JP7461104B2 - Pharmaceutical composition containing pyrazolopyridine derivative having GLP-1 receptor agonist activity - Google Patents

Description

The present invention relates to a pharmaceutical composition containing, as an active ingredient, a compound or a salt thereof, or a solvate thereof, which acts as a GLP-1 receptor agonist similar to GLP-1. The present invention also relates to a method for preventing or treating non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity using the pharmaceutical composition.

Glucagon-like peptide-1 (GLP-1) is an incretin secreted from L-cells in the small intestine when nutrients pass through the digestive tract. It is known to have a variety of actions, such as promoting glucose-dependent insulin secretion, suppressing glucagon secretion, delaying gastric emptying, and suppressing food intake, via the GLP-1 receptor. GLP-1 analogues have already been put to practical use as diabetes treatment drugs, and are considered to be one of the most effective diabetes treatment drugs due to their strong HbA1c-lowering and weight-lowering effects. However, all of these require invasive subcutaneous administration. Therefore, there is a demand for the development of GLP-1 receptor agonists that can be administered non-invasively. For example, the absorption enhancer sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC) has been developed, which is a novel GLP-1 receptor agonist that can be administered non-invasively.
Attempts have been made to improve the bioavailability of a GLP-1 analog, Semaglutide, when orally administered using the compound (Patent Document 1), and to create a small molecule GLP-1 receptor agonist (Patent Documents 2 and 3). However, there is a demand for further improvements in pharmaceutical properties, including activity, metabolic stability, and bioavailability.

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

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

International Publication No. 2012/080471 WO 2009/111700 International Publication No. 2010/114824 International Publication No. 2016/038045

The problem to be solved by the present invention is to provide a compound or compound that has the same action as a GLP-1 peptide as a GLP-1 receptor agonist, can be administered noninvasively, and has improved activity, metabolic stability, and bioavailability. The object of the present invention is to provide a pharmaceutical composition containing a salt thereof or a solvate thereof, and a method for preventing or treating non-insulin dependent diabetes (type 2 diabetes) or obesity using the pharmaceutical composition. It is to provide.

The present inventors conducted extensive research to solve such problems, and found that a compound represented by formula (I) in which an indole ring and a pyrazolopyridine skeleton are bonded via a substituent has been found to be GLP-1 It was discovered that it has a similar effect as a GLP-1 peptide as a receptor agonist, leading to the completion of the present invention.

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

[wherein X represents -N= or -CR ^a =; R ^a is selected from a hydrogen atom, a halogen atom, and a C _1-6 alkyl;
Y is selected from -C(=O)-, -CHR-, and -S(=O) ₂ -; R represents a hydrogen atom or C _1-6 alkyl;
Q ¹ represents C _6-10 aryl or 5-10 membered heteroaryl, where C _6-10 aryl and 5-10 membered heteroaryl represent a halogen atom, C _1-6 alkyl (herein, C _1-6 alkyl may be optionally substituted with one or more halogen atoms) and 1 to 5 substituents independently selected from C _1-6 alkoxy;
Q ² represents a 3- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl, where the 3- to 12-membered heterocyclyl and the 5- to 10-membered heteroaryl represent a halogen atom, C _1-6 alkyl (herein C _1-6 alkyl optionally substituted with one or more halogen atoms), C _1-6 alkoxy, and -NR ^Qa R ^Qb substituted with 1 to 3 substituents independently selected from R ^Qa and R ^Qb _{are independently} is selected from a hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl)carbonyl;
R ¹ , R ² , and R ³ are each independently selected from a hydrogen atom and C _1-6 alkyl (where C _1-6 alkyl is independently selected from a halogen atom, C _1-6 alkoxy, and hydroxy); optionally substituted with one or more substituents);
R ⁴ , R ⁵ , and R ⁶ are each independently selected from a hydrogen atom, a halogen atom, and a C _1-6 alkyl;
R ⁷ and R ⁸ independently represent a hydrogen atom or C _1-6 alkyl, where C _1-6 alkyl is one or more atoms independently selected from a halogen atom and C _3-15 cycloalkyl. may be substituted with substituents or R ⁷ and R ⁸ may be taken together with the carbon atom to which they are attached to form a C _3-15 cycloalkane ring, where R ⁷ and The C _3-15 cycloalkane ring formed by R ⁸ together may be substituted with 1 to 3 C _1-6 alkyl, where C _1-6 alkyl is a halogen atom, hydroxy, -NR ^7a Optionally substituted with one or more substituents independently selected from R ^7b , C _1-6 alkoxy, and 3- to 12-membered heterocyclyl, and R ^7a and R ^7b are independently 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 represents formula (IIa), (IIb), (IIc), (IId):

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 optionally substituted with one or more substituents independently selected from halogen atoms and C _1-6 alkoxy), and (C _1-6 alkyl); ₆ alkyl) carbonyl, R ^9e represents a hydrogen atom or C _1-6 alkyl optionally substituted with one or more halogen atoms, and R ^9f represents a hydrogen atom or C _1-6 alkyl , R ^9h represents a hydrogen atom, C _1-6 alkyl, (C _1-6 alkyl) carbonyl, cyano, or -S(=O) _n3 -R ⁹ⁱ ; n3 represents an integer from 0 to 2; R ⁹ⁱ represents C _1-6 alkyl;
Z ¹ has formulas (IIIa), (IIIb), (IIIc), (IIId), and (IIIe):

R ^za is selected from a hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl)carbonyl, and R ^zb and R ^zc are independently selected from a hydrogen atom or a C _1-6 alkyl carbonyl; _-6 alkyl, n4 represents an integer of 1 to 3, n5 and n6 independently represent an integer of 0 to 10 (* represents the bonding site with the pyrazolopyridine skeleton, ** represents the each represents the binding site with ^Z2 );
Z ² is selected from C _1-6 alkyl, C _3-15 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl, where C _3-15 cyclo alkyl, 3- to 12-membered heterocyclyl, C _6-10 aryl, and 5- to
The 10-membered heteroaryl is group A:
Group A: a) oxo,
b) halogen atom,
c) cyano,
d) -NR ^zd R ^ze ; where R ^zd and R ^ze are each independently selected from a hydrogen atom, C _1-6 alkyl and (C _1-6 alkyl)carbonyl, where C _1-6 alkyl may be substituted with one or more substituents independently selected from hydroxy, halogen atoms, and C _1-6 alkoxy,
e) -C(=O)-NR ^zf R ^zg ; where R ^zf and R ^zg are each independently selected from a hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl)carbonyl; , C _1-6 alkyl may be substituted with one or more substituents independently selected from hydroxy, halogen atom, and C _1-6 alkoxy,
f) -S(=O) _n7 -R ^zh ; where n7 represents an integer of 0 to 2, and R ^zh represents a hydrogen atom or C _1-6 alkyl;
g) C _1-6 alkyl; where C _1-6 alkyl is 1 independently selected from a halogen atom, hydroxy, -NR ^zi R ^zz , C _1-6 alkoxy, and 3- to 12-membered heterocyclyl; It may be substituted with the above substituents, where R ^zi and R ^zz independently represent a hydrogen atom or C _1-6 alkyl, and the 3- to 12-membered heterocyclyl is hydroxy, C _1-6 optionally substituted with one or more substituents independently selected from alkyl, and 3- to 12-membered heterocyclyl,
h) C _1-6 alkoxy; where C _1-6 alkoxy is optionally substituted with one or more substituents independently selected from hydroxy, halogen atoms, and C _1-6 alkoxy;
i) 3-12 membered heterocyclyl; wherein the 3-12 membered heterocyclyl is substituted with one or more substituents independently selected from C _1-6 alkyl and (C _1-6 alkyl)carbonyl; Good,
j) C _6-10 aryl; where C _6-10 aryl is optionally substituted with one or more (C _1-6 alkyl)carbonyl; and k) 5-10 membered heteroaryl; where 5 The ~10-membered heteroaryl is substituted with one or more substituents independently selected from C _1-6 alkyl, C _1-6 alkoxy, -NR ^zk R ^zl , and 3-12 membered heterocyclyl. and where R ^zk and R ^zl are independently selected from a hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl)carbonyl, and the 3- to 12-membered heterocyclyl is C _1-6 optionally substituted with one or more substituents independently selected from alkyl and (C _1-6 alkyl)carbonyl,
may be substituted with 1 to 5 substituents independently selected from]
A pharmaceutical composition containing a compound represented by, a salt thereof, or any solvate thereof.

[2] The pharmaceutical composition according to [1], wherein ^Q1 is phenyl or pyridyl, wherein the phenyl and pyridyl are substituted with 1 to 4 substituents independently selected from halogen atoms and _C1-6 alkyl.

[3] The pharmaceutical composition according to [1] or [2], wherein R ⁷ and R ⁸ are both hydrogen atoms; R ⁷ and R ⁸ are both C _1-6 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 atom to which they are attached, form a C _3-8 cycloalkane ring, wherein the C _3-8 cycloalkane ring formed by R ⁷ and R ⁸ together is optionally substituted with 1 to 2 C _1-6 alkyl, and wherein the C _1-6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy, C _1-6 alkoxy, and 3 to 12 membered heterocyclyl.

[4] Z ² is selected from C _1-6 alkyl, C _3-15 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl, where C _{3- 15} cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl are group B:
Group B: a) oxo;
b) halogen atom,
c) -NR ^zd1 R ^ze1 ; where R ^zd1 and R ^ze1 are independently selected from a hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl)carbonyl, where C _1-6 alkyl may be substituted with one or more substituents independently selected from C _1-6 alkoxy,
d) -S(=O) _n7 -R ^zh1 ; where n7 represents an integer from 0 to 2, and R ^zh1 represents C _1-6 alkyl;
e) C _1-6 alkyl; where C _1-6 alkyl is 1 independently selected from a halogen atom, hydroxy, -NR ^zi R ^zz , C _1-6 alkoxy, and 3- to 12-membered heterocyclyl; It may be substituted with the above substituents, where R ^zi and R ^zz independently represent a hydrogen atom or C _1-6 alkyl, and the 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 may be substituted with one or more hydroxy;
g) 3-12 membered heterocyclyl; wherein the 3-12 membered heterocyclyl is optionally substituted with one or more (C _1-6 alkyl)carbonyl; and h) 5-10 membered heteroaryl; The 5-10 membered heteroaryl may be substituted with one or more substituents independently selected from C _1-6 alkyl, and -NR ^zk1 R ^zl1 , where R ^zk1 and R ^zl1 are independently selected from hydrogen atoms and C _1-6 alkyl,
The pharmaceutical composition according to any one of [1] to [3], which may be substituted with 1 to 4 substituents independently selected from.

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

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

and R ^9b is selected from a hydrogen atom, a C _1-6 alkyl (wherein the C _1-6 alkyl is optionally substituted with one or more substituents independently selected from a halogen atom and a C _1-6 alkoxy), and a (C _1-6 alkyl)carbonyl. The pharmaceutical composition according to any of [1] to [7],

[9] The pharmaceutical composition according to any one of [1] to [8], wherein X is -N=, -CH=, or -CF=.
[10] Z ¹ is the formula (IIIa):

The pharmaceutical composition according to any one of [1] to [9], wherein * represents a bonding site to the pyrazolopyridine skeleton, and ** represents a bonding site to ^Z2 .
[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.

[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. Here, examples of dementia include Alzheimer's disease.

[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 to a subject the pharmaceutical composition according to any one of [1] to [12]. Examples of dementia include Alzheimer's disease.

[16] A method for preventing or treating non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity, comprising administering to a subject the pharmaceutical composition according to any one of [1] to [12].

The compound represented by formula (I), its salt, or solvate thereof contained in the pharmaceutical composition of the present invention has an action as a GLP-1 receptor agonist similar to that of a GLP-1 peptide, and provides a non-peptide preventive or therapeutic agent for non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity that is expected to have sufficient oral bioavailability.

The results of powder X-ray diffraction measurement of the sodium salt hydrate crystals of Compound 1 (Sample 160a) obtained in Example 163 are shown. The vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2θ (°). 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 (°). 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 (°). The results of powder X-ray diffraction measurement of the crystals of Example Compound 66 (Sample 161b) obtained in Example 163 are shown. The vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2θ (°). 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 (°). 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 (°). The results of thermogravimetry and differential thermal analysis of the sodium salt hydrate crystals of Compound 1 obtained in Example 164 are shown. The horizontal axis is temperature (° C.), and the right vertical axis is the weight change (%) of the sample in thermogravimetry. The left vertical axis represents the heat flow observed in differential thermal analysis. The results of thermogravimetry and differential thermal analysis of calcium salt hydrate crystals of Example Compound 67 obtained in Example 164 are shown. The horizontal axis is temperature (°C), and the right vertical axis is the weight change (%) of the sample in the thermogravimetry. The left vertical axis represents the heat flow observed in the differential thermal analysis. Effect of Example Compound 67 and exenatide on insulin secretion after intravenous administration of glucose in male cynomolgus monkeys. Area under the insulin curve is shown as mean ± standard error (n=6). Each drug was administered in a crossover manner. * indicates P<0.025, ** indicates P<0.005, indicating significance relative to the vehicle group (Williams test). Each drug concentration represents the average value of the actually measured plasma drug concentrations. Effects of Example Compound 67 and exenatide on plasma glucose levels after intravenous administration of glucose in male cynomolgus monkeys. Area under the plasma glucose curve is shown as mean ± standard error (n=6). Each drug was administered in a crossover manner. * indicates P<0.025, ** indicates P<0.005, indicating significance relative to the vehicle group (Williams test). Each drug concentration represents the average value of the actually measured plasma drug concentrations. Effects of Example Compound 67 and exenatide on food intake of 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, ** indicates P<0.005, indicating significance relative to the vehicle group (Williams test). Changes in plasma drug concentration when this substance was orally administered to cynomolgus monkeys. For both plasma concentration and each dose, the average value of n=2 is displayed.

The present invention will now be described in further non-limiting terms.
Definition
In the present invention, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. In the present invention, when a halogen atom serves as a substituent for aryl or the like (for example, R ^a when X in formula (I) is -CR ^a =), preferred examples of the halogen atom include a fluorine atom and a chlorine atom. In the present invention, when a halogen atom serves as a substituent for alkyl or the like (for example, when a C _6-10 aryl or 5- to 10-membered heteroaryl of Q ¹ in formula (I) is further substituted with a C _1-6 alkyl, the further preferred examples of the halogen atom include a fluorine atom and a chlorine atom. Specific examples of C _1-6 alkyl having a halogen atom as a substituent include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, pentafluoroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, heptafluoropropyl, 3,3,3-trifluoropropyl, 2,3-dichloropropyl, 1-fluoro-3-bromopropyl, 4-bromobutyl, 3,3,3,4,4-pentafluorobutyl, 4
, 4-dichlorobutyl, 5-iodopentyl, 5,5-difluoropentyl, 6-chlorohexyl, 6,6,6-trifluorohexyl, and the like.

In the present invention, "C _1-6 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.

In the present invention, "C _1-6 alkoxy" means a C _1-6 alkyl-O- group, where C _1-6 alkyl is as defined above. For example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, 1-methylpropoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, 1 , 1-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy, 2-ethylbutoxy and the like.

In the present invention, "(C _1-6 alkyl)carbonyl" means a (C _1-6 alkyl)-C(O)- group, where C _1-6 alkyl is as defined above. For example, methylcarbonyl (acetyl), ethylcarbonyl (propionyl), n-propylcarbonyl, i-propylcarbonyl, n-butylcarbonyl, i-butylcarbonyl, sec-butylcarbonyl, t-butylcarbonyl, 1-methylpropylcarbonyl, Examples include n-pentylcarbonyl, isopentylcarbonyl, 2-methylbutylcarbonyl, 1,1-dimethylpropylcarbonyl, 1-ethylpropylcarbonyl, n-hexylcarbonyl, 4-methylpentylcarbonyl, 2-ethylbutylcarbonyl, and the like.

In the present invention, "C _6-10 aryl" means an aromatic carbocyclic group, which may have a non-aromatic moiety in addition to the aromatic moiety. The ring may be monocyclic or bicyclic aryl fused to a benzene ring or a monocyclic aryl ring. For example, phenyl, 1-naphthyl, 2-naphthyl, azulenyl, isochromanyl, 2,4-dihydro-1H
-isoquinolin-3-onyl, 1,3-dihydrobenzimidazol-2-onyl and the like, preferably phenyl.

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

In the present invention, "heterocyclyl" refers to a non-aromatic cyclic group containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may be fully saturated or partially unsaturated. The ring may be 3-12 membered, preferably 3-10 membered, monocyclic, or bicyclic or spirocyclic. For example, oxetanyl, azetidinyl, 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2-thia-6-azaspiro[3.3]heptyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrazolidinyl, thianyl, oxanyl, thioxanyl, indolinyl, isoindolinyl, tetrahydroindolinyl, quinuclidinyl, azepinyl, tropanyl, and the like.

In the present invention, "C _3-15 cycloalkyl" refers to a monovalent group derived by removing any one hydrogen atom from a cyclic saturated aliphatic hydrocarbon having 3 to 15 carbon atoms. Furthermore, "C _3-8 cycloalkyl" refers to a cycloalkyl having 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Furthermore, "C _3-6 cycloalkyl" refers to a cycloalkyl having 3 to 6 carbon atoms. When two groups are combined to form a C _3-15 cycloalkane ring, the group becomes a divalent group. Examples include cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, cycloheptane-1,1-diyl, and cyclooctane-1,1-diyl.

When the groups on two carbon atoms are taken together to form a C _3-8 carbocycle, the rings form a fused ring. For example, between two carbon atoms, -CH ₂ -, -CH ₂ CH 2 -, -CH _{2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - , -CH 2 CH 2} CH ₂ CH Examples include ring structures connected by ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH 2 CH ₂ CH ₂ CH ₂ -, and the like.

Further, the cyclic hydrocarbon in the cycloalkane ring, carbocycle, and cycloalkyl may be a bridged ring. Examples of the bridged ring in C _3-15 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 ]decane-2-ylidene (2-adamantylidene), pentacyclo[4.2.0.0 ^2,5 . 0 ^3,8 . 0 ^4,7 ] octane (cubane), and examples of C _3-15 cycloalkyl consisting of a bridged ring 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.

The present invention provides a pharmaceutical composition containing a compound represented by formula (I), a salt thereof, or any solvate thereof.

X represents -N= or -CR ^a =; R ^a is selected from a hydrogen atom, a halogen atom, and C _1-6 alkyl. X is preferably -N=, -CH= or -CF=, more preferably -CH=.

Y is selected from -C(=O)-, -CHR-, and -S(=O) ₂ -; R represents a hydrogen atom or C _1-6 alkyl.
Q ¹ represents C _6-10 aryl or 5-10 membered heteroaryl, where C _6-10 aryl and 5-10 membered heteroaryl represent a halogen atom, C _1-6 alkyl (herein, C _1-6 alkyl may be optionally substituted with one or more halogen atoms) and 1 to 5 substituents independently selected from C _1-6 alkoxy. Q ¹ is preferably phenyl or pyridyl, where the phenyl or pyridyl is substituted with 1 to 4 substituents independently selected from halogen atoms and C _1-6 alkyl. More preferably, Q ¹ is phenyl substituted with 2 to 3 substituents independently selected from halogen atoms and C _1-6 alkyl.

Q ² represents a 3- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl, where the 3- to 12-membered heterocyclyl and the 5- to 10-membered heteroaryl represent a halogen atom, C _1-6 alkyl (herein C _1-6 alkyl optionally substituted with one or more halogen atoms), C _1-6 alkoxy, and -NR ^Qa R ^Qb substituted with 1 to 3 substituents independently selected from R ^Qa and R ^Qb _{are independently} is selected from a hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl)carbonyl. Preferably, Q ² represents i) 6-membered heterocyclyl, where _the 6-membered heterocyclyl is optionally substituted with one or more C _1-6 alkyl and furthermore Alkyl may be taken together with the carbon atom to which they are attached to form a C _3-8 carbocycle, or ii) represent a 5-6 membered heteroaryl, where the 5-6 membered heteroaryl may be substituted with 1 to 3 substituents independently selected from halogen atoms, C _1-6 alkyl, C _1-6 alkoxy, and -NR ^Qc R ^Qd ; R ^Qc and R ^Qd are independently selected from hydrogen atoms and C _1-6 alkyl. Also preferably, Q ² represents 5-6 membered heterocyclyl or heteroaryl, where 5-6 membered heterocyclyl and 5-6 membered heteroaryl have 1-3 C _1-6 Optionally substituted with alkyl.

