57-6, synthesis was carried out in the same manner as in step 51-1 of Example 51 using appropriate reagents.

[0426] LC / MS mass spectrometry: m / z602([M+H] + ). LC / MS retention time: 0.85 min (Analysis conditions: SQD-FA05-1). (Step 57-8) (4S)-tert-Butyl 3-[3-[4-[acetyl(2-methoxyethyl)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 (Compound 57i) From compound 57h obtained in step 57-7, the compound was synthesized by the same procedure as in step 57-5 of Example 57 using an appropriate reagent.

[0427] 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) From compound 57i obtained in step 57-8, the compound was synthesized by the same procedure as in step 11-8 of Example 11 using appropriate reagents.

[0428] LC / MS mass spectrometry: m / z560([M+H] + ). LC / MS retention time: 0.53 minutes (analysis conditions: SQD-FA05-1). Compound 58e used in the synthesis of Example Compound 58 was synthesized as follows.

[0429] [ka]

[0430] (Step 58-1) tert-Butyl 3-amino-2-(4-fluoro-3-methylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 58a) The compound was synthesized from compound 1b obtained in step 1-1 and compound 46a obtained in step 46-1 using appropriate reagents in the same manner as in step 1-2 of Example 1.

[0431] LC / MS mass spectrometry: m / z347([M+H]+ ). LC / MS retention time: 0.98 min (Analysis conditions: SMD-FA05-3). (Step 58-2) tert-Butyl 3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3-methylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 58b) Compound 58a obtained in step 58-1 was synthesized using an appropriate reagent in the same manner as in steps 1-3 of Example 1.

[0432] LC / MS mass spectrometry: m / z478([M+H] + ). LC / MS retention time: 1.03 minutes (Analysis conditions: SMD-FA05-3). (Step 58-3) tert-Butyl 2-(4-fluoro-3-methylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Compound 58c) Compound 58b obtained in step 58-2 was synthesized using an appropriate reagent in the same manner as in step 11-7 of Example 11.

[0433] LC / MS mass spectrometry: m / z414([M+H] + ). LC / MS retention time: 0.72 min (Analysis conditions: SQD-FA05-1). (Step 58-4) tert-Butyl 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 (Compound 58d) The compound 58c obtained in step 58-3 and 5-bromo-1-(2-methoxyethyl)indazole (compound 56a) were synthesized using an appropriate reagent in the same manner as in step 1-11 of Example 1.

[0434] 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 using an appropriate reagent in the same manner as in step 11-9 of Example 11.

[0435] LC / MS mass spectrometry: m / z488([M+H] + ). LC / MS retention time: 0.50 min (Analysis conditions: SQD-FA05-1). Compound 60c used in the synthesis of Example Compound 60 was synthesized as follows.

[0436] [ka]

[0437] (Step 60-1) tert-Butyl 2-(3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Compound 60a) Compound 1g obtained in step 1-4 was synthesized using appropriate reagents in the same manner as in step 51-1 of Example 51.

[0438] LC / MS mass spectrometry: m / z410([M+H] + ). LC / MS retention time: 0.77 min (Analysis conditions: SQD-FA05-1). (Step 60-2) tert-Butyl 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 (Compound 60b) The compound was synthesized from compound 60a obtained in step 60-1 and 5-bromo-1-methylindazole (compound 1q) using an appropriate reagent in the same manner as in step 1-11 of Example 1.

[0439] 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 using an appropriate reagent in the same manner as in step 11-8 of Example 11.

[0440] LC / MS mass spectrometry: m / z440([M+H] + ). LC / MS retention time: 0.74 min (Analysis conditions: SMD-FA05-2). Compound 61b used in the synthesis of Example Compound 61 was synthesized as follows.

[0441] [ka]

[0442] (Step 61-1) (4S)-tert-Butyl 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 (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.

[0443] 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 appropriate reagents.

[0444] LC / MS mass spectrometry: m / z472([M+H] + ). LC / MS retention time: 0.79 min (Analysis conditions: SMD-FA05-1). Compound 62b used in the synthesis of Example Compound 62 was synthesized as follows.

[0445] [ka]

[0446] (Step 62-1) (4S)-tert-Butyl 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 (Compound 62a) The compound was synthesized from compound 11k obtained in step 11-7 and 5-bromo-1-(2-methoxyethyl)indazole (compound 56a) using an appropriate reagent in the same manner as in step 1-11 of Example 1.

[0447] 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 using an appropriate reagent in the same manner as in step 11-8 of Example 11.