R ¹ , R ² , and R ³ are each independently selected from a hydrogen atom and C _1-6 alkyl (where C _1-6 alkyl is independently selected from a halogen atom, C _1-6 alkoxy, and hydroxy); (optionally substituted with one or more substituents). Preferably, the combination of R ¹ , R ² , and R ³ is all a hydrogen atom; R ¹ is a hydrogen atom, R ² is a hydrogen atom, R ³ is a C _1-6 alkyl; and R ¹ is a hydrogen atom, and R ² is selected from C _1-6 alkyl and R ³ is selected from C _1-6 alkyl.

R ⁴ , R ⁵ , and R ⁶ are each independently selected from a hydrogen atom, a halogen atom, and a C _1-6 alkyl. It is preferable that R ⁴ , R ⁵ and R ⁶ are each independently a hydrogen atom or a fluorine atom. More preferably, the combination of R ⁴ , R ⁵ , and R ⁶ is all a hydrogen atom; or R ⁴ is a hydrogen atom, R ⁵ is a hydrogen atom, and R ⁶ is a fluorine atom.

R ⁷ and R ⁸ independently represent a hydrogen atom or a C _1-6 alkyl, where the C _1-6 alkyl is optionally substituted with one or more substituents independently selected from a halogen atom and a C _3-15 cycloalkyl, and further, R ⁷ and R ⁸ together with the carbon atom to which they are attached may form a C _3-15 cycloalkane ring, where R ⁷
and R ⁸ taken together to form a C _3-15 cycloalkane ring may be substituted with 1 to 3 C _1-6 alkyl, where C _1-6 alkyl may be substituted with one or more substituents independently selected from halogen atom, hydroxy, -NR ^7a R ^7b , C _1-6 alkoxy, and 3- to 12-membered heterocyclyl, and R ^7a and R ^7b are independently selected from hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl)carbonyl. R ⁷ and R ⁸ are preferably taken together with the carbon atom to which they are attached to form a C _3-8 cycloalkane ring, where C _3-8 cycloalkyl taken together to form R ⁷ and R ⁸ may be substituted with one or more C _1-6 alkyl, where C _1-6 alkyl may be substituted with one or more hydroxy. Also, C _3-8 cycloalkyl is preferably C _3-6 cycloalkyl. Preferred C _3-6 cycloalkyl include, for example, cyclopentyl.

n1 represents an integer of 0 to 3; n2 represents an integer of 0 to 5. n1 and n2 are each preferably 0 to 2, more preferably 0 to 1, and even more preferably 0. Further, the combination of n1 and n2 is preferably 0 and 0, 0 and 1, 0 and 2, 1 and 0, 1 and 1, 2 and 0, 0 and 0, 0 and 1, 1 and 0, 2 and 0. is more preferred, and 0 and 0 are even more preferred.

R ⁹ is represented by formula (IIa), (IIb), (IIc), (IId):

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 optionally substituted with one or more substituents independently selected from halogen atoms and C _1-6 alkoxy), and (C _1-6 alkyl); ₆ alkyl) carbonyl, R ^9e represents C _1-6 alkyl optionally substituted with one or more substituents independently selected from a hydrogen atom or a halogen atom, and R ^9f is hydrogen atom or C _1-6 alkyl; R ^9h represents a hydrogen atom, C _1-6 alkyl, (C _1-6 alkyl)carbonyl, cyano, or -S(=O) _n3 -R ⁹ⁱ ; n3 is , represents an integer from 0 to 2, and R ⁹ⁱ represents C _1-6 alkyl.

Z ¹ has formulas (IIIa), (IIIb), (IIIc), (IIId), and (IIIe):

R ^za is selected from a hydrogen atom, a C _1-6 alkyl, and a (C _1-6 alkyl)carbonyl, R ^zb and R ^zc independently represent a hydrogen atom or a C _1-6 alkyl, n4 represents an integer from 1 to 3, and n5 and n6 independently represent an integer from 0 to 10.

* represents a binding site with the pyrazolopyridine skeleton, and ** represents a binding site with ^Z2 .
Z ² is selected from C _1-6 alkyl, C _3-15 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl, where C _3-15 cycloalkyl , 3- to 12-membered heterocyclyl, C _6-10 aryl, and 5- to 10-membered heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from Group A.

Group A: a) oxo,
b) a halogen atom,
c) cyano,
d) ^-NRzdRze ; wherein ^Rzd and ^{Rze are} each independently selected from a hydrogen atom, a _C1-6 alkyl, and a ( _C1-6 alkyl)carbonyl, wherein the _C1-6 alkyl is optionally substituted with one or more substituents independently selected from a hydroxyl, a halogen atom, and a _C1-6 alkoxy;
e) -C(=O) ^-NRzfRzg ; wherein ^Rzf and ^{Rzg are} each independently selected from a hydrogen atom, a _C1-6 alkyl, and a ( _C1-6 alkyl)carbonyl, wherein the _C1-6 alkyl is optionally substituted with one or more substituents independently selected from a hydroxyl, a halogen atom, and a _C1-6 alkoxy;
f) -S(=O) _n7 -R ^zh ; where n7 represents an integer of 0 to 2, and R ^zh represents a hydrogen atom or a C _1-6 alkyl;
g) C _1-6 alkyl; wherein C _1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen atoms, hydroxy, -NR ^zi R ^zj , C _1-6 alkoxy, and 3- to 12-membered heterocyclyl, wherein R ^zi and R ^zj independently represent a hydrogen atom or C _1-6 alkyl, and the 3- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from hydroxy, C _1-6 alkyl, and 3- to 12-membered heterocyclyl;
h) C _1-6 alkoxy; wherein the C _1-6 alkoxy is optionally substituted with one or more substituents independently selected from hydroxy, halogen atoms, and C _1-6 alkoxy;
i) 3- to 12-membered heterocyclyl; wherein the 3- to 12-membered heterocyclyl is optionally substituted by one or more substituents independently selected from C _1-6 alkyl and (C _1-6 alkyl)carbonyl;
j) C _6-10 aryl; wherein the C _6-10 aryl is optionally substituted by one or more (C _1-6 alkyl)carbonyl; and k) 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl is optionally substituted by one or more substituents independently selected from C _1-6 alkyl, C _1-6 alkoxy, -NR ^zk R ^zl , and 3-12 membered heterocyclyl, wherein R ^zk and R ^zl are independently selected from a hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl)carbonyl, and the 3-12 membered heterocyclyl is optionally substituted by one or more substituents independently selected from C _1-6 alkyl and (C _1-6 alkyl)carbonyl.

When C _1-6 alkyl in R ^zd , R ^ze , R ^zf and R ^zg is substituted with hydroxy, C _1-6 alkyl is preferably C _2-6 alkyl, more preferably C _{2-6 alkyl. 4} alkyl.

Also when C _1-6 alkoxy is substituted with one or more hydroxy, C _1-6 alkyl is preferably C _2-6 alkyl, more preferably C _2-4 alkyl.
Preferably, Z ² is i) C _3-15 cycloalkyl optionally substituted with one or more -NR ^zd R ^ze , ii) with 1 to 3 substituents independently selected from group C selected from optionally substituted C _6-10 aryl, and iii) 5-10 membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from group D.

More preferably, ^Z2 is selected from i) a C _6-10 aryl optionally substituted with 1 to 3 substituents independently selected from the C group, and ii) a 5 to 10 membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the D group.

Group C: a) a halogen atom,
b) ^-NRzd2Rze2 ; wherein ^Rzd2 and ^{Rze2 are} independently selected from a hydrogen atom, _C1-6 alkyl, and ( _C1-6 alkyl)carbonyl, wherein the _C1-6 alkyl is optionally substituted with one or more _C1-6 alkoxy;
c) -S(=O) _n7 -R ^zh1 ; where n7 represents an integer from 0 to 2 and R ^zh1 represents a C _1-6 alkyl;
d) C _1-6 alkyl,
e) C _1-6 alkoxy; wherein C _1-6 alkoxy is optionally substituted with one or more hydroxy;
f) 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl is optionally substituted ^with one or more substituents independently selected from -NRzk1Rzl1, where ^Rzk1 and ^{Rzl1 are} independently selected from a hydrogen atom and a _C1-6 alkyl.

Group D: a) oxo,
b) a halogen atom,
c) C _1-6 alkyl; wherein the C _1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen atoms, hydroxy, C _1-6 alkoxy, and 3- to 12-membered heterocyclyl, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more C _1-6 alkyl; and d) 3- to 12-membered heterocyclyl.

In the present invention, in the compound represented by formula (I), Z ¹ is a group represented by formula (IIIa), Y is -C(=O)-, and R ⁹ is a group represented by formula (IIb ), R ^9b is a hydrogen atom, and R ⁷ and R ⁸ together with the carbon atoms to which they are bonded are substituted with 1 to 3 C _1-6 alkyl It is preferable that a C _3-15 cycloalkane ring is formed, and the 1 to 3 C _1-6 alkyls are unsubstituted, and 3-[(1S,2S)-1-[5-[(4S)- 2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole- 5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2- More preferred is methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (Example Compound 67).

Next, examples of methods for producing the compound represented by formula (I), a salt thereof, or a solvate thereof will be explained using the following scheme group.
The compound represented by formula (I), a salt thereof, or a solvate thereof is manufactured by i) general manufacturing method A1 or general manufacturing method A2, ii) general manufacturing method B, and iii) general manufacturing method C. In this production method, in the compound represented by formula (I), Z ¹ is a group represented by formula (IIIa), Y is -C(=O)-, and R ⁹ is a group represented by formula (IIb ), and when R ^9b is a hydrogen atom, this is an example of a preferred method for producing the compound represented by formula (Ia).

Furthermore, when R ⁷ and R ⁸ together with the carbon atoms to which they are bonded form a C _3-15 cycloalkane ring substituted with 1 to 3 C _1-6 alkyl, the 1 to An example of a preferred production method is when three C _1-6 alkyls are unsubstituted.

If 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 the step can be obtained by, for example, protecting and deprotecting the functional group. I can do it. Regarding the selection of protecting groups and the selection of protection and deprotection methods, see, for example, T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons, Inc. , New York (2007). Some protection and deprotection of functional groups are also described in the schemes below.

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

During the ceremony,
P ² represents a hydrogen atom or C _1-6 alkyl, P ^1a represents an amino protecting group, P ^3a and P ^3b independently represent C _1-6 alkyl, or P ^3a and P ^3b may be taken 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 is represented, Y ² represents =O or =NH, and X ¹ represents a leaving group.

Examples of amino-protecting groups include formyl, (C _1-6 alkyl)carbonyl (acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.), carbamoyl, C _1-6 alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, etc.), substituted silyl (trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, etc.), aralkyloxycarbonyl (benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, etc.), allyl, and aralkyl.

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

Examples of bases include metal hydrides such as sodium hydride, potassium hydride, and lithium hydride; metal alkoxides such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-pentoxide; and preferably metal alkoxides such as potassium t-butoxide.

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

The reaction time is usually 15 minutes to 5 hours, preferably 30 minutes to 3 hours.
Compound a1 may be isolated or may be subjected to step A1-1b without being isolated.
Compound a can be purchased commercially from Aldlab Chemicals, LLC, Tokyo Kasei Kogyo, or the like. It can also be synthesized with reference to Bioorganic Medicinal Chemistry, 1999, 7, 795-809, CN 103086955.

Compound a1 may be obtained as an alkali metal salt such as a potassium salt upon contact with the base used in the reaction, and such salts can also be subjected to the next step.
Step A1-1b :
Compound a1 can be reacted with compound a2 to obtain compound b. This reaction is preferably carried out in the presence of an acid.

Examples of the acid include hydrochloric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like, and salts of strong acids and weak bases such as pyridine hydrochloride.
Examples of the solvent include hydrocarbon solvents (hexane, heptane, benzene, toluene, xylene, etc.) and alcohol solvents (methanol, ethanol, etc.). Water may be present in the system.

The reaction temperature is usually from 40°C to 200°C, preferably from 60°C to 150°C.
The reaction time is usually 6 minutes to 30 hours, preferably 30 minutes to 3 hours.
Compound a2 can be purchased commercially as a salt with hydrogen chloride or the like from Alfa Aesar or the like. Compound a2, in which the hydrazine moiety is protected with t-butoxycarbonyl, can be deprotected with an acid such as methanesulfonic acid before use, with reference to Journal of
It can also be synthesized using the compound Q ¹ -NH ₂ as a starting material, with reference to Medicinal Chemistry 2003, 46, 1546-1553.

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

Examples of bases include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.), nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine, pyrazine, pyridazine, etc.) ), metal hydrides such as sodium hydride, potassium hydride, lithium hydride; potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, etc. Examples include metal alkoxides. When compound b2 is used, it is preferably a metal alkoxide such as potassium t-butoxide.

Examples of solvents include alcohol solvents such as methanol and ethanol; ether solvents such as THF and diethyl ether; ester solvents such as ethyl acetate and methyl acetate; nitrile solvents such as acetonitrile, benzonitrile, and benzyl cyanide; Amide solvents such as N-dimethylacetamide (DMA), N,N-dimethylimidazolidinone (DMI), and DMF can be used, but amide solvents such as DMA are preferred.

The reaction temperature is usually -50°C to 70°C, preferably -30°C to 50°C.
The reaction time is usually 15 minutes to 72 hours, preferably 1 hour to 30 hours.
Compound b1 was obtained from Enamine LTD. Commercially available products can be purchased from. It can also be synthesized by reacting the compound: H ₂ NCH ₂ CH (OP ^3a ) (OP ^3b ) with phosgene or triphosgene, with reference to WO2006/048727. Compound b2 was obtained from UkrOrgSyntez Ltd. You can also purchase commercially available products. It can also be synthesized by reacting the compound: H ₂ NCH ₂ CH (OP ^3a ) (OP ^3b ) with a diisocyanate such as CDI, with reference to WO99/50262.

Process A1-3 :
Compound d can be obtained by reacting compound c with an acid.
Examples of acids include inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acids (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.), 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 acids, glutaric acid, etc.).

Examples of solvents include ether solvents (ether, tetrahydrofuran, dioxane, dimethoxyethane, cyclopentyl methyl ether, etc.), aromatic hydrocarbon solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), and aliphatic hydrocarbon solvents (pentane, etc.). , 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. Preferably, ether solvents such as tetrahydrofuran are used. be.

The reaction temperature is usually 0°C to 100°C, preferably 10°C to 80°C.
The reaction time is usually 10 minutes to 20 hours, preferably 30 minutes to 5 hours.
Step A1-4 :
a) When Z ² is C _1-6 alkyl, C _3-15 cycloalkyl, and 3-12 membered heterocyclyl, compound d can be reacted with compound d1 in the presence of a base to give compound e.

Examples of bases include metal hydrides such as sodium hydride, potassium hydride, and lithium hydride; metal alkoxides such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-pentoxide; and alkyl metals such as butyllithium and ethyllithium.

Examples of solvents include ether 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.), with N,N-dimethylacetamide and other amide solvents being preferred.

The reaction temperature is usually from 0°C to 150°C, preferably from 20°C to 120°C.
The reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 5 hours.
b) When Z ² is C _6-10 aryl and 5-10 membered heteroaryl, compound d can be reacted with compound d1 in the presence of a base, a copper catalyst and a ligand to give compound e.

Examples of bases include weakly basic inorganic salts (sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate, etc.) and organic bases (triethylamine, pyridine, tetrabutylammonium fluoride, etc.), with a weakly basic inorganic salt such as potassium carbonate being preferred.

Examples of copper catalysts include copper (I) iodide, copper (I) bromide, copper (I) chloride, copper (II) acetate, copper (II) oxide, copper (I) trifluoromethanesulfonate, etc.). , preferably copper(I) iodide.

Examples of the ligand include diamines such as phenanthroline, quinolin-8-ol, 2,2,6,6-tetramethylheptane-3,5-dione, N,N'-dimethylethane-1,2-diamine, trans-cyclohexane-1,2-diamine, and trans-N,N'-dimethylcyclohexane-1,2-diamine, with trans-N,N'-dimethylcyclohexane-1,2-diamine being preferred.

Examples of solvents include ether solvents (ether, tetrahydrofuran, dioxane, dimethoxyethane, cyclopentyl methyl ether, etc.), aromatic hydrocarbon solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), and aliphatic hydrocarbon solvents (pentane, etc.). , 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-based solvents (methyl acetate, ethyl acetate, isopropyl acetate, etc.), acetonitrile, and preferably amide-based solvents such as N-methylpyrrolidone.

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

When the protecting group P ^1a is a C _1-6 alkoxycarbonyl such as t-butoxycarbonyl, it is preferably deprotected using an acid.
Examples of acids include inorganic acids (hydrogen chloride, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acids (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.), carboxylic acids (formic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid, fluoroacetic acid, trifluoroacetic acid, tartaric acid, propionic acid, glutaric acid, etc.).

Examples of solvents 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.). etc.) amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.), and halogen solvents (dichloromethane, chloroform, carbon tetrachloride, etc.), preferably N-methyl An amide solvent such as pyrrolidone.

The reaction temperature is usually from 0°C to 200°C, preferably from 10°C to 120°C.
The reaction time is usually 30 minutes to 10 hours, preferably 1 hour to 6 hours.
Compound f may be obtained as a salt with the acid used in the reaction, and such a salt may also be subjected to the next step.

<General manufacturing method A2>
When Z ² is a bulky group such as a C _3-15 cycloalkyl substituted with —NR ^zd R ^ze , compound p corresponding to compound f can also be synthesized by General Process A2 shown in the following scheme.

In the formula, Z ^2a represents unsubstituted C _3-15 cycloalkyl or 3- to 12-membered heterocyclyl.
P ^1a and P ^2a represent amino protecting groups,
X ² , X ³ , X ⁴ and X ⁵ each independently represent a leaving group,
R ^10a and R ^10b independently represent C _1-6 alkyl, or R ^10a and R ^10b together with the oxygen atom to which they are bonded and the carbon atom to which the oxygen atom is bonded represent 5 to 7 A membered 1,3-dioxacycloalkane ring may be formed.

Examples of amino protecting groups include formyl, (C _1-6 alkyl) carbonyl (acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.), carbamoyl, C _1-6 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, aralkyl, etc.

Examples of the leaving group include a halogen atom, acetyloxy, trifluoroacetyloxy, methanesulfonyloxy, paratoluenesulfonyloxy, and the like.
Process A2-1 :
Compound h can be obtained by reacting compound g with azide in the presence of a base.

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, with diphenylphosphoryl azide being preferred.

Examples of solvents 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.), preferably hydrocarbon solvents such as toluene.

The reaction temperature is usually 0°C to 150°C, preferably 10°C to 100°C.
The reaction time is usually 1 hour to 10 hours, preferably 2 hours to 6 hours.
Compound g is described, for example, in Journal of the American Chemical Society, 2016, 138, 1698-1708, WO2009/152133, and the like. In addition, Enamine Ltd. You can also purchase commercially available products.

Step A2-2 :
Compound i can be obtained by reacting compound b obtained in step A1-1b with compound h in the presence of a base.

Examples of bases include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.) and nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine, pyrazine, pyridazine, etc.).

Examples of solvents include ether solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane; and hydrocarbon solvents such as hexane, heptane, benzene, and toluene. Bases such as pyridine can also be used as solvents.

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

Examples of the base include weakly basic inorganic salts (sodium carbonate, potassium carbonate, cesium carbonate, etc.), metal hydrides (sodium hydride, potassium hydride, etc.), and preferably weakly basic inorganic salts such as cesium carbonate. It's salt.

Examples of the compound i1 include 1,2-dichloro-1-methoxyethane, 1,2-dichloro-1-ethoxyethane, 1,2-dichloro-1-i-propoxyethane, 1,2-dichloro-1- Examples include t-butoxyethane, and 1,2-dichloro-1-ethoxyethane is preferred. Compound i1 can be purchased commercially from Tokyo Kasei Kogyo, FCH Group, etc.

Examples of compound i2 include 2-chloro-1,1-dimethoxyethane, 2-chloro-1,1-diethoxyethane, 2-bromo-1,1-dimethoxyethane, and 2-bromo-1,1-ethoxyethane. Compound i2 can be purchased commercially from Tokyo Chemical Industry Co., Ltd., etc.