[0448] LC / MS mass spectrometry: m / z516([M+H] + ). LC / MS retention time: 0.76 min (Analysis conditions: SMD-FA05-1). Compound 63g used in the synthesis of Example Compound 63 was synthesized as follows.

[0449] [ka]

[0450] (Step 63-1) 5-Bromo-7-fluoro-N-methyl-N-phenyl-1H-indole-2-carboxamide (Compound 63b) Synthesis was carried out from 5-bromo-7-fluoro-1H-indole-2-carboxylic acid (Compound 63a) using appropriate reagents in the same manner as in Steps 1-10 of Example 1.

[0451] (Step 63-2) 5-Bromo-1-(cyanomethyl)-7-fluoro-N-methyl-N-phenylindole-2-carboxamide (Compound 63c) From compound 63b obtained in step 63-1, the compound was synthesized by the same procedure as in step 9-1 of Example 9 using appropriate reagents.

[0452] LC / MS mass spectrometry: m / z386([M+H] + ). LC / MS retention time: 3.17 minutes (Analysis conditions: SMD-FA10-long). (Step 63-3) 5-Bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-7-fluoro-N-methyl-N-phenylindole-2-carboxamide (compound 63d) Compound 63c obtained in step 63-2 was synthesized using an appropriate reagent in the same manner as in steps 1-6 of Example 1.

[0453] 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).

[0454] (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) using an appropriate reagent in the same manner as in step 8-1 of Example 8.

[0455] 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.

[0456] 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) Compound 63f obtained in step 63-5 was synthesized using an appropriate reagent in the same manner as in step 6-4 of Example 6.

[0457] LC / MS mass spectrometry: m / z402([M+H] + ). LC / MS retention time: 0.97 minutes (analysis conditions: SMD-FA05-1). Compound 64b used in the synthesis of Example Compound 64 was synthesized as follows.

[0458] [ka]

[0459] (Step 64-1) (4S)-tert-Butyl 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 (Compound 64a) The compound was synthesized from compound 11k obtained in step 11-7 and compound 8f obtained in step 8-4 using appropriate reagents in the same manner as in step 1-11 of Example 1.

[0460] 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) Compound 64a obtained in step 64-1 was synthesized using an appropriate reagent in the same manner as in step 11-8 of Example 11.

[0461] LC / MS mass spectrometry: m / z528([M+H] + ). LC / MS retention time: 0.78 min (Analysis conditions: SMD-FA05-1). Compound 65c used in the synthesis of Example Compound 65 was synthesized as follows.

[0462] [ka]

[0463] (Step 65-1) (4S)-tert-Butyl 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 (Compound 65b) The compound was synthesized from compound 42e obtained in step 42-4 and 5-bromo-4-fluoro-1-methylindazole (compound 65a) using an appropriate reagent in the same manner as in step 1-11 of Example 1.

[0464] 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.

[0465] LC / MS mass spectrometry: m / z506([M+H] + ). LC / MS retention time: 0.86 min (Analysis conditions: SMD-FA05-1). Compound 67b used in the synthesis of Example Compound 67 was synthesized as follows.

[0466] [ka]

[0467] (Step 67-1) (4S)-tert-Butyl 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 (Compound 67a) The compound was synthesized from compound 11k obtained in step 11-7 and 5-bromo-4-fluoro-1-methylindazole (compound 65a) using an appropriate reagent in the same manner as in step 1-11 of Example 1.

[0468] 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 using an appropriate reagent in the same manner as in step 11-8 of Example 11.

[0469] LC / MS mass spectrometry: m / z490([M+H] + ). LC / MS retention time: 0.80 min (Analysis conditions: SMD-FA05-1). Compound 68c used in the synthesis of Example Compound 68 was synthesized as follows.

[0470] [ka]

[0471] (Step 68-1) (4S)-tert-Butyl 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 (Compound 68b) The compound 68a was synthesized from compound 11k obtained in step 11-7 and 5-bromo-4-chloro-1-methylindazole (compound 68a) using an appropriate reagent in the same manner as in step 1-11 of Example 1.

[0472] 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) Compound 68b obtained in step 68-1 was synthesized using an appropriate reagent in the same manner as in step 11-8 of Example 11.

[0473] LC / MS mass spectrometry: m / z506([M+H] + ). LC / MS retention time: 0.83 minutes (Analysis conditions: SMD-FA05-1). Compound 69b used in the synthesis of Example Compound 69 was synthesized as follows.

[0474] [ka]

[0475] (Step 69-1) ( 4S)-tert-Butyl 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 (Compound 69a) The compound was synthesized from compound 46d obtained in step 46-3 and 5-bromo-4-fluoro-1-methylindazole (compound 65a) using an appropriate reagent in the same manner as in step 1-11 of Example 1.

[0476] 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) Compound 69a obtained in step 69-1 was synthesized using an appropriate reagent in the same manner as in step 11-8 of Example 11.

[0477] LC / MS mass spectrometry: m / z476([M+H] + ). LC / MS retention time: 0.77 min (Analysis conditions: SMD-FA05-1). Compound 70c used in the synthesis of Example Compound 70 was synthesized as follows.

[0478] [ka]

[0479] (Step 70-1) (4S)-tert-Butyl 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 (Compound 70b) The compound was synthesized from compound 11k obtained in step 11-7 and 5-bromo-6-fluoro-1-methylindazole (compound 70a) using an appropriate reagent in the same manner as in step 1-11 of Example 1.

[0480] 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 using an appropriate reagent in the same manner as in step 11-8 of Example 11.

[0481] LC / MS mass spectrometry: m / z490([M+H] + ). LC / MS retention time: 0.81 min (Analysis conditions: SMD-FA05-1). Compound 71b used in the synthesis of Example Compound 71 was synthesized as follows.

[0482] [ka]

[0483] (Step 71-1) 5-Bromo-6-fluoro-1-(2-methoxyethyl)indazole (Compound 71b) This 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.

[0484] LC / MS mass spectrometry: m / z273([M+H] + ). LC / MS retention time: 1.06 minutes (Analysis conditions: SMD-FA05-1). (Step 71-2) (4S)-tert-Butyl 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 (Compound 71c) The compound was synthesized from compound 11k obtained in step 11-7 and compound 71b obtained in step 71-1 using appropriate reagents in the same manner as in step 1-11 of Example 1.

[0485] 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 using an appropriate reagent in the same manner as in step 11-8 of Example 11.

[0486] LC / MS mass spectrometry: m / z534([M+H] +). LC / MS retention time: 0.83 minutes (Analysis conditions: SMD-FA05-1). 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)

[0487] [ka]

[0488] To a DMF (1.5 mL) solution of the racemate (compound 73a, 29.6 mg, 0.058 mmol) synthesized in a similar manner to the compound obtained in step 61-2 and compound 1o (26.8 mg, 0.064 mmol) obtained in step 1-9, HATU (26.6 mg, 0.070 mmol) and N,N-diisopropylethylamine (18.1 mg, 0.14 mmol) were added and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with distilled water. The organic layer was concentrated under reduced pressure to give a residue containing a mixture of stereoisomers. The stereoisomers were separated by reverse-phase HPLC to give 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.

[0489] 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] + ).

[0490] LC / MS retention time: 0.99 minutes (Analysis conditions: SMD-FA05-3). Entity B (Compound 73) LC / MS mass spectrometry: m / z872([M+H] + ).

[0491] LC / MS retention time: 1.01 min (Analysis conditions: SMD-FA05-3). 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)

[0492] [ka]

[0493] (Step 74-1) 5-Bromo-6-fluoro-N-methyl-N-phenyl-1H-indole-2-carboxamide (compound 74b) This was synthesized from 5-bromo-6-fluoro-1H-indole-2-carboxylic acid (Compound 74a) using appropriate reagents in the same manner as in Steps 1-10 of Example 1.

[0494] 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) Compound 74b obtained in step 74-1 was synthesized using an appropriate reagent in the same manner as in step 9-1 of Example 9.

[0495] 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 was synthesized from compound 74c obtained in step 74-2 and (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (compound 1k) using an appropriate reagent in the same manner as in step 1-6 of Example 1.

[0496] 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) Compound 74d obtained in step 74-3 was synthesized using appropriate reagents in the same manner as in steps 1-8 of Example 1.

[0497] 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) From compound 74e obtained in step 74-4, the compound was synthesized by the same procedure as in step 6-4 of Example 6 using appropriate reagents.

[0498] 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 was synthesized from compound 74f obtained in step 74-5 and compound 61b obtained in step 61-2 using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0499] 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.

[0500] LC / MS mass spectrometry: m / z892([M+H] + ). LC / MS retention time: 1.48 minutes (Analysis conditions: SMD-TFA05-1). <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, and Example Compounds 75 to 77 shown in Table 2-6 were obtained by the following reaction.

[0501] [ka]

[0502] [Table 2-29]

[0503] 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)

[0504] [ka]

[0505] This compound was synthesized from 9-iodo-6-oxaspiro[4.5]decane (Compound 75a) using appropriate reagents in the same manner as in Step 41-1 of Example 41. This compound was used directly in the next step.

[0506] Compound 76a used in the synthesis of Example Compound 76 was synthesized as follows.