Examples of solvents include alcohol solvents such as methanol and ethanol; ether solvents such as THF and diethyl ether; ester solvents such as ethyl acetate and methyl acetate; nitrile solvents such as acetonitrile, benzonitrile, and benzyl cyanide; Examples include amide solvents such as N-dimethylacetamide (DMA), N,N-dimethylimidazolidinone (DMI), and DMF, and amide solvents such as DMA are preferred.

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

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, 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.) Sulfonic acids such as methanesulfonic acid are preferred.

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

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.

Examples of compound k1 include C _1-6 alkyl halides such as methyl iodide, and (C _1-6 alkyl)carbonyl halides such as acetyl chloride. When R ^zd is (C _1-6 alkyl)carbonyl, it is also preferable to use an acid anhydride represented by ((C _1-6 alkyl)carbonyl) ₂ O, for example, acetic anhydride, instead of compound k1.

Examples of bases include metal hydrides such as sodium hydride, potassium hydride, and lithium hydride; metal alkoxides such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-pentoxide; and preferably metal alkoxides such as potassium pentoxide.

Examples of the solvent include ether solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane; and hydrocarbon solvents such as hexane, heptane, benzene, and toluene, with THF being preferred.

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.

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 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, 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.) Among them, carboxylic acids such as trifluoroacetic acid are preferred.

Examples of the solvent include ether-based solvents such as diethyl ether, THF, and dimethoxyethane; halogen-based solvents such as dichloromethane (CH ₂ Cl ₂ ), chloroform, and carbon tetrachloride; N,N-dimethylformamide; and acetonitrile, with preference given to halogen-based solvents such as CH ₂ Cl ₂ .

The reaction temperature is usually 0°C to 60°C, preferably 10°C to 40°C.
The reaction time is usually 30 minutes to 10 hours, preferably 1 hour to 5 hours.
Note that 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.

Step 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, but when the protecting group is a C _1-6 alkoxycarbonyl, it is preferable to react with a base.

Compounds used for protection include methoxycarbonyl chloride, ethoxycarbonyl chloride, 2,2,2-trichloroethoxycarbonyl chloride, benzoyl chloride (Z-Cl), 9-fluorenylmethyloxycarbonyl chloride (Fmoc-Cl), and dichloroethoxycarbonyl chloride. -t-butyl dicarbonate, preferably di-t-butyl dicarbonate.

Examples of bases include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.), nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine, pyrazine, pyridazine, etc.), and preferably tertiary amines such as triethylamine.

Examples of the solvent include ether solvents such as diethyl ether, THF, and dimethoxyethane; halogen solvents such as dichloromethane (CH ₂ Cl ₂ ), chloroform, and carbon tetrachloride; N,N-dimethylformamide; and acetonitrile. is a halogen solvent such as CH ₂ Cl ₂ .

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

Examples of compound n1 include C _1-6 alkyl halides such as methyl iodide, and (C _1-6 alkyl) carbonyl halides such as acetyl chloride. When R ^ze is C _1-6 alkyl, the C _1-6 alkyl is preferably unsubstituted or substituted with C _1-6 alkoxy.

This step is carried out in the same manner as step A2-5, and the base, solvent, reaction temperature, and reaction time used in the reaction are also the same as in step A2-5.
Process A2-9 :
Compound p can be obtained by deprotecting compound o.

For deprotection, appropriate reagents and reaction conditions can be selected depending on the type of protecting group, but when the protecting group P ^1a is C _1-6 alkoxycarbonyl such as t-butoxycarbonyl, deprotection using acid is recommended. preferable.

This step is carried out in the same manner as 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 production method B shown in the scheme below.

During the ceremony,
P ²¹ represents hydroxy, C _1-6 alkoxy, or -NR ^21a R ^21b , R ^21a and R ^21b independently represent a hydrogen atom, C _1-6 alkyl, or C _6-10 aryl,
X ²¹ represents a hydrogen atom, a halogen atom, or -Zn-X ^21a ,
X ^21a represents a bromine atom or an iodine atom,
X ²² represents a leaving group.

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

As the palladium catalyst, a complex formed in the system by adding a palladium compound and a ligand separately can be used. Alternatively, the complex prepared separately may be used as it is. Examples of the ligand include 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, trimethylenebis(diphenylphosphine), 2-(di-t-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-(di-t-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl, and 2-di-t-butylphosphino-2',4',6'-triisopropylbiphenyl. Examples of the palladium compound to be combined with the ligand include di-μ-chlorobis[(η-allyl)palladium(II)], tetrakis(triphenylphosphine)palladium(0), and the like.

Examples of palladium catalysts that can be used in this step include tris(dibenzylideneacetone)dipalladium(0), 5,10,15,20-tetraphenyl-21H,23H-porphine cobalt(II), and palladium acetate(II). ), bis(di-t-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, dichlorobis(trichloromethane), phenylphosphine)palladium(II), palladium hydroxide, tetrakis(triphenylphosphine)palladium(0), and di-μ-chlorobis[(η-allyl)palladium(II)]. In step 11, di-μ-chlorobis[(η-allyl)palladium(II)] is used as a palladium compound, and 2-(di-t-butylphosphino)-2',4',6'-triisopropyl- Preferably, a complex formed using 1,1'-biphenyl as a ligand is used as a catalyst.

Note that this step may be performed 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.).

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 may also be used.

The reaction temperature is usually from 10°C to 200°C, preferably from 40°C to 130°C.
The reaction time is usually from 1 minute to 20 hours, preferably from 10 minutes to 10 hours.
Compound ba can be purchased as a commercial product from Aurora Fine Chemicals, etc. It can also be synthesized with reference to Synthetic Communications, 39(14), 2506-2515, 2009. It can also be obtained by esterifying or amidating compound ba in which -COP ²¹ is -COOH.

Compound ba1 in which X ²¹ is -Zn-X ^21a can be purchased as a commercially available product from Focus Synthesis LLC, etc. It can also be synthesized with reference to WO2014/201206, etc.

Process B-2 :
Compound bc can be obtained by reacting compound bb with compound bb1 in the presence of a base.

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, preferably potassium hydroxide. It is.

Reaction solvents include amide solvents such as N,N-dimethylacetamide (DMA), N,N-dimethylimidazolidinone (DMI), and DMF, with DMI being preferred. A mixed solvent with water may also be used.

The reaction temperature is usually -10°C to 100°C, preferably 0°C to 45°C.
The reaction time is usually 30 minutes to 10 hours, preferably 1 hour to 5 hours.
Compound bb can be purchased commercially from Aquila Pharmatech LLC or the like. It can also be synthesized with reference to WO2013/010904, Organic Letters, 7(18), 3965-3968, 2005, US5998438, etc.

Process B-3 :
Compound bd can be obtained by reacting compound bc with hydroxyamine (H ₂ NOH).

Examples of the reaction solvent include aprotic polar solvents such as dimethyl sulfoxide (DMSO), dimethylformamide, dimethylacetamide, and 1-methyl-2-pyrrolidinone, and alcoholic solvents such as methanol and ethanol, preferably. It is DMSO. Moreover, a mixed solvent with water may be used.

The reaction temperature is usually -10°C to 100°C, preferably 20°C to 45°C.
The reaction time is usually 2 hours to 72 hours, preferably 3 hours to 36 hours.
Compound bd may be subjected to step B-4 without being isolated or purified.

Step B-4 :
Compound bd can be reacted with triphosgene, a chlorocarbonate (methyl chlorocarbonate, ethyl chlorocarbonate, isopropyl chlorocarbonate, etc.), carbonyldiimidazole, etc., preferably carbonyldiimidazole, in the presence of a base to obtain compound be.

Examples of bases 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.

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

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.
Step B-5 :
Compound be protected with ^P21 can be deprotected with a base to give compound bf.

Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide, potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, and sodium hydroxide. Examples include metal alkoxides such as t-pentoxide and lithium t-pentoxide.

Examples of the solvent include alcohol solvents such as methanol, ethanol, methoxyethanol, and t-butyl alcohol, ether solvents such as THF and diethyl ether, and amide solvents such as N,N-dimethylacetamide (DMA), N,N-dimethylimidazolidinone (DMI), and DMF. A mixed solvent with water may also be used.

The reaction temperature is usually from -20°C to 120°C, preferably from 20°C to 100°C.
The reaction time is usually 20 minutes to 10 hours, preferably 30 minutes to 5 hours. The order of steps B-1, B-2, B-3, B-4, and B-5 can be interchanged. For example, compound bc can be obtained by subjecting compound ba to steps B-2 and B-1 in that order. Compound bf can be obtained by subjecting compound ba to steps B-2, B-3, B-4, B-5, and B-1 in that order. Compound bf can be obtained by subjecting compound ba to steps B-2, B-3, B-4, B-1, and B-5 in that order.

Step B-Aa and Step B-Ab :
Furthermore, when X ²¹ is a halogen atom, compound bb can also be obtained by subjecting compound ba to the following steps B-Aa and B-Ab, which is then subjected to step B-2. You can.

In the formula, R ^Qc and R ^Qd independently represent a hydrogen atom or C _1-6 alkyl, or R ^Qc and R ^Qd are combined together 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.

Step 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.

This step is carried out in the same manner as in Step B-1, and the palladium catalyst, base, solvent, reaction temperature and reaction time used in the reaction are also the same as in Step B-1.
Examples of the compound ba2 include pinacol borane and 4,6,6-trimethyl-1,3,2-dioxaborinane. Examples of the compound ba3 include diboronic acid, pinacol diborane (4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)), bis(neopentyl glycolato)diboron, and bis(hexylene glycolato)diboron. These compounds can be purchased as commercial products from Tokyo Chemical Industry Co., Ltd., etc. It can also be synthesized using i) pinacol and ii) diborane, BH ₃ ·THF complex or BH ₃ ·dimethyl sulfide complex, with reference to Journal of the American Chemical Society, 131 (45), 16346-16347, 2009 and Organic Synthesis, 77, 176-185, 2000.

The organic boron compound baa may be subjected to Step B-Ab without being isolated.
Process B-Ab :
Compound bb can be obtained by reacting organic boron compound baa with compound ba1 in the presence of a base.

Examples of bases include weakly basic inorganic salts (sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, etc.), preferably sodium carbonate.

The solvent used in the reaction, reaction temperature, and reaction time are the same as in Step B-1.
Note that compound bb can also be obtained by converting compound ba1 into an organic boron compound in the same manner as the conversion of compound ba to compound baa, and reacting this with compound ba.

Process BB :
Further, when compound bb1 is represented by X ²¹ -(CH ₂ ) _n1 -CH ₂ -CN, compound bca corresponding to compound bc obtained in step B-2 is subjected to the following step BB, , in the presence of a base, R ⁷ and R ⁸ together with the carbon atom to which they are attached form a C _3-15 cycloalkane ring, where R ⁷ and R ⁸ together form a C _3-15 cycloalkane ring, which may be substituted with 1 to 3 C _1-6 alkyl, to obtain a compound bcb corresponding to the compound bc, This may be subjected to step B-3.

In the formula, R ^7c , R ^7e and R ^7d in n8 each independently represent a hydrogen atom or C _1-6 alkyl, and n8 represents an integer of 0 to 3.
Examples of the base include sodium hydride, potassium hydride, lithium bis(trimethylsilyl)amide (LiHMDS), and sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), and lithium diisopropylamide (LDA). ), and metal hydrides such as lithium 2,2,6,6-tetramethylpyrrolidide, preferably KHMDS.

Examples of solvents 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.

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., etc. It can also be synthesized with reference to Organic Letters, 12(17), 3938-3941, 2010.

<General manufacturing method C>
Process C-1 :

Compound f (or compound p) and compound bf are condensed using a condensing agent in the presence of a base to obtain compound (Ia).
Examples of the 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), and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium Examples of such compounds include tetrafluoroborate (TBTU), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium hexafluorophosphate (HATU), and ethyl(hydroxyimino)cyanoacetate (Oxyma), and preferably HATU.

Examples of the base include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.), nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine, pyrazine, pyridazine, etc.), preferably tertiary amines such as diisopropylethylamine.

Examples of the solvent include ether solvents such as THF, diethyl ether, and dioxane, and aprotic polar solvents such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide, and 1-methyl-2-pyrrolidinone. Preferably, an aprotic polar solvent such as DMF is used.

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.
For example, compound d is sequentially applied to step A1-5, step C-1, step A1-4, compound ba is applied to step B-2, step B-3, step B-4, step B-5, Compound (Ia) can also be obtained by changing the order of the steps, such as sequentially applying Step C-1 and Step B-1.
Further, 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, such as inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.) , sulfonates (methanesulfonate, ethanesulfonic acid, benzenesulfonate, toluenesulfonate, etc.), carboxylates (formate, acetate, oxalate, maleate, fumarate, citric acid) Salt, malate, succinate, malonate, gluconate, mandelate, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, glutarate, adipine salts, 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.), basic amino acid salts (lysine salts, arginine salts, etc.), alkali metal salts and alkaline earth metal salts are preferred, and sodium salts , calcium salts are more preferred. For example, the free form of the compound represented by formula (I) is suspended or dissolved in an alcohol such as methanol or ethanol, acetonitrile, acetone, dimethyl sulfoxide, etc., and a basic aqueous solution containing sodium ions such as sodium hydroxide is prepared. The sodium salt of the compound represented by formula (I) can be obtained by adding a methanol solution containing sodium methoxide or an ethanol solution containing sodium ethoxide. The reaction temperature is, for example, 0°C to 80°C, preferably 20°C to 60°C.

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

A solvate of the compound represented by formula (I) or a salt thereof can be obtained by a conventional method such as precipitating the compound represented by formula (I) or a salt thereof from a solvent. The hydrate can also be obtained by precipitating the compound represented by formula (I) or a salt thereof from a water-containing organic solvent.

The 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 conventional methods, 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.

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

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

In the present invention, the atoms constituting the compound molecule represented by formula (I) include isotopes, and at least one atom is replaced with an atom having the same atomic number (proton number) and a different mass number (sum of the number of protons and neutrons). Examples of isotopes contained in the compound represented by formula (I) include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, fluorine atom, and chlorine atom, and include ^2H , ^3H , ^13C , ^14C , ^15N , ^17O , ^18O , ^31P , ^32P , ^35S , ^18F , and ^36Cl , respectively. In particular, radioisotopes that decay by emitting radiation, such as ^3H and ^14C , are useful in tissue distribution tests of pharmaceuticals or compounds. Stable isotopes do not decay, their abundance hardly changes, and they do not have radioactivity, so they can be used safely. When the atoms constituting the compound molecule represented by formula (I) are isotopes, they can be converted in a conventional manner by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.
The pharmaceutical composition of the present invention has a GLP1 receptor agonist effect and a blood glucose lowering effect, and by administering a pharmacologic 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.

In the present invention, "diabetes" refers to a disease or condition in which the body is unable to maintain an appropriate blood glucose level, 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).

"Hyperglycemia" refers to a state in which the plasma glucose level during fasting or after glucose administration is higher than the normal value (for example, 80 to 110 mg/dL during fasting in humans), and is one of the typical symptoms of diabetes. There is also.

"Glucose intolerance" includes insulin-resistant glucose intolerance and insulin secretion deficiency.
"Diabetic complication" means a complication caused by diabetes or hyperglycemia, and may be either an acute complication or a chronic complication. Examples of "acute complications" include ketoacidosis, infections (e.g., skin infections, soft tissue infections, biliary tract infections, respiratory infections, urinary tract infections), and "chronic complications" include, for example, , microangiopathy (eg, nephropathy, retinopathy), neuropathy (eg, sensory neuropathy, motor neuropathy, autonomic neuropathy), and foot necrosis. Major diabetic complications include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. "Coronary heart disease" includes myocardial infarction, angina pectoris, and the like.

"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, etc.

The pharmaceutical composition of the present invention is usually formulated into a certain formulation (dosage form) before use. Such formulations include, for example, tablets, capsules, granules, powders, fine granules, pills, aqueous or non-aqueous solutions or suspensions, and the like. Furthermore, 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 used by being implanted in the body, and those that are applied to the oral or nasal mucosa. Note that the solution or suspension can be stored in containers suitable for subdividing into individual doses.

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

Examples of excipients include starch (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, calcium hydrogen phosphate, and the like.
Examples of the lubricant (coating agent) include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, and paraffin.

Examples of the binder include polyvinylpyrrolidone, macrogol, and the same compounds as the excipients described above.
Examples of the disintegrant include chemically modified starches such as croscarmellose sodium, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone, celluloses, and the same compounds as the excipients described above.

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

Examples of flavoring agents include commonly used sweeteners, acidulants, fragrances, and the like.
Examples of the base include fats such as lard; vegetable oils such as olive oil and sesame oil; higher alcohols such as stearyl alcohol and cetanol; animal oils; lanolic acid; petrolatum; paraffin; bentonite; glycerin; and glycol oil. .

Examples of dispersants include cellulose derivatives (gum arabic, tragacanth, methylcellulose, etc.), stearic acid polyesters, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbates, and sorbitan fatty acid esters.

Examples of the solvent or diluent in the liquid preparation include phenol, chlorocresol, purified water, and distilled water.
Examples of surfactants or emulsifiers include polysorbate 80, polyoxyl 40 stearate, and lauromacrogol.

The content of the compound represented by formula (I), a salt thereof, or a solvate thereof in the formulation varies depending on the dosage form, but is generally 0.01 to 100% by weight.
The formulation may contain only one type of compound represented by formula (I), a salt thereof, or a solvate thereof, or may contain two or more types.

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, the presence or absence of concomitant drugs, the administration method, etc. For example, when the subject of administration is a warm-blooded animal, particularly a human, the dosage as the amount of the active ingredient per day is, for example, 0.01 to 10,000 mg, preferably 0.1 to 1,000 mg, for oral administration. Also, for parenteral administration, it is, for example, 0.001 to 3,000 mg, preferably 0.01 to 300 mg. The dosage may be administered once per day to several weeks, or may be administered in two or more divided doses per day.

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

The content of the present invention will be further explained in the following Examples and Reference Examples. All starting materials and reagents were obtained from commercial suppliers or synthesized using known methods. Room temperature (rt) refers to 5-35°C. The silica gel is SHOKO Scientific Purif-Pack (registered trademark) SI 60 μm (manufactured by Shoko Scientific), Biotage (registered trademark) SNAP Ultra Silica Cartridge (manufactured by Biotage), or SNAP KP-Sil Cart. ridge (manufactured by Biotage), reversed phase silica gel Wakosil (registered trademark) 25C18 (Wako Pure Chemical Industries, Ltd.) or Biotage (registered trademark) SNAP Ultra C18 Cartridge (manufactured by Biotage) was used. HPLC purification of compounds was performed using an AutoPurification HPLC/MS System (manufactured by Waters) or a Prepative HPLC system with injection/fractionation function (manufactured by Gilson). It was. ¹ H-NMR spectra were measured using ECP-400 (manufactured by JEOL), Agilent400-MR (manufactured by Agilent Technologies), AVANCE3 300MHz (manufactured by Bruker) or AVANCE3 600MHz, with or without Me ₄ Si as an internal standard. Measured using Cryo-TCI (manufactured by Bruker) (s = singlet, brs = broad single red, d = doublet, t = triplet, q = quartet, dd = double doublet, ddd = double double doublet, m = multiplet ). Chemical shifts in NMR data are based on Me ₄ Si or deuterated solvents and are expressed in ppm (parts per million, δ), and coupling constants (J) are expressed in Hz (Hertz). For LC/MS, retention time measurement and mass spectrometry were performed using the apparatus and analysis conditions shown in Table 1. Microwave was irradiated using InitiatorTM (manufactured by Biotage). Mass spectrometry in LC/MS was measured using a mass spectrometer: SQD (manufactured by Waters), SQD2 (manufactured by Waters), 2020 (manufactured by Shimadzu), or 2010EV (manufactured by Shimadzu).

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]pyridin-5-carbonyl]-5-(2-ethyl-3-methylpyridin-4-yl)indol-1-yl]-2 Synthesis of -methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 1)

(Step 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) was added a THF solution (179 mL) of 1M potassium tert-butoxide, and the mixture was stirred at room temperature for 1 hour. Stirred. The reaction mixture was collected by filtration, washed with THF (50 mL), and then dried under reduced pressure to obtain the title compound 1b (23.8 g, yield 83%) as a light brown solid.

LC/MS mass spectrometry: m/z 124 ([M+H] ⁺ ).
LC/MS retention time: 0.14 minutes (analysis conditions: SMD-FA05-1).
¹ H-NMR (400 MHz, MeOH-d ₄ ) δ: 3.33 (2H, t, J=1.3 Hz), 2.90 (2H, t, J=5.9 Hz), 2.21 (2H, tt, J=5.9, 1.3 Hz).