[0507] [ka]

[0508] (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 using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0509] LC / MS mass spectrometry: m / z861([M+H] + ). LC / MS retention time: 1.45 minutes (Analysis conditions: SMD-FA05-2). Example 77

[0510] [ka]

[0511] (Step 77-1) 2-Ethyl-4-iodooxane (compound 77b) To a solution of but-3-en-1-ol (0.588 mL, 6.93 mmol) in acetic acid (2.48 mL), propionaldehyde (0.650 mL, 9.01 mmol) and lithium iodide (2.78 g, 20.8 mmol) were added sequentially and stirred at 60 °C for 1 hour. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure (150 hPa minimum). The residue was purified by silica gel chromatography (ethyl acetate / hexane = 0:1 to 1:9) to afford the title compound 77b as a pale yellow oil (1.12 g, 67% yield, syn:anti = 1.00:0.45) as a diastereomeric mixture.

[0512] 1 H-NMR (400 MHz, CDCl3): syn δ:4.31-4.23(1H,m),3.90-3.82(1H,m),3.44-3.37(1H,m),3.21-3.15(1H,m),2.37-1.38(6H,m),0.92(3H,t,J=7.4Hz).

[0513] 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).

[0514] (Step 77-2) (2-Ethyloxan-4-yl)-iodozinc (Compound 77c) To a solution of zinc (102 mg, 1.56 mmol) in DMA (0.25 mL) was slowly added dropwise a mixture of chloro(trimethyl)silane (0.017 mL, 0.137 mmol) and 1,2-dibromoethane (0.012 mL, 0.137 mmol) under a nitrogen atmosphere, maintaining the temperature below 65°C, and the mixture was stirred at room temperature for 15 minutes. Subsequently, a solution of compound 77b (300 mg, 1.25 mmol) obtained in step 77-1 in DMA (0.625 mL) was slowly added dropwise, maintaining the temperature below 65°C, and the mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes to give a DMA solution (0.86 M) of the diastereomeric mixture of title compound 77c.

[0515] (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. The mixture was degassed under reduced pressure, purged with nitrogen, and stirred at room temperature for 5 minutes. Subsequently, a solution of compound 77c (0.86 M, 0.398 mL, 0.342 mmol) in DMA (0.86 M, 0.398 mL, 0.342 mmol) obtained in step 77-2 was added and stirred at room temperature for 1.5 hours. Formic acid was added to the reaction mixture, and the mixture was purified by reverse-phase silica gel chromatography (acetonitrile / water, 0.1% formic acid) to obtain a syn-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.

[0516] Fractionation conditions Column: CHIRALCEL OD-RH 5 μm, 4.6 mm × 150 mm (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] + ).

[0517] 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] + ).

[0518] HPLC retention time: 6.64 minutes (preparative conditions). LC / MS retention time: 1.46 minutes (Analysis conditions: SMD-FA05-1). 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)

[0519] [ka]

[0520] (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) using an appropriate reagent in the same manner as in step 1-10 of Example 1.

[0521] 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) using an appropriate reagent in the same manner as in step 8-1 of Example 8.

[0522] 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) Compound 78b obtained in step 78-2 was synthesized using an appropriate reagent in the same manner as in steps 1-6 of Example 1.

[0523] 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) Compound 78d obtained in step 78-2 was synthesized using an appropriate reagent in the same manner as in steps 1-8 of Example 1.

[0524] LC / MS mass spectrometry: m / z837([M+H] + ). LC / MS retention time: 1.39 minutes (Analysis conditions: SMD-TFA05-2). 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)

[0525] [ka]

[0526] (Step 79-1) 5-Bromo-1-[(1S,2S)-1-cyano-2-(phenylmethoxymethyl)cyclopropyl]-N-methyl-N-phenylindole-2-carboxamide (compound 79b) Compound 79a was synthesized from compound 6c obtained in step 6-1 and (4R)-4-(phenylmethoxymethyl)-1,3,2-dioxathiolane 2,2-dioxide (compound 79a) using appropriate reagents in the same manner as in step 1-6 of Example 1.

[0527] 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) using an appropriate reagent in the same manner as in step 8-1 of Example 8.

[0528] 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) Compound 79c obtained in step 79-2 was synthesized using appropriate reagents in the same manner as in steps 1-8 of Example 1.

[0529] 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) From compound 79d obtained in step 79-3, the compound was synthesized by the same procedure as in step 6-4 of Example 6 using appropriate reagents.

[0530] 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 using appropriate reagents in the same manner as in step 1-10 of Example 1.

[0531] 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 1 M 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. 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 brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (18.5 mg, 50% yield).

[0532] LC / MS mass spectrometry: m / z839([M+H] + ). LC / MS retention time: 1.20 minutes (Analysis conditions: SMD-TFA05-1). 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)

[0533] [ka]

[0534] (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 mixture 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 give the title compound 80c (9.5 g, 58% yield) as a yellow oil.

[0535] 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) To a solution of compound 80c (10 g, 51.0 mmol) obtained in step 80-1 and sodium triacetoxyborohydride (43.3 g, 204 mmol) in dichloromethane (200 mL), acetic acid (3 mL) was added and stirred at room temperature for 16 hours. Water and acetic acid were added to the reaction mixture to adjust the pH to 5, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 1:4) to obtain title compound 80d (5.5 g, 54% yield) as a yellow oil.

[0536] LC / MS retention time: 0.83 minutes (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.

[0537] 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, followed by the slowly added dropwise solution of (6S)-4-hydroxy-2,6-dimethyl-1,2,3,6-tetrahydropyridine-5-carbonitrile in toluene. After stirring at 110° C. for 16 hours, the mixture was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure to remove the solvent, yielding a mixture (1.3 g) containing the title compound 80e as an oil.

[0538] (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) Compound 80e (1.30 g, 7.21 mmol) obtained in step 80-3 and (4-fluoro A solution of (3,5-dimethylphenyl)(chloro-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. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1:0 to 9:1) to give the title compound 80f (two steps from Step 80-3, 800 mg, 35% yield) as a yellow solid.

[0539] 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) To a solution of N,N'-carbodiimidazole (1.63 g, 10.1 mmol) in DMA (50 mL) was added 2,2-dimethoxyethane-1-amine (1.14 g, 10.8 mmol) at 0°C and stirred for 30 minutes. To the solution, potassium tert-butoxide (5.62 g, 50.1 mmol) and compound 80f (2.64 g, 8.34 mmol) obtained in step 80-4 were added sequentially. After stirring at room temperature for 6 hours, water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound 80g (2.80 g, 75% yield) as a brown oil.

[0540] 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) Compound 80g (2.50 g, 5.59 mmol) obtained in step 80-5 and 4-methyl A solution of benzenesulfonic acid (1.06 g, 6.16 mmol) in DMF (30 mL) was heated to 80 °C and stirred for 2 hours. After cooling to room temperature, water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to afford a diastereomeric mixture (480 mg) containing the title compound (Compound 80h) as a white solid.

[0541] 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).

[0542] 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.

[0543] LC / MS mass spectrometry: m / z384([M+H] + ). LC / MS retention time: 2.15 minutes (Analysis conditions: SMD-FA1060-1). 1H-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).

[0544] The fact that compound 80h is a 6R isomer was confirmed by 2D-NOESY, which showed that the configuration was cis. Entity B SFC retention time: 5.60 minutes.

[0545] LC / MS mass spectrometry: m / z384([M+H] + ). LC / MS retention time: 2.16 minutes (Analysis conditions: SMD-FA1060-1). 1 H-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).

[0546] (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) To a solution of compound 80h (100 mg, 0.261 mmol) obtained in step 80-6 in ethanol (1.0 mL), 5 M aqueous sodium hydroxide solution (0.261 mL) was added and stirred at 80° C. for 10 hours. After cooling to room temperature and stirring for 60 hours, saturated aqueous ammonium chloride solution was added and extracted with ethyl acetate to synthesize the title compound 80i (79%, 73 mg) as a white solid. .

[0547] 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 To a suspension of 1-methylindazole (compound 1q, 10.7 mg, 0.051 mmol), (1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine (6.00 mg, 0.042 mmol), and potassium carbonate (17.5 mg, 0.127 mmol) in N-methylpiperazine (0.188 mL), copper(I) iodide (4.02 mg, 0.021 mmol) was added at room temperature, and the mixture was stirred at 130 °C under a nitrogen atmosphere for 90 min. The reaction mixture was purified by reverse-phase silica gel chromatography (acetonitrile / water, 0.1% formic acid) and concentrated under reduced pressure. The residue was added saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to give title compound 80j (17.4 mg, 85% yield).

[0548] 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. Saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. After concentration, the resulting residue was purified by normal phase column chromatography (ethyl acetate / hexane) to give 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 solution of compound 80k (147 mg, 0.228 mmol) obtained in step 80-9 in dichloromethane (2.3 mL), magnesium bromide diethyl ether complex (295 mg, 1.14 mmol) was added and stirred at 0°C for 6.5 hours. After warming to room temperature and stirring for 30 minutes, saturated aqueous ammonium chloride was added, extracted with ethyl acetate, and concentrated. The residue was diluted with DMSO and water and purified by reverse-phase chromatography (acetonitrile / water, 0.1% formic acid) to give title compound 80l (60 mg, 51% yield).