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

LC/MS mass spectrometry: m/z 343 ([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)
2-isocyanato-1,1-dimethoxyethane (compound 1e, 1.94 g, 14.8 mmol) was added to a pyridine (7.39 mL) solution of compound 1d (2.53 g, 7.39 mmol) obtained in step 1-2, and the mixture was stirred at room temperature. After 3 hours and 15 minutes, diethylamine (1.08 g, 14.8 mmol) was added, and the mixture was stirred at room temperature for 5 minutes, and then water (50.6 mL) was added and the mixture was stirred at room temperature for 20 minutes. The reaction mixture that became a suspension was filtered, and the solid collected by filtration was washed with water (12.7 mL) and then dried under reduced pressure to obtain the title compound 1f (3.20 g, yield 91%) as a pale yellow solid.

LC/MS mass spectrometry: m/z 474 ([M+H] ⁺ ).
LC/MS retention time: 0.78 minutes (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)
Formic acid (3.84 mL, 100 mmol) was added to Compound 1f (158 mg, 0.334 mmol) obtained in Step 1-3, and the mixture was stirred at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure, toluene was added, and the solvent was distilled off under reduced pressure. After dichloromethane (1 mL) was added to the residue to dissolve it, hydrogen chloride (4M 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 distilled off under reduced pressure to obtain 1 g of the title compound as a crude product (176 mg).

LC/MS mass spectrometry: m/z 310 ([M+H] ⁺ ).
LC/MS retention time: 0.39 minutes (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 a 1.11 M lithium diisopropylamide n-hexane-THF solution was added. (35.8 mL, 39.8 mmol) was added slowly. 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 after stirring for 30 minutes, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate) to obtain the title compound 1i (6.98 g, yield 92%) as an orange oil.

LC/MS mass spectrometry: m/z 200 ([M+H] ⁺ ).
LC/MS retention time: 0.38 minutes (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'-dimethylpropyleneurea (117 mL) was degassed under reduced pressure, substituted with nitrogen, and cooled to 0°C. Under a nitrogen atmosphere, a 1.0 M solution of potassium bis(trimethylsilyl)amide in THF (46.9 mL, 46.9 mmol) was slowly added dropwise. After stirring at 0°C for 2.5 hours, formic acid (5.30 mL, 141 mmol) was added, and the mixture was extracted with a mixed solution of hexane/ethyl acetate (1:3). The organic layer was washed three times with water, twice with a saturated aqueous solution of sodium bicarbonate, and once with saturated saline, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:19 to 1:4) to obtain the title compound 1l (1.70 g, yield 42%) as a white solid.

LC/MS mass spectrometry: m/z 347 ([M+H] ⁺ ).
LC/MS retention time: 0.69 minutes (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 replaced with nitrogen. Under a nitrogen atmosphere, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.29 g, 1.56 mmol) was added and stirred at 100°C for 3 hours. After cooling to room temperature, 4-bromo-2-ethyl-3-methylpyridine (compound 1i, 2.33 g, 11.7 mmol), sodium carbonate (2.47 g, 23.3 mmol), and water (7.4 mL) were added to the solution, which was then degassed under reduced pressure, replaced with nitrogen, and stirred at 100° C. for 2 hours. After cooling to room temperature, water (5.4 mL) and N-acetylcysteine (0.635 g, 3.89 mmol) were added and stirred for 0.5 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed once with saturated saline and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1:19 to 2:3) to obtain the title compound 1m (2.92 g, yield 97%) as a pale yellow gum.

LC/MS mass spectrometry: m/z 388 ([M+H] ⁺ ).
LC/MS retention time: 1.06 minutes (Analysis conditions: SQD-AA05-2).
(Step 1-8)
5-(2-ethyl-3-methylpyridin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3 -yl)cyclopropyl]ethyl indole-2-carboxylate (compound 1n)
A 50% aqueous hydroxyamine solution (0.356 mL, 5.81 mmol) was added to a solution of the compound 1 m (0.225 g, 0.581 mmol) obtained in step 1-7 in dimethyl sulfoxide (DMSO) (2.9 mL), Stirred at room temperature for 17 hours. Ethyl acetate (50 mL) was added, washed with water (10 mL) and saturated brine (10 mL), and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in DMSO (1.9 mL), and carbonyldiimidazole (188 mg, 1.16 mmol) and 1,8-diazabicycloundec-7- Ene (0.219 mL, 1.45 mmol) was added and stirred at room temperature for 0.5 hour. Formic acid was added and the mixture was directly purified by reverse phase chromatography (acetonitrile/water, 0.1% formic acid) to obtain the title compound 1n (169 mg, yield 65%) as a white powder.

LC/MS mass spectrometry: m/z 447 ([M+H] ⁺ ).
LC/MS retention time: 0.80 minutes (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-oxadiazole-3 -yl)cyclopropyl]indole-2-carboxylic acid (compound 1o)
A 2M aqueous sodium hydroxide solution (10.1 mL, 20.2 mmol) was added to a DMSO (40 mL) solution of the compound 1n (3.61 g, 8.08 mmol) obtained in Step 1-8, and the mixture was diluted with 1.5 mL at room temperature. Stir for hours. Formic acid was added and the mixture was directly purified by reverse phase chromatography (acetonitrile/water, 0.1% formic acid) to obtain the title compound 1o (3.38 g, yield 100%) as a white powder.

LC/MS mass spectrometry: m/z 419 ([M+H] ⁺ ).
LC/MS retention time: 0.83 minutes (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) in N,N'-dimethylformamide (DMF) (24.1 mL) were added to the solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified as it was by reverse phase column chromatography (acetonitrile/water, 0.1% formic acid) to obtain the title compound 1p (2.44 g, yield 95%) as a light brown foam.

LC/MS mass spectrometry: m/z 710 ([M+H] ⁺ ).
LC/MS retention time: 0.85 minutes (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)
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 A suspension of -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) was added with iodide. Copper(I) (1.1 mg, 0.0056 mmol) was added at room temperature, and the mixture was stirred at 130° C. for 3 hours under nitrogen atmosphere. The reaction mixture was purified by reverse phase silica gel chromatography (acetonitrile/water, 0.1% formic acid) to obtain the title compound 1 (17.2 mg, yield 73%) as a pale brown foam.

LC/MS mass spectrometry: m/z 840 ([M+H] ⁺ ).
LC/MS retention time: 1.12 minutes (Analysis conditions: SMD-TFA05-3).
<Examples 2 to 50>
Using the combination of the 2-oxoimidazole compound shown in Table 2-2 below and the halogen compound shown in Table 2-3, and an appropriate reagent, the same operation as in Step 1-11 of Example 1 was carried out, and the following reaction was carried out. Example compounds 2 to 50 shown in Table 2-1 were obtained.

The compounds in Table 2-1 have rotamers; for example, ^{the 1} H-NMR of Example Compound 2 is as follows.
Rotamer A
^1H -NMR (600MHz, CDCl ₃ ) 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 (1H, s), 7.45 (1H, dd, J=9.0, 1. 5Hz), 7.38 (1H, d, J = 9.0Hz), 7.28 (1H, m), 7.14 (1H, d, J = 5.2Hz), 7.04 (2H, d, J _HF =5.9Hz), 6.82 (1H, s), 6.59 (1H, d, J = 3.0Hz), 6.08 (1H, d, J = 3.0Hz), 4.96 (1H, d, J=16.0Hz), 4.92 (1H, d, J=16.0Hz), 4.69 (1H, ddd, J=13.1, 4.4, 4.4Hz), 4.06 (3H, s), 3.75 (1H, ddd, J = 13.1, 9.5, 5.0Hz), 3.07 (2H, m), 2.97 (2H, q, J =7.6Hz), 2.26 (3H, s), 2.25 (6H, s), 1.88 (1H, s), 1.51 (2H, m), 1.37 (3H, t, J=7.6Hz), 1.17 (3H, d, J=5.6Hz).

Rotamer B
^1H -NMR (600MHz, _CDCl3 ) δ: 11.29 (1H,s), 8.44 (1H,d,J=5.2Hz), 8.04 (1H,s), 7.90 (1H,d,J=1.4Hz), 7.73 (1H,d,J=8.8Hz), 7.63 (1H,dd,J=9.0,1.4Hz), 7.60 (1H,s), 7.51 (1H,d,J=9.0Hz), 7.30 (1H,m), 7.20 (1H,d,J=5.2Hz), 7.11 (2H,d,J=6.2Hz), 7.20 (2H,d,J=5.2Hz), 7.20 (2H,d,J= ₆ ... = 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), 3.1 7 (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).

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.

(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 concentrated hydrochloric acid (20 mL) and water (20 mL) at room temperature while stirring. The mixture was stirred at that temperature for 1 hour, and the solid in the reaction mixture was filtered and dried. Methoxycyclopentane (20 mL) was further added to the obtained solid, and the mixture was stirred at 50° C. for 1 hour and then at room temperature for 1.5 hours. The precipitated solid was filtered and washed with methoxycyclopentane (12 mL). The obtained solid was dried under reduced pressure to give the title compound 2b (4.88 g, yield 97%) as an off-white solid.

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, and the mixture was stirred at 0° C. for 30 minutes. Then, a solution of tin(II) chloride (2.27 g, 12.0 mmol) in water (2.4 mL) was added over 2 minutes. Water (7 mL) was further added, and the mixture was stirred at room temperature for 1 hour. The solid in the reaction mixture was filtered, washed with water (2 mL), and then dried to obtain the title compound 2c (1.75 g, yield 77%, content 48%) as a gray solid.

LC/MS mass spectrometry: m/z 155 ([M+H] ⁺ ).
LC/MS retention time: 0.54 minutes (analysis conditions: SMD-FA05-1).
(Step 2-3)
3-Amino-2-(4-fluoro-3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (compound 2d)
This 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.

LC/MS mass spectrometry: m/z 361 ([M+H] ⁺ ).
LC/MS retention time: 1.04 minutes (Analysis conditions: SMD-FA05-3).
(Step 2-4)
3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl (compound 2e)
Compound 2d obtained in Step 2-3 was synthesized in the same manner as in Step 1-3 of Example 1 using appropriate reagents.
LC/MS mass spectrometry: m/z 492 ([M+H] ⁺ ).
LC/MS retention time: 1.07 minutes (Analysis conditions: SMD-FA05-3).

(Step 2-5)
3-[2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-1H-imidazol-2-one hydrochloride (compound 2f)
Compound 2e obtained in step 2-4 was synthesized by the same procedure as in step 1-4 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 328 ([M+H] ⁺ ).
LC/MS retention time: 0.61 minutes (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)
Compound 2f obtained in step 2-5 and compound 1o obtained in step 1-9 were synthesized by the same procedure as in step 1-10 of Example 1 using appropriate reagents.

The 2-oxoimidazole compound (3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2- oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl) Indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 6i) was synthesized as follows.

(Step 6-1)
5-Bromo-1-(cyanomethyl)-N-methyl-N-phenylindole-2-carboxamide (compound 6c)
The compound was synthesized from 5-bromo-1-(cyanomethyl)indole-2-carboxylic acid (compound 6a) and N-methylaniline (compound 6b) using an appropriate reagent in the same manner as in steps 1-10 of Example 1.

LC/MS mass spectrometry: m/z 368 ([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 in the same manner as in Step 1-6 of Example 1 using appropriate reagents.

LC/MS retention time: 1.37 minutes (analysis conditions: SMD-FA05-1).
^1H -NMR (400MHz, DMSO- _d6 ) δ: 7.69 (1H,s), 7.6
5-7.25 (7H, m), 6.02 (1H, brs), 3.44 (3H, s), 3.31 (3H, d, J = 9.5 Hz), 2.04-1.74 (3H, m).

(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 in the same manner as in Step 1-8 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 467 ([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 obtained solid was dried under reduced pressure to obtain the title compound 6f (7.42 g, yield 95%) as a light brown solid.

LC/MS mass spectrometry: m/z 376 ([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-oxadiazole-3 -yl)cyclopropyl]indole-2-carboxylic acid (compound 6h)
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'- A suspension of 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. After that, the atmosphere was replaced with nitrogen. After stirring at 100° C. for 0.5 hour under a nitrogen atmosphere, the mixture was cooled to room temperature. 4-Iodo-2-methoxy-3-methylpyridine (compound 6g, 1.98g, 7.93mmol) and water (4.96mL) were added to the solution, degassed under reduced pressure, and then replaced with nitrogen at 100°C. Stirred for .5 hours. After cooling to room temperature, water (12.4 mL) and formic acid (6 mL) were added, and after filtration, the filtrate was directly purified by reverse phase chromatography (acetonitrile/water, 0.1% formic acid) to obtain the title compound. 6h (1.83 g, yield 55%) was obtained.

LC/MS mass spectrometry: m/z 421 ([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)
Compound 2f obtained in step 2-5 and compound 6h obtained in step 6-5 were synthesized by the same procedure as in step 1-10 of Example 1 using appropriate reagents.

The halogen compound (1-(5-bromoindazol-1-yl)-2-methylpropan-2-ol, compound 6l) used in the synthesis of Example Compound 6 was synthesized as follows.

(Step 6-7)
1-(5-bromoindazol-1-yl)-2-methylpropan-2-ol (compound 6k)

Dissolve 5-bromoindazole (Compound 6j, 150 mg, 0.761 mmol) and 2,2-dimethyloxirane (Compound 6k, 274 mg, 3.81 mmol) in 1-methylpyrrolidin-2-one (NMP) (1.52 mL). and potassium carbonate (526 mg, 3.81 mmol) was added. Stirred at 180° C. for 30 minutes under microwave. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was distilled off under reduced pressure. Purification was performed by silica gel column chromatography (ethyl acetate/hexane = 1:1) to obtain 6 l (115 mg, yield 56%) of the title compound.

LC/MS mass spectrometry: m/z 269 ([M+H] ⁺ ).
LC/MS retention time: 1.00 minutes (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]indole- 1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 7c) was synthesized as follows.

(Step 7-1)
5-(2,2-Dimethylmorpholin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 7b)
A suspension of 2,2-dimethylmorpholine (compound 7a, 1.98 g, 17.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.121 g, 0.132 mmol), 2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl (0.123 g, 0.264 mmol), and sodium tert-butoxide (5.08 g, 529 mmol) in NMP (44 mL) was degassed under reduced pressure at room temperature, and then substituted with nitrogen. Under a nitrogen atmosphere, compound 6f (5.0 g, 13.2 mmol) obtained in step 6-4 was added, and the mixture was stirred at 100°C for 0.5 hours, 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 obtain the title compound 7b (5.26 g, yield 96%).

LC/MS mass spectrometry: m/z 413 ([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 by the same procedure as in step 1-10 of Example 1 using an appropriate reagent.

The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[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.

(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, replaced with nitrogen, and stirred at room temperature for 15 minutes. Under a nitrogen atmosphere, a DMA solution (7.9 mL, 7.93 mmol) of 1M (tetrahydro-2H-pyran-4-yl)zinc(II) iodide (compound 8a) was added, stirred at 80°C for 15 minutes, and then cooled to room temperature. Formic acid was added, and the mixture was purified by reverse phase chromatography (methanol/water) to obtain the title compound 8b (0.19 g, yield 61%).

LC/MS mass spectrometry: m/z 382 ([MH] ⁻ ).
LC/MS retention time: 1.00 minutes (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 in the same manner as in Step 1-10 of Example 1 using appropriate reagents.

The halogen compound (5-bromo-1-[(3R)-oxolan-3-yl]indazole, compound 8f) used in the synthesis of Example Compound 8 was synthesized as follows.

(Step 8-3)
4-Methylbenzenesulfonic acid [(3S)-oxolan-3-yl] (compound 8e)
Pyridine (1.28 mL, 15.9 mmol) and 4-methylbenzenesulfonyl chloride were added to a dichloromethane solution (3.78 mL) of (3S)-oxolan-3-ol (compound 8d, 500 mg, 5.68 mmol) at 0°C. (1.51 g, 7.95 mmol) was added. After stirring at room temperature for 15 hours, water and 1N hydrochloric acid were added and the organic layer was separated. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The solvent was distilled off under reduced pressure to obtain the title compound 8e (1.36 g, yield 99%).

LC/MS retention time: 0.96 minutes (analysis conditions: SMD-FA05-1).
^1H -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).

(Step 8-4)
5-bromo-1-[(3R)-oxolan-3-yl]indazole (compound 8f)
In a DMF (3.8 mL) solution of 5-bromo-1H-indazole (compound 6j, 300 mg, 1.52 mmol), cesium carbonate (992 mg, 3.05 mmol) and compound 8e obtained in step 8-3 (369 mg, 1.52 mmol) was added thereto, and the mixture was stirred at 100°C for 2 hours. After cooling to room temperature, water was added to the reaction solution and 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) gave the title compound 8f (198 mg, yield 49%) as a colorless oil.

LC/MS mass spectrometry: m/z 267 ([M+H] ⁺ ).
LC/MS retention time: 1.07 minutes (Analysis conditions: SMD-FA05-1).
The halogen compound (N-(4-bromo-2-methoxyphenyl)-N-(3-methoxypropyl)acetamide, Compound 9c) used in the synthesis of Example Compound 9 was synthesized as follows.

(Step 9-1)

To a solution of N-(4-bromo-2-methoxyphenyl)acetamide (compound 9a, 80 mg, 0.33 mmol) in DMF (0.8 mL) was added 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 the mixture was stirred at room temperature for 12 hours. Formic acid was added to the reaction mixture, and the mixture was purified by reverse phase silica gel chromatography (acetonitrile/water, 0.1% formic acid) to obtain the title compound 9c (103 mg, yield 99%) as a colorless gum.

LC/MS mass spectrometry: m/z 316 ([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.

(Step 10-1)

From 2,2,2-trifluoroethyl trifluoromethanesulfonate (Compound 10a) and 5-bromo-1H-indazole (Compound 6j), using appropriate reagents, by the same operation as Step 8-4 of Example 8. Synthesized.

LC/MS mass spectrometry: m/z 279 ([M+H] ⁺ ).
LC/MS retention time: 1.17 minutes (Analysis conditions: SMD-FA05-1).
2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)) used in the synthesis of Example Compounds 11 to 13 -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) was synthesized as follows. did.

(Step 11-1)
N-(4-fluoro-3,5-dimethylphenyl)-N-[(2-methylpropan-2-yl)oxycarbonylamino]carbamic acid tert-butyl (compound 11b)
5-Bromo-2-fluoro-1,3-dimethylbenzene (Compound 11a, 4.66 g,
22.6 mmol) was dissolved in THF (47.6 mL) and cooled to an external temperature of -70 ° C. 1.55 M n-butyllithium (13.1 mL, 20.4 mmol) was added dropwise at -70 ° C. or less and stirred for 1 hour. A toluene solution of 20 wt % di-tert-butyl azodicarboxylate (25.0 g, 21.7 mmol) was added dropwise at an internal temperature of -40 ° C. or less and stirred for 30 minutes, and then the temperature was raised to room temperature over 1 hour, and heptane (23.8 mL) and a 20% aqueous ammonium chloride solution (47.6 mL) were added and extracted. The organic layer was concentrated, heptane (7.14 mL) was added, and the mixture was heated to an external temperature of 70 ° C. to dissolve the mixture, and the mixture was cooled over 1 hour to precipitate crystals. The crystals were collected by filtration and washed with heptane (2.38 mL). The crystals were dried to synthesize a crude product of the title compound 11b (3.53 g, yield 44%).

^1H -NMR (400MHz, DMSO- _D6 ) δ: 9.64-9.51 (0.8H
, m), 9.24-9.07 (0.2H, m), 7.09-6.91 (2H, m), 2.29-2.09 (6H, m), 1.53-1.32 (18H, m).

LC/MS retention time: 1.40 minutes (Analysis conditions: SMD-FA05-3).
(Steps 11-2, 3, and 4)
tert-butyl (2S)-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), triethylamine (13.9 mL, 99.5 mmol) and ethyl acrylate (10 .8 mL, 99.5 mmol) was added at room temperature. The solution was stirred at an external temperature of 70° C. for 3 hours and cooled to room temperature to obtain a mixture containing ethyl 3-[[(2S)-1-cyanopropan-2-yl]amino]propanoate (Compound 11e).

Di-tert-butyl dicarbonate (21.7 mL, 99.5 mmol) was added to the reaction solution at room temperature. The solution was stirred at room temperature for 14 hours, then 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, containing ethyl 3-[[(2S)-1-cyanopropan-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoate (compound 11f). A mixture was obtained.

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

LC/MS mass spectrometry: m/z 237 ([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-carboxylic acid tert -Butyl (compound 11h)
Compound 11b (2.13 g, 6.01 mmol) obtained in step 11-1 was dissolved in NMP (6.39 mL), methanesulfonic acid (1.30 g, 13.2 mmol) was added, and the mixture was heated at an external temperature of 80°C. Stirred 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 11 g (1.43 g, 6.01 mmol) of the compound obtained in step 11-4 in toluene (6.3 mL), pyridine hydrochloride (71.0 mg, 0.60 mmol), and toluene were added. (4.2 mL) was added and stirred for 1 hour at an external temperature of 90°C. The reaction solution was cooled and washed with 1M aqueous sodium hydroxide solution (12.6 mL). The organic layer was concentrated under reduced pressure to synthesize the title compound 11h (1.68 g, yield 75%).

LC/MS mass spectrometry: m/z 375 ([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, and the mixture was stirred at an external temperature of 25° C. for 4 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was distilled off under reduced pressure. The mixture was purified by silica gel column chromatography (ethyl acetate/hexane=3:2) to obtain the title compound 11j (105 mg, yield 73%).

LC/MS mass spectrometry: m/z 506 ([M+H] ⁺ ).
LC/MS retention time: 1.09 minutes (analysis conditions: SMD-FA05-1).
(Step 11-7)
(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (Compound 11k)
Compound 11j (4.45 g, 8.79 mmol) obtained in step 11-6 was added to THF (44.5 mL) to suspend, methylsulfonic acid (0.676 g, 7.03 mmol) was added, and the mixture was stirred at an external temperature of 60° C. for 2 hours. After cooling to room temperature, a solution of tripotassium phosphate (1.87 g, 8.79 mmol) in water (17.8 mL) was added, and di-tert-butyl dicarbonate (0.768 g, 3.52 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. After filtration, the organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate/hexane=3:7) to obtain the title compound 11k (3.43 g, yield 88%).

LC/MS mass spectrometry: m/z 442 ([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)
A 4M hydrogen chloride dioxane solution (10.5 mL, 41.9 mmol) was added to a dichloromethane (8.38 ml) solution of compound 11k (1.85 g, 4.19 mmol) obtained in Step 11-7. After stirring the mixture at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to obtain a crude product (1.63 g) containing 11 L of the title compound as a brown solid.

LC/MS mass spectrometry: m/z 342 ([M+H] ⁺ ).
LC/MS retention time: 0.63 minutes (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 by the same procedure as in step 1-10 of Example 1 using appropriate reagents.

The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(3-fluoro-2-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 14d) used in the synthesis of Example Compound 14 was synthesized as follows.

(Step 14-1)
5-(2-chloro-3-fluoropyridin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 14b)
The compound 6f obtained in step 6-4 and 2-chloro-3-fluoro-4-iodopyridine (compound 14a) were synthesized by the same procedure as in step 6-5 of Example 6 using an appropriate reagent.

LC/MS mass spectrometry: m/z 429 ([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 mixed suspension of compound 14b (810 mg, 1.32 mmol) obtained in step 14-1, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (48 mg, 0.066 mmol), potassium carbonate (2.74 g, 19.8 mmol), and methylboronic acid (792 mg, 13.2 mmol) in DMSO/water 7:1 (13.2 mL) was degassed under reduced pressure at room temperature, and then substituted with nitrogen. The mixture was stirred at 100°C for 0.5 hours under a nitrogen atmosphere, and then cooled to room temperature. Formic acid was added, and the mixture was purified directly by reverse phase chromatography (acetonitrile/water, 0.1% formic acid) to obtain the title compound 14c (124 mg, 23% yield) as a pale yellow solid.

LC/MS mass spectrometry: m/z 409 ([M+H] ⁺ ).
LC/MS retention time: 0.85 minutes (analysis conditions: SMD-FA05-3).
(Step 14-3)
3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethyl
1-fluoro-2-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 14d).
The compound 11l obtained in step 11-8 and the compound 14c obtained in step 14-2 were synthesized by the same procedure as in step 1-10 of Example 1 using appropriate reagents.

The 2-oxoimidazole reagent used in the synthesis of Example Compound 15 (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) can be prepared as follows: Synthesized.

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

LC/MS mass spectrometry: m/z 263 ([M+H] ⁺ ).
LC/MS retention time: 0.52 minutes (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)
Compound 6f obtained in step 6-4 and compound 15b obtained in step 15-1 were used to synthesize the compound in the same manner as in step 6-5 of Example 6 using appropriate reagents.

LC/MS mass spectrometry: m/z 432 ([M−H] ⁻ ).
LC/MS retention time: 0.51 minutes (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 by the same procedure as in step 1-10 of Example 1 using appropriate reagents.

The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 16a) used in the synthesis of example compounds 16 to 30 was synthesized as follows.

(Step 16-1)
3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3 -yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]- 4H-1,2,4-oxadiazol-5-one (compound 16a)
Compound 11l obtained in step 11-8 and compound 8b obtained in step 8-1 were synthesized in the same manner as in step 1-10 of Example 1 using appropriate reagents.

The halogen compound (5-bromo-1-[(3-methyloxetan-3-yl)methyl]indazole, Compound 17b) used in the synthesis of Example Compound 17 was synthesized as follows.
(Step 17-1)

From 3-methyl-3-[(4-methylphenyl)sulfonylmethyl]oxetane (compound 17a) and 5-bromo-1H-indazole (compound 6j), using appropriate reagents, step 9-1 of Example 9 and It was synthesized using the same procedure.

LC/MS mass spectrometry: m/z 281 ([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.

(Step 20-1)
2-(4-bromo-2-methoxyphenoxy)-2-methylpropan-1-ol (compound 20b)

Under a nitrogen atmosphere, a THF solution of borane (0.0. 95M, 4.37 mL, 4.15 mmol) was added dropwise at 0°C and stirred for 24 hours. After adding 1M aqueous sodium hydroxide solution and stirring, 1N hydrochloric acid was added to neutralize. Ethyl acetate was added for extraction. The organic layer was washed with water, and the solvent was distilled off under reduced pressure to obtain the title compound 20b (339 mg, yield 89%).

LC/MS retention time: 1.04 minutes (analysis conditions: SMD-FA05-3).
^1H -NMR (400MHz, _CDCl3 ) δ: 7.04-7.01 (2H,m), 6.90-6.86 (1H,m), 3.85 (3H,s), 3.44 (2H,m), 3.34 (1H,m), 1.28 (6H,s).

The halogen compound (5-bromo-1-[(3S)-oxolan-3-yl]indazole, Compound 22c) used in the synthesis of Example Compound 22 was synthesized as follows.

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

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

LC/MS mass spectrometry: m/z 267 ([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.

(Step 24-1)
Trifluoromethanesulfonic acid (1,1-dimethyl-3,4-dihydroisochromen-6-yl) (compound 24b)
Step 8-3 of Example 8 using appropriate reagents from 1,1-dimethyl-3,4-dihydroisochromen-6-ol (compound 24a) and trifluoromethylsulfonyl trifluoromethanesulfonate (anhydrous triflate) It was synthesized by the same procedure.

LC/MS retention time: 0.96 minutes (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)
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)
A solution of 2,3-dichloro-2,4-dioxane (2.58 mL) containing 2,3-diethylamine (0.162 mL, 1.16 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.2 mg, 0.019 mmol) was degassed under reduced pressure, substituted with nitrogen, and stirred at 100°C for 14 hours. After cooling to room temperature, formic acid was added and the mixture was purified by reverse phase chromatography (acetonitrile/water, 0.1% formic acid) to give a mixture (134 mg) containing the title compound 24c as a light brown liquid.

LC/MS mass spectrometry: m/z 289 ([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)
An aqueous solution (1.9 mL) of copper(II) bromide (258 mg, 1.16 mmol) was added to a methanol (1.9 mL) solution of compound 24c (111 mg, 0.385 mmol) obtained in step 24-2, and 60 Stirred at ℃ for 6 hours. After cooling to room temperature, a saturated aqueous ammonium chloride solution was added, extracted twice with dichloromethane, and the organic layer was dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1:4) to obtain the title compound 24d (47.7 mg, yield 51%) as a colorless liquid. Ta.

^1H -NMR (400MHz, _CDCl3 ) δ: 7.29 (1H, dd, J=2.0, 8.4Hz), 7.24-7.22 (1H, m), 6.97 (1H, d, J = 8.4Hz), 3.92 (2H, t, J = 5.6Hz), 2.80 (2H, t, J = 5.6Hz), 1.50 (6H, s).

LC/MS retention time: 0.96 minutes (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.

(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
A 2M dimethylamine THF solution (0.227 mL, 0.455 mmol) was added to a solution of 2.9 mg, 0.045 mmol) in methanol (0.2 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by reverse phase silica gel column chromatography (acetonitrile/water, 0.1% formic acid) to synthesize the title compound 25b (9.2 mg, yield 69%) as an off-white solid.

LC/MS mass spectrometry: m/z 292 ([M+H] ⁺ ).
LC/MS retention time: 0.67 minutes (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.

(Step 28-1)
5-Bromo-4-fluoro-1-(2,2,2-trifluoroethyl)indazole (compound 28b)
The compound was synthesized from 2,2,2-trifluoroethyl trifluoromethanesulfonate (compound 10a) and 5-bromo-4-fluoro-1H-indazole (compound 28a) using an appropriate reagent in the same manner as in step 8-4 of Example 8.

LC/MS mass spectrometry: m/z 297 ([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.

(Step 29-1)
5-Bromo-4-fluoro-1-[(3-methyloxetan-3-yl)methyl]indazole (compound 29a)
The compound was synthesized from 3-methyl-3-[(4-methylphenyl)sulfonylmethyl]oxetane (compound 17a) and 5-bromo-4-fluoro-1H-indazole (compound 28a) using an appropriate reagent in the same manner as in step 8-4 of Example 8.

LC/MS mass spectrometry: m/z 299 ([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.

(Step 30-1)
1-(5-bromo-4-fluoroindazol-1-yl)-2-methylpropan-2-ol (compound 30a)
It was synthesized from 5-bromo-4-fluoro-1H-indazole (compound 28a) and 2,2-dimethyloxirane (compound 6k) in the same manner as in step 6-7 of Example 6 using appropriate reagents.

LC/MS mass spectrometry: m/z 287 ([M+H] ⁺ ).
LC/MS retention time: 1.01 min (analysis conditions: SMD-FA05-1).
2-oxoimidazole reagent (3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2) used in the synthesis of example compounds 31 to 40 -[(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) It was synthesized as follows.

(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 suspension was purged with nitrogen. Chlorotrimethylsilane (0.417 mL, 3.28 mmol) and 1,2-dibromoethane (0.284 mL, 3.28 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. A solution of 4-iodo-2,2-dimethyltetrahydropyran (5.37 g, 22.4 mmol) in DMF (9 mL) was added dropwise, and the mixture was stirred at room temperature for 20 minutes. To this solution were added palladium(II) acetate (0.084 g, 0.373 mmol), 4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (0.198 g, 0.746 mol), 5-bromo Ethyl indole-2-carboxylate (2.0 g, 7.46 mmol) was added and the mixture was purged with nitrogen. After stirring for 1 hour at an external temperature of 50°C, the external temperature was cooled to 0°C and neutralized with 5N hydrochloric acid (6 mL). A 30% aqueous sodium chloride solution (50 mL) and ethyl acetate (100 mL) were added, and insoluble materials were removed using Celite. The filtrate was extracted with ethyl acetate and washed with 30% aqueous sodium chloride solution. The mixture was dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to synthesize the title compound 31c (1.86 g, yield 83%) as a pale pink solid.

LC/MS mass spectrometry: m/z 302 ([M+H] ⁺ ).
LC/MS retention time: 0.90 minutes (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%).

Preparative conditions Equipment: SFC15 (Waters)
Column: CHIRALPAK-IE/SFC, 10 x 250 mm, 5 μm (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: 1 mL/min, room temperature Title compound retention time: 9.98 minutes, isomer retention time: 6.86 minutes It was determined by X-ray crystal structure analysis of Compound 31j that the title compound was S-form.

(Step 31-3)
5-[(4S)-2,2-Dimethyloxan-4-yl]-1H-indole-2-carboxylic acid (compound 31e)
Compound 31d (993 mg, 3.29 mmol) obtained in step 31-2 was dissolved in methanol (14.9 mL), 2M aqueous sodium hydroxide solution (3.62 mL, 7.25 mmol) was added dropwise, and the mixture was stirred at an external temperature of 65° C. for 1 hour. The reaction solution was cooled to an external temperature of 15° C., and 5N hydrochloric acid (1.52 mL, 7.58 mmol) was added dropwise. Water (7.45 mL) was added dropwise, and the precipitated solid was collected by filtration. The obtained solid was washed with water (5.0 mL) and dried under reduced pressure to obtain the title compound 31e (827 mg, yield 96%).

LC/MS mass spectrometry: m/z 274 ([M+H] ⁺ ).
LC/MS retention time: 0.65 minutes (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 lower. 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 below 10° C., and the mixture was stirred at room temperature for 1 hour. Water (4.0 mL) was added dropwise, and the precipitated solid was collected by filtration. The obtained solid was washed with water (8.0 mL) and dried under reduced pressure to obtain the title compound 31f (995 mg, yield 93%).

LC/MS mass spectrometry: m/z 363 ([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 8M potassium hydroxide aqueous solution (0.0 .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 stirred for 2.5 hours. 5N hydrochloric acid (0.193 mL), water (0.10 mL), and cyclopentyl methyl ether (1.0 mL) were added to the reaction solution for extraction, and the aqueous layer was extracted again with cyclopentyl methyl ether (1.0 mL). The combined organic layers were washed with a 15% aqueous sodium chloride solution (1.0 mL) and concentrated under reduced pressure at an external temperature of 40°C to obtain the title compound 31h as a light brown oil, which was passed on to the next step without purification. Used in 31-6.

LC/MS mass spectrometry: m/z 402 ([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 in the same manner as in Step 1-6 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 442 ([M+H] ⁺ ).
LC/MS retention time: 0.95 minutes (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 in the same manner as in Step 1-6 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 501 ([M+H] ⁺ ).
LC/MS retention time: 0.99 minutes (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 by the same procedure as in step 6-4 of Example 6 using an appropriate reagent.

LC/MS mass spectrometry: m/z 401 ([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]indole-1- yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 31l)
Compound 11l obtained in step 11-8 and compound 31k obtained in step 31-8 were synthesized in the same manner as in step 1-10 of Example 1 using appropriate reagents.

The halogen compound 5-bromo-1-(2-methoxyethyl)-3-methylbenzimidazol-2-one (compound 33b) used in the synthesis of example compound 33 was synthesized as follows.

(Step 33-1)

The compound was synthesized from 5-bromo-3-methyl-1H-benzimidazol-2-one (compound 33a) using an appropriate reagent in the same manner as in step 8-4 of Example 8.
LC/MS mass spectrometry: m/z 285 ([M+H] ⁺ ).

LC/MS retention time: 0.95 minutes (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.

(Step 36-1)

It was synthesized 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/z 273 ([M+H] ⁺ ).

LC/MS retention time: 1.10 minutes (analysis conditions: SMD-FA05-1).
The halogen compound (5-bromo-4-fluoro-1-[(3S)-oxolan-3-yl]indazole, compound 40a) used in the synthesis of Example compound 40 was synthesized as follows.

(Step 40-1)

Synthesized from 5-bromo-4-fluoro-1H-indazole (compound 28a) and 4-methylbenzenesulfonic acid [(3R)-oxolan-3-yl] (compound 22b) using appropriate reagents and the same procedure as in step 8-4 of Example 8.

LC/MS mass spectrometry: m/z 285 ([M+H] ⁺ ).
LC/MS retention time: 1.10 minutes (Analysis conditions: SMD-FA05-1).
2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4) used in the synthesis of Example Compound 41 -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) was synthesized as follows. .

(Steps 41-1 and 2)
1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-N-methyl-5-[(2S,4S)-2-methyloxan-4-yl]-N-phenylindole-2-carboxamide (Compound 41c)
A suspension of zinc (29 mg, 0.44 mmol) in DMA (0.12 mL) was degassed under reduced pressure at room temperature, and then replaced with nitrogen. Under a nitrogen atmosphere, a 7:5 mixed solution of chlorotrimethylsilane/1,2-dibromoethane (0.0083 mL, chlorotrimethylsilane: 0.039 mmol) was added, and after stirring for 15 minutes, (2S)-4-iodo -2-Methyltetrahydro-2H-pyran (80 mg, 0.35 mmol) was added dropwise at room temperature and stirred for 30 minutes to form a mixture containing iodo-[(2S)-2-methyloxan-4-yl]zinc (compound 41b). I got it. 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, degassed under reduced pressure, and then replaced with nitrogen. The mixture was stirred at 80°C for 1 hour. After cooling to room temperature, adding ethyl acetate and 1N hydrochloric acid and filtering, the filtrate was extracted with ethyl acetate. The organic layer was washed once with saturated brine, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1:1) to obtain the title compound 41c (31 mg, yield 51%). Ta.

LC/MS mass spectrometry: m/z 428 ([M+H] ⁺ ).
LC/MS retention time: 1.01 minutes (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 by the same procedure as in step 1-8 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 487 ([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-oxadiazole- 3-yl)cyclopropyl]indole-2-carboxylic acid (compound 41e)
Compound 41d obtained in Step 41-3 was synthesized in the same manner as in Step 6-4 of Example 6 using appropriate reagents.

LC/MS mass spectrometry: m/z 396 ([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-imidazole-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)
Compound 41e obtained in Step 41-4 was synthesized in the same manner as in Step 1-10 of Example 1 using appropriate reagents.

The 2-oxoimidazole reagent (3-[(
1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 42g) was synthesized as follows.

(Steps 42-1, 2)
(4S)-3-amino-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert -Butyl (compound 42c)
From 4-chloro-3,5-dimethylaniline (compound 42a), (4-chloro-3,5-dimethylphenyl)hydrazine was prepared using an appropriate reagent and in the same manner as in Step 2-2 of Example 2. After obtaining the hydrochloride (Compound 42b), Compound 42c was synthesized in the same manner as in Example 1, Step 1-2 using Compound 11g obtained in Step 11-4 and an appropriate reagent.

LC/MS mass spectrometry: m/z 391 ([M+H] ⁺ ).
LC/MS retention time: 1.22 minutes (Analysis conditions: SMD-FA10-4).
(Step 42-3)
(4S)-2-(4-chloro-3,5-dimethylphenyl)-3-(2,2-dimethoxyethylcarbamoylamino)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3- c] tert-butyl pyridine-5-carboxylate (compound 42d)
Compound 42c obtained in Step 42-2 was synthesized in the same manner as in Step 1-3 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 522 ([M+H] ⁺ ).
LC/MS retention time: 1.55 minutes (Analysis conditions: SMD-TFA05-5).
(Step 42-4)
(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4 , 3-c] tert-butyl pyridine-5-carboxylate (compound 42e)
Compound 42d obtained in Step 42-3 was synthesized in the same manner as in Step 11-8 of Example 11 using appropriate reagents.

LC/MS mass spectrometry: m/z 458 ([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)
Compound 42e obtained in Step 42-4 was synthesized in the same manner as in Step 111-8 of Example 11 using appropriate reagents.

LC/MS mass spectrometry: m/z 358 ([M+H] ⁺ ).
LC/MS retention time: 0.69 minutes (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 by the same procedure as in step 1-10 of Example 1 using appropriate reagents.

2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethylphenyl)) used in the synthesis of Example Compounds 44 and 45 -4-Methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxane-4 -yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 44a) was synthesized as follows.

(Step 44-1)
3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethyl
phenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 44a)
The compound 42f obtained in step 42-5 and the compound 8b obtained in step 8-1 were synthesized by the same procedure as in step 1-10 of Example 1 using appropriate reagents.

2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3-methylphenyl)-4) used in the synthesis of Example Compounds 46 and 47 -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) was synthesized as follows.