[0549] 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 give the crude product of title compound 80m, which was used directly in the next step.

[0550] (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), and 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. The mixture was stirred at room temperature for 22 hours, and then methanol and formic acid were added. The mixture was concentrated, and the residue was diluted with DMSO and water. The residue was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound 80n (32 mg, 91% yield).

[0551] 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) To a solution of compound 80n (32 mg, 0.033 mmol) obtained in step 80-12 in THF (0.326 mL), acetic acid (0.0019 mL, 0.033 mmol) and a 1 M tetrabutylammonium fluoride THF solution (0.065 mL, 0.065 mmol) were added and the mixture was stirred at 80 °C for 66 h. Acetic acid (0.0019 mL, 0.033 mmol) and a 1 M tetrabutylammonium fluoride THF solution (0.065 mL, 0.065 mmol) were added and the mixture was stirred for 23.5 h. A 1 M tetrabutylammonium fluoride THF solution (0.065 mL, 0.065 mmol) was then added and stirred for 7 h. Formic acid was then added. The mixture was concentrated, diluted with DMSO and water, and purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound 80 (18 mg, 65% yield).

[0552] LC / MS mass spectrometry: m / z851([M+H] + ). LC / MS retention time: 1.42 minutes (Analysis conditions: SMD-TFA05-1). Furthermore, in the same manner as in Examples 1 to 80, Example Compounds 101 to 159 shown in Table 2-7 below were obtained.

[0553] [Table 2-30]

[0554] [Table 2-31]

[0555] [Table 2-32]

[0556] [Table 2-33]

[0557] Table 2-34

[0558] Table 2-35

[0559] Table 2-36

[0560] Table 2-37

[0561] Table 2-38

[0562] Table 2-39

[0563] Table 2-40

[0564] Table 2-41

[0565] Table 2-42

[0566] Table 2-43

[0567] [Table 2-44]

[0568] [Table 2-45]

[0569] [Table 2-46]

[0570] [Table 2-47]

[0571] [Table 2-48]

[0572] Example 160: Preparation of monosodium salt hydrate crystals of Compound 1 Obtained in Example 1 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 Acetonitrile (3.02 mL) was added to (Compound 1, 1005.5 mg) and dissolved at room temperature. 5 M aqueous sodium hydroxide solution (0.495 mL) and seed crystals of the sodium salt hydrate of Compound 1 were added to this solution and stirred at room temperature for 2 hours. tert-Butyl methyl ether (3.02 mL) was then added and stirred at room temperature for 1 hour. tert-Butyl methyl ether (9.05 mL) was then added and stirred at room temperature for 2 hours to obtain powdery crystals of the sodium salt hydrate of the title compound (1007.0 mg) (Sample 160a). The seed crystals were obtained by the following method.

[0573] DMSO (0.244 mL) and 2 M aqueous sodium hydroxide solution (0.032 mL) were added to compound 1 (26.9 mg). This solution (0.030 mL) was freeze-dried at -20 °C for 2 days. Acetonitrile (0.015 mL) was added to the resulting 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 powdered crystals of the sodium salt hydrate of compound 1 (Sample 160b).

[0574] 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 for 5 minutes at 70 ° C. After stirring this suspension at 50 ° C. for 1 hour, crystals of Example compound 66 (381.1 mg) were obtained as powder crystals by stirring at room temperature for 17 hours (Sample 161a). The seed crystals were obtained by the following method.

[0575] 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 at room temperature for 22 hours to obtain crystals of Example compound 66 (24.2 mg) as powdery crystals (Sample 161b).

[0576] 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 2 M aqueous sodium hydroxide solution (0.75 mL), and dissolved at room temperature. To this solution, 1.26 M calcium acetate aqueous solution (0.68 mL), seed crystals of calcium salt hydrate of Example Compound 67, and water (0.68 mL) were added and stirred at room temperature for 3 hours. Further water (1.2 mL) was added and stirred at room temperature for 1 hour, followed by addition of water (2.3 mL) and stirring at room temperature for 1 hour to obtain calcium salt hydrate crystals of Example Compound 67 (973.0 mg) as powder crystals (Sample 162a). The seed crystals were obtained by the following method.

[0577] 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 lyophilized at -20°C for 2 days. A water-acetonitrile mixture (3:1, 0.015 mL) was added to the lyophilized product, and the mixture was shaken and stirred at room temperature for 7 days to obtain calcium salt hydrate crystals of Example compound 67 as powdery crystals (Sample 162b).