(Step 46-1)
(4S)-3-amino-2-(4-fluoro-3-methylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (Compound 46b)
The compound was synthesized from (4-fluoro-3-methylphenyl)hydrazine hydrochloride (compound 46a) and compound 11g obtained in step 11-4 by the same procedure as in step 1-2 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 361 ([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 by the same procedure as in step 1-3 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 492 ([M+H] ⁺ ).
LC/MS retention time: 1.03 minutes (Analysis conditions: SMD-FA05-1).
(Step 46-3)
(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3 -c] tert-butyl pyridine-5-carboxylate (compound 46d)
Compound 46c obtained in Step 46-2 was synthesized in the same manner as in Step 11-7 of Example 11 using appropriate reagents.

LC/MS mass spectrometry: m/z 428 ([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 in the same manner as in Step 11-8 of Example 11 using appropriate reagents.

LC/MS mass spectrometry: m/z 328 ([M+H] ⁺ ).
LC/MS retention time: 0.59 minutes (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)
Compound 46e obtained in step 46-4 and compound 8b obtained in step 8-1 were synthesized by the same procedure as in step 1-10 of Example 1 using appropriate reagents.

The 2-oxoimidazole reagent (3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 48a) used in the synthesis of example compounds 48 to 50 was synthesized as follows.

(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)
Compound 46e obtained in step 46-5 and compound 31k obtained in step 31-8 were synthesized in the same manner as in step 1-10 of Example 1 using appropriate reagents.

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

Compound 51d was synthesized as follows.

(Step 51-1)
2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5 -tert-butyl 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) were added triethylamine (0.936 mL, 6.72 mmol) and di-t-butyl dicarbonate (0 .425 mL, 1.85 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. After adding water (20.0 mL) and 5% aqueous potassium hydrogen sulfate solution (20.0 mL) to the reaction solution, the mixture was extracted with dichloromethane and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane = 0:1 to 1:0) to obtain the title compound 51a (0.360 g, yield 50%). Obtained.

LC/MS mass spectrometry: m/z 428 ([M+H] ⁺ ).
LC/MS retention time: 1.06 minutes (Analysis conditions: SMD-FA05-3).
(Step 51-2)
2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo tert-butyl [4,3-c]pyridine-5-carboxylate (compound 51b)
It was synthesized from Compound 51a obtained in Step 51-1 and 5-bromo-1-methylindazole in the same manner as in Step 1-11 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 558 ([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)
Compound 51b obtained in step 51-2 can be synthesized in step 11 of Example 11 using an appropriate reagent.
It was synthesized by the same procedure as in -9.

LC/MS mass spectrometry: m/z 458 ([M+H] ⁺ ).
LC/MS retention time: 0.78 minutes (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)
Compound 51c obtained in step 51-3 and compound 6f obtained in step 6-4 were synthesized in the same manner as in step 1-10 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 817 ([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 Step 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.

The compounds in Tables 2-5 have rotational isomers. For example, the ¹ H-NMR of Example Compounds 66 and 67 are as follows.
Example Compound 66
Main Rotamer
^1H -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=1.0Hz), 7.06 (1H,m), 7.04 (1H,s), 7.06 (1H,d,J=1.0Hz), 7.06 (1H,m), 7.06 (1H, _{s ...} = 6.0 Hz), 6.74 (1H, d, J = 3.1 Hz), 6.70 (1H, s), 6.32 (1H, d, J = 3.1 Hz), 5.79 (1H, q, J = 6.6 Hz), 4.47 (1H, dd, J = 13.6, 5.0 Hz), 4.12 (3H, s), 3.89-3.81 (2H, m), 3.60 (1H, ddd, J = 13.6, 13.1, 3.6 Hz), 3.15 (1H, ddd, J = 16.0, 13.1, 5.0 Hz), 3.09-2.98 (2H, m), 2.27 (6H, d, J _HF = 1.4 Hz), 1.91 (1H, dd, J = 6.0 Hz), 1.82-1.60 (4H, m), 1.60-1.50 (2H, m), 1.55 (3H, d, J = 6.6 Hz), 1.34 (3H, s), 1.28 (3H, s), 1.19 (3H, d, J = 5.9 Hz).

minor rotamer
¹ H-NMR (600 MHz, CDCl ₃ ) 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).

Example Compound 67
Main Rotamer
^1H -NMR (600MHz, _CDCl3 ) δ: 11.32 (1H,s), 8.13 (1H,d, _JHF =0.7Hz), 7.59 (1H,d,J=8.6Hz), 7.52
(1H,s), 7.48 (1H,dd,J = 8.9Hz, _JHF = 6.9Hz), 7.28 (1H,d,J = 8.9Hz), 7.26 (1H,dd,J = 8.6,1.7Hz), 7.16 (2H,d, _JHF = 6.1Hz), 6.70 (1H,s), 6.61 (1H,dd,J = 3.0Hz, _JHF = 1.1 Hz), 6.31 (1H, d, J = 3.0 Hz), 5.79 (1H, q, J = 6.7 Hz), 4.47 (1H, dd, J = 13.5, 5.2 Hz), 4.12 (3H, s), 3.88 (1H, m), 3.83 (1H, m), 3.60 (1H, ddd, J = 13.5, 12.9, 3.6 Hz), 3.15 (1H, ddd, J = 15.8, 12.9, 5.2 Hz), 3.04 (1H, m), 3.00 (1H, m), 2.29 (6H, d, J _HF = 1.1 Hz), 1.91 (1H, dd, J = 6.1, 5.8 Hz), 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, 5.8 Hz), 1.34 (3H, s), 1.28 (3H, s), 1.20 (3H, d, J = 6.0 Hz).

minor rotamer
^1H -NMR (600MHz, CDCl ₃ ) 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 = 8.8 Hz), 7.06 (2H, d, J _HF = 6.0 Hz), 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 , 12.2, 4.6Hz), 3.08-2.97 (3H, m), 2.25 (6H, s), 1.79-1.73 (3H, m), 1.67 (3H , d, J=6.6Hz), 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).

Compound 55e, used in the synthesis of Example Compound 55, was synthesized as follows.

(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)
Compound 42a obtained in Step 42-1 and Compound 1b obtained in Step 1-1 were synthesized in the same manner as in Step 1-2 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 377 ([M+H] ⁺ ).
LC/MS retention time: 0.87 minutes (analysis conditions: SQD-FA05-1).
(Step 55-2)
2-(4-chloro-3,5-dimethylphenyl)-3-(2,2-dimethoxyethylcarbamoylamino)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (Compound 55b)
The compound 55a obtained in step 55-1 was synthesized by the same procedure as in step 1-3 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 508 ([M+H] ⁺ ).
LC/MS retention time: 0.83 minutes (Analysis conditions: SQD-FA05-1).
(Step 55-3)
2-(4-chloro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5 -tert-butyl 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 hour. did. 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 hour. Water was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1:4 to 1:0) to give the title compound 55c (799 mg, yield) as a pale yellow foam. 100%) was obtained.

LC/MS mass spectrometry: m/z 444 ([M+H] ⁺ ).
LC/MS retention time: 0.82 minutes (analysis conditions: SQD-FA05-1).
(Step 55-4)
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 tert-butyl (Compound 55d)
The compound 55c obtained in step 55-3 and 5-bromo-1-methylindazole (compound 1q) were synthesized by the same procedure as in step 1-11 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 574 ([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.

LC/MS mass spectrometry: m/z 474 ([M+H] ⁺ ).
LC/MS retention time: 0.81 minutes (analysis conditions: SMD-FA05-1).
Compound 56c used in the synthesis of Example Compound 56 was synthesized as follows.

(Step 56-1)
2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1-(2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (Compound 56b)
The compound 51a obtained in step 51-1 and 5-bromo-1-(2-methoxyethyl)indazole (compound 56a) were synthesized by the same procedure as in step 1-11 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 602 ([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 used to synthesize the compound in the same manner as in step 11-8 of Example 11 using an appropriate reagent.

LC/MS mass spectrometry: m/z 502 ([M+H] ⁺ ).
LC/MS retention time: 0.54 minutes (analysis conditions: SQD-FA05-1).
The amine derivative (compound 57j) used in the synthesis of example compound 57 was synthesized as follows.

(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) was added triethylamine (0.0676 mL, 0.0 .487 mmol) and diphenylphosphoryl azide (0.10 mL, 0.465 mmol) were added at room temperature and stirred at room temperature for 100 minutes and then at 85° C. for 3.5 hours. The solvent of the reaction mixture was distilled off under reduced pressure to obtain the title compound 57b as a crude product.

^1H -NMR (400MHz, _CDCl3 ) δ: 12.3 (1H, brs), 3.95 (6H, brs), 1.45 (9H, s).
(Step 57-2)
(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[[4-[(2-methylpropan-2-yl)oxycarbonylamino]cuban-1-yl]carbamoylamino]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (Compound 57c)
The compound 57b obtained in step 57-1 and the compound 11h obtained in step 11-5 were synthesized by the same procedure as in step 1-3 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 636 ([M+H] ⁺ ).
LC/MS retention time: 0.93 minutes (analysis conditions: SQD-FA05-1).
(Step 57-3)
(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[5-hydroxy-3-[4-[(2-methylpropan-2-yl)oxycarbonylamino]cuban-1-yl]-2-oxoimidazolidin-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (Compound 57d)
1,2-dichloro-1-ethoxyethane (0.0155mL, 0.127mmol) was added to a suspension of compound 57c (31.6mg, 0.050mmol) obtained in step 57-2 and cesium carbonate (82.8mg, 0.254mmol) in DMA (0.25mL) at room temperature, and the mixture was stirred at room temperature for 170 minutes. Cesium carbonate (104mg, 0.32mmol) and then 1,2-dichloro-1-ethoxyethane (0.0184mL, 0.162mmol) were added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and water, and 1N hydrochloric acid (0.54mL) was added to adjust the pH to 7, and then the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was removed under reduced pressure, toluene was added, and the solvent was removed under reduced pressure to obtain the title compound 57d as a crude product.

LC/MS mass spectrometry: m/z 678 ([M+H] ⁺ ).
LC/MS retention time: 0.98 minutes (Analysis conditions: SQD-FA05-1).
(Step 57-4)
(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-[4-[(2-methylpropan-2-yl)oxycarbonylamino]cubane-1- tert-butyl]-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Compound 57e)
Methylsulfonic acid (0.011 mL, 0.17 mmol) was added to a THF (1.1 mL) solution of compound 57d (115 mg, 0.17 mmol) obtained in step 57-3 at room temperature, and the mixture was heated at 60°C for 90 min. Stir for a minute. Potassium phosphate (36.5 mg, 0.172 mmol), water (0.45 mL) and (2-methylpropan-2-yl)oxycarbonyl tert-butyl carbonate (0.012 mL, 0.052 mmol) were added to the reaction mixture. Stirred for 1 hour. The reaction mixture was diluted with dichloromethane and then washed with water. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1:2 to 1:1) to obtain the title compound 57e (48.5 mg, yield 43%).

LC/MS mass spectrometry: m/z 660 ([M+H] ⁺ ).
LC/MS retention time: 1.04 minutes (Analysis conditions: SQD-FA05-1).
(Step 57-5)
(4S)-3-[3-[4-[acetyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]cuban-1-yl]-2-oxoimidazol-1-yl]-2- tert-butyl (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 a 1.7 M potassium pentoxide toluene solution (0.024 mL, 0.02 mmol) at -26°C. 041 mmol) was added thereto, and the mixture was stirred at -30°C for 3 minutes. Acetic anhydride (8 μL, 0.085 mmol) was added to the reaction mixture at -30°C, and the mixture was stirred at -30°C to -25°C for 5 minutes and at -25°C to room temperature for 3 minutes. After adding water (0.5 mL) to the reaction mixture, it was 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 distilled off under reduced pressure, and purified by silica gel column chromatography (ethyl acetate/hexane = 1:3 to 2:3) to obtain the title compound 57f (9.2 mg, yield 54%). I got it.

LC/MS mass spectrometry: m/z 701 ([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)
TFA (0.019 mL) was added to a solution of Compound 57f (8.5 mg, 0.012 mmol) obtained in Step 57-5 in dichloromethane (0.097 mL) at room temperature, and the mixture was stirred at room temperature for 3 hours. After evaporating the solvent from the reaction mixture under reduced pressure, toluene was added and the solvent was evaporated, and hexane-dichloromethane was added and the solvent was evaporated to obtain 57 g (9.4 mg) of the title compound as a crude product.

LC/MS mass spectrometry: m/z 501 ([M+H] ⁺ ).
LC/MS retention time: 0.49 minutes (analysis conditions: SQD-FA05-1).
(Step 57-7)
(4S)-3-[3-(4-acetamidocuban-1-yl)-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (Compound 57h)
From compound 57g obtained in step 57-6, the compound was synthesized in the same manner as in step 51-1 of Example 51 using an appropriate reagent.

LC/MS mass spectrometry: m/z 602 ([M+H] ⁺ ).
LC/MS retention time: 0.85 minutes (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)
The compound 57h obtained in step 57-7 was synthesized by the same procedure as in step 57-5 of Example 57 using an appropriate reagent.

LC/MS mass spectrometry: m/z 660 ([M+H] ⁺ ).
LC/MS retention time: 0.93 minutes (Analysis conditions: SQD-FA05-1).
(Step 57-9)
N-[4-[3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c] Pyridin-3-yl]-2-oxoimidazol-1-yl]cuban-1-yl]-N-(2-methoxyethyl)acetamide hydrochloride (Compound 57j)
Compound 57i obtained in Step 57-8 was synthesized in the same manner as in Step 11-8 of Example 11 using appropriate reagents.

LC/MS mass spectrometry: m/z 560 ([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.

(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)
Compound 1b obtained in step 1-1 and compound 46a obtained in step 46-1 were synthesized in the same manner as in step 1-2 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 347 ([M+H] ⁺ ).
LC/MS retention time: 0.98 minutes (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)
The compound 58a obtained in step 58-1 was synthesized by the same procedure as in step 1-3 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 478 ([M+H] ⁺ ).
LC/MS retention time: 1.03 minutes (Analysis conditions: SMD-FA05-3).
(Step 58-3)
2-(4-fluoro-3-methylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carvone tert-butyl acid (compound 58c)
Compound 58b obtained in Step 58-2 was synthesized in the same manner as in Step 11-7 of Example 11 using appropriate reagents.

LC/MS mass spectrometry: m/z 414 ([M+H] ⁺ ).
LC/MS retention time: 0.72 minutes (analysis conditions: SQD-FA05-1).
(Step 58-4)
2-(4-fluoro-3-methylphenyl)-3-[3-[1-(2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (Compound 58d)
The compound 58c obtained in step 58-3 and 5-bromo-1-(2-methoxyethyl)indazole (compound 56a) were synthesized by the same procedure as in step 1-11 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 588 ([M+H] ⁺ ).
LC/MS retention time: 0.88 minutes (analysis conditions: SQD-FA05-1).
(Step 58-5)
1-[2-(4-fluoro-3-methylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[1-(2-methoxyethyl)indazol-5-yl]imidazol-2-one hydrochloride (compound 58e)
The compound 58d obtained in step 58-4 was synthesized by the same procedure as in step 11-9 of Example 11 using an appropriate reagent.

LC/MS mass spectrometry: m/z 488 ([M+H] ⁺ ).
LC/MS retention time: 0.50 minutes (Analysis conditions: SQD-FA05-1).
Compound 60c used in the synthesis of Example Compound 60 was synthesized as follows.

(Step 60-1)
tert 2-(3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid -Butyl (compound 60a)
Synthesis was performed from 1 g of the compound obtained in Step 1-4 in the same manner as in Step 51-1 of Example 51 using appropriate reagents.

LC/MS mass spectrometry: m/z 410 ([M+H] ⁺ ).
LC/MS retention time: 0.77 minutes (Analysis conditions: SQD-FA05-1).
(Step 60-2)
2-(3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3 -c] tert-butyl pyridine-5-carboxylate (compound 60b)
It was synthesized from Compound 60a obtained in Step 60-1 and 5-bromo-1-methylindazole (Compound 1q) in the same manner as in Step 1-11 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 540 ([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)
Compound 60b obtained in step 60-2 can be synthesized in step 11 of Example 11 using an appropriate reagent.
It was synthesized in the same manner as in -8.

LC/MS mass spectrometry: m/z 440 ([M+H] ⁺ ).
LC/MS retention time: 0.74 minutes (analysis conditions: SMD-FA05-2).
Compound 61b used in the synthesis of Example Compound 61 was synthesized as follows.

(Step 61-1)
(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6 ,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl (compound 61a)
It was synthesized from Compound 11k obtained in Step 11-7 and 5-bromo-1-methylindazole (Compound 1q) in the same manner as in Step 1-11 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 572 ([M+H] ⁺ ).
LC/MS retention time: 1.30 minutes (analysis conditions: SMD-FA05-1).
(Step 61-2)
1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1-methylindazol-5-yl)imidazol-2-one hydrochloride (compound 61b)
The compound 61a obtained in step 61-1 was synthesized by the same procedure as in step 11-8 of Example 11 using an appropriate reagent.

LC/MS mass spectrometry: m/z 472 ([M+H] ⁺ ).
LC/MS retention time: 0.79 minutes (analysis conditions: SMD-FA05-1).
Compound 62b used in the synthesis of Example Compound 62 was synthesized as follows.

(Step 62-1)
(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1-(2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (Compound 62a)
The compound 11k obtained in step 11-7 and 5-bromo-1-(2-methoxyethyl)indazole (compound 56a) were synthesized by the same procedure as in step 1-11 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 616 ([M+H] ⁺ ).
LC/MS retention time: 1.29 minutes (analysis conditions: SMD-FA05-1).
(Step 62-2)
1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[1-(2-methoxyethyl)indazol-5-yl]imidazol-2-one hydrochloride (compound 62b)
The compound 62a obtained in step 62-1 was synthesized by the same procedure as in step 11-8 of Example 11 using an appropriate reagent.

LC/MS mass spectrometry: m/z 516 ([M+H] ⁺ ).
LC/MS retention time: 0.76 minutes (analysis conditions: SMD-FA05-1).
Compound 63g used in the synthesis of Example Compound 63 was synthesized as follows.

(Step 63-1)
5-bromo-7-fluoro-N-methyl-N-phenyl-1H-indole-2-carboxamide (compound 63b)
It was synthesized from 5-bromo-7-fluoro-1H-indole-2-carboxylic acid (Compound 63a) by the same procedure as in Step 1-10 of Example 1 using appropriate reagents.

(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 an appropriate reagent.

LC/MS mass spectrometry: m/z 386 ([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 in the same manner as in Step 1-6 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 426 ([M+H] ⁺ ).
LC/MS retention time: 1.36 minutes (analysis conditions: SMD-FA05-1).
^1H -NMR (300MHz, _CDCl3 ) δ: 7.75 (1H,s), 7.43-7.30 (6H,m), 6.08 (1H,brs), 3.44 (3H,s), 2.11-1.69 (3H,m), 1.40-1.35 (3H,m).

(Step 63-4)
1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-7-fluoro-N-methyl-5-(oxan-4-yl)-N-phenylindole-2-carboxamide (compound 63e)
From Compound 63d obtained in Step 63-3 and (tetrahydro-2H-pyran-4-yl)zinc(II) iodide (Compound 8a), the same procedure as in Step 8-1 of Example 8 was carried out using an appropriate reagent. It was synthesized by a simple procedure.

LC/MS mass spectrometry: m/z 432 ([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 step 1-8 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 491 ([M+H] ⁺ ).
LC/MS retention time: 1.21 minutes (analysis conditions: SQD-FA05-01).
(Step 63-6)
7-Fluoro-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-5-(oxan-4-yl)indole-2-carboxylic acid (compound 63g)
The compound 63f obtained in step 63-5 was synthesized by the same procedure as in step 6-4 of Example 6 using an appropriate reagent.

LC/MS mass spectrometry: m/z 402 ([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.

(Step 64-1)
(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[2-oxo-3-[1-[(3R)-oxolan-3-yl]indazole-5- tert-butyl]imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 64a)
Compound 11k obtained in step 11-7 and compound 8f obtained in step 8-4 were synthesized in the same manner as in step 1-11 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 628 ([M+H] ⁺ ).
LC/MS retention time: 1.32 minutes (analysis conditions: SMD-FA05-1).
(Step 64-2)
1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[1-[(3R)-oxolan-3-yl]indazol-5-yl]imidazol-2-one hydrochloride (compound 64b)
The compound 64a obtained in step 64-1 was synthesized by the same procedure as in step 11-8 of Example 11 using an appropriate reagent.

LC/MS mass spectrometry: m/z 528 ([M+H] ⁺ ).
LC/MS retention time: 0.78 minutes (analysis conditions: SMD-FA05-1).
Compound 65c used in the synthesis of Example Compound 65 was synthesized as follows.

(Step 65-1)
(4S)-2-(4-chloro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-
Methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (Compound 65b)
The compound 42e obtained in step 42-4 and 5-bromo-4-fluoro-1-methylindazole (compound 65a) were synthesized by the same procedure as in step 1-11 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 606 ([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)
Compound 65b obtained in Step 65-1 was synthesized by the same procedure as in Step 11-8 of Example 11 using appropriate reagents.

LC/MS mass spectrometry: m/z 506 ([M+H] ⁺ ).
LC/MS retention time: 0.86 minutes (analysis conditions: SMD-FA05-1).
Compound 67b used in the synthesis of Example Compound 67 was synthesized as follows.

(Step 67-1)
(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-butyl (Compound 67a)
The compound 11k obtained in step 11-7 and 5-bromo-4-fluoro-1-methylindazole (compound 65a) were synthesized by the same procedure as in step 1-11 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 590 ([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)
Compound 67a obtained in Step 67-1 was synthesized by the same procedure as in Step 11-8 of Example 11 using appropriate reagents.

LC/MS mass spectrometry: m/z 490 ([M+H] ⁺ ).
LC/MS retention time: 0.80 minutes (Analysis conditions: SMD-FA05-1).
Compound 68c used in the synthesis of Example Compound 68 was synthesized as follows.

(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 11k obtained in step 11-7 and 5-bromo-4-chloro-1-methylindazole (compound 68a) were synthesized by the same procedure as in step 1-11 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 606 ([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 in the same manner as in Step 11-8 of Example 11 using appropriate reagents.

LC/MS mass spectrometry: m/z 506 ([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.

(Step 69-1)
( 4S)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-2-(4-fluoro-3-methylphenyl)-4-methyl -6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl (compound 69a)
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. .

LC/MS mass spectrometry: m/z 576 ([M+H] ⁺ ).
LC/MS retention time: 1.25 minutes (analysis conditions: SMD-FA05-1).
(Step 69-2)
1-(4-Fluoro-1-methylindazol-5-yl)-3-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one hydrochloride (compound 69b)
The compound 69a obtained in step 69-1 was synthesized by the same procedure as in step 11-8 of Example 11 using an appropriate reagent.

LC/MS mass spectrometry: m/z 476 ([M+H] ⁺ ).
LC/MS retention time: 0.77 minutes (analysis conditions: SMD-FA05-1).
Compound 70c used in the synthesis of Example Compound 70 was synthesized as follows.

(Step 70-1)
(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(6-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4 -methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl (compound 70b)
Synthesized from Compound 11k obtained in Step 11-7 and 5-bromo-6-fluoro-1-methylindazole (Compound 70a) using appropriate reagents in the same manner as in Step 1-11 of Example 1. .

LC/MS mass spectrometry: m/z 590 ([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)
From Compound 70b obtained in Step 70-1, using an appropriate reagent, Step 11 of Example 11
Synthesized by the same procedure as -8.

LC/MS mass spectrometry: m/z 490 ([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.

(Step 71-1)
5-Bromo-6-fluoro-1-(2-methoxyethyl)indazole (compound 71b)
The compound was synthesized from 5-bromo-6-fluoro-1H-indazole (compound 71a) using an appropriate reagent in the same manner as in step 8-4 of Example 8.

LC/MS mass spectrometry: m/z 273 ([M+H] ⁺ ).
LC/MS retention time: 1.06 minutes (Analysis conditions: SMD-FA05-1).
(Step 71-2)
(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[6-fluoro-1-(2-methoxyethyl)indazol-5-yl]-2-oxoimidazole-1 tert-butyl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 71c)
Compound 11k obtained in step 11-7 and compound 71b obtained in step 71-1 were synthesized in the same manner as in step 1-11 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 634 ([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)
Compound 71c obtained in Step 71-2 was synthesized in the same manner as in Step 11-8 of Example 11 using appropriate reagents.

LC/MS mass spectrometry: m/z 534 ([M+H] ⁺ ).
LC/MS retention time: 0.83 minutes (Analysis conditions: SMD-FA05-1).
<Example 73> 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] Synthesis of pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 73)
(Step 73-1)

Racemic compound (compound 73a, 29.6 mg, 0.058 mmol) synthesized in the same manner as the compound obtained in step 61-2 and compound 1o (26.8 mg, 0.064 mmol) obtained in step 1-9 HATU (26.6 mg, 0.070 mmol) and N,N-diisopropylethylamine (18.1 mg, 0.14 mmol) were added to a DMF (1.5 mL) solution of and stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and washed with distilled water. The organic layer was concentrated under reduced pressure to obtain a residue that was a mixture of stereoisomers. The stereoisomers were separated by reverse phase HPLC to obtain Entity A (14.5 mg, 29% yield) and Entity B (15.5 mg, 31% yield), which is the title compound 73 as a white solid.

Preparation 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/z 872 ([M+H] ⁺ ).

LC/MS retention time: 0.99 minutes (Analysis conditions: SMD-FA05-3).
Entity B (compound 73)
LC/MS mass spectrometry: m/z 872 ([M+H] ⁺ ).

LC/MS retention time: 1.01 minutes (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)

(Step 74-1)
5-Bromo-6-fluoro-N-methyl-N-phenyl-1H-indole-2-carboxamide (compound 74b)
The compound was synthesized from 5-bromo-6-fluoro-1H-indole-2-carboxylic acid (compound 74a) using an appropriate reagent in the same manner as in steps 1-10 of Example 1.

LC/MS mass spectrometry: m/z 347 ([M+H] ⁺ ).
LC/MS retention time: 1.06 minutes (Analysis conditions: SMD-TFA05-4).
(Step 74-2)
5-bromo-1-(cyanomethyl)-6-fluoro-N-methyl-N-phenylindole-2-carboxamide (compound 74c)
Compound 74b obtained in Step 74-1 was synthesized in the same manner as in Step 9-1 of Example 9 using appropriate reagents.

LC/MS mass spectrometry: m/z 386 ([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)
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, Step 1- of Example 1 was prepared. It was synthesized by the same procedure as in 6.

LC/MS mass spectrometry: m/z 426 ([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 in the same manner as in Step 1-8 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 485 ([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 in the same manner as in step 6-4 of Example 6 using an appropriate reagent.

LC/MS mass spectrometry: m/z 396 ([M+H] ⁺ ).
LC/MS retention time: 0.80 minutes (analysis conditions: SQD-FA05-1).
(Step 74-6)
3-[(1S,2S)-1-[5-bromo-6-fluoro-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 74g)
The compound 74f obtained in step 74-5 and the compound 61b obtained in step 61-2 were synthesized by the same procedure as in step 1-10 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 849 ([M+H] ⁺ ).
LC/MS retention time: 1.42 minutes (analysis conditions: SMD-FA05-1).
(Step 74-7)
3-[(1S,2S)-1-[6-fluoro-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 74)
The compound was synthesized in the same manner as in step 6-5 of Example 6 using compound 74g obtained in step 74-6, 4-iodo-2-methoxy-3-methylpyridine (compound 6g), and an appropriate reagent.

LC/MS mass spectrometry: m/z 892 ([M+H] ⁺ ).
LC/MS retention time: 1.48 minutes (analysis conditions: SMD-TFA05-1).
<Examples 75 to 77>
Using an indole bromide compound and an iodo(oxan-4-yl)zinc derivative, as well as an appropriate reagent, the same procedure as in Step 8-1 of Example 8 was carried out to obtain Example Compounds 75 to 77 shown in Table 2-6 according to the following reaction.

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)

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

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

(Step 76-1)
3-[(1S,2S)-1-[5-bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1-(2-methoxyethyl)indazole-] 5-yl]-2-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)
Compound 56b obtained in step 56-1 and compound 6f obtained in step 6-4 were synthesized in the same manner as in step 1-10 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 861 ([M+H] ⁺ ).
LC/MS retention time: 1.45 minutes (analysis conditions: SMD-FA05-2).
<Example 77>

(Step 77-1)
2-ethyl-4-iodooxane (compound 77b)
A solution of but-3-en-1-ol (0.588 mL, 6.93 mmol) in acetic acid (2.48 mL) was mixed with propionaldehyde (0.650 mL, 9.01 mmol) and lithium iodide (2.78 g, 20. 8 mmol) were added one after another, and the mixture was stirred at 60°C for 1 hour. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with a 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium bicarbonate solution, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure (150 hpa was the lower limit), and the residue was purified by silica gel chromatography (ethyl acetate/hexane = 0:1 to 1:9) to obtain the title compound 77b as a pale yellow oil. was obtained as a diastereomer mixture (1.12 g, yield 67%, syn:anti=1.00:0.45).

^1H -NMR (400MHz, _CDCl3 ):
syn δ: 4.31-4.23 (1H, m), 3.90-3.82 (1H, m), 3.44-3.37 (1H, m), 3.21-3.15 (1H, m), 2.37-1.38 (6H, m), 0.92 (3H, t, J = 7.4 Hz).

Anti δ: 4.87-4.84 (1H,m), 3.90-3.82 (2H,m), 3.70-3.64 (1H,m), 2.37-1.38 (6H,m), 0.94 (3H,t,J=7.6Hz).

(Step 77-2)
(2-ethyloxan-4-yl)-iodozinc (compound 77c)
To a solution of zinc (102 mg, 1.56 mmol) in DMA (0.25 mL) under a nitrogen atmosphere were added chloro(trimethyl)silane (0.017 mL, 0.137 mmol) and 1,2-dibromoethane (0.012 mL, 0.05 mmol). A mixture of 137 mmol) was slowly added dropwise while 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 while maintaining the temperature at 65° C. or lower, and the mixture was added dropwise at room temperature under a nitrogen atmosphere. The mixture was stirred for 30 minutes to obtain a DMA solution (0.86M) of a mixture of diastereomers of the title compound 77c.

(Step 77-3)
3-[(1S,2S)-1-[5-(2-ethyloxan-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1- methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl cyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 77)
Palladium(II) acetate (2.20 mg, 0.00978 mmol) and 2-(2-dicyclohexyl Phosphanylphenyl)-1-N,1-N,3-N,3-N-tetramethylbenzene-1,3-diamine (8.54 mg, 0.020 mmol) was added, degassed under reduced pressure, and then replaced with nitrogen. and stirred at room temperature for 5 minutes. Subsequently, a solution of Compound 77c obtained in Step 77-2 in DMA (0.86M, 0.398mL, 0.342mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. Formic acid was added to the reaction mixture, and the mixture was purified by reverse phase silica gel chromatography (acetonitrile/water, 0.1% formic acid) to obtain a syn diastereomer mixture. The syn diastereomer mixture was separated into stereoisomers by reverse phase HPLC, and Entity A (17.4 mg, yield 41%) was a white amorphous product and Entity B (the title compound 77) was a white amorphous product. 14.9 mg, yield 37%) was obtained.

Preparation conditions column: CHIRALCEL OD-RH 5μm, 4.6mm x 150mm (Daicel)
Solvent: 0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution = 20/80 (homogeneous system)
Flow rate: 1.0 mL/min, room temperature
Entity A
LC/MS mass spectrometry: m/z 851 ([M+H] ⁺ ).

HPLC retention time: 4.99 minutes (preparative separation conditions).
LC/MS retention time: 1.46 minutes (Analysis conditions: SMD-FA05-1).
Entity B (compound 77)
LC/MS mass spectrometry: m/z 851 ([M+H] ⁺ ).

HPLC retention time: 6.64 minutes (preparative separation conditions).
LC/MS retention time: 1.46 minutes (Analysis conditions: SMD-FA05-1).
<Example 78> 3-[(1S,2S)-2-ethyl-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazole-) 5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indole-1 Synthesis of -yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 78)

(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 51c obtained in step 51-3 and 5-bromo-1-(cyanomethyl)indole-2-carboxylic acid (compound 6a) were synthesized by the same procedure as in step 1-10 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 718 ([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 78a obtained in step 78-1 and (tetrahydro-2H-pyran-4-yl)zinc(II) iodide (compound 8a) were synthesized by the same procedure as in step 8-1 of Example 8 using an appropriate reagent.

LC/MS mass spectrometry: m/z 724 ([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-oxo imidazol-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 in the same manner as in Step 1-6 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 778 ([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)
From compound 78d obtained in step 78-2, the compound was synthesized by the same procedure as in step 1-8 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 837 ([M+H] ⁺ ).
LC/MS retention time: 1.39 minutes (Analysis conditions: SMD-TFA05-2).
<Example 79> 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]- Synthesis of 2-(hydroxymethyl)cyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 79)

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

LC/MS mass spectrometry: m/z 514 ([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)
From compound 79b obtained in step 79-1 and (tetrahydro-2H-pyran-4-yl)zinc(II) iodide (compound 8a), the same procedure as in step 8-1 of Example 8 was carried out using an appropriate reagent. It was synthesized by a simple procedure.

LC/MS mass spectrometry: m/z 520 ([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 in the same manner as in Step 1-8 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 579 ([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)
Compound 79d obtained in Step 79-3 was synthesized in the same manner as in Step 6-4 of Example 6 using appropriate reagents.

LC/MS mass spectrometry: m/z 490 ([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-oxoimidazole -1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-(phenylmethoxy methyl)cyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 79f)
Compound 79e obtained in step 79-4 and compound 51c obtained in step 51-3 were synthesized in the same manner as in step 1-10 of Example 1 using appropriate reagents.

LC/MS mass spectrometry: m/z 929 ([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-oxoimidazole -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 hexane solution of 1M boron trichloride (0.191 mL, 0.191 mmol) was added. was added slowly. The reaction solution was heated to room temperature, and after stirring for 105 minutes, a saturated aqueous sodium bicarbonate solution 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, yield 50%). .

LC/MS mass spectrometry: m/z 839 ([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)

(Step 80-1)
(E)-Ethyl 3-[[(2S)-1-cyanopropan-2-yl]amino]but-2-enoate (compound 80c)
Ethyl 3-oxobutanoate (compound 80a, 13 g, 99.9 mmol) was added to a solution of (3S)-3-aminobutanenitrile (compound 80b, 7.0 g, 83.2 mmol) and iodine (2.12 g, 8.35 mmol) in acetonitrile (50 mL), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 3:2) to obtain the title compound 80c (9.5 g, 58% yield) as a yellow oily substance.

LC/MS mass spectrometry: m/z 197 ([M+H] ⁺ ).
LC/MS retention time: 0.86 minutes (Analysis conditions: SMD-FA10-1).
(Step 80-2)
Ethyl 3-[[(2S)-1-cyanopropan-2-yl]amino]butanoate (compound 80d)
Acetic acid (3 mL) was added to a dichloromethane (200 mL) solution of compound 80c (10 g, 51.0 mmol) obtained in Step 80-1 and sodium triacetoxyborohydride (43.3 g, 204 mmol), and the mixture was stirred at room temperature for 16 hours. . After water and acetic acid were added to the reaction solution to adjust the pH to 5, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 1:4) to obtain the title compound 80d (5.5 g, yield 54%). was obtained as a yellow oil.

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.

At 0°C, a solution of acetic anhydride (12.1 g, 118 mmol) in toluene (5 mL) was slowly added dropwise to formic acid (7.26 g) and stirred at 0°C for 30 minutes, after which the prepared toluene solution of (6S)-4-hydroxy-2,6-dimethyl-1,2,3,6-tetrahydropyridine-5-carbonitrile was slowly added dropwise. After stirring at 110°C for 16 hours, the mixture was cooled to room temperature, the reaction solution was concentrated under reduced pressure, the solvent was distilled off, and a mixture (1.3 g) containing the title compound 80e was obtained as an oily substance.

(Step 80-4)
(4S)-3-Amino-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbaldehyde (compound 80f)
A solution of compound 80e (1.30 g, 7.21 mmol) obtained in step 80-3 and (4-fluoro-3,5-dimethylphenyl)hydrazine hydrochloride (compound 2c, 690 mg, 3.62 mmol) in ethanol (30 mL) was heated to 75° C. and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1:0 to 9:1) to obtain the title compound 80f (step 8).
From 0-3, 800 mg, 35% yield was obtained as a yellow solid.

LC/MS mass spectrometry: m/z 317 ([M+H] ⁺ ).
LC/MS retention time: 0.79 minutes (analysis conditions: SMD-FA10-3).
(Step 80-5)
1-(2,2-dimethoxyethyl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-5-formyl-4,6-dimethyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]urea (Compound 80g)
2,2-Dimethoxyethan-1-amine (1.14 g, 10.8 mmol) was added to a solution of N,N'-carbodiimidazole (1.63 g, 10.1 mmol) in DMA (50 mL) at 0°C, and the mixture was 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 in sequence. After stirring at room temperature for 6 hours, water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 80g (2.80 g, yield 75%) as a brown oily substance.

LC/MS mass spectrometry: m/z 448 ([M+H] ⁺ ).
LC/MS retention time: 0.84 minutes (analysis conditions: SMD-FA10-2).
(Step 80-6)
(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbaldehyde (compound 80h)
A solution of compound 80g (2.50 g, 5.59 mmol) obtained in step 80-5 and 4-methylbenzenesulfonic acid (1.06 g, 6.16 mmol) in DMF (30 mL) was heated to 80° C. and stirred for 2 hours. After cooling to room temperature, water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 3:1) to obtain a diastereomeric mixture (480 mg) containing the title compound (compound 80h) as a white solid.

LC/MS mass spectrometry: m/z 384 ([M+H] ⁺ ).
LC/MS retention time: 1.64 minutes (Analysis conditions: SMD-TFA05-6).
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) (480 mg, 5.59 mmol) was separated into stereoisomers by SFC, and the title compound 80h was obtained. Entity A (155 mg, yield 7.0%) and Entity B (270 mg, yield 12%) were obtained.

SFC preparative conditions Column: CHIRALPAK AD-H, 50 x 500 mm, 3 μm (Daicel)
Solvent: Supercritical carbon dioxide/ethanol = 70:30 (homogeneous system)
Flow rate: 150 mL/min, 35° C.
Detection wavelength: 254 nm
Entity A (Compound 80h)
SFC retention time: 4.07 min.

LC/MS mass spectrometry: m/z 384 ([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).

The fact that compound 80h is a 6R form was confirmed by 2D-NOESY that the configuration is cis.
Entity B
SFC retention time: 5.60 min.

LC/MS mass spectrometry: m/z 384 ([M+H] ⁺ ).
LC/MS retention time: 2.16 minutes (Analysis conditions: SMD-FA1060-1).
¹ H-NMR (300 MHz, DMSO-D ₆ ) δ: 10.35 (1 H, s), 8.31 (1 H, s), 7.08 (2 H, d, J = 6.3 Hz), 6.61 -6.54 (2H, m), 5.39 (1H, q, J = 6.9Hz), 3.89-3.84 (1H, m), 2.90 (1H, dd, J = 3. 3, 15.6Hz), 2.59-2.51 (1H, m), 2.20 (6H, d, J = 2.1Hz), 1.55 (3H, d, J = 6.6Hz), 1.18 (3H, d, J = 6.6Hz).

(Step 80-7)
3-[(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine- 3-yl]-1H-imidazol-2-one (compound 80i)
A 5M aqueous sodium hydroxide solution (0.261 mL) was added to a solution of compound 80h (100 mg, 0.261 mmol) obtained in Step 80-6 in ethanol (1.0 mL), and the mixture was stirred at 80° C. for 10 hours. After cooling to room temperature and stirring for 60 hours, saturated ammonium chloride aqueous solution was added and extracted with ethyl acetate to synthesize the title compound 80i (79%, 73 mg) as a white solid.

LC/MS mass spectrometry: m/z 356 ([M+H] ⁺ ).
LC/MS retention time: 0.44 minutes (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)
To a suspension of compound 80i (15 mg, 0.042 mmol) obtained in step 80-7, 5-bromo-1-methylindazole (compound 1q, 10.7 mg, 0.051 mmol), (1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine (6.00 mg, 0.042 mmol), and potassium carbonate (17.5 mg, 0.127 mmol) in N-methylpiperazine (0.188 mL), copper (I) iodide (4.02 mg, 0.021 mmol) was added at room temperature, and the mixture was stirred at 130° C. for 90 minutes under a nitrogen atmosphere. The reaction mixture was purified by reversed-phase silica gel chromatography (acetonitrile/water, 0.1% formic acid) and concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue, which was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain the title compound 80j (17.4 mg, 85% yield).