[0578] <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.

[0579] 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° 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 using the following measurement methods. The results are shown in Figures 7 and 8. Sample 160a was dehydrated by around 110°C and did not show a clear melting point. Sample 162a was dehydrated by around 240°C and did not show a clear melting point.

[0580] Measuring equipment: EXSTAR TG / DTA6200R (Seiko Instruments (current company) Name: Hitachi High-Tech Science Measurement range: 30 to 350°C Heating rate: 10°C / min Atmosphere: Nitrogen Example 165 Karl Fischer moisture content measurement The water 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.

[0581] From the results of Examples 164 and 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.

[0582] <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.

[0583] (cell culture) Human GLP1R stably expressing cell line (hGLP1R-HEK293) was used for the experiments. 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.

[0584] (cAMP assay) 2.0 × 10 hGLP1R-HEK293 cells per well 4 The cells were seeded in a 96-well plate at 1000 x g for 1 hour 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-methacrylate copolymer). The cells were then replaced with medium B (DMEM, 20 mM HEPES, 0.05% ethanol) and incubated at 37°C for 30 minutes. %BSA, 0.5mM 3-isobutyl-1-methylxanthine) The mixture was then incubated at 37°C for 30 minutes. Lysis buffer (Applied Bioscience) was added, and the mixture was incubated for 30 minutes at 37° C. The cAMP concentration was quantified using a cAMP HiRange kit (Cisbio Bioassays).

[0585] (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 set as 100%. A dose-response curve for each compound was created using four-parameter logistic regression analysis according to the method of (8). The 50% effective concentration (EC 50 The results are shown in Table 3.

[0586] [Table 3]

[0587] <Test Example 2>: Insulin secretion promoting effect and blood glucose lowering effect Male cynomolgus monkeys were anesthetized and administered a solution of Example Compound 67 (solvent: PEG400 (10 vol%): propylene glycol (10 vol%): 100 mM Glycine-NaO H buffer, pH 9.0 (80 vol%)) was continuously administered intravenously for 40 minutes, maintaining steady-state plasma drug concentrations of 0.94, 1.6, or 4.8 nmol / L. A control drug, exenatide solution (solvent: Tween 0.05% / PBS(-)), was administered in the same manner, maintaining steady-state plasma drug concentrations of 9.2 or 23.9 pmol / L. The vehicle group received the solvent for Example Compound 67 solution. Next, a 50% glucose solution was administered intravenously at a glucose concentration of 0.5 g / kg. Blood samples were collected at 5- or 10-minute intervals, and plasma insulin and glucose concentrations were measured. The area under the curve was calculated from the time course of each parameter after drug administration, and the insulin secretagogue effect and blood glucose lowering effect were evaluated.

[0588] 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 following continuous intravenous administration.

[0589] The exenatide 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 (50-350 pg / mL) (Pharmaceutical 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 demonstrated that Example Compound 67 exhibits insulin secretion-promoting and blood glucose-lowering effects equivalent to those of exenatide at plasma concentrations of 1.6 nmol / L or higher.

[0590] <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 starting from 3 hours after administration on each day was examined. In addition, the control drug exenatide was subcutaneously administered for 5 consecutive days, and the effect on food intake for 90 minutes starting from 30 minutes after administration was examined. The solvent group contained the solvent for oral administration of Example Compound 67 (DMSO (10 vol%): Cremophor Both EL (10 vol%): PEG400 (15 vol%): 100 mM Glycine-NaOH buffer pH 10 (65 vol%), 1 mL / kg and exenatide subcutaneous administration vehicle (0.05 w / v% Tween / PBS(-), 0.1 mL / kg) were administered. In addition, subcutaneous administration vehicle was additionally administered to the Example Compound 67 administration group (administration drug concentration, 0.05 or 0.1 mg / mL), and oral administration vehicle was additionally administered to the exenatide administration group (administration drug concentration, 3 or 6 μg / mL).

[0591] Example compound 67 dose-dependently suppressed food intake (Fig. 11A). The degree of suppression was almost equivalent to that of the control drug, exenatide (Fig. 11B). The plasma drug concentrations (mean ± standard error) immediately after measuring food intake in each group were 8.0 ± 1.0 nM (0.05 mg / kg group) and 16.3 ± 2.3 nM (0.1 mg / kg group) in the Example compound 67 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. μg / kg group).

[0592] <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 (AUC 0-24h ) are shown in Table 4.

[0593] After oral administration, plasma drug concentrations were C at 2 hours after administration for all doses. max After reaching 1.35 mg / kg, plasma drug 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) It was shown that this substance was absorbed and eliminated from the gastrointestinal tract in a dose-dependent manner.

[0594] [Table 4]

Claims

1. Formula (I): 【Chemistry 1】 wherein X is —N═ or —CR ａ =; R ａ represents 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, wherein C ６－１０ The aryl and 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 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, wherein 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 alkyl may be substituted with one or more halogen atoms), C １－６ Alkoxy, and —NR Ｑａ R Ｑｂ and optionally substituted with 1 to 3 substituents independently selected from two C １－６ Alkyl groups taken together with the carbon atoms 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 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 The alkyl group may be a halogen atom or a 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, where R ７ and R ８ Together they form C ３－１５ The cycloalkane ring is a ring having 1 to 3 C １－６ may be substituted with alkyl, where C １－６ Alkyl is a halogen atom, hydroxy, -NR ７ａ R ７ｂ , C １－６ and optionally substituted with one or more substituents independently selected from 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 are each independently a hydrogen atom, C １－６ Alkyl (where C １－６ The alkyl group may be a halogen atom or a C １－６ alkoxy), and (C １－６ alkyl)carbonyl, R ９ｅ is a hydrogen atom or C optionally substituted with one or more halogen atoms. １－６ represents alkyl, and R ９ｆ is a hydrogen atom or C １－６ represents alkyl, and 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, and R ９ｉ is C １－６ represents alkyl; Z １ are represented by formulas (IIIa), (IIIb), (IIIc), (IIId), and (IIIe): 【Transformation 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, n5 and n6 independently represent an integer of 0 to 10 (* represents a bonding site to the pyrazolopyridine skeleton, ** represents a bonding site to the Z ２ and (representing the binding site for each); 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 included 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, 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 are each independently 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, 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, hydroxy, -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- 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; 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 the 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 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, wherein 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 pharmaceutical composition comprising a compound represented by the formula (I):

2. Q １ is phenyl or pyridyl, wherein phenyl and pyridyl are １－６ 10. The pharmaceutical composition of claim 1, substituted with 1 to 4 substituents independently selected from alkyl.

3. R ７ and R ８ are both hydrogen atoms; R ７ and R ８ Both are C １－６ Is alkyl; R ７ is a hydrogen atom and R ８ is 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 R ７ and R ８ Together they form C ３－８ The cycloalkane ring has 1 to 2 C １－６ may be substituted with alkyl, where C １－６ Alkyl is hydroxy, C １－６ The pharmaceutical composition according to claim 1 or 2, which is optionally substituted with one or more substituents independently selected from alkoxy and 3- to 12-membered heterocyclyl.

4. Z ２ But C １－６ Alkyl, C ３－１５ cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１０ aryl, and 5- to 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, and 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, wherein 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 alkoxy optionally substituted with one or more hydroxy; g) 3- to 12-membered heterocyclyl; wherein the 3- to 12-membered heterocyclyl is selected from the group consisting of 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 and optionally substituted with one or more substituents independently selected from ｚｋ１ and R ｚｌ１ are independently a hydrogen atom and C １－６ selected from alkyl, The pharmaceutical composition according to any one of claims 1 to 3, optionally substituted with 1 to 4 substituents independently selected from:

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein Y is -C(=O)-.

6. R １ The pharmaceutical composition according to any one of claims 1 to 5, wherein is a hydrogen atom.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein n1 and n2 are both 0.

8. R ９ is represented by formula (IIb): 【Chemistry 4】 is a group represented by R ９ｂ is a hydrogen atom, C １－６ Alkyl (where C １－６ The alkyl group may be a halogen atom or a C １－６ alkoxy), and (C １－６ The pharmaceutical composition according to any one of claims 1 to 7, wherein the aryl group is selected from the group consisting of alkyl)carbonyl.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein X is -N=, -CH=, or -CF=.

10. Z １ is of formula (IIIa): 【Transformation 5】 The pharmaceutical composition according to any one of claims 1 to 9, wherein * represents a bonding site to the pyrazolopyridine skeleton, ** represents Z ２ and the binding sites for α, β, and β, respectively).

11. The pharmaceutical composition according to any one of claims 1 to 10, comprising 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, or a salt thereof.

12. The pharmaceutical composition according to any one of claims 1 to 11, comprising the compound represented by formula (I) or a salt thereof as a hydrate.

13. The pharmaceutical composition according to any one of claims 1 to 12, for use in 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, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, Parkinson's disease, or dementia.

14. 14. A pharmaceutical composition according to claim 13 for use in the prevention or treatment of non-insulin dependent diabetes mellitus (type 2 diabetes) or obesity.

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