LC/MS mass spectrometry: m/z 486 ([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)
In a DMF (2.6 mL) solution of compound 8b (100 mg, 0.261 mmol) obtained in step 8-1, 55 wt% sodium hydride (34.1 mg, 0.782 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride ( 0.116 mL, 0.652 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, concentrated, and the resulting residue was purified by normal phase column chromatography (ethyl acetate/hexane) to give the title compound 80k (147 mg, yield 88%) as a yellow gum. %) was obtained.
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) was added magnesium bromide diethyl ether complex (295 mg, 1.14 mmol), and the mixture was heated at 0°C for 6. Stirred for 5 hours. After heating to room temperature and stirring for 30 minutes, saturated ammonium chloride aqueous solution was added, extracted with ethyl acetate, concentrated, the residue was diluted with DMSO and water, and subjected to reverse phase chromatography (acetonitrile/water, 0.1% formic acid). was purified to synthesize 80 liters (60 mg, yield 51%) of the title compound.

LC/MS mass spectrometry: m/z 512 ([M−H] ⁻ ).
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 801 (18 mg, 0.036 mmol) obtained in step 80-10 in acetonitrile (0.36 mL), 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.0057 mL, 0.043 mmol) was added, and the mixture was stirred at room temperature for 2 hours and then concentrated to obtain a crude product of the title compound 80m. This compound was used directly in the next step.

(Step 80-12)
3-[(1S,2S)-2-[2-[(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-[3-(1- methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl) indol-1-yl]-2-methylcyclopropyl]-4-(2-trimethylsilylethoxymethyl)-1,2,4-oxadiazol-5-one (compound 80n)
Compound 80m obtained in step 80-11 was dissolved in THF (0.717 mL), and compound 80j (19.1 mg, 0.036 mmol) obtained in step 80-8 and N,N-diisopropylethylamine (0.71 mL) were dissolved in THF (0.717 mL). After stirring at room temperature for 22 hours, methanol and formic acid were added. After concentration, the residue was diluted with DMSO and water and purified by reverse phase column chromatography (acetonitrile/water, 0.1% formic acid) to synthesize the title compound 80n (32 mg, yield 91%).

LC/MS mass spectrometry: m/z 982 ([M+H] ⁺ ).
LC/MS retention time: 1.12 minutes (analysis conditions: SQD-FA50-1).
(Step 80-13)
3-[(1S,2S)-1-[2-[(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 80)
Acetic acid (0.0019mL, 0.033mmol) and 1M tetrabutylammonium fluoride in THF solution (0.065mL, 0.065mmol) were added to the THF (0.326mL) solution of compound 80n (32mg, 0.033mmol) obtained in step 80-12, and the mixture was stirred at 80°C for 66 hours. Acetic acid (0.0019mL, 0.033mmol) and 1M tetrabutylammonium fluoride in THF solution (0.065mL, 0.065mmol) were added and the mixture was stirred for 23.5 hours, and then 1M tetrabutylammonium fluoride in THF solution (0.065mL, 0.065mmol) was added, and the mixture was stirred for 7 hours, and formic acid was added. After concentration, the mixture was diluted with DMSO and water, and purified by reverse phase column chromatography (acetonitrile/water, 0.1% formic acid) to synthesize the title compound 80 (18mg, yield 65%).

LC/MS mass spectrometry: m/z 851 ([M+H] ⁺ ).
LC/MS retention time: 1.42 minutes (analysis conditions: SMD-TFA05-1).
Moreover, in the same manner as in Examples 1 to 80, Example Compounds 101 to 159 shown in the following Table 2-7 were obtained.

Example 160: Preparation of monosodium salt hydrate crystals of Compound 1 Acetonitrile (3.02 mL) was added to 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, 1005.5 mg) obtained in Example 1, and the mixture was dissolved at room temperature. 5M aqueous sodium hydroxide solution (0.495 mL) and seed crystals of sodium salt hydrate of Compound 1 were added to the solution, and the mixture was stirred at room temperature for 2 hours. Further, tert-butyl methyl ether (3.02 mL) was added, and the mixture was stirred at room temperature for 1 hour, and then tert-butyl methyl ether (9.05 mL) was added, and the mixture was stirred at room temperature for 2 hours to obtain a sodium salt hydrate crystal of the title compound (1007.0 mg) as a powder crystal (Sample 160a). Note that the seed crystal was obtained by the following method.

Compound 1 (26.9 mg) was mixed with DMSO (0.244 mL) and 2 M aqueous sodium hydroxide solution (0.032 mL). This solution (0.030 mL) was freeze-dried at -20°C for 2 days. Acetonitrile (0.015 mL) was added to the resulting freeze-dried product, which was then 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 the sodium salt hydrate crystals of compound 1 as powder crystals (sample 160b).

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), and seed crystals of Example Compound 66 were added and stirred at 70° C. for 5 minutes. The suspension was stirred at 50° C. for 1 hour, and then at room temperature for 17 hours to obtain crystals of Example Compound 66 (381.1 mg) as powder crystals (Sample 161a). The seed crystals were obtained by the following method.

Example compound 66 (31.8 mg) was suspended in ethanol (0.636 mL), and 80
Stir at ℃. This suspension was stirred at 40° C. for 1 hour and then at room temperature for 22 hours to obtain crystals (24.2 mg) of Example Compound 66 as powdered crystals (Sample 161b).

Example 162: Preparation of 1/2 calcium salt hydrate crystals of Example Compound 67 Ethanol (5.60 mL) and 2M aqueous sodium hydroxide solution ( 0.75 mL) were added to 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), and the mixture was dissolved at room temperature. To this solution, 1.26M calcium acetate aqueous solution (0.68mL), seed crystals of calcium salt hydrate of Example Compound 67, and water (0.68mL) were added, and the mixture was stirred at room temperature for 3 hours. Water (1.2mL) was further added, and the mixture was stirred at room temperature for 1 hour, and then water (2.3mL) was added, and the mixture was stirred at room temperature for 1 hour to obtain calcium salt hydrate crystals of Example Compound 67 (973.0mg) as powder crystals (Sample 162a). The seed crystals were obtained by the following method.

Example compound 67 (69.0 mg) was dissolved in DMSO (0.229 mL), and 1.06 M calcium methoxyethoxide (0.147 mL) was added. This lysate (0.015 mL) was freeze-dried at -20°C for 2 days. A water-acetonitrile mixture (3:1, 0.015 mL) was added to the obtained 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 powder crystals. (Sample 162b).

<Example 163> Powder X-ray diffraction measurement Sodium salt hydrate crystals of Compound 1 obtained in Example 160 (Samples 160a and 160b), crystals of Example Compound 66 obtained in Example 161 (Samples 161a and 161b) ), the calcium salt hydrate crystals of Example Compound 67 (Samples 162a and 162b) obtained in Example 162 were each subjected to powder X-ray diffraction measurement using the following measurement method. The results are shown in Figures 1 to 6.

Measurement device: D8 Discover with GADDS CS diffractometer (manufactured by Bruker AXS)
Anticathode: Cu
Tube voltage: 40 kV
Tube current: 40mA
Scanning range: 5 to 25.3°
Sampling width: 0.02°
<Example 164> Thermogravimetry/Differential Thermal Analysis
The sodium salt hydrate crystals of Compound 1 (Sample 160a) and the calcium salt hydrate crystals of Example Compound 67 (Sample 162a) were subjected to thermogravimetry and differential thermal analysis by the following measurement method. The results are shown in Figures 7 and 8. Sample 160a was dehydrated to about 110°C and did not show a clear melting point. Sample 162a was dehydrated to about 240°C and did not show a clear melting point.

Measuring device: EXSTAR TG/DTA6200R (manufactured by Seiko Instruments (current company name: Hitachi High-Tech Science))
Measurement range: 30-350℃
Heating rate: 10℃/min Atmosphere: Nitrogen
<Example 165> Karl Fischer moisture measurement
The water percentage contained in the sodium salt hydrate crystals of Compound 1 (Sample 160a) and the calcium salt hydrate crystals of Example Compound 67 (Sample 162a) was measured using a coulometric Karl Fischer moisture meter (756 KF Coulometer manufactured by Metrohm). . The results were 7.4% for sample 160a and 6.2% for sample 162a.

The results of Examples 164 and 165 confirmed that the water contained in the sodium salt hydrate crystals of Compound 1 and the calcium salt hydrate crystals of Example Compound 67 was mainly water of crystallization.

<Test Example 1> In vitro cAMP signal activation measurement of compounds in human GLP1R
(peptide)
Human GLP-1 (7-37) was purchased from Peptide Institute, dissolved in phosphate buffered saline to a concentration of 200 μM, and stored in a −80° C. freezer.

(cell culture)
A cell line stably expressing human GLP1R (hGLP1R-HEK293) was used in the experiment. Cells were grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (Sigma-Aldrich), 100 units/mL penicillin G and 100 μg/mL streptomycin sulfate (Gibco), 500 μg/mL geneticin (Gibco). Culture was performed at 37° C. in a humidified atmosphere containing % _CO2 .

(cAMP assay)
hGLP1R-HEK293 was seeded in a 96-well plate at 2.0 x 10 cells ^per well and cultured overnight. The next day, add 50 μL of medium for cell culture to medium A (DMEM, 20mM HEPES, 0.05% BSA, 0.5mM 3-isobutyl-1-meth
ylxanthine) and incubated at 37°C for 30 minutes. Subsequently, 50 μL of medium B (DMEM, 20 mM HEPES, 0.05
%BSA, 0.5mM 3-isobutyl-1-methylxanthine) and further incubated at 37°C for 30 minutes. Then, 100 μL of Assay
lysis buffer (Applied Bioscience) was added and incubated at 37°C for 30 minutes. cAMP concentration was quantified using cAMP HiRange kit (Cisbio Bioassays).

(Calculation of _EC50 )
The cAMP concentration in each well was converted into a reaction rate (%), with the cAMP concentration when human GLP-1 (7-37) was applied at a concentration of 1 nM as 100%. XLfit (ver5.4.0
．． A dose-response curve for each example compound was created using four-parameter logistic regression analysis according to 8), and the 50% effective concentration (EC ₅₀ ) was calculated. The results are shown in Table 3.

Test Example 2: Insulin secretion promoting effect and blood glucose lowering effect Male cynomolgus monkeys were anesthetized and each was treated with 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, and the plasma drug concentration was set to a steady state of 0.94, 1.6, or 4.8 nmol/L. A control drug, exenatide solution (solvent: Tween 0.05%/PBS(-)), was also administered in the same manner, and the plasma drug concentration was set to a steady state of 9.2 or 23.9 pmol/L. The solvent group was administered with the solvent of Example Compound 67 solution. Next, a 50% glucose solution was administered intravenously so that the glucose amount was 0.5 g/kg, and blood was collected at 5- or 10-minute intervals to measure the plasma insulin concentration and glucose concentration. The area under the curve was calculated from the time course of each parameter after the drug administration time, and the insulin secretion promoting effect and blood glucose lowering effect were evaluated.

In the group administered 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 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 were observed at steady-state plasma concentrations of 9.2 to 23.9 pmol/L due to continuous intravenous administration (Figure 10).

In addition, the exenatide concentration of 9.2 pmol/L (38.5 pg/mL) is within the therapeutic concentration range of exenatide in human diabetic patients (50-350 pg/mL) (Drug Interview Form, Byetta Subcutaneous Injection 5 μg Pen 300, Byetta Subcutaneous Injection 10 μg Pen 300,
The values were close to the lower limit of the 9th revised edition (September 2016). From the above, it was demonstrated that Example Compound 67 exhibits insulin secretion promoting action and blood glucose lowering action equivalent to those of exenatide at a plasma concentration of 1.6 nmol/L or more.

Test Example 3: Food intake suppression effect Example compound 67 was orally administered to male cynomolgus monkeys for 5 consecutive days, and the effect on food intake for 90 minutes from 3 hours after administration was examined on each day. In addition, a control drug, exenatide, was subcutaneously administered for 5 consecutive days, and the effect on food intake for 90 minutes from 30 minutes after administration was examined. The solvent group contained a 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 a vehicle for subcutaneous administration of exenatide (0.05 w/v% Tween/PBS(-), 0.1 mL/kg) were administered. In accordance with this, a vehicle for subcutaneous administration was additionally administered to the Example Compound 67 administration group (administration drug concentration, 0.05 or 0.1 mg/mL), and a vehicle for oral administration was additionally administered to the exenatide administration group (administration drug concentration, 3 or 6 μg/mL).

Example compound 67 suppressed food intake in a dose-dependent manner (Figure 11A). The degree of suppression was almost equivalent to that of the control drug, exenatide (Figure 11B). The plasma drug concentrations (mean ± standard error) immediately after food intake measurement in each group were 8.0 ± 1.0 nM (0.05 mg/kg group) and 16.3 ± 2.3 nM (0.1 mg/kg group) in the Example compound 67 group, and 91 ± 8.5 pM (0.3 μg/kg group) and 199 ± 13.1 pM (0.6 μg/kg group) in the exenatide group.

<Test Example 4> Pharmacokinetics of Compound Suspension of calcium salt hydrate crystals (sample 162a) of Example Compound 67 obtained in Example 162 (dose: 0.05, 0.15, 0.45 and 1.35 mg/kg) to male cynomolgus monkeys (n = 2 for each dose) (forced intragastric administration using a gastric catheter), blood was collected from a vein over time and plasma was collected. The drug concentration in plasma was determined by liquid chromatography tandem mass spectrometry. The lower limit of quantification was 0.3 ng/mL. Figure 12 shows the change in plasma drug concentration, and shows the time to reach the maximum plasma drug concentration (T _max ), the maximum plasma drug concentration (C _max ), and the area under the plasma drug concentration-time curve (AUC _0-24h ) up to 24 hours after administration.
) are shown in Table 4.

Plasma drug concentrations after oral administration decreased with a similar time course pattern after reaching C _max 2 hours after administration at all doses. The increase in plasma drug exposure at doses of 0.05, 0.15, 0.45 and 1.35 mg/kg (dose ratio: 1:3:9:27) was approximately proportional to the dose increase (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 in the gastrointestinal tract in a dose-dependent manner and disappeared.

Claims (1)

In the manufacture of a medicament for non-invasive administration for use in the prevention or treatment of non-insulin dependent diabetes mellitus (type 2 diabetes) or obesity,
wherein X represents -N= or -CR ^a =; R ^a is selected from a hydrogen atom, a halogen atom, and a C _1-6 alkyl;
Y is selected from -C(=O)-, -CHR-, and -S(=O) ₂ -; R represents a hydrogen atom or a C _1-6 alkyl;
Q ¹ represents a C _6-10 aryl or a 5-10 membered heteroaryl, wherein the C _6-10 aryl and the 5-10 membered heteroaryl are optionally substituted by 1 to 5 substituents independently selected from halogen atoms, C _1-6 alkyl (wherein the C _1-6 alkyl is optionally substituted by one or more halogen atoms), and C _1-6 alkoxy;
Q ² represents a 3-12 membered heterocyclyl or a 5-10 membered heteroaryl, where the 3-12 membered heterocyclyl and the 5-10 membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from halogen atoms, C _1-6 alkyl (wherein C _1-6 alkyl is optionally substituted with one or more halogen atoms), C _1-6 alkoxy, and -NR ^Qa R ^Qb , and further, when Q ² is a 3-12 membered heterocyclyl, two C _1-6 alkyls may be joined together with one carbon atom to which they are both attached to form a C _3-8 carbocyclic ring; R ^Qa and R ^Qb are independently selected from a hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl)carbonyl;
R ¹ , R ² , and R ³ are each independently selected from a hydrogen atom and a C _1-6 alkyl (wherein the C _1-6 alkyl may be substituted with one or more substituents independently selected from a halogen atom, a C _1-6 alkoxy, and a hydroxyl);
R ⁴ , R ⁵ , and R ⁶ are each independently selected from a hydrogen atom, a halogen atom, and a C _1-6 alkyl;
R ⁷ and R ⁸ independently represent a hydrogen atom or a C _1-6 alkyl, where the C _1-6 alkyl may be substituted with one or more substituents independently selected from a halogen atom and a C _3-15 cycloalkyl, or R ⁷ and R ⁸ together with the carbon atom to which they are attached may form a C _3-15 cycloalkane ring, where the C _3-15 cycloalkane ring formed by R ⁷ and R ⁸ together may be substituted with one to three C _1-6 alkyl, where the C _1-6 alkyl may be substituted with one or more substituents independently selected from a halogen atom, a hydroxyl, -NR ^7a R ^7b , a C _1-6 alkoxy, and a 3- to 12-membered heterocyclyl, and R ^7a and R ^7b are independently selected from a hydrogen atom, a 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;
^R9 is represented by the formula (IIa), (IIb), (IIc), or (IId):
R ^9a , R ^9b , R ^9c , R ^9d and R ^9g are each independently selected from ^{a hydrogen} atom, a C _1-6 alkyl (wherein the C _1-6 alkyl may be substituted with one or more substituents independently selected from a halogen atom and a C _1-6 alkoxy), and (C _1-6 alkyl)carbonyl, R ^9e represents a hydrogen atom or a C _1-6 alkyl optionally substituted with one or more halogen atoms, R ^9f represents a hydrogen atom or a C _1-6 alkyl, R ^9h represents _{a hydrogen atom, a C 1-6 alkyl, a (C 1-6 alkyl )} carbonyl, cyano, or -S(=O) _n3 -R ⁹ⁱ ; n3 represents an integer of 0 to 2, ^and R ⁹ⁱ is selected from C represents _1-6 alkyl;
^Z1 is represented by the formula (IIIa), (IIIb), (IIIc), (IIId), and (IIIe):
R ^za is selected from a hydrogen atom, a C _1-6 alkyl, and a (C _1-6 alkyl)carbonyl, R ^zb and R ^zc independently represent a hydrogen atom or a C _1-6 alkyl, n4 represents an integer of 1 to 3, and n5 and n6 independently represent an integer of 0 to 10 (* represents a bonding site to the pyrazolopyridine skeleton, and ** represents a bonding site to Z ² );
Z ² is selected from C _1-6 alkyl, C _3-15 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl, where C _3-15 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl are selected from the group A:
Group A: a) oxo,
b) a halogen atom,
c) cyano,
d) ^-NRzdRze ; wherein ^Rzd and ^{Rze are} each independently selected from a hydrogen atom, a _C1-6 alkyl, and a ( _C1-6 alkyl)carbonyl, wherein the _C1-6 alkyl is optionally substituted with one or more substituents independently selected from a hydroxyl, a halogen atom, and a _C1-6 alkoxy;
e) -C(=O) ^-NRzfRzg ; wherein ^Rzf and ^{Rzg are} each independently selected from a hydrogen atom, a _C1-6 alkyl, and a ( _C1-6 alkyl)carbonyl, wherein the _C1-6 alkyl is optionally substituted with one or more substituents independently selected from a hydroxyl, a halogen atom, and a _C1-6 alkoxy;
f) -S(=O) _n7 -R ^zh ; where n7 represents an integer of 0 to 2, and R ^zh represents a hydrogen atom or a C _1-6 alkyl;
g) C _1-6 alkyl; wherein C _1-6 alkyl is optionally substituted by one or more substituents independently selected from halogen atoms, hydroxy, -NR ^zi R ^zj , C _1-6 alkoxy, and 3- to 12-membered heterocyclyl, wherein R ^zi and R ^zj independently represent a hydrogen atom or C _1-6 alkyl, and the 3- to 12-membered heterocyclyl is optionally substituted by one or more substituents independently selected from hydroxy, C _1-6 alkyl, and 3- to 12-membered heterocyclyl;
h) C _1-6 alkoxy; wherein the C _1-6 alkoxy is optionally substituted with one or more substituents independently selected from hydroxy, halogen atoms, and C _1-6 alkoxy;
i) 3- to 12-membered heterocyclyl; wherein the 3- to 12-membered heterocyclyl is optionally substituted by one or more substituents independently selected from C _1-6 alkyl and (C _1-6 alkyl)carbonyl;
j) C _6-10 aryl; wherein the C _6-10 aryl is optionally substituted with one or more (C _1-6 alkyl)carbonyl; and k) 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl is optionally substituted with one or more substituents independently selected from C _1-6 alkyl, C _1-6 alkoxy, -NR ^zk R ^zl , and 3-12 membered heterocyclyl, wherein R ^zk and R ^zl are independently selected from a hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl)carbonyl, and the 3-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from C _1-6 alkyl and (C _1-6 alkyl)carbonyl;
and optionally substituted with 1 to 5 substituents independently selected from
Use of a compound represented by the formula: