JP2019099571A - Pharmaceutical composition containing pyrazolopyridine derivative having GLP-1 receptor agonist activity - Google Patents

Abstract

To provide pharmaceutical compositions which have the same action as GLP-1 peptide as a GLP-1 receptor agonist, are capable of noninvasive administration, and contain a compound having improved activity, metabolic stability, and bioavailability or a salt thereof or a solvate thereof; and to provide methods for preventing or treating non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus) or obesity using the pharmaceutical composition.SOLUTION: The present invention provides a pharmaceutical composition which contains as active ingredient a compound having a base skeleton represented by formula (I) in which an indole ring and a pyrazolopyridine skeleton are linked via a substituent, or a salt thereof or a solvate thereof, and is used in the prevention and treatment of diabetes mellitus non-insulin-dependent (type 2 diabetes mellitus) or obesity.SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical composition comprising, as an active ingredient, a compound having the same action as GLP-1 as a GLP-1 receptor agonist or a salt thereof, or a solvate thereof. 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: glucagon-like peptide-1) is an incretin which is secreted from L cells in the small intestine when nutrients pass through the digestive tract, and glucose is mediated via the GLP-1 receptor It is known to exhibit various actions such as dependent insulin secretion promotion, glucagon secretion suppression, gastric emptying delay, food intake suppression and the like. GLP-1 analogues have already been put into practical use as anti-diabetic agents and are considered to be one of the most effective anti-diabetic agents because they show potent HbA1c reducing action and weight-reducing action, but they are all invasive Subcutaneous administration is required. Therefore, the creation of a non-invasively administrable GLP-1 receptor agonist is expected. For example, absorption promoter (sodium N- (8- (2-hydroxybenzoyl) amino) caprylate: SNAC
1) GLP-1 analogues: improvement of bioavailability when orally administered Semaglutide (Patent Document 1) and creation of low molecular weight GLP-1 receptor agonists (Patent Documents 2 and 3) There is a need for further improvement in the properties as a drug including activity, metabolic stability and bioavailability.

2-[(2,4,6,7-tetrahydro-5H-pyrazolo [4,3-c] pyridin-5-yl) carbonyl] -1H-indole (2-[(2,4,6,7-tetrahydro) The following two compounds for chemical library are known as -5H-pyrazolo [4,3-c] pyridine-5-yl) carbonyl] -1H-indol).

  Patent Document 4 discloses eukaryotes such as blastocrithidia: the following pyrazolopyridines as compounds useful for the prevention and treatment of sleeping sickness, leishmaniasis and the like caused by parasitism of Trypanosomatida. Derivatives have been described.

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

  The problem to be solved by the present invention is a compound having the same action as a GLP-1 receptor agonist as a GLP-1 receptor agonist, capable of non-invasive administration and capable of improving activity, metabolic stability and bioavailability. It is intended to provide a pharmaceutical composition containing the salt, or a solvate thereof, and also a method for preventing or treating non-insulin dependent diabetes mellitus (type 2 diabetes) or obesity using the pharmaceutical composition. It is to provide.

  The inventors of the present invention conducted intensive studies to solve such problems, and found that the compound represented by the formula (I) in which an indole ring and a pyrazolopyridine skeleton are linked via a substituent is GLP-1 As a receptor agonist, it has been found to have the same action as GLP-1 peptide, and the present invention has been completed.

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- to 10-membered heteroaryl, wherein C _6-10 aryl and 5- to 10-membered heteroaryl are each a halogen atom, C _1-6 alkyl (where C is _1-6 alkyl may be substituted by one to five substituents independently selected from one or more halogen atoms), and C _1-6 alkoxy;
Q ² represents 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl, wherein the 3 to 12 membered heterocyclyl and 5 to 10 membered heteroaryl are halogen atoms, C _1-6 alkyl (herein And C _1-6 alkyl may be substituted with one or more halogen atoms), C _1-6 alkoxy, and substituted with 1 to 3 substituents independently selected from -NR ^Qa R ^Qb Further, two C _1-6 alkyls may be taken together with the carbon atom to which they are attached to form a C _3-8 carbocyclic ring; R ^Qa and R ^Qb are independent Selected from hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl) carbonyl;
R ¹ , R ² and R ³ are each independently a hydrogen atom and C _1-6 alkyl (wherein C _1-6 alkyl is independently selected from a halogen atom, C _1-6 alkoxy and hydroxy Selected from one or more substituents);
R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen atom, halogen atom, and C _1-6 alkyl;
R ⁷ and R ⁸ independently represent a hydrogen atom or C _1-6 alkyl, wherein C _1-6 alkyl is one or more independently selected from a halogen atom and C _3-15 cycloalkyl It may be substituted by a substituent, 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, wherein C _1-6 alkyl is a halogen atom, hydroxy, R ^7a R ^7b , C _1-6 alkoxy, and one or more substituents independently selected from 3 to 12 membered heterocyclyl, and R ^7a and R ^7b are independently hydrogen atom, _1-6 is selected 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 is a group of the formulas (IIa), (IIb), (IIc), (IId):

R ^9a , R ^9b , R ^9c , R ^9d , and R ^9g are each independently a hydrogen atom, selected from the group represented by —CO ₂ R ^9f and —C (= O) —NR ^9g R ^9h ; , _{C 1-6} alkyl (wherein _{C 1-6} alkyl may be optionally substituted with one or more substituents independently selected from halogen atoms and _{C 1-6} alkoxy), and _{(C 1- 6} alkyl) is selected from ^{carbonyl, R 9e} represents a hydrogen atom or one or more _{C 1-6} alkyl optionally substituted by a halogen ^{atom,, 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) _{n 3} -R ⁹ⁱ ; n 3 represents an integer of 0 to 2, R ⁹ⁱ is, _{C 1} It represents _alkyl;
Z ¹ is any of the formulas (IIIa), (IIIb), (IIIc), (IIId), and (IIIe):

R ^z is selected from a hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl) carbonyl, and R ^zb and R ^zc are independently a hydrogen atom or C _{1 -6} alkyl, n4 represents an integer of 1 to 3, n5 and n6 each independently represent an integer of 0 to 10 (* represents a binding site to a pyrazolopyridine skeleton, and ** represents Each represents a binding site to Z ² );
Z ² _{is, C 1-6 alkyl, C 3-15} cycloalkyl, 3-12 membered _{heterocyclyl,} heteroaryl of _{C 6-10} aryl, and 5-10 membered, _{where, C 3-15} cycloalkyl Alkyl, 3-12 membered heterocyclyl, C _6-10 aryl, and 5
10-membered heteroaryl is a group A:
Group A: a) oxo,
b) halogen atom,
c) cyano,
d) -NR ^zd R ^ze ; wherein each of R ^zd and R ^ze is independently selected from hydrogen atom, C _1-6 alkyl and (C _1-6 alkyl) carbonyl, wherein C _1-6 alkyl Is optionally substituted with one or more substituents independently selected from hydroxy, a halogen atom, and C _1-6 alkoxy
e) —C (= O) —NR ^zf R ^zg ; wherein each of R ^zf and R ^zg is independently selected from hydrogen atom, C _1-6 alkyl and (C _1-6 alkyl) carbonyl, and _Wherein C _1-6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy, halogen atoms, and C _1-6 alkoxy
f) -S (= O) _n7 -R ^zh ; wherein 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; wherein C _1-6 alkyl is independently selected from a halogen atom, hydroxy, —NR ^zi R ^zj , C _1-6 alkoxy, and 3- to 12-membered heterocyclyl 1 The substituent may be substituted by the above substituent, wherein R ^zi and R ^zj independently represent a hydrogen atom or C _1-6 alkyl, and a 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; wherein C _1-6 alkoxy may be substituted with one or more substituents independently selected from hydroxy, a halogen atom, and C _1-6 alkoxy,
i) 3-12 membered heterocyclyl; heterocyclyl wherein 3 to 12 _members, optionally substituted by _{C 1-6} alkyl and _{(C 1-6} alkyl) 1 or more substituents independently selected from carbonyl Also,
j) C _6-10 aryl; wherein C _6-10 aryl may be substituted with one or more (C _1-6 alkyl) carbonyl, and k) 5-10 membered heteroaryl; The ^10- to 10-membered heteroaryl is substituted by one or more substituents independently selected from C _1-6 alkyl, C _1-6 alkoxy, -NR ^zk R ^zl , and ^{3- to} 12-membered heterocyclyl R ^zk and R ^zl are independently selected from hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl) carbonyl, and ^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,
And may be substituted with 1 to 5 substituents independently selected from
The pharmaceutical composition containing the compound represented by these, its salt, or the solvate of any one of them.

[2] Q ¹ is phenyl or pyridyl, wherein phenyl and pyridyl are substituted with 1 to 4 substituents independently selected from a halogen atom and C _1-6 alkyl, [1 ] The pharmaceutical composition as described in.

[3] Whether 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 R ⁷ and R ⁸ are together formed C _{3 -8} cycloalkane ring may be substituted with one to two _{C 1-6} alkyl, wherein _{C 1-6} alkyl is _hydroxy, heterocyclyl of _{C 1-6} alkoxy, and 3-12 membered The pharmaceutical composition according to [1] or [2], which may be substituted with one or more substituents selected independently.

[4] ^{Z 2} _{is, C 1-6 alkyl, C 3-15} cycloalkyl, 3-12 membered _{heterocyclyl,} heteroaryl of _{C 6-10} aryl, and 5-10 membered, wherein _{C 3- 15} cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl are groups B:
Group B: a) oxo,
b) halogen atom,
c) -NR ^zd1 R ^ze1 ; wherein R ^zd1 and R ^ze1 are independently selected from hydrogen atom, C _1-6 alkyl and (C _1-6 alkyl) carbonyl, wherein C _1-6 alkyl And may be substituted with one or more substituents independently selected from C _1-6 alkoxy,
d) -S (= O) _n7 -R ^zh1 ; wherein n7 represents an integer of 0 to 2 and R ^zh1 represents a C _1-6 alkyl;
e) C _1-6 alkyl; wherein C _1-6 alkyl is independently selected from a halogen atom, hydroxy, —NR ^zi R ^zj , C _1-6 alkoxy, and 3- to 12-membered heterocyclyl 1 The substituent may be substituted by the above substituent, wherein R ^zi and R ^zj independently represent a hydrogen atom or C _1-6 alkyl, and a 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; wherein C _1-6 alkoxy may be substituted with one or more hydroxy,
g) 3 to 12 membered heterocyclyl; wherein the 3 to 12 membered heterocyclyl may be optionally substituted by one or more (C _1-6 alkyl) carbonyl, and h) 5 to 10 membered heteroaryl; And 5- to 10-membered heteroaryl may be substituted by C _1-6 alkyl, and one or more substituents independently selected from -NR ^zk1 R ^zl 1, wherein R ^zk1 and R ^{zl 1} Is independently selected from hydrogen atom 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 compound of formula (IIb):

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

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

The pharmaceutical composition according to any one of [1] to [9] (* represents a binding site to a pyrazolopyridine skeleton, and ** represents a binding site to Z ² ) .
[11] 3-[(1S, 2S) -1- [5-[(4S) -2,2-dimethylan-4-yl] -2-[(4S) -2- (4-fluoro-3)] 5,5-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, The pharmaceutical composition in any one of [1]-[10].

[12] The pharmaceutical composition according to any one of [1] to [11], which contains the compound represented by the formula (I) or a salt thereof as a hydrate.
[13] non-insulin dependent diabetes (type 2 diabetes), hyperglycemia, glucose intolerance, insulin dependent diabetes (type 1 diabetes), diabetic complications, obesity, hypertension, dyslipidemia, arteriosclerosis The pharmaceutical composition according to any one of [1] to [12] for use in the prevention or treatment of coronary heart disease, cerebral infarction, nonalcoholic steatohepatitis, Parkinson's disease, or dementia . Here, examples of dementia include, for example, 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] Non-insulin dependent diabetes mellitus (type 2 diabetes), hyperglycemia, glucose intolerance disorder, insulin dependency comprising administering the pharmaceutical composition according to any of [1] to [12] to a subject Diabetes mellitus (type 1 diabetes), diabetic complications, obesity, hypertension, dyslipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, nonalcoholic steatohepatitis, Parkinson's disease, or dementia Methods of prevention or treatment. Here, examples of dementia include, for example, Alzheimer's disease.

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

  The compound represented by the formula (I), a salt thereof or a solvate thereof contained in the pharmaceutical composition of the present invention has the same action as the GLP-1 peptide as a GLP-1 receptor agonist There is provided a preventive or therapeutic agent for non-peptide non-insulin dependent diabetes (type 2 diabetes) or obesity which is expected to have sufficient bioavailability orally.

The result of the powder X-ray-diffraction measurement of the sodium salt hydrate crystal (sample 160a) of the compound 1 obtained in Example 163 is shown. The vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2θ (°). The result of the powder X-ray-diffraction measurement of the sodium salt hydrate crystal (sample 160b) of the compound 1 obtained in Example 163 is shown. The vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2θ (°). The result of the powder X-ray-diffraction measurement of the crystal (sample 161a) of the example compound 66 obtained in Example 163 is shown. The vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2θ (°). The result of the powder X-ray-diffraction measurement of the crystal (sample 161b) of the example compound 66 obtained in Example 163 is shown. The vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2θ (°). The result of the powder X-ray diffraction measurement of the calcium salt hydrate crystal of the example compound 67 (sample 162a) obtained in Example 163 is shown. The vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2θ (°). The result of the powder X-ray diffraction measurement of the calcium salt hydrate crystal (sample 162b) of the example compound 67 obtained in Example 163 is shown. The vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2θ (°). The results of thermogravimetric measurement / differential thermal analysis of sodium salt hydrate crystals of Compound 1 obtained in Example 164 are shown. The horizontal axis is the 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 thermogravimetric measurement / differential thermal analysis of calcium salt hydrate crystals of Example Compound 67 obtained in Example 164 are shown. The horizontal axis is the 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. Effects of example compound 67 and exenatide on insulin secretion after intravenous administration of glucose in male cynomolgus monkeys. The area under the insulin curve is shown as mean ± standard error (n = 6). Each drug was administered by crossover method. * Indicates P <0.025 and ** indicates P <0.005, which is significant with respect to the solvent group (Williams test). Each drug concentration shows the average value of the measured plasma drug concentration. Effects of example compound 67 and exenatide on plasma glucose levels after intravenous administration of glucose in male cynomolgus monkeys. The area under the plasma glucose curve is shown as mean ± standard error (n = 6). Each drug was administered by crossover method. * Indicates P <0.025 and ** indicates P <0.005, which is significant with respect to the solvent group (Williams test). Each drug concentration shows the average value of the measured plasma drug concentration. Effects of example compound 67 and exenatide on food consumption of male cynomolgus monkeys. Food intake is shown as mean ± standard deviation (n = 6). Each drug was administered by crossover method. * Indicates P <0.025 and ** indicates P <0.005, which is significant with respect to the solvent group (Williams test). Changes in plasma drug concentrations when the substance is orally administered to cynomolgus monkeys. Both plasma concentrations and each dose display the mean value of n = 2.

Hereinafter, the present invention will be further described in a nonlimiting manner.
Definitions In the present invention, "halogen atom" means fluorine atom, chlorine atom, bromine atom, iodine atom and the like. In the present invention, when the halogen atom is a substituent such as aryl (for example, R ^a in the case where X in the formula (I) is —CR ^a =), preferred halogen atoms include fluorine and chlorine atoms. Be In the present invention, when the halogen atom is a substituent such as alkyl (for example, C _6-10 aryl of Q ¹ in the formula (I) or 5- to 10-membered heteroaryl is substituted by C _1-6 alkyl) Further, as the substituent) in the case, preferred halogen atoms include fluorine atom and 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-pentafluoro Butyl, 4
2,4-dichlorobutyl, 5-iodopentyl, 5,5-difluoropentyl, 6-chlorohexyl, 6,6,6-trifluorohexyl and the like.

In the present invention, “C _1-6 alkyl” is a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethyl Propyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 2-ethylbutyl and the like can be mentioned.

The _{"C 1-6} alkoxy" in the present _invention means a _{C 1-6} alkyl -O- group wherein _{C 1-6} alkyl is as previously defined. 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-methyl pentyloxy, 2-ethyl butoxy and the like.

The _{"(C 1-6} alkyl) carbonyl" in the present _{invention, (C 1-6} alkyl) -C (O) -, group, _{C 1-6} alkyl this is as previously defined. For example, methylcarbonyl (acetyl), ethylcarbonyl (propionyl), n-propylcarbonyl, i-propylcarbonyl, n-butylcarbonyl, i-butylcarbonyl, sec-butylcarbonyl, t-butylcarbonyl, 1-methylpropylcarbonyl, n-Pentylcarbonyl, isopentylcarbonyl, 2-methylbutylcarbonyl, 1,1-dimethylpropylcarbonyl, 1-ethylpropylcarbonyl, n-hexylcarbonyl, 4-methylpentylcarbonyl, 2-ethylbutylcarbonyl and the like.

In the present invention, “C _6-10 aryl” means an aromatic carbocyclic group, and may have a nonaromatic 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
-Isoquinoline-3-onyl, 1,3-dihydrobenzimidazole-2-onyl and the like can be mentioned, with preference given to phenyl.

  In the present invention, “heteroaryl” is an aromatic 5- to 10-membered member containing one or more hetero atoms selected from nitrogen atom, oxygen atom, and sulfur atom in atoms constituting a ring. In addition to the aromatic moiety, it may have a nonaromatic moiety. The ring may be monocyclic or bicyclic heteroaryl fused to a benzene ring or a monocyclic heteroaryl ring. For example, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyridazinyl, triazinyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzothiazolyl, Benzoxazolyl, benzooxadiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyridyl, benzoisoxazolyl, benzisothiazolyl, etc. It can be mentioned.

In the present invention, "heterocyclyl" means a non-aromatic cyclic group containing one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms, and is completely saturated or a moiety May be 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” is a monovalent group derived by removing one arbitrary hydrogen atom from a cyclic saturated aliphatic hydrocarbon having 3 to 15 carbon atoms. Moreover, " _C3-8 cycloalkyl" is a C3-C8 cycloalkyl. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned. Moreover, " _C3-6 cycloalkyl" is a C3-C6 cycloalkyl. When two groups are taken together to form a C _3-15 cycloalkane ring, the group is a divalent group. For example, cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, cycloheptane-1,1-diyl, cyclooctane-1, 1-diyl etc. are mentioned.

When groups on two carbon atoms combine to form a C _3-8 carbocyclic ring, 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 ₂ CH _2- , -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH _{2-, and the} like.

In addition, the cyclic hydrocarbon in the cycloalkane ring, the carbon ring and the cycloalkyl may be a bridged ring. As a bridged ring in C _3-15 cycloalkyl, for example, 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 the like, and examples of C _3-15 cycloalkyl comprising 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, cuvanil and the like.

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

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

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

Q ² represents 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl, wherein the 3 to 12 membered heterocyclyl and 5 to 10 membered heteroaryl are halogen atoms, C _1-6 alkyl (herein And C _1-6 alkyl may be substituted with one or more halogen atoms), C _1-6 alkoxy, and substituted with 1 to 3 substituents independently selected from -NR ^Qa R ^Qb Further, two C _1-6 alkyls may be taken together with the carbon atom to which they are attached to form a C _3-8 carbocyclic ring; R ^Qa and R ^Qb are independent the hydrogen _atom, is selected from _{C 1-6} alkyl, and _{(C 1-6} alkyl) carbonyl. Preferably, Q ² represents i) a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl may be substituted by one or more C _1-6 alkyl, and further, two C _1-6 Alkyl together with the carbon atom to which they are attached may form a C _3-8 carbocycle, or ii) represents a 5-6 membered heteroaryl, wherein 5-6 membered heteroaryl is halogen _{atom, C 1-6 alkyl, C 1-6} alkoxy, and ^-NR Qc ^{R Qd} independently from may be substituted with 1-3 substituents ^{selected; R Qc} and ^{R Qd} It is independently selected from hydrogen atoms and _{C 1-6} alkyl. Also preferably, Q ² represents 5-6 membered heterocyclyl or heteroaryl, wherein 5-6 membered heterocyclyl and 5-6 membered heteroaryl are 1 to 3 C _1-6 It may be substituted by alkyl.

R ¹ , R ² and R ³ are each independently a hydrogen atom and C _1-6 alkyl (wherein C _1-6 alkyl is independently selected from a halogen atom, C _1-6 alkoxy and hydroxy Selected from one or more substituents). Preferably, the combinations of R ¹ , R ² and R ³ are all hydrogen atoms; 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, R ² is _{C 1-6} alkyl, ^{R 3} is selected from _{C 1-6} alkyl.

R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen atom, halogen atom and C _1-6 alkyl. Each of R ⁴ , R ⁵ and R ⁶ is preferably independently a hydrogen atom or a fluorine atom. More preferably, the combinations of R ⁴ , R ⁵ and R ⁶ are all hydrogen atoms; 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 C _1-6 alkyl, wherein C _1-6 alkyl is one or more independently selected from a halogen atom and C _3-15 cycloalkyl And 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, wherein R ⁷
And the C _3-15 cycloalkane ring formed together with R ⁸ may be substituted with 1 to 3 C _1-6 alkyl, wherein C _1-6 alkyl is a halogen atom, hydroxy , -NR ^7a R ^7b , C _1-6 alkoxy, and 3- to 12-membered heterocyclyl optionally substituted with one or more substituents, wherein R ^7a and R ^7b are independently hydrogen _atom, is selected from _{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 R ⁷ and R ⁸ are formed together C _3-8 cycloalkyl may be optionally substituted with one or more _{C 1-6} alkyl, wherein _{C 1-6} alkyl may be optionally substituted with one or more hydroxy. _{Also, C 3-8 cycloalkyl,} preferably a _{C 3-6} cycloalkyl. As preferable _C3-6 cycloalkyl, a cyclopentyl is mentioned, for example.

  n1 represents an integer of 0 to 3; n2 represents an integer of 0 to 5; Each of n1 and n2 is preferably 0-2, more preferably 0-1, and still more preferably 0. Moreover, 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 more preferred.

R ⁹ is a group of the formulas (IIa), (IIb), (IIc), (IId):

R ^9a , R ^9b , R ^9c , R ^9d , and R ^9g are each independently a hydrogen atom, selected from the group represented by —CO ₂ R ^9f and —C (= O) —NR ^9g R ^9h ; , _{C 1-6} alkyl (wherein _{C 1-6} alkyl may be optionally substituted with one or more substituents independently selected from halogen atoms and _{C 1-6} alkoxy), and _{(C 1- 6} alkyl) selected from carbonyl, R 9 ^e represents a hydrogen atom, or C _1-6 alkyl optionally substituted with one or more substituents independently selected from a halogen atom, R ^{9 f} is hydrogen R ^9h represents a hydrogen atom, C _1-6 alkyl, (C _1-6 alkyl) carbonyl, cyano, or -S (= O) _{n 3} -R ⁹ⁱ ; n 3 represents an atom or C _1-6 alkyl; 0-2 Represents the ^{number, R 9i} _{represents C 1-6} alkyl.

Z ¹ is any of the formulas (IIIa), (IIIb), (IIIc), (IIId), and (IIIe):

R ^z is selected from a hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl) carbonyl, and R ^zb and R ^zc are independently a hydrogen atom or C _{1 And} n4 represents an integer of 1 to 3; n5 and n6 independently represent an integer of 0 to 10;

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

Group A: a) oxo,
b) halogen atom,
c) cyano,
d) -NR ^zd R ^ze ; wherein each of R ^zd and R ^ze is independently selected from hydrogen atom, C _1-6 alkyl and (C _1-6 alkyl) carbonyl, wherein C _1-6 alkyl Is optionally substituted with one or more substituents independently selected from hydroxy, a halogen atom, and C _1-6 alkoxy
e) —C (= O) —NR ^zf R ^zg ; wherein each of R ^zf and R ^zg is independently selected from hydrogen atom, C _1-6 alkyl and (C _1-6 alkyl) carbonyl, and _Wherein C _1-6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy, halogen atoms, and C _1-6 alkoxy
f) -S (= O) _n7 -R ^zh ; wherein 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; wherein C _1-6 alkyl is independently selected from a halogen atom, hydroxy, —NR ^zi R ^zj , C _1-6 alkoxy, and 3- to 12-membered heterocyclyl 1 The substituent may be substituted by the above substituent, wherein R ^zi and R ^zj independently represent a hydrogen atom or C _1-6 alkyl, and a 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; wherein C _1-6 alkoxy may be substituted with one or more substituents independently selected from hydroxy, a halogen atom, and C _1-6 alkoxy,
i) 3-12 membered heterocyclyl; heterocyclyl wherein 3 to 12 _members, optionally substituted by _{C 1-6} alkyl and _{(C 1-6} alkyl) 1 or more substituents independently selected from carbonyl Also,
j) C _6-10 aryl; wherein C _6-10 aryl may be substituted with one or more (C _1-6 alkyl) carbonyl, and k) 5-10 membered heteroaryl; The ^10- to 10-membered heteroaryl is substituted by one or more substituents independently selected from C _1-6 alkyl, C _1-6 alkoxy, -NR ^zk R ^zl , and ^{3- to} 12-membered heterocyclyl R ^zk and R ^zl are independently selected from hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl) carbonyl, and ^3- to 12-membered heterocyclyl is C _1-6 It may be substituted by one or more substituents independently selected from alkyl and (Ci- 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- alkyl. ₄ alkyl.

Sometimes 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) 1 to 3 substituents independently selected from group C It is selected from C _6-10 aryl which may be substituted, and 5-10 membered heteroaryl which may be substituted by 1 to 3 substituents independently selected from iii) D group.

More preferably, Z ² is independently selected from i) C _6-10 aryl optionally substituted with 1 to 3 substituents independently selected from C group, and ii) D group It is selected from 5- to 10-membered heteroaryl optionally substituted by 1 to 3 substituents.

Group C: a) halogen atom,
b) -NR ^zd2 R ^ze2 ; wherein R ^zd2 and R ^ze2 are independently selected from hydrogen atom, C _1-6 alkyl and (C _1-6 alkyl) carbonyl, wherein C _1-6 alkyl And may be substituted with one or more C _1-6 alkoxy,
c) -S (= O) _n7 -R ^zh1 ; wherein n7 represents an integer of 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 may be substituted by one or more hydroxy,
f) 5- to 10-membered heteroaryl; wherein the 5- to 10-membered heteroaryl may be optionally substituted with one or more substituents independently selected from -NR ^zk1 R ^zl 1, wherein ^zk1 and ^{R ZL1} are independently selected from hydrogen atoms and _{C 1-6} alkyl.

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

In the present invention, as a compound represented by the formula (I), Z ¹ is a group represented by the formula (IIIa), Y is represented by —C (= O) —, and R ⁹ is a formula (IIb) And R ^9b is a hydrogen atom, and R ⁷ and R ⁸ together with the carbon atom to which they are attached 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 alkyl is unsubstituted, 3-[(1S, 2S) -1- [5-[(4S)- 2,2-Dimethyl- oxane-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-pyra [4,3-c] pyridine-5-carbonyl] indol-1-yl] -2-methylcyclopropyl] -4H-1,2,4-oxadiazol-5-one (example compound 67) More preferable.

Next, an example of a method for producing a compound represented by formula (I), a salt thereof or a solvate thereof is described by the following scheme group.
The compound represented by the formula (I), a salt thereof, or a solvate thereof is produced via i) General Process A1 or General Process A2, ii) General Process B, and iii) General Process C. In this production method, among the compounds represented by the formula (I), Z ¹ is a group represented by the formula (IIIa), Y is represented by —C (= O) —, and R ⁹ is a formula (IIb) And R ^9b is a hydrogen atom, that is, an example of a preferred process for producing the compound represented by the formula (Ia).

Also, when R ⁷ and R ⁸ are taken together with the carbon atom to which they are attached to form a C _3-15 cycloalkane ring substituted with 1 to 3 C _1-6 alkyl, 3 C _1-6 alkyl is an example of a preferred method when it is unsubstituted.

  In addition, when the starting material or the desired product of a certain process undergoes undesired chemical conversion under the reaction conditions of that process, for example, protection and deprotection of functional groups are performed to obtain the desired product of the relevant process. Can. For the selection of protecting groups, and the selection of methods of protection and deprotection, see, for example, T.W. W. Greene, P .; G. M. Wuts, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons, Inc. , New York (2007). Some of the protection and deprotection of functional groups are also described in the following scheme.

<General manufacturing method A1>
The compound f can be synthesized according to the general production method A1 shown by 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 ^{3 3b} may be taken together with the oxygen atom to which they are attached and the carbon atom to which the oxygen atom is attached to form a 5- to 7-membered 1,3-dioxacycloalkane ring, and Y ¹ is cyano or -CO-OP ² is represented, Y ² is = O or NHNH, and X ¹ is a leaving group.

Examples of the protecting group of amino 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 and the like), allyl and aralkyl.

As the leaving group, for example, a halogen atom, acetyloxy, trifluoroacetyloxy, methanesulfonyloxy, paratoluenesulfonyloxy and the like can be mentioned.
Process A1-1a :
Compound a1 can be obtained by reacting compound a with a base.

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

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

The reaction time is generally 15 minutes to 5 hours, preferably 30 minutes to 3 hours.
Compound a1 may be isolated or may be subjected to step A1-1b without isolation.
Compound a can be purchased commercially from Aldlab Chemicals, LLC, Tokyo Chemical Industry, and the like. Alternatively, they can be synthesized with reference to Bioorganic Medicinal Chemistry, 1999, 7, 795-809, CN 103086955.

Compound a1 may be obtained as an alkali metal salt such as a potassium salt by contact with a base used in the reaction, but such a salt can also be added to the next step.
Process A1-1b :
Compound b can be obtained by reacting compound a1 with compound a2. The reaction is preferably carried out in the presence of an acid.

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

The reaction temperature is generally 40 ° C to 200 ° C, preferably 60 ° C to 150 ° C.
The reaction time is generally 6 minutes to 30 hours, preferably 30 minutes to 3 hours.
Compound a2 can be purchased commercially from Alfa Aesar etc. as a salt to which hydrogen chloride and the like are added. With reference to Synlett, 2011, 17, 2555-2558, the compound a2 in which the hydrazine moiety is protected with t-butoxycarbonyl can also be used after being deprotected with an acid such as methanesulfonic acid. Also, the Journal of
The compound: Q ¹ -NH ₂ can also be synthesized 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.

  As the base, tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO etc.), nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-) lutidine, pyrazine, pyridazine etc. And metal hydrides such as sodium hydride, potassium hydride and lithium hydride; potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide and the like) Metal alkoxides and the like can be mentioned. When compound b2 is used, it is preferably a metal alkoxide such as potassium t-butoxide.

  As the solvent, 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; Although amide solvents such as N-dimethylacetamide (DMA), N, N-dimethylimidazolidinone (DMI), and DMF can be used, amide solvents such as DMA are preferable.

The reaction temperature is generally -50 ° C to 70 ° C, preferably -30 ° C to 50 ° C.
The reaction time is generally 15 minutes to 72 hours, preferably 1 hour to 30 hours.
Compound b1 is prepared by Enamine LTD. Commercial products can be purchased from The compound can also be synthesized by reacting the compound: H ₂ NCH ₂ CH (OP ^3a ) (OP ^3b ) with phosgene or triphosgene, with reference to WO 2006/048727. Compound b2 is prepared by UkrOrgSyntez Ltd. Commercial products can also be purchased from The compound 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 WO 99/50262.

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

  As the solvent, ether solvents (ether, tetrahydrofuran, dioxane, dimethoxyethane, cyclopentyl methyl ether, etc.), aromatic hydrocarbon solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), 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 glucone (1, 3-propanediol, 1,4-butanediol, 1,5-pentanediol, etc.), acetic acid ester solvents (eg, methyl acetate, ethyl acetate, isopropyl acetate), acetonitrile, and their mixed solvents. Preferably, it is an ether solvent such as tetrahydrofuran.

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

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

  As the solvent, ether solvents (ether, tetrahydrofuran, dioxane, dimethoxyethane, cyclopentyl methyl ether, etc.), aromatic hydrocarbon solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), aliphatic hydrocarbon solvents (pentane, etc.) , Hexane, heptane, octane, cyclohexane, etc., amide solvents (N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone etc.), preferably amides such as N, N-dimethylacetamide It is a system solvent.

The reaction temperature is generally 0 ° C to 150 ° C, preferably 20 ° C to 120 ° C.
The reaction time is generally 15 minutes to 24 hours, preferably 30 minutes to 5 hours.
b) obtaining compound e by reacting compound d with compound d1 in the presence of a base, a copper catalyst and a ligand when Z ² is C _6-10 aryl and 5-10 membered heteroaryl Can.

  Examples of the base include weak basic inorganic salts (sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate etc.) and organic bases (triethylamine, pyridine, tetrabutylammonium fluoride etc.), preferably potassium carbonate etc. It is a basic inorganic salt.

  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.

  As ligands, phenanthroline, quinolin-8-ol, 2,2,6,6-tetramethylheptane-3,5-dione, N, N'-dimethylethane-1,2-diamine, trans-cyclohexane-1,2- Examples thereof include diamines and diamines such as trans-N, N'-dimethylcyclohexane-1,2-diamine and the like, with preference given to trans-N, N'-dimethylcyclohexane-1,2-diamine.

As the solvent, ether solvents (ether, tetrahydrofuran, dioxane, dimethoxyethane, cyclopentyl methyl ether, etc.), aromatic hydrocarbon solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), 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 glucone And 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, etc., acetic acid ester solvents (eg, methyl acetate, ethyl acetate, isopropyl acetate), and acetonitrile, preferably N- Amide-based solvents such as methyl pyrrolidone.

The reaction temperature is generally 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 C _1-6 alkoxycarbonyl such as t-butoxycarbonyl, it is preferred to deprotect using an acid.
Examples of the acid include inorganic acids (such as hydrogen chloride, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid), sulfonic acids (such as methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid), and carboxylic acids (formic acid) Acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid, fluoroacetic acid, trifluoroacetic acid, tartaric acid, propionic acid, glutaric acid, etc. Can be mentioned.

  As the solvent, ether solvents (tetrahydrofuran, methyl tetrahydrofuran, 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-methyl pyrrolidone etc.), and halogen solvents (dichloromethane, chloroform, carbon tetrachloride etc.), and preferably N-methyl Amide solvents such as pyrrolidone.

The reaction temperature is generally 0 ° C to 200 ° C, preferably 10 ° C to 120 ° C.
The reaction time is generally 30 minutes to 10 hours, preferably 1 hour to 6 hours.
In addition, although the compound f may be obtained as a salt with the acid used for reaction, such a salt can also be attached to the following process.

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

In the formula, Z ^2a represents unsubstituted C _3-15 cycloalkyl or 3-12 membered heterocyclyl.
P ^1a and P ^2a represent an amino protecting group,
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 attached and the carbon atom to which the oxygen atom is attached, 5 to 7 It may form a membered 1,3-dioxacycloalkane ring.

Examples of the protecting group of amino 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 and the like), allyl, aralkyl and the like.

As the leaving group, for example, a halogen atom, acetyloxy, trifluoroacetyloxy, methanesulfonyloxy, paratoluenesulfonyloxy and the like can be mentioned.
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, preferably diphenylphosphoryl azide.

  As the solvent, ether solvents (tetrahydrofuran, methyl tetrahydrofuran, 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-methyl pyrrolidone, etc.), preferably hydrocarbon solvents such as toluene.

The reaction temperature is generally 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.
The compound g is described in, for example, Journal of the American Chemical Society, 2016, 138, 1698-1708, WO2009 / 152133 and the like. Also, Enamine Ltd. Commercial products can also be purchased for example.

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.

  As the base, for example, tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.), nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-) lutidine, pyrazine, And pyridazine etc.).

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

The reaction temperature is generally 0 ° C to 60 ° C, preferably 5 ° C to 45 ° C.
The reaction time is generally 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 the like, preferably a weakly basic inorganic matter such as cesium carbonate It is salt.

  As compound i1, for example, 1,2-dichloro-1-methoxyethane, 1,2-dichloro-1-ethoxyethane, 1,2-dichloro-1-i-propoxyethane, 1,2-dichloro-1-one Examples thereof include t-butoxyethane and the like, preferably 1,2-dichloro-1-ethoxyethane. Compound i1 can be purchased commercially from Tokyo Chemical Industry Co., Ltd., FCH Group, and the like.

  As compound i2, for example, 2-chloro-1,1-dimethoxyethane, 2-chloro-1,1-diethoxyethane, 2-bromo-1,1-dimethoxyethane, 2-bromo-1,1-ethoxy Ethane etc. are mentioned. Compound i2 can be purchased from Tokyo Chemical Industry Co., Ltd. or the like.

  As the solvent, 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 may be mentioned, with preference given to amide solvents such as DMA.

The reaction temperature is generally 0 ° C to 60 ° C, preferably 20 ° C to 45 ° C.
The reaction time is generally 1 hour to 72 hours, preferably 12 minutes to 35 hours.
Process A2-4 :
Compound k can be obtained by reacting compound j with an acid.

  Examples of the acid include inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid etc.), sulfonic acids (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid etc.), 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.) Preferably, it is a sulfonic acid such as methanesulfonic acid.

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

The reaction time is generally 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.

The compound k1, for example, halogenated _{C 1-6} alkyl, such as methyl iodide, and halogenated _{(C 1-6} alkyl) carbonyl such as acetyl chloride. When R ^zd is (C _1-6 alkyl) carbonyl, an acid anhydride represented by ((C _1-6 alkyl) carbonyl) ₂ O, for example, acetic anhydride, is used in place of compound k1. Is also preferred.

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

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

The reaction temperature is generally -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.

Although deprotection can select a suitable reagent and reaction conditions by the kind of protecting group, when a protecting group is t-butoxycarbonyl, it is preferable to make it react with an acid.
Examples of the acid include inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid etc.), sulfonic acids (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid etc.), carboxylic acids (formic acid, Acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid, fluoroacetic acid, trifluoroacetic acid, tartaric acid, propionic acid, glutaric acid, etc.) And is preferably a carboxylic acid such as trifluoroacetic acid.

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; acetonitrile and the like, preferably Is a halogen-based solvent such as CH ₂ Cl ₂ .

The reaction temperature is generally 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.
In addition, although the compound m may be obtained as a salt with the acid used for reaction, such a salt can also be attached to process A2-7.

Process A2-7 :
Compound n can be obtained by protecting one of the amino in compound m.
Although protection can select a suitable reagent and reaction conditions by the kind of protecting group, when a protecting group is _C1-6 alkoxy carbonyl, it is preferable to make it react with a base.

  As a compound used for protection, methoxycarbonyl chloride, ethoxycarbonyl chloride, 2,2,2-trichloroethoxycarbonyl chloride, benzoyl chloride (Z-Cl), 9-fluorenylmethyloxycarbonyl chloride (Fmoc-Cl), -T-butyldicarbonic acid is mentioned, preferably di-t-butyldicarbonic acid.

  As the base, for example, tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.), nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-) lutidine, pyrazine, And pyridazine etc., 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; acetonitrile and the like, preferably Is a halogen-based solvent such as CH ₂ Cl ₂ .

The reaction temperature is generally 0 ° C to 60 ° C, preferably 15 ° C to 40 ° C.
The reaction time is generally 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.

As compound n1, for example, halogenated C _1-6 alkyl such as methyl iodide and halogenated (C _1-6 alkyl) carbonyl such as acetyl chloride can be mentioned. When R ^ze is C _1-6 alkyl, 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 step A2-5.
Step A2-9 :
Compound p can be obtained by deprotecting compound o.

For deprotection, an appropriate reagent and reaction conditions can be selected depending on the kind of protective group, but when the protective group P ^1a is C _1-6 alkoxycarbonyl such as t-butoxycarbonyl etc., deprotection is carried out using an acid preferable.

This step is carried out in the same manner as in step A1-5, and the acid used in the reaction, the solvent, the reaction temperature, and the reaction time are also the same as in step A1-5.
<General manufacturing method B>
Compound bf can be synthesized according to General Production Method B shown in the following scheme.

During the ceremony
P ²¹ represents hydroxy, C _1-6 alkoxy or -NR ^21a R ^21b , and 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.

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

  As a palladium catalyst, a complex formed separately by adding a palladium compound and a ligand can be used. Alternatively, the complex prepared separately may be used as it is. As a ligand, for example, 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 and the like. As a palladium compound to be combined with the ligand, for example, di-μ-chlorobis [(η-allyl) palladium (II)], tetrakis (triphenylphosphine) palladium (0) and the like can be used.

Examples of palladium catalysts usable in this step include tris (dibenzylideneacetone) dipalladium (0), 5,10,15,20-tetraphenyl-21H, 23H-porphine cobalt (II), palladium acetate (II) ), Bis (di-t-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct, dichlorobis (triol) 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- It is preferred to use as a catalyst a complex formed with 1,1'-biphenyl as a ligand.

In addition, this step may be performed in the presence of a base.
Examples of the base 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 (potassium t) -Butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide and the like) and the like.

  As a reaction solvent, ether solvents such as tetrahydrofuran (THF), diethyl ether, dioxane or the like, or amide solvents such as N, N-dimethylacetamide (DMA), N, N-dimethylimidazolidinone (DMI), DMF Can be mentioned. Moreover, the mixed solvent with water may be sufficient.

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

The compound ba1 in which X ²¹ is -Zn-X ^21a can be purchased commercially from Focus Synthesis LLC or the like. It can also be synthesized with reference to WO 2014/201206 and the like.

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, with preference given to potassium hydroxide It is.

  As the reaction solvent, amide solvents such as N, N-dimethylacetamide (DMA), N, N-dimethylimidazolidinone (DMI), DMF and the like can be mentioned, with preference given to DMI. Moreover, the mixed solvent with water may be sufficient.

The reaction temperature is generally -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 and the like. It can also be synthesized with reference to WO 2013/010904, Organic Letters, 7 (18), 3965-3968, 2005, US Pat.

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 dimethylsulfoxide (DMSO), dimethylformamide, dimethylacetamide and 1-methyl-2-pyrrolidinone, alcohol solvents such as methanol and ethanol, and the like. It is DMSO. Moreover, the mixed solvent with water may be sufficient.

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

Process B-4 :
Compound be can be obtained by reacting compound bd with triphosgene, chlorocarbonic acid ester (methyl chlorocarbonate, ethyl chlorocarbonate, isopropyl chlorocarbonate etc.), carbonyldiimidazole etc., preferably carbonyldiimidazole, in the presence of a base, preferably carbonyldiimidazole it can.

  As a base, for example, tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, 1,8-diazabicycloundec-7-ene (DBU), DABCO, etc.), metal hydroxides (sodium hydroxide, Potassium hydroxide), preferably tertiary amines such as DBU.

  As the solvent, for example, aprotic polar solvents such as dimethylsulfoxide (DMSO), dimethylformamide, dimethylacetamide, and 1-methyl-2-pyrrolidinone, alcohol solvents such as methanol and ethanol, tetrahydrofuran (THF), diethyl ether And ether solvents such as dioxane, and the like, preferably DMSO.

The reaction temperature is generally -10 ° C to 100 ° C, preferably 20 ° C to 45 ° C.
The reaction time is usually 10 minutes to 10 hours, preferably 15 minutes to 2 hours.
Process B-5 :
Compound bf can be obtained by deprotecting compound be protected by P ²¹ using a base.

  As the base, for example, 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, sodium Examples include metal alkoxides such as t-pentoxide and lithium t-pentoxide.

As the solvent, alcohol solvents such as methanol, ethanol, methoxyethanol and t-butyl alcohol; ether solvents such as THF and diethyl ether, N, N-dimethylacetamide (DMA), N, N-dimethylimidazolidinone ( Amide solvents such as DMI) and DMF can be mentioned. Moreover, the mixed solvent with water may be sufficient.

The reaction temperature is generally -20 ° C to 120 ° C, preferably 20 ° C to 100 ° C.
The reaction time is usually 20 minutes to 10 hours, preferably 30 minutes to 5 hours. Steps B-1, B-2, B-3, B-4 and B-5 can be switched in order. . For example, compound bc can be obtained by sequentially applying compound ba to step B-2 and step B-1. Compound bf can be obtained by sequentially applying compound ba to step B-2, step B-3, step B-4, step B-5, and step B-1. Compound bf can be obtained by sequentially applying Compound ba to Step B-2, Step B-3, Step B-4, Step B-1, and Step B-5.

Step B-Aa and Step B-Ab :
When X ²¹ is a halogen atom, compound bb can also be obtained by subjecting compound ba to the following step B-Aa and step B-Ab, and the compound bb can be given to step B-2 May be

In the formula, R ^Qc and R ^Qd independently represent a hydrogen atom or C _1-6 alkyl, or R ^Qc and R ^Qd together together with the oxygen atom to which they are attached and the boron atom to which the oxygen atom is attached To form 1,3,2-dioxaborolanyl or 1,3,2-dioxaborinanyl.

Process B-Aa :
The organic boron compound baa can be obtained by reacting the compound ba with the compound ba2 or the compound Ba3 in the presence of a palladium catalyst. This step may be performed 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. As compound ba3, for example, diboronic acid, pinacol diborane (4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) And bis (neopentyl glycolato) diboron and bis (hexylene glycolato) diboron). These compounds can be purchased commercially from Tokyo Chemical Industry and the like. Journal of the American Chemical Society, 131 (45), 16346-16347, 2009 and Organic Synthesis, 77, 176-185, 2000, i) pinacol, ii) diborane, BH ₃ · THF complex or BH ₃ -It can also be synthesized using a dimethyl sulfide complex.

The organoboron compound baa may be subjected to step B-Ab without isolation.
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 the base include weakly basic inorganic salts (sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like), preferably sodium carbonate.

The solvent used for the reaction, the reaction temperature, and the reaction time are the same as in step B-1.
Compound bb can also be obtained by converting compound ba1 into an organic boron compound and reacting it with compound ba, similarly to the conversion of compound ba to compound baa.

Process B-B :
The compound bb1 is ^X 21 _- If the _(CH 2) represented by n1 _-CH 2 -CN, a compound bca corresponding to the compound bc obtained in Step B-2, subjected to the following steps B-B, i.e. By reacting with compound bc1 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 the C _3-15 cycloalkane ring formed by R ⁸ and R ⁸ together may give a compound bcb corresponding to the compound bc, which may be substituted by 1 to 3 C _1-6 alkyl; This may be added to step B-3.

^Wherein, R ^{7c, R 7e} and n8 is ^{R 7d} each independently represent a hydrogen atom or _{C 1-6} alkyl, 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), lithium diisopropylamide (LDA) And metal hydrides such as lithium 2,2,6,6-tetramethyl pyrrolidine and the like, and preferably KHMDS.

  Examples of the solvent include ether solvents such as THF, diethyl ether and dioxane, N, N-dimethylacetamide (DMA), N, N-dimethylimidazolidinone (DMI), DMF, N, N'-dimethylpropylene Amide solvents such as urea (DMPU) can be mentioned, and preferably amide solvents such as DMPU.

The reaction temperature is, for example, -20 ° C to 40 ° C, preferably -10 ° C to 10 ° C.
The reaction time is, for example, 30 minutes to 8 hours, preferably 1 hour to 4 hours.
The compound bc1 is CGeneTech. Inc. Commercial products can be purchased from It can also be synthesized with reference to Organic Letters, 12 (17), 3938-3941, 2010.

<General production method C>
Process C-1 :

Compound (Ia) can be obtained by condensing Compound f (or Compound p) and Compound bf using a condensing agent in the presence of a base.
As the condensing agent, for example, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxy-tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP (registered trademark)), BOP condensing agent such as PyAOP, BroP, PyCloP, PyBroP (registered trademark), DEPBT, 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride n Hydrate (DMT-MM), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), [dimethylamino (triazolo [4 ,. 5-b] pyridin-3-yloxy) methylide ] -Dimethylazanium hexafluorophosphoric acid (HATU), ethyl (hydroxyimino) cyanoacetate (Oxyma) and the like, preferably HATU and the like.

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

  As the solvent, for example, ether solvents such as THF, diethyl ether, and dioxane, aprotic polar solvents such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide, and 1-methyl-2-pyrrolidinone, etc. And preferably an aprotic polar solvent such as DMF.

The reaction temperature is, for example, 0 ° C to 80 ° C, preferably 20 ° C to 60 ° C.
The reaction time is, for example, 1 minute to 10 hours, preferably 30 minutes to 5 hours.
In addition, for example, compound d is sequentially applied to step A1-5, step C-1 and step A1-4. Compound ba is obtained in step B-2, step B-3, step B-4, step B-5, The compound (Ia) can also be obtained by switching the order of the steps, such as sequentially adding to step C-1 and step B-1.
In addition, the compound represented by the formula (I) can be obtained by contacting or reacting an acid or a base that can be used for the preparation of a pharmaceutical, to obtain a salt thereof. The salt may be any pharmaceutically acceptable salt, and such salts include, for example, mineral acid salts (hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, etc.) , Sulfonates (methane sulfonate, ethanesulfonic acid, benzene sulfonate, toluene sulfonate, etc.), carboxylates (formate, acetate, oxalate, maleate, fumarate, citric acid) Salt, malate, succinate, malonate, gluconate, mandelic acid, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, glutarate, adipine Acid salts, nicotinate salts, etc., alkali metal salts (lithium salts, sodium salts, potassium salts, cesium salts, rubidium salts etc.), alkaline earth metal salts (magnesium salts, calcium salts etc.), Monium salts (ammonium salts, alkyl ammonium salts, dialkyl ammonium salts, trialkyl ammonium salts, tetraalkyl ammonium salts etc.), basic amino acid salts (lysine salts, arginine salts etc.), alkali metal salts, alkaline earth metals Salts are preferred, and sodium salts and calcium salts are more preferred. For example, a free body of a compound represented by the formula (I) is suspended or dissolved in an alcohol such as methanol or ethanol, acetonitrile, acetone, dimethyl sulfoxide or the like, and a basic aqueous solution containing sodium ions such as sodium hydroxide By adding a methanol solution containing sodium methoxide or an ethanol solution containing sodium ethoxide, the sodium salt of the compound represented by formula (I) can be obtained. The reaction temperature is, for example, 0 ° C to 80 ° C, preferably 20 ° C to 60 ° C.

  The compound represented by the formula (1) or a salt thereof may be a solvate or a nonsolvate. The solvent contained in the solvate may be either water or an organic solvent. As the organic solvent, alcohols (for example, methanol, ethanol, n-propanol), dimethylformamide, acetonitrile, acetone, dimethyl sulfoxide and the like can be used. The compounds of the formula (I) and salts thereof are preferably used in the form of hydrates and also preferably in the form of non-solvates. The ratio of solvent molecules (preferably water molecules) to one molecule of the compound represented by the formula (I) or a salt thereof is, for example, 0.1 to 10, and more preferably 0.5 to 6. Also, this ratio may vary depending on the humidity, the manufacturing method, the manufacturing time, and the like.

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

The solvate of the compound represented by the formula (I) or a salt thereof can be converted to the compound represented by the formula (I) or a salt thereof by a conventional method such as heating under reduced pressure.
As a solvate of the compound represented by the formula (I) or a salt thereof, the compound represented by the formula (I) itself (free form), hydrate of free form, salt of free form, hydration of salt The free form, the free form hydrate, the free form sodium salt, the sodium salt hydrate, the free form calcium salt and the calcium salt hydrate are more preferable.

  In the present invention, the compound represented by the formula (I) or a salt thereof, or a solvate thereof may be used in the form of crystals or in the form of amorphous (amorphous). .

  In the present invention, all stereoisomers (eg, enantiomers, diastereomers (including cis and trans geometric isomers) of the compound represented by the formula (I)), racemates of the isomers, and others Contains a mixture. For example, compounds of formula (I) may have one or more asymmetric points, 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 the formula (I) include those whose isotope is an isotope, and at least one atom has the same atomic number (proton number), and the mass number (proton and neutron) The sum of the numbers of) is substituted by different atoms. Examples of isotopes contained in the compound represented by formula (I), a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom, include a chlorine atom, respectively, ² H ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl and the like. In particular, radioactive isotopes that decay by emitting radiation, such as ³ H and ¹⁴ C, are useful in studies of tissue distribution in the body of drugs or compounds. Stable isotopes can be used safely because they do not decay, hardly change in abundance, and have no radioactivity. Those in which the atom constituting the compound molecule represented by the formula (I) is an isotope can be converted according to a conventional method by replacing the reagent used in the synthesis with a reagent containing the corresponding isotope .
The pharmaceutical composition of the present invention has GLP1 receptor agonistic action and hypoglycemic action, and by administering a pharmaceutically effective amount thereof to a patient by an appropriate administration method, non-insulin dependent diabetes mellitus (type 2 diabetes) ), Hyperglycemia, glucose intolerance, insulin dependent diabetes (type 1 diabetes), diabetic complications, obesity, hypertension, dyslipidemia, arteriosclerosis, myocardial infarction, coronary heart disease, brain It can be used for the prevention or treatment of infarction, non-alcoholic steatohepatitis, Parkinson's disease or dementia.

  In the present invention, "diabetes" refers to a disease or condition that causes abnormal metabolism in glucose production and utilization by failing to maintain proper blood sugar levels in the body, and insulin-dependent diabetes (type 1 diabetes) ), Non-insulin dependent diabetes mellitus (type 2 diabetes).

  "Hyperglycemia" refers to conditions in which plasma glucose levels during fasting and after glucose administration are higher than normal (e.g. 80-110 mg / dL on fasting in humans) and is one of the typical symptoms of diabetes It is also.

"Impaired glucose intolerance" includes insulin resistance glucose intolerance and impaired insulin secretion.
By "diabetic complications" is meant complications resulting from diabetes or hyperglycemia and may be either acute or chronic complications. "Acute complications" include, for example, ketoacidosis, infections (eg, skin infections, soft tissue infections, biliary infections, respiratory infections, urinary tract infections), and "chronic complications" include, for example, Small angiopathy (eg, nephropathy, retinopathy), neuropathy (eg, sensory neuropathy, motor neuropathy, autonomic neuropathy), foot scurvy. The major diabetic complications include diabetic retinopathy, diabetic nephropathy and diabetic neuropathy. "Coronary heart disease" includes myocardial infarction, angina pectoris and the like.

Examples of "dementia" include Alzheimer's disease, vascular dementia and diabetic dementia.
The administration method of the pharmaceutical composition of the present invention includes oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, vaginal administration, intraperitoneal administration, intravesical administration, systemic administration such as inhaled administration, and ointment It may be any of topical administration by gel, cream and the like.

The pharmaceutical composition of the present invention is usually formulated into a certain formulation (dosage form) and used. Such preparations include, for example, tablets, capsules, granules, powders, fine granules, pills, aqueous or non-aqueous solutions or suspensions, and the like. The pharmaceutical composition of the present invention can also be used in the form of various controlled release formulations. Such controlled release preparations include, for example, those which are used by being implanted in the body, and those which are applied to the oral mucosa or nasal mucosa. In addition, the solution or suspension can be stored in a container suitable for dispensing into individual doses.

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

As the excipient, for example, starch (starch, potato starch, corn starch and the like), lactose, crystalline cellulose, calcium hydrogen phosphate and the like can be mentioned.
The lubricant (coating agent) includes, for example, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, paraffin and the like.

Examples of the binder include polyvinyl pyrrolidone, macrogol, and the same compounds as the above-mentioned excipients.
Examples of the disintegrant include croscarmellose sodium, sodium carboxymethyl starch, crosslinked polyvinyl pyrrolidone and the like, chemically modified starches, and celluloses, as well as compounds similar to the above-mentioned excipients and the like.

  Examples of the stabilizer include p-hydroxybenzoic acid esters such as methylparaben and propylparaben; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; sorbic acid and the like.

As a flavoring agent, a sweetener, an acidulant, a flavoring agent etc. which are normally used are mentioned, for example.
As the base, for example, fats such as pork fat; vegetable oils such as olive oil and sesame oil; higher alcohols such as stearyl alcohol and cetanol; animal oil; lanolinic acid; vaseline; paraffin; bentonite; glycerin; .

  Examples of the dispersant include cellulose derivatives (eg, gum arabic, tragacanth, methyl cellulose etc.), polyester stearates, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbates, sorbitan fatty acid esters and the like.

Examples of the solvent or diluent in the solution include phenol, chlorocresol, purified water, distilled water and the like.
As surfactant or an emulsifier, for example, polysorbate 80, polyoxyl stearate, lauromacrogol and the like can be mentioned.

The content of the compound represented by the formula (I) or a salt thereof, or a solvate thereof in a preparation varies depending on the dosage form, but is generally 0.01 to 100% by weight.
The preparation may contain only one type of the compound represented by the formula (I) or 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 prophylactic or therapeutic agent for non-insulin dependent diabetes mellitus (type 2 diabetes) or obesity, the dosage as the amount of the active ingredient may be: weight of symptoms, age, body weight, It can be determined as appropriate according to the relative health status, presence or absence of concomitant drug, administration method and the like. As an example, when the administration subject is a temperature-controlled animal, particularly a human, the dose as an amount of the active ingredient per day is, for example, 0.01 to 10000 mg, preferably 0.1 to 1000 mg for oral administration. Moreover, also in parenteral administration, it is 0.001 to 3000 mg, for example, preferably 0.01 to 300 mg. The above dose may be administered once per day to several weeks, or may be divided into two or more times per day.

  In the present invention, “effective amount” means a therapeutically or prophylactically effective amount of the compound represented by the formula (I), a salt thereof, or a solvate of any of them, which is an active ingredient, It can be determined as appropriate according to the weight, age, weight, relative health condition, presence or absence of concomitant drug, administration method and the like.

The contents of the present invention will be further described in the following examples and reference examples. All starting materials and reagents were obtained from commercial suppliers or synthesized using known methods. Room temperature (rt) refers to 5-35 ° C. Silica gel: SHOKO Scientific Purif-Pack (registered trademark) SI 60 μm (manufactured by Shoko Scientific), Biotage (registered trademark) SNAP Ultra Silica Cartridge (manufactured by Biotage), or SNAP KP-Sil Cartridge (manufactured by Biotage); reverse 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. The HPLC purification of the compound was carried out using an AutoPurification HPLC / MS System (manufactured by Waters) or a Predictive HPLC system with injection / fractionation function (manufactured by Gilson). ¹ H-NMR spectra use Me ₄ Si as an internal standard substance or without ECP-400 (manufactured by JEOL), Agilent 400-MR (manufactured by Agilent Technologies), AVANCE 3 300 MHz (manufactured by Bruker) or AVANCE 3 600 MHz Measured using Cryo-TCI (Bruker) (s = singlet, brs = broading red, d = doublet, t = triplet, q = quartet, dd = double doublet, dd = double double doublet, m = multiplet ). Chemical shifts in NMR data are relative to Me ₄ Si or deuterated solvents and are given in ppm (parts per million, δ) and coupling constants (J) are shown in Hz (Hertz). LC / MS performed retention time measurement and mass spectrometry according to the apparatus and analysis conditions of Table 1. The 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 2010 EV (manufactured by Shimadzu).

EXAMPLE 1 3-[(1S, 2S) -1- [2- [2- (3,5-dimethylphenyl) -3- [3- (1-methylindazol-5-yl) -2-oxo] Imidazole-1-i
[L] -6,7-Dihydro-4H-pyrazolo [4,3-c] pyridine-5-carbonyl] -5- (2-ethyl-3-methylpyridin-4-yl) indol-1-yl] -2 Of 1-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), add a solution of 1 M potassium tert-butoxide in THF (179 mL), and at room temperature for 1 hour It stirred. The reaction mixture was collected by filtration, washed with THF (50 mL) and dried under reduced pressure to give the title compound 1b (23.8 g, yield 83%) as a pale 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 (2 H, t, J = 1.3 Hz), 2.90 (2 H, t, J = 5.9 Hz), 2.21 (2 H, 2 H, 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 a solution of compound 1b (4.67 g, 29.0 mmol) obtained in step 1-1 in ethanol (57.9 mL), add 2 N hydrochloric acid (23.2 mL, 46.3 mmol), and add 1 at 50 ° C. Stir for hours. The reaction mixture was cooled to 0 ° C., 5 M aqueous solution of sodium hydroxide (9.27 mL, 46.3 mmol), 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, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate / hexane = 0: 1 to 1: 1) to give the title compound 1d (7.82 g, yield as pale yellow solid) 79%).

LC / MS mass spectrometry: m / z 343 ([M + H] &lt; ⁺ &gt;).
LC / MS retention time: 0.99 minutes (analysis conditions: SMD-FA05-3).
(Step 1-3)
3- (2,2-Dimethoxyethylcarbamoylamino) -2- (3,5-dimethylphenyl) -6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carboxylate tert-butyl ( Compound 1f)
2-isocyanato-1,1-dimethoxyethane (compound 1e, 1.94 g, 14.8 mmol) in a solution of compound 1d (2.53 g, 7.39 mmol) obtained in step 1-2 in pyridine (7.39 mL) ) Was added and stirred at room temperature. After 3 hours and 15 minutes, diethylamine (1.08 g, 14.8 mmol) was added and stirred for 5 minutes at room temperature, then water (50.6 mL) was added and stirred at room temperature for 20 minutes. The reaction mixture that has become a suspension is filtered, and the filtered solid is washed with water (12.7 mL) and then dried under reduced pressure to give the title compound 1f (3.20 g, yield 91%) as a pale yellow solid. The

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 1 f (158 mg, 0.334 mmol) obtained in Steps 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 evaporated under reduced pressure. The residue was dissolved by adding dichloromethane (1 mL), and then hydrogen chloride (4 M solution in dioxane, 0.835 mL, 3.34 mol) was added at room temperature. The reaction mixture was concentrated under reduced pressure, toluene was added, and the solvent was evaporated under reduced pressure to give a crude product (176 mg) of the title compound 1 g.

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) is cooled to -78 ° C. and a 1.11 M lithium diisopropylamide n-hexane-THF solution (35.8 mL, 39.8 mmol) was added slowly. After stirring for 5 minutes at −78 ° C., iodomethane (2.84 mL, 45.5 mmol) was added. After stirring for 5 minutes at −78 ° C., the reaction solution was slowly warmed to room temperature, stirred for 30 minutes, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate) to give the title compound 1i (6.98 g, yield 92%) as an orange oil.

LC / MS mass spectrometry: m / z 200 ([M + H] &lt; ⁺ &gt;).
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)
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 A solution of compound 1k, 4.86 g, 35.2 mmol) in N, N′-dimethylpropyleneurea (117 mL) was degassed under reduced pressure, purged with nitrogen, and cooled to 0 ° C. Under nitrogen atmosphere, a THF solution (46.9 mL, 46.9 mmol) of 1.0 M potassium bis (trimethylsilyl) amide 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 saturated aqueous sodium hydrogen carbonate solution and once with saturated brine, and dried over sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate / hexane = 1: 19 to 1: 4) to give the title compound 1l (1.70 g, yield 42%) Obtained 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)
1-[(1S, 2S) -1-Cyano-2-methylcyclopropyl] -5- (2-ethyl-3-methylpyridin-4-yl) indole-2-carboxylate ethyl ester (compound 1m)
Compound 1 1 (2.70 g, 7.78 mmol) obtained in Step 1-6, 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi A suspension of 2,3,2-dioxaborolane) (2.17 g, 8.55 mmol), and potassium acetate (1.15 g, 11.7 mmol) in dioxane (44 mL) was vacuum degassed at room temperature and then purged with nitrogen. . In a nitrogen atmosphere, 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (1.29 g, 1.56 mmol) was added, and the mixture was stirred at 100 ° C. for 3 hours. After cooling to room temperature, a solution of 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) is dissolved. After degassing under reduced pressure, the solution was purged with nitrogen and stirred at 100.degree. C. for 2 hours. After cooling to room temperature, water (5.4 mL) and N-acetylcysteine (0.635 g, 3.89 mmol) were added and stirred for 0.5 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed once with saturated brine and dried over sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate / hexane = 1: 19 to 2: 3) to give the title compound 1m (2.92 g, collection) as a pale yellow gum The rate is 97%).

LC / MS mass spectrometry: m / z 388 ([M + H] &lt; ⁺ &gt;).
LC / MS retention time: 1.06 minutes (analytical 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] indole-2-carboxylate (Compound 1n)
50% aqueous solution of hydroxyamine (0.356 mL, 5.81 mmol) is added to a solution of compound 1m (0.225 g, 0.581 mmol) obtained in Step 1-7 in dimethyl sulfoxide (DMSO) (2.9 mL), Stir 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 is concentrated under reduced pressure, and the obtained residue is dissolved in DMSO (1.9 mL), carbonyldiimidazole (188 mg, 1.16 mmol) and 1,8-diazabicycloundeca-7- En (0.219 mL, 1.45 mmol) was added and stirred at room temperature for 0.5 h. Formic acid was added, and the resultant was directly purified by reverse phase chromatography (acetonitrile / water, 0.1% formic acid) to give 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 (analytical 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)
To a solution of compound 1n (3.61 g, 8.08 mmol) obtained in step 1-8 in DMSO (40 mL), 2 M aqueous sodium hydroxide solution (10.1 mL, 20.2 mmol) is added, and it is 1.5 at room temperature Stir for hours. Formic acid was added, and the resultant was directly purified by reverse phase chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound 1o (3.38 g, 100% yield) as a white powder.

LC / MS mass spectrometry: m / z 419 ([M + H] &lt; ⁺ &gt;).
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 1 p)
1 g (1.25 g, 3.61 mmol) of the compound 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 hexafluorophosphoric acid (1.51 g, 3.98 mmol) in N, N'-dimethylformamide (DMF) (24.1 mL) in diisopropylethylamine ( 3.15 mL, 18.1 mmol) was added and stirred at room temperature for 30 minutes. The reaction mixture was directly purified by reverse phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound 1p (2.44 g, yield 95%) as a pale brown foam.

LC / MS mass spectrometry: m / z 710 ([M + H] ^< +>).
LC / MS retention time: 0.85 minutes (analytical 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 I-iodination 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) suspension 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 a nitrogen atmosphere. The reaction mixture was purified by reverse phase silica gel chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound 1 (17.2 mg, 73% yield) as a pale brown foam.

LC / MS mass spectrometry: m / z 840 ([M + H] ^< +>).
LC / MS retention time: 1.12 minutes (analytical conditions: SMD-TFA 05-3).
Examples 2 to 50
Perform the same operation as in step 1-11 of Example 1 using a combination of the 2-oxoimidazole compound shown in Table 2-2 below and the halogen compound shown in Table 2-3, and using the following reaction: Thus, Example compounds 2 to 50 shown in Table 2-1 were obtained.

Although rotamers exist in the compounds in Table 2-1, for example, ¹ H-NMR of Example Compound 2 is as follows.
Rotamer A
¹ H-NMR (600 MHz, CDCl ₃ ) δ: 11.29 (1 H, s), 8. 40 (1 H, d, J = 5.2 Hz), 7.93 (1 H, s), 7.74 (1 H , D, J = 1.5 Hz), 7.70 (1 H, d, J = 8.6 Hz), 7.56 (1 H, s), 7.45 (1 H, dd, J = 9.0, 1. 5 Hz), 7.38 (1 H, d, J = 9.0 Hz), 7.28 (1 H, m), 7.14 (1 H, d, J = 5.2 Hz), 7.04 (2 H, d, J) J _HF = 5.9 Hz), 6.82 (1 H, s), 6.59 (1 H, d, J = 3.0 Hz), 6.08 (1 H, d, J = 3.0 Hz), 4.96 (1H, d, J = 16.0 Hz), 4.92 (1 H, d, J = 16.0 Hz), 4.69 (1 H, ddd, J = 13.1, 4.4, 4.4 Hz), 4.06 ( H, s), 3.75 (1 H, ddd, J = 13.1, 9.5, 5.0 Hz), 3.07 (2 H, m), 2.97 (2 H, q, J = 7.6 Hz ), 2.26 (3H, s), 2.25 (6H, s), 1.88 (1H, s), 1.51 (2H, m), 1.37 (3H, t, J = 7). 6 Hz), 1.17 (3 H, d, J = 5.6 Hz).

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

  Example 2-oxoimidazole Compound (3-[(1S, 2S) -1- [5- (2-Ethyl-3-Methylpyridin-4-yl) -2- [2 Used in Synthesis of Compounds 2 to 5 -(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) 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 at room temperature while stirring with concentrated hydrochloric acid (20 mL) and water (20 mL). The mixture was stirred at the same temperature for 1 hour, and the solid in the reaction mixture was collected by filtration and dried. The obtained solid was further added with methoxycyclopentane (20 mL), stirred at 50 ° C. for 1 hour, and then stirred at room temperature for 1.5 hours. The precipitated solid was collected by filtration 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) is added to compound 2b (1.00 g, 5.69 mmol) obtained in step 2-1, and sodium nitrite (511 mg, 7.40 mmol) is stirred while being vigorously stirred at 0 ° C. A solution of water (2.4 mL) was added over 1 minute and 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. Further water (7 mL) was added and stirred at room temperature for 1 hour. The solid in the reaction mixture was collected by filtration, washed with water (2 mL) and dried to give 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-carboxylic acid tert-butyl (compound 2d)
The compound 1b obtained in Step 1-1 and the compound 2c obtained in Step 2-2 were obtained by the same procedure as Step 1-2 in Example 1 using an appropriate reagent.

LC / MS mass spectrometry: m / z 361 ([M + H] &lt; ⁺ &gt;).
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)
The compound 2d obtained in Step 2-3 was synthesized by the same procedure as in Step 1-3 of Example 1, using a suitable reagent.
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)
The compound 2e obtained in Step 2-4 was synthesized by the same procedure as Step 1-4 in Example 1 using an appropriate reagent.

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- (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 2 g)
It synthesize | combined by operation similar to the process 1-10 of Example 1 from the compound 2f obtained at the process 2-5, and the compound 1o obtained at the process 1-9 using a suitable reagent.

  Example 2-oxoimidazole Compound (3-[(1S, 2S) -1- [2- [2- (4-Fluoro-3,5-dimethylphenyl) -3- (2-) Used in the Synthesis of Compound 6 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)
From 5-bromo-1- (cyanomethyl) indole-2-carboxylic acid (Compound 6a) and N-methylaniline (Compound 6b), using appropriate reagents and synthesizing in the same manner as in Steps 1-10 of Example 1 did.

LC / MS mass spectrometry: m / z 368 ([M + H] ^< +>).
LC / MS retention time: 1.25 minutes (analytical conditions: SMD-FA05-3).
(Step 6-2)
5-Bromo- 1-[(1S, 2S) -1-cyano-2-methylcyclopropyl] -N-methyl-N-phenylindole-2-carboxamide (compound 6d)
The compound 6c obtained in Step 6-1 was synthesized by the same procedure as Step 1-6 in Example 1 using an appropriate reagent.

LC / MS retention time: 1.37 minutes (analysis conditions: SMD-FA05-1).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.69 (1 H, 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)
The compound 6d obtained in Step 6-2 was synthesized by the same procedure as Step 1-8 in Example 1 using a suitable reagent.

LC / MS mass spectrometry: m / z 467 ([M + H] ^< +>).
LC / MS retention time: 1.33 minutes (analysis conditions: SMD-FA 05-01).
(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)
Stir a mixed solution of compound 6e (9.70 g, 20.8 mmol), potassium hydroxide (11.7 g, 208 mmol) and methoxyethanol (41.5 mL) obtained in step 6-3 at 100 ° C. for 4 hours did. Under ice-cooling, 6N hydrochloric acid (51.9 mL) was added, and the suspension was stirred at room temperature for 30 minutes. The crystals were collected by filtration and washed with water (29.1 mL), and the obtained solid was dried under reduced pressure to give the title compound 6f (7.42 g, yield 95%) as a pale brown solid.

LC / MS mass spectrometry: m / z 376 ([M-H] ^- ).
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- [6 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), potassium phosphate (10.1 g, 47.6 mmol) in DMSO (34.7 mL) was vacuum degassed at room temperature After that, it was replaced with nitrogen. After stirring for 0.5 hours at 100 ° C. under a nitrogen atmosphere, the mixture was cooled to room temperature. Add 4-iodo-2-methoxy-3-methylpyridine (Compound 6 g, 1.98 g, 7.93 mmol), water (4.96 mL) to the solution, degass under reduced pressure, then purge with nitrogen at 100 ° C. Stir for .5 hours. After cooling to room temperature, water (12.4 mL) and formic acid (6 mL) are added and filtered, and the filtrate is directly purified by reverse phase chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound 6h (1.83 g, 55% yield) 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)
The compound 2f obtained in Step 2-5 and the compound 6h obtained in Step 6-5 were synthesized by the same procedure as in Step 1-10 of Example 1, using an appropriate reagent.

  The halogen compound (1- (5-bromoindazol-1-yl) -2-methylpropan-2-ol, compound 6l) used in the synthesis of the 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. Stir at 180 ° C. for 30 minutes under microwave. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 1) to give 6 l (115 mg, yield 56%) of the title compound.

LC / MS mass spectrometry: m / z 269 ([M + H] &lt; ⁺ &gt;).
LC / MS retention time: 1.00 minutes (analysis conditions: SMD-FA05-2).
Example 2-oxoimidazole reagent (3-[(1S, 2S) -1- [5- (2,2-dimethylmorpholin-4-yl) -2- [2- (4-) used in the synthesis of compound 7 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)
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 A suspension of '-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 removed under reduced pressure at room temperature. After the reaction, it was replaced with nitrogen. Under a nitrogen atmosphere, the 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 resultant was directly purified by reverse phase chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound 7b (5.26 g, yield 96%).

LC / MS mass spectrometry: m / z 413 ([M + H] ^< +>).
LC / MS retention time: 1.00 minutes (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)
The compound 7b obtained in Step 7-1 was synthesized by the same procedure as Step 1-10 in Example 1 using a suitable reagent.

  Example 2-oxoimidazole reagent (3-[(1S, 2S) -1- [2- [2- (4-fluoro-3,5-dimethylphenyl) -3- (2) used in the synthesis of compounds 8-10 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 8c) 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)
Compound 6f (0.30 g, 0.793 mmol) obtained in step 6-4, palladium (II) acetate (35.6 mg, 0.159 mmol), 2-dicyclohexylphosphino-2 ′, 6′-diisopropoxy A suspension of biphenyl (0.148 g, 0.317 mmol) in N, N-dimethylacetamide (DMA) (2.64 mL) was degassed under vacuum, then purged with nitrogen, and stirred at room temperature for 15 minutes. Under a nitrogen atmosphere, 1 M (tetrahydro-2H-pyran-4-yl) zinc (II) iodide (compound 8a) in DMA solution (7.9 mL, 7.93 mmol) is added and stirred at 80 ° C. for 15 minutes It cooled to room temperature. Formic acid was added, and the resultant was directly purified by reverse phase chromatography (methanol / water) to give the title compound 8b (0.19 g, yield 61%).

LC / MS mass spectrometry: m / z 382 ([M-H] ^- ).
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)
The compound 8b obtained in Step 8-1 was synthesized by the same procedure as Step 1-10 in Example 1 using an appropriate reagent.

  The halogen compound (5-bromo-1-[(3R) -oxolan-3-yl] indazole, compound 8f) used in the synthesis of the 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 in dichloromethane solution (3.78 mL) of (3S) -oxolan-3-ol (compound 8d, 500 mg, 5.68 mmol) and 4-methylbenzenesulfonyl chloride (1.51 g, 7.95 mmol) was added. The mixture was stirred at room temperature, and after 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 evaporated under reduced pressure to give the title compound 8e (1.36 g, yield 99%).

LC / MS retention time: 0.96 minutes (analytical conditions: SMD-FA05-1).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.79 (2 H, d, J = 8 Hz), 7. 35 (2 H, d, J = 8 Hz), 5.12 (1 H, 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)
A solution of 5-bromo-1H-indazole (compound 6j, 300 mg, 1.52 mmol) in DMF (3.8 mL) with cesium carbonate (992 mg, 3.05 mmol) and compound 8e obtained in step 8-3 (369 mg, 1.52 mmol) was added and 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 evaporated 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 the example compound 9 was synthesized as follows.

  (Step 9-1)

  Sodium hydride (50 wt% oil dispersion) (18.9 mg, 0.39 mmol) in a solution of N- (4-bromo-2-methoxyphenyl) acetamide (compound 9a, 80 mg, 0.33 mmol) in DMF (0.8 mL) ) And 1-bromo-3-methoxypropane (75 mg, 0.49 mmol) were sequentially added and stirred at room temperature for 12 hours. Formic acid was added to the reaction solution, and purification was conducted 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 the example compound 10 was synthesized as follows.

  (Step 10-1)

  Using a suitable reagent from trifluoromethanesulfonic acid 2,2,2-trifluoroethyl (compound 10a) and 5-bromo-1H-indazole (compound 6j), in the same manner as in 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).
Example 2-oxoimidazole reagent (3-[(1S, 2S) -1- [2-[(4S) -2- (4-fluoro-3,5-dimethylphenyl) used in the synthesis of compounds 11-13] -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) is synthesized as follows did.

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

¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 9.64-9.51 (0.8 H)
, M), 9.24-9.07 (0.2 H, m), 7.09-6. 91 (2 H, m), 2.29-2.09 (6 H, m), 1.5 3-1 .32 (18 H, m).

LC / MS retention time: 1.40 minutes (analysis conditions: SMD-FA05-3).
(Steps 11-2, 3 and 4)
(2S) -3-Cyano-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl (compound 11 g)
Dissolve (3S) -3-aminobutane nitrile hydrochloride (compound 11c, 10.0 g, 82.9 mmol) in ethanol (50.0 mL) and add triethylamine (13.9 mL, 99.5 mmol) and ethyl acrylate (10 .8 mL, 99.5 mmol) were added at room temperature. The solution was stirred at an external temperature of 70 ° C. for 3 hours and cooled to room temperature to obtain a mixture containing ethyl 3-[[(2S) -1-cyanopropan-2-yl] amino] propanoate (Compound 11e).

  To the reaction solution was added di-tert-butyl dicarbonate (21.7 mL, 99.5 mmol) at room temperature. The solution was stirred at room temperature for 14 hours, N-methylpiperazine (2.76 mL, 24.9 mmol) was added and stirred for 4 hours. 1N hydrochloric acid (50 mL) was added and extracted with toluene (50 mL). The organic layer was washed with 15% aqueous sodium chloride solution (50.0 mL). The organic layer is concentrated under reduced pressure and ethyl 3-[[(2S) -1-cyanopropan-2-yl]-[(2-methylpropan-2-yl) oxycarbonyl] amino] propanoate (compound 11f) is contained. A mixture was obtained.

  To this mixture was added THF (50.0 mL), 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 adjusted to 15 ° C., 2N hydrochloric acid (82.9 mL, 99.5 mmol) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 15% aqueous sodium chloride solution (50.0 mL) and concentrated to give 11 g (15.8 g, yield 80%) of the title compound.

LC / MS mass spectrometry: m / z 237 ([M-H] ^- ).
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)
The compound 11b (2.13 g, 6.01 mmol) obtained in Step 11-1 is dissolved in NMP (6.39 mL), methanesulfonic acid (1.30 g, 13.2 mmol) is added, and the external temperature is 80 ° C. Stir 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 liquid, and stirred at room temperature for 10 minutes. The aqueous layer is 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 (4.2 mL) was added and stirred at an external temperature of 90 ° C. for 1 hour. The reaction was cooled and washed with 1 M aqueous sodium hydroxide (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] &lt; ⁺ &gt;).
LC / MS retention time: 1.08 minutes (analysis conditions: SMD-FA05-1).
(Step 11-6)
(4S) -3- (2,2-dimethoxyethylcarbamoylamino) -2- (4-fluoro-3,5-dimethylphenyl) -4-methyl-6,7-dihydro-4H-pyrazolo [4,3- c tert-Butyl pyridine-5-carboxylate (compound 11j)
N- (2,2-dimethoxyethyl) imidazole-1-carboxamide (compound 11i, 62.0 mg) in a solution of compound 11h (106 mg, 0.283 mmol) obtained in step 11-5 in DMA (0.53 mL) 0.311 mol) was added, and under a nitrogen atmosphere, potassium tert-butoxide (95.0 mg, 0.849 mol) was added, and the mixture was stirred at an external temperature of 25 ° C for 4 hours. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3: 2) to give 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-carboxylic acid tert-butyl (compound 11k)
THF (44.5 mL) is added to the compound 11j (4.45 g, 8.79 mmol) obtained in step 11-6 to suspend it, methylsulfonic acid (0.676 g, 7.03 mmol) is added, and the external temperature is 60 ° C. The mixture was stirred for 2 hours. After cooling to room temperature, a solution of tripotassium phosphate (1.87 g, 8.79 mmol) in water (17.8 mL) is added, di-tert-butyl dicarbonate (0.768 g, 3.52 mmol) is added, and at room temperature Stir for 1 hour. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with 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 give 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 11 l)
To a solution of compound 11k (1.85 g, 4.19 mmol) obtained in step 11-7 in dichloromethane (8.38 ml) was added 4 M hydrogen chloride solution in dioxane (10.5 mL, 41.9 mmol). After stirring this mixture at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to give 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-imidazole-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)
It synthesize | combined by operation similar to the process 1-10 of Example 1 from the compound 11l obtained at the process 11-8, and the compound 6h obtained at the process 6-5 using a suitable reagent.

  Example 2-oxoimidazole reagent (3-[(1S, 2S) -1- [2-[(4S) -2- (4-fluoro-3,5-dimethylphenyl) -4] used in the synthesis of compound 14 -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) 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-oxadiazole-3] -Yl) cyclopropyl] indole-2-carboxylic acid (compound 14b)
It was synthesized from Compound 6f obtained in Step 6-4 and 2-chloro-3-fluoro-4-iodopyridine (Compound 14a) by an operation similar to Step 6-5 in Example 6 using an appropriate reagent. .

LC / MS mass spectrometry: m / z 429 ([M + H] ^< +>).
LC / MS retention time: 1.14 minutes (analytical conditions: SMD-TFA 05-3).
(Step 14-2)
5- (3-Fluoro-2-methylpyridin-4-yl) -1-[(1S, 2S) -2-methyl-1- (5-oxo-4H-1,2,4-oxadiazole-3] -Yl) cyclopropyl] indole-2-carboxylic acid (compound 14c)
Compound 14b obtained in Step 14-1 (810 mg, 1.32 mmol), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride (48 mg, 0.066 mmol), potassium carbonate (2 A mixed suspension of 7: 1 (13.2 mL) of methylboronic acid (792 mg, 13.2 mmol) in DMSO / water 7: 1 (13.2 mL) was vacuum degassed at room temperature and then purged with nitrogen. After stirring for 0.5 hours at 100 ° C. under a nitrogen atmosphere, the mixture was cooled to room temperature. Formic acid was added, and the residue was directly purified by reverse phase chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound 14c (124 mg, 23% yield) as a pale yellow solid.

LC / MS mass spectrometry: m / z 409 ([M + H] ⁺ ).
LC / MS retention time: 0.85 minutes (analytical conditions: SMD-FA05-3).
(Step 14-3)
3-[(1S, 2S) -1- [2-[(4S) -2- (4-fluoro-3,5-dimethy]
Ruphenyl) -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)
Using the appropriate reagent, the compound 11l obtained in Step 11-8 and the compound 14c obtained in Step 14-2 were synthesized by the same procedure as Step 1-10 in Example 1.

  Example 2-oxoimidazole reagent used in the synthesis of 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) is 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), 2 M 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, 50% yield) 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-oxadi] Azol-3-yl) cyclopropyl] indole-2-carboxylic acid (Compound 15c)
The compound 6f obtained in Step 6-4 and the compound 15b obtained in Step 15-1 were synthesized by the same procedure as in Step 6-5 of Example 6, using an appropriate reagent.

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] indole-1- [Il] -2-Methylcyclopropyl] -4H-1,2,4-oxadiazol-5-one (Compound 15d)
It synthesize | combined by operation similar to the process 1-10 of Example 1 from the compound 15c obtained at the process 15-2, and the compound 11 1 obtained at the process 11-8 using a suitable reagent.

  Example 2-oxoimidazole reagent (3-[(1S, 2S) -1- [2-[(4S) -2- (4-fluoro-3,5-dimethylphenyl) used in the synthesis of compounds 16-30] -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 16a) 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- (oxane-4-yl) indol-1-yl] -2-methylcyclopropyl]- 4H-1,2,4-oxadiazol-5-one (compound 16a)
Using the appropriate reagent from compound 11 1 obtained in step 11-8 and compound 8b obtained in step 8-1, the compound was synthesized by the same procedure as step 1-10 in Example 1.

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

  Using appropriate reagents from 3-methyl-3-[(4-methylphenyl) sulfonylmethyl] oxetane (compound 17a) and 5-bromo-1H-indazole (compound 6j), using step 9-1 of Example 9 and It synthesize | combined by the same operation.

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 the example compound 20 was synthesized as follows.

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

  In a THF solution (1.38 mL) of 2- (4-bromo-2-methoxyphenoxy) -2-methylpropanecarboxylic acid (compound 20a, 400 mg, 1.38 mmol) under a nitrogen atmosphere, a THF solution of borane (0. 95M, 4.37 mL, 4.15 mmol) was added dropwise at 0 ° C. and stirred for 24 hours. After adding and stirring 1 M sodium hydroxide aqueous solution, 1N hydrochloric acid was added and it neutralized. Ethyl acetate was added and extracted. The organic layer was washed with water and the solvent was evaporated under reduced pressure to give the title compound 20b (339 mg, yield 89%).

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

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

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

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

LC / MS mass spectrometry: m / 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 the example compound 24 was synthesized as follows.

(Step 24-1)
Trifluoromethanesulfonic acid (1,1-dimethyl-3,4-dihydroisochromen-6-yl) (compound 24b)
Using the appropriate reagents from 1,1-dimethyl-3,4-dihydroisochromen-6-ol (compound 24a) and trifluoromethylsulfonyl trifluoromethanesulfonate (triflate anhydride), step 8-3 of Example 8 It synthesize | combined by the same operation.

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-dioxaborolane -2-yl) -1,3,2-dioxaborolane (147 mg, 0.580 mmol)
), Triethylamine (0.162 mL, 1.16 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (14.2 mg, 0.019 mmol) in 1,4-dioxane (2. The solution was degassed under reduced pressure, purged with nitrogen, and stirred at 100 ° C. for 14 hours. After cooling to room temperature, formic acid was added and purification was conducted by reverse phase chromatography (acetonitrile / water, 0.1% formic acid) to obtain a light brown liquid mixture (134 mg) containing the title compound 24c.

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)
A solution of copper bromide (II) (258 mg, 1.16 mmol) in water (1.9 mL) is added to a solution of compound 24c (111 mg, 0.385 mmol) obtained in step 24-2 in methanol (1.9 mL), 60 Stir for 6 hours at ° C. After cooling to room temperature, a saturated aqueous ammonium chloride solution was added, extraction was performed twice with dichloromethane, and the organic layer was dried over magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate / hexane = 1: 4) to give the title compound 24d (47.7 mg, yield 51%) as a colorless liquid The

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.29 (1 H, dd, J = 2.0, 8.4 Hz), 7.24-7.22 (1 H, m), 6.97 (1 H, 1 H, d, J = 8.4 Hz), 3.92 (2 H, t, J = 5.6 Hz), 2. 80 (2 H, t, J = 5.6 Hz), 1.50 (6 H, 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 the 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
To a solution of 2.9 mg (0.045 mmol) in methanol (0.2 mL) was added 2 M dimethylamine in THF (0.227 mL, 0.455 mmol) and stirred at room temperature for 3 hours. The reaction mixture was purified by reverse phase silica gel column chromatography (acetonitrile / water, 0.1% formic acid) to 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 (analytical conditions: SMD-FA05-3).
The halogen compound (5-bromo-4-fluoro-1- (2,2,2-trifluoroethyl) indazole, compound 28b) used in the synthesis of the example compound 28 was synthesized as follows.

(Step 28-1)
5-bromo-4-fluoro-1- (2,2,2-trifluoroethyl) indazole (compound 28b)
Using appropriate reagents from trifluoromethanesulfonic acid 2,2,2-trifluoroethyl (compound 10a) and 5-bromo-4-fluoro-1H-indazole (compound 28a), using step 8-4 of Example 8 and It synthesize | combined by the same operation.

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)
Using the appropriate reagents from 3-methyl-3-[(4-methylphenyl) sulfonylmethyl] oxetane (compound 17a) and 5-bromo-4-fluoro-1H-indazole (compound 28a), the process of example 8 It synthesize | combined by the operation similar to 8-4.

LC / MS mass spectrometry: m / z 299 ([M + H] &lt; ⁺ &gt;).
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 the 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) by the same procedure as in step 6-7 of Example 6 using an appropriate reagent.

LC / MS mass spectrometry: m / z 287 ([M + H] ^< +>).
LC / MS retention time: 1.01 minutes (analysis conditions: SMD-FA05-1).
Example 2-oxoimidazole reagent (3-[(1S, 2S) -1- [5-[(4S) -2,2-dimethyloxane-4-yl] -2 used in the synthesis of 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 31 1) It was synthesized as follows.

(Step 31-1)
Ethyl 5- (2,2-dimethyl-anthoxy-4-yl) -1H-indole-2-carboxylate (compound 31c)
Zinc dust (1.95 g, 29.8 mmol) was suspended in DMF (6 mL) and purged with nitrogen. Chlorotrimethylsilane (0.417 mL, 3.28 mmol), 1,2-dibromoethane (0.284 mL, 3.28 mmol) were added and stirred at room temperature for 5 minutes. A solution of 4-iodo-2,2-dimethyltetrahydropyran (5.37 g, 22.4 mmol) in DMF (9 mL) was added dropwise and stirred at room temperature for 20 minutes. In this solution, palladium (II) acetate (0.084 g, 0.373 mmol), 4- (N, N-dimethylamino) phenyl] di-tert-butylphosphine (0.198 g, 0.746 mol), 5-bromo Ethyl indole-2-carboxylate (2.0 g, 7.46 mmol) was added to carry out nitrogen substitution. After stirring for 1 hour at an external temperature of 50 ° C., the external temperature was cooled to 0 ° C. and neutralized with 5 N hydrochloric acid (6 mL). A 30% aqueous sodium chloride solution (50 mL) and ethyl acetate (100 mL) were added, and the insolubles were removed with Celite. The filtrate was extracted with ethyl acetate and washed with 30% aqueous sodium chloride solution. The extract was dried over magnesium sulfate and filtered, and the solvent was evaporated 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 (analytical conditions: SQD-FA05-4).
(Step 31-2)
Ethyl 5-[(4S) -2,2-dimethyloxane-4-yl] -1H-indole-2-carboxylate (Compound 31d)
The stereoisomer contained in Compound 31c (900 mg) obtained in Step 31-1 was separated by supercritical fluid chromatography to obtain the title compound 31d (423 mg, yield 47%).

Preparation conditions Equipment: SFC15 (Waters)
Column: CHIRALPAK-IE / SFC, 10 × 250 mm, 5 μm (Daicel)
Column temperature: 40 ° C
Solvent: supercritical carbon dioxide / methanol: ethyl acetate (1: 1) = 60/40 (homogeneous system)
Flow rate: 15 mL / min, 140 bar
Analysis conditions Equipment: Nexera (Shimadzu)
Column: CHIRALPAK-IE, 4.6 × 250 mm, 5 μm (Daicel)
Column temperature: 25 ° C
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 is determined by X-ray crystal structure analysis of compound 31j that the title compound is S isomer.

(Step 31-3)
5-[(4S) -2,2-dimethyl-anthoxy-4-yl] -1H-indole-2-carboxylic acid (compound 31e)
The compound 31d (993 mg, 3.29 mmol) obtained in Step 31-2 is dissolved in methanol (14.9 mL), 2 M aqueous solution of sodium hydroxide (3.62 mL, 7.25 mmol) is added dropwise, and the external temperature is 65 ° C. The mixture was stirred for 1 hour. The reaction solution was cooled at an external temperature of 15 ° C., and 5 N 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 give the title compound 31e (827 mg, yield 96%).

LC / MS mass spectrometry: m / z 274 ([M + H] ^< +>).
LC / MS retention time: 0.65 minutes (Analytical conditions: SQD-FA05-4).
(Step 31-4)
5-[(4S) -2,2-dimethyl-anthoxy-4-yl] -N-methyl-N-phenyl-1H-indole-2-carboxamide (compound 31f)
Compound 31e (805 mg, 2.95 mmol) obtained in step 31-3 was dissolved in DMA (8.0 mL), and thionyl chloride (0.256 mL, 3.53 mmol) was added dropwise at an internal temperature of 10 ° C. or less. After stirring for 1 hour, N-methylaniline (0.384 mL, 3.53 mmol) and triethylamine (0.985 mL, 7.07 mmol) were added dropwise at 10 ° C. or less, and stirred at room temperature for 1 hour. Water (4.0 mL) was added dropwise, and the precipitated solid was collected by filtration. The obtained solid was washed with water (8.0 mL) and dried under reduced pressure to give the title compound 31f (995 mg, yield 93%).

LC / MS mass spectrometry: m / z 363 ([M + H] &lt; ⁺ &gt;).
LC / MS retention time: 1.20 minutes (analysis conditions: SMD-FA05-1).
(Step 31-5)
1- (Cyanomethyl) -5-[(4S) -2,2-dimethyloxane-4-yl] -N-methyl-N-phenylindole-2-carboxamide (compound 31h)
Compound 31f (101 mg, 0.276 mmol) obtained in step 31-4 is dissolved in 1,3-dimethyl-2-imidazolidinone (DMI) (1.0 mL) at room temperature, and 8 M aqueous potassium hydroxide solution (0%) .103 mL, 0.828 mmol), water (0.10 mL) were added. To the resulting solution was added 2-chloroacetonitrile (0.026 mL, 0.414 mmol) at an external temperature of 10 ° C., and stirred for 2.5 hours. The reaction solution was extracted by adding 5N hydrochloric acid (0.193 mL), water (0.10 mL) and cyclopentyl methyl ether (1.0 mL), and the aqueous layer was extracted again with cyclopentyl methyl ether (1.0 mL). The combined organic layer is washed with a 15% aqueous sodium chloride solution (1.0 mL) and then concentrated under reduced pressure at an external temperature of 40 ° C. The title compound 31h of a pale brown oil obtained in the next step without purification It used for 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-dimethyloxane-4-yl] -N-methyl-N-phenylindole-2 -Carboxamide (compound 31i)
The compound 31h obtained in Step 31-5 was synthesized by the same procedure as Step 1-6 in Example 1 using a suitable reagent.

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-dimethyl-anthoxy-4-yl] -N-methyl-1-[(1S, 2S) -2-methyl-1- (5-oxo-4H-1,2,5 4-Oxadiazol-3-yl) cyclopropyl] -N-phenylindole-2-carboxamide (Compound 31j)
The compound 31i obtained in Step 31-6 was synthesized by the same procedure as Step 1-6 in Example 1 using an appropriate reagent.

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-dimethyl-anthoxy-4-yl] -1-[(1S, 2S) -2-methyl-1- (5-oxo-4H-1,2,4-oxadi] Azol-3-yl) cyclopropyl] indole-2-carboxylic acid (Compound 31k)
The compound 31j obtained in Step 31-7 was synthesized by the same procedure as Step 6-4 of Example 6, using an appropriate reagent.

LC / MS mass spectrometry: m / z 401 ([M−H] ⁻ ).
LC / MS retention time: 1.05 minutes (analysis conditions: SMD-FA05-1).
(Step 31-9)
3-[(1S, 2S) -1- [5-[(4S) -2,2-dimethyl- oxane-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- [Il] -2-Methylcyclopropyl] -4H-1,2,4-oxadiazol-5-one (Compound 31l)
Using the appropriate reagent from compound 11 l obtained in step 11-8 and compound 31k obtained in step 31-8, the compound was synthesized by the same procedure as step 1-10 in Example 1.

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

  (Step 33-1)

It was synthesized from 5-bromo-3-methyl-1H-benzoimidazol-2-one (Compound 33a) by an operation similar to step 8-4 of Example 8 using an appropriate reagent.
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 the example compound 36 was synthesized as follows.

  (Step 36-1)

It was synthesized from 5-bromo-4-fluoro-1H-indazole (Compound 28a) by the same procedure as in step 8-4 of Example 8 using a suitable reagent.
LC / MS mass spectrometry: m / z 273 ([M + H] &lt; ⁺ &gt;).

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 the example compound 40 was synthesized as follows.

  (Step 40-1)

  Using the appropriate reagents from 5-bromo-4-fluoro-1H-indazole (compound 28a) and 4-methylbenzenesulfonic acid [(3R) -oxolan-3-yl] (compound 22b), the process of example 8 It synthesize | combined by the operation similar to 8-4.

LC / MS mass spectrometry: m / z 285 ([M + H] ^< +>).
LC / MS retention time: 1.10 minutes (analysis conditions: SMD-FA05-1).
Example 2-oxoimidazole reagent (3-[(1S, 2S) -1- [2-[(4S) -2- (4-fluoro-3,5-dimethylphenyl) -4] used in the synthesis of 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-methyloxane-4-yl] -N-phenylindole-2-carboxamide (Compound 41c)
A suspension of zinc (29 mg, 0.44 mmol) in DMA (0.12 mL) was vacuum degassed at room temperature and then purged with nitrogen. Under nitrogen atmosphere, a 7: 5 mixed solution of chlorotrimethylsilane / 1,2-dibromoethane (0.0083 mL, 0.039 mmol of chlorotrimethylsilane) is added, and after stirring for 15 minutes, (2S) -4-iodo Add -2-Methyltetrahydro-2H-pyran (80 mg, 0.35 mmol) dropwise at room temperature, stir for 30 minutes, and mix it with iodo-[(2S) -2-methyloxane-4-yl] zinc (compound 41b) I got Palladium (II) acetate (6.4 mg, 0.028 mmol), 2-dicyclohexylphosphino-2 ', 6'-diisopropoxybiphenyl (26 mg, 0.057 mmol), 5-bromo-1-[(1S, 2S) ) -L-Cyano-2-methylcyclopropyl] -N-methyl-N-phenylindole-2-carboxamide (58 mg, 0.14 mmol), DMA (0.123 mL), and after degassing under reduced pressure, nitrogen substitution And stirred at 80 ° C. for 1 hour. The reaction solution was cooled to room temperature, ethyl acetate and 1N hydrochloric acid were added, and after filtration, the filtrate was extracted with ethyl acetate. The organic layer is washed once with saturated brine and concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate / hexane = 1: 1) to give the title compound 41c (31 mg, yield 51%) The

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-methyloxane-4-yl] -1-[(1S, 2S) -2-methyl-1- (5-oxo-4H-1,2,4-) Oxadiazol-3-yl) cyclopropyl] -N-phenylindole-2-carboxamide (Compound 41d)
The compound 41c obtained in Step 41-2 was synthesized by the same procedure as Step 1-8 in Example 1 using a suitable 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-Methyloxane-4-yl] -1-[(1S, 2S) -2-methyl-1- (5-oxo-4H-1,2,4-oxadiazole- 3-yl) cyclopropyl] indole-2-carboxylic acid (compound 41e)
The compound 41d obtained in Step 41-3 was synthesized by the same procedure as Step 6-4 of Example 6, using a suitable reagent.

LC / MS mass spectrometry: m / z 396 ([M-H] ^- ).
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-methyloxane-4-yl] indol-1-yl] -2-Methylcyclopropyl] -4H-1,2,4-oxadiazol-5-one (Compound 41f)
The compound 41e obtained in Step 41-4 was synthesized by the same procedure as Step 1-10 in Example 1 using a suitable reagent.

Example 1 The 2-oxoimidazole reagent (3-[(3) used in the synthesis of compounds 42 and 43
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-dimethyl-anthoxy-4-yl] indol-1-yl] -2 -Methylcyclopropyl] -4H-1,2,4-oxadiazol-5-one, compound 42 g) was synthesized as follows.

(Step 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), using the appropriate reagent, and following the procedure as described in Step 2-2 of Example 2, (4-chloro-3,5-dimethylphenyl) hydrazine After the hydrochloride salt (compound 42b) was obtained, compound 42c was synthesized by the same operation as in Example 1 and step 1-2, using the 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-FA 10-4).
(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)
The compound 42c obtained in Step 42-2 was synthesized by the same procedure as Step 1-3 in Example 1 using a suitable reagent.

LC / MS mass spectrometry: m / z 522 ([M + H] ^< +>).
LC / MS retention time: 1.55 minutes (analytical conditions: SMD-TFA 05-5).
(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)
The compound 42d obtained in Step 42-3 was synthesized by the same procedure as Step 11-8 of Example 11, using an appropriate reagent.

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)
The compound 42e obtained in Step 42-4 was synthesized by the same procedure as Step 111-8 in Example 11 using an appropriate reagent.

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-imidazole-3] -Yl) -6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carbonyl] -5-[(4S) -2,2-dimethyl- oxane-4-yl] indole-1- [I] -2-Methylcyclopropyl] -4H-1,2,4-oxadiazol-5-one (Compound 42 g)
The compound 42f obtained in Step 42-5 and the compound 31k obtained in Step 31-8 were synthesized in the same manner as in Step 1-10 of Example 1, using an appropriate reagent.

  Example 2-oxoimidazole reagent (3-[(1S, 2S) -1- [2-[(4S) -2- (4-chloro-3,5-dimethylphenyl)] used in the synthesis of 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- (oxane -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 an appropriate reagent.

  Example 2-oxoimidazole reagent (3-[(1S, 2S) -1- [2-[(4S) -2- (4-fluoro-3-methylphenyl) -4] used in the synthesis of 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-carboxylic acid tert-butyl (Compound 46b)
Using the appropriate reagent from (4-fluoro-3-methylphenyl) hydrazine hydrochloride (Compound 46a) and the compound 11g obtained in Step 11-4, synthesis was carried out by the same procedure as in Step 1-2 of Example 1 did.

LC / MS mass spectrometry: m / z 361 ([M + H] &lt; ⁺ &gt;).
LC / MS retention time: 1.02 minutes (analysis conditions: SMD-FA05-1).
(Step 46-2)
(4S) -3- (2,2-dimethoxyethylcarbamoylamino) -2- (4-fluoro-3-methylphenyl) -4-methyl-6,7-dihydro-4H-pyrazolo [4,3-c] Pyridine-5-carboxylic acid tert-butyl (compound 46c)
The 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)
The compound 46c obtained in Step 46-2 was synthesized by the same procedure as Step 11-7 of Example 11, using an appropriate reagent.

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)
The compound 46d obtained in Step 46-3 was synthesized by the same procedure as Step 11-8 of Example 11, using an appropriate reagent.

LC / MS mass spectrometry: m / z 328 ([M + H] ^< +>).
LC / MS retention time: 0.59 minutes (analytical 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- (oxane-4-yl) indol-1-yl] -2-methylcyclopropyl] -4H- 1,2,4-oxadiazol-5-one (compound 46f)
The compound 46e obtained in Step 46-4 and the compound 8b obtained in Step 8-1 were synthesized by the same procedure as Step 1-10 in Example 1 using an appropriate reagent.

  Example 2-oxoimidazole reagent (3-[(1S, 2S) -1- [5-[(4S) -2,2-dimethyl- oxane-4-yl] -2 used in the synthesis of compounds 48 to 50 -[(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) is Synthesized.

(Step 48-1)
3-[(1S, 2S) -1- [5-[(4S) -2,2-dimethyloxane-4-yl] -2-[(4S) -2- (4-fluoro-3-methylphenyl) ) -4-Methyl-3- (2-oxo-1H-imidazol-3-yl) -6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carbonyl] indol-1-yl] -2-Methylcyclopropyl] -4H-1,2,4-oxadiazol-5-one (Compound 48a)
The compound 46e obtained in Step 46-5 and the compound 31k obtained in Step 31-8 were synthesized by the same procedure as Step 1-10 in Example 1 using an appropriate reagent.

Examples 51 to 53
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, The same operation as in step 7-1 of Example 7 is carried out using 2,4-oxadiazol-5-one (compound 51d) and substituted morpholine, and an appropriate reagent, and the following reaction is carried out according to Table 2-4 The example compound 51-53 shown to was obtained.

  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)
Triethylamine (0.936 mL, 6.72 mmol) in a suspension of the compound 2f (0.611 g, 1.68 mmol) obtained in step 2-5 in dichloromethane (16.8 mL), di-t-butyl dicarbonate (0 .425 mL, 1.85 mmol) was added and stirred at room temperature for 2 hours. Water (20.0 mL) and 5% aqueous potassium hydrogen sulfate solution (20.0 mL) were added to the reaction mixture, and the mixture was extracted with dichloromethane and dried over magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate / hexane = 0: 1 to 1: 0) to give 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)
The compound 51a obtained in Step 51-1 and 5-bromo-1-methylindazole were synthesized by the same procedure as in Step 1-11 of Example 1 using an appropriate reagent.

LC / MS mass spectrometry: m / z 558 ([M + H] &lt; ⁺ &gt;).
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-methylindazole -5-yl) imidazol-2-one hydrochloride (Compound 51c)
Using the appropriate reagent from compound 51b obtained in step 51-2, step 11 of Example 11
It synthesize | combined by the operation similar to -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)
Using the appropriate reagent, the compound 51c obtained in Step 51-3 and the compound 6f obtained in Step 6-4 were synthesized by the same procedure as in Step 1-10 of Example 1.

LC / MS mass spectrometry: m / z 817 ([M + H] &lt; ⁺ &gt;).
LC / MS retention time: 1.41 minutes (analysis conditions: SMD-FA05-1).
Examples 54 to 73
The amine derivative and the carboxylic acid derivative were used to carry out the same procedure as in Step 1-10 of Example 1, and Example Compounds 54 to 72 and Example Compound 73 shown in Table 2-5 were obtained by the following reactions. .

In addition, although a rotamer exists in the compound in Table 2-5, ¹ H-NMR of Example compounds 66 and 67 is as follows, for example.
Example Compound 66
Major rotamer
¹ H-NMR (600 MHz, CDCl ₃ ) δ: 11.32 (1 H, s), 8.04 (1 H, d, J = 0.4 Hz), 7.86 (1 H, d, J = 1.4 Hz) , 7.61 (1 H, m), 7.59 (1 H, m), 7.52 (1 H, s), 7. 50 (H, d, J = 9.0 Hz), 7.27 (1 H, m) _{), 7.15 (2H, d,} J HF = 6.0Hz), 6.74 (1H, d, J = 3.1Hz), 6.70 (1H, s), 6.32 (1H, d, J = 3.1 Hz), 5.79 (1 H, q, J = 6.6 Hz), 4.47 (1 H, dd, J = 13.6, 5.0 Hz), 4.12 (3 H, 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 _{0Hz), 3.09-2.98 (2H, m} ), 2.27 (6H, d, J HF = 1.4Hz), 1.91 (1H, dd, J = 6.0Hz), 1.82 -1.60 (4H, m), 1.60-1.50 (2H, m), 1.55 (3H, d, J = 6.6 Hz), 1.34 (3 H, 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 (1 H, s), 7.93 (1 H, s), 7.65 (1 H, s), 7.57 (1 H, d, J = 8 .6 Hz), 7.49 (1 H, m), 7.34 (2 H, s), 7. 25 (1 H, m), 7.05 (2 H, d, J _HF = 6.0 Hz), 6.69 (1H, s), 6.59 (1 H, d, J = 3.1 Hz), 6.09 (1 H, d, J = 3.1 Hz), 5.26 (1 H, q, J = 6.6 Hz) , 4.87 (1 H, dd, J = 12.8, 5.1 Hz), 4.07 (3 H, s), 3.90-3. 78 (2 H, m), 3. 40 (1 H, ddd, J = 12.8, 12.6, 4.5 Hz), 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
Major rotamer
¹ H-NMR (600 MHz, CDCl ₃ ) δ: 11.32 (1 H, s), 8.13 (1 H, d, J _HF = 0.7 Hz), 7.59 (1 H, d, J = 8.6 Hz ), 7.52
_{(1H, s), 7.48 (} 1H, dd, J = 8.9Hz, J HF = 6.9Hz), 7.28 (1H, d, J = 8.9Hz), 7.26 (1H, dd , J = 8.6, 1.7 Hz), 7.16 (2 H, d, J _HF = 6.1 Hz), 6. 70 (1 H, s), 6.61 (1 H, dd, J = 3.0 Hz) , J _HF = 1.1 Hz), 6. 31 (1 H, d, J = 3.0 Hz), 5.79 (1 H, q, J = 6.7 Hz), 4.47 (1 H, dd, J = 13) .5, 5.2 Hz), 4.12 (3 H, s), 3.88 (1 H, m), 3. 83 (1 H, m), 3. 60 (1 H, ddd, J = 13.5, 12) .9, 3.6 Hz), 3.15 (1 H, ddd, J = 15.8, 12.9, 5.2 Hz), 3.04 (1 H, m), 3.00 (1 H, m), 2 .29 (6 H, d _{J HF = 1.1Hz), 1.91 (} 1H, dd, J = 6.1,5.8Hz), 1.79-1.76 (2H, m), 1.74 (1H, m), 1 .65 (1 H, m), 1.57 (3 H, d, J = 6.7 Hz), 1.60-1.55 (1 H, m), 1.52 (1 H, dd, J = 9.5, 5.8 Hz), 1.34 (3 H, s), 1. 28 (3 H, s), 1. 20 (3 H, d, J = 6.0 Hz).

Minor rotamer
¹ H-NMR (600 MHz, CDCl ₃ ) δ: 11.27 (1 H, s), 8.04 (1 H, s), 7.55 (1 H, d, J = 8.7 Hz), 7.52 (1 H) , S), 7.25-7.22 (2 H, m), 7.12 (1 H, d, J = 8.8 Hz), 7.06 (2 H, d, J _HF = 6.0 Hz), 6. 71 (1 H, s), 6.47 (1 H, m), 6.08 (1 H, d, J = 3.0 Hz), 5.26 (1 H, q, J = 6.6 Hz), 4.87 ( 1H, dd, J = 13.1, 4.8 Hz), 4.07 (3H, s), 3.90-3.80 (2H, m), 3.39 (1H, ddd, J = 13.1) , 12.2, 4.6 Hz), 3.08-2.97 (3 H, m), 2. 25 (6 H, s), 1.79-1.73 (3 H, m), 1.67 (3 H) , D, J = 6. Hz), 1.64 (1H, m), 1.45 to 1.37 (2H, m), 1.34 (3H, s), 1.28 (3H, s), 1.06 (3H, d) , J = 6.0 Hz).

  The compound 55e used in the synthesis of the example compound 55 was synthesized as follows.

(Step 55-1)
3-Amino-2- (4-chloro-3,5-dimethylphenyl) -6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carboxylate tert-butyl (Compound 55a)
The compound 42a obtained in Step 42-1 and the compound 1b obtained in Step 1-1 were synthesized by the same procedure as in Step 1-2 of Example 1, using an appropriate reagent.

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-carboxylic acid tert-Butyl (compound 55b)
The compound 55a obtained in Step 55-1 was synthesized by the same procedure as Step 1-3 in Example 1 using a suitable 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 the compound 55b obtained in Step 55-2 (903 mg, 1.78 mmol), p-toluenesulfonic acid monohydrate (338 mg, 1.78 mmol) in DMF (7.11 mL) is 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 the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, extraction was performed 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 as a pale yellow foam (799 mg, yield) 100%).

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 Tert-Butyl [4,3-c] pyridine-5-carboxylate (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-methylindazole -5-yl) imidazol-2-one hydrochloride (Compound 55e)
The compound 55d obtained in Step 55-4 was synthesized by the same procedure as Step 11-8 of Example 11, using a suitable reagent.

LC / MS mass spectrometry: m / z 474 ([M + H] ^< +>).
LC / MS retention time: 0.81 minutes (analysis conditions: SMD-FA05-1).
The compound 56c used in the synthesis of the 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- Tert-Butyl dihydro-4H-pyrazolo [4,3-c] pyridine-5-carboxylate (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. did.

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)
The compound 56b obtained in Step 56-1 was synthesized by the same procedure as Step 11-8 of Example 11, using an appropriate reagent.

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

(Step 57-1)
Tert-Butyl N- (4-isocyanatocuban-1-yl) carbamate (Compound 57b)
Triethylamine (0.0676 mL, 0) in 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) 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 reaction mixture was evaporated under reduced pressure to give the title compound 57b as a crude product.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 12.3 (1 H, brs), 3.95 (6 H, brs), 1.45 (9 H, 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 Step 1-3 in Example 1 using an appropriate reagent.

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- [Ill] -2-Oxoimidazolidin-1-yl] -4-methyl-6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carboxylate tert-butyl (Compound 57d)
In a suspension of compound 57c (31.6 mg, 0.050 mmol) obtained in step 57-2 and cesium carbonate (82.8 mg, 0.254 mmol) in DMA (0.25 mL), Ethoxyethane (0.0155 mL, 0.127 mmol) was added at room temperature and stirred at room temperature for 170 minutes. Cesium carbonate (104 mg, 0.32 mmol) and then 1,2-dichloro-1-ethoxyethane (0.0184 mL, 0.162 mmol) were added to the reaction mixture at room temperature and stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH 7 with ethyl acetate and water and adjusted to pH 7 with 1N hydrochloric acid (0.54 mL), and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Toluene was added and the solvent was evaporated under reduced pressure to give the title compound 57d as a crude product.

LC / MS mass spectrometry: m / z 678 ([M + H] &lt; ⁺ &gt;).
LC / MS retention time: 0.98 minutes (analytical conditions: SQD-FA05-1).
(Step 57-4)
(4S) -2- (4-Fluoro-3,5-dimethylphenyl) -4-methyl-3- [3- [4-[(2-methylpropan-2-yl) oxycarbonylamino] cuban-1- [Ill-2-oxoimidazol-1-yl] -6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carboxylate tert-butyl (Compound 57e)
After adding methylsulfonic acid (0.011 mL, 0.17 mmol) to a solution of compound 57d (115 mg, 0.17 mmol) obtained in Step 57-3 in THF (1.1 mL) at room temperature, 90 at 60 ° C. Stir for a minute. To the reaction mixture was added 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) Stir for 1 hour. The reaction mixture was diluted with dichloromethane and then washed with water. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 2 to 1: 1) to give the title compound 57e (48.5 mg, 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- (4-Fluoro-3,5-dimethylphenyl) -4-methyl-6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carboxylate tert-butyl (Compound 57f)
A solution of compound 57e (16.1 mg, 0.024 mmol) obtained in Step 57-4 in THF (0.22 mL) at −26 ° C. in 1.7 M potassium pentoxide toluene solution (0.024 mL, 0. 2). 041 mmol) was added and stirred at -30 ° C for 3 minutes. Acetic anhydride (8 μL, 0.085 mmol) was added to the reaction mixture at -30 ° C and stirred for 5 minutes at -30 ° C to -25 ° C and for 3 minutes at -25 ° C to room temperature. Water (0.5 mL) was added to the reaction mixture and then diluted with ethyl acetate, water was further added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / hexane = 1: 3 to 2: 3) to give the title compound 57f (9.2 mg, yield 54%) I got

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 57 g)
To a solution of compound 57f (8.5 mg, 0.012 mmol) obtained in Step 57-5 in dichloromethane (0.097 mL) was added TFA (0.019 mL) at room temperature, and stirred at room temperature for 3 hours. The reaction mixture was evaporated under reduced pressure, toluene was added and the solvent was evaporated, 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)
An appropriate reagent was used to synthesize from the compound 57g obtained in Step 57-6 by the same operation as Step 51-1 of Example 51.

LC / MS mass spectrometry: m / z 602 ([M + H] ^< +>).
LC / MS retention time: 0.85 minutes (analytical conditions: SQD-FA05-1).
(Step 57-8)
(4S) -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 tert-butyl (compound 57i)
The compound 57h obtained in Step 57-7 was synthesized by the same procedure as Step 57-5 of Example 57 using a suitable 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)
The compound 57i obtained in Step 57-8 was synthesized by the same procedure as Step 11-8 of Example 11, using an appropriate reagent.

LC / MS mass spectrometry: m / z 560 ([M + H] ^< +>).
LC / MS retention time: 0.53 minutes (analysis conditions: SQD-FA05-1).
The compound 58e used in the synthesis of the example compound 58 was synthesized as follows.

(Step 58-1)
3-Amino-2- (4-fluoro-3-methylphenyl) -6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carboxylate tert-butyl (Compound 58a)
It synthesize | combined by operation similar to the process 1-2 of Example 1 from the compound 1b obtained at the process 1-1, and the compound 46a obtained at the process 46-1 using a suitable reagent.

LC / MS mass spectrometry: m / z 347 ([M + H] ^< +>).
LC / MS retention time: 0.98 minutes (analysis conditions: SMD-FA05-3).
(Step 58-2)
3- (2,2-Dimethoxyethylcarbamoylamino) -2- (4-fluoro-3-methylphenyl) -6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert- Butyl (compound 58b)
The compound 58a obtained in Step 58-1 was synthesized by the same procedure as Step 1-3 in 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 Acid tert-butyl (compound 58c)
The compound 58b obtained in Step 58-2 was synthesized by the same procedure as Step 11-7 of Example 11, using an appropriate reagent.

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. did.

LC / MS mass spectrometry: m / z 588 ([M + H] ^< +>).
LC / MS retention time: 0.88 minutes (Analytical 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-methoxy) Ethyl) indazol-5-yl] imidazol-2-one hydrochloride (Compound 58e)
The compound 58d obtained in Step 58-4 was synthesized by the same procedure as Step 11-9 in Example 11 using an appropriate reagent.

LC / MS mass spectrometry: m / z 488 ([M + H] ^< +>).
LC / MS retention time: 0.50 minutes (analytical conditions: SQD-FA05-1).
The compound 60c used in the synthesis of the example compound 60 was synthesized as follows.

(Step 60-1)
2- (3,5-Dimethylphenyl) -3- (2-oxo-1H-imidazol-3-yl) -6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert -Butyl (compound 60a)
An appropriate reagent was used to synthesize from 1 g of the compound obtained in Step 1-4, in the same manner as in Step 51-1 of Example 51.

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)
The compound 60a obtained in Step 60-1 and 5-bromo-1-methylindazole (Compound 1q) were synthesized by the same procedure as in Step 1-11 of Example 1, using an appropriate reagent.

LC / MS mass spectrometry: m / 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)
Using the appropriate reagent from compound 60b obtained in Step 60-2, Step 11 of Example 11
It synthesize | combined by the operation similar to -8.

LC / MS mass spectrometry: m / z 440 ([M + H] ^< +>).
LC / MS retention time: 0.74 minutes (analytical conditions: SMD-FA05-2).
The compound 61b used in the synthesis of the 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)
The compound 11k obtained in Step 11-7 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 572 ([M + H] &lt; ⁺ &gt;).
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 Step 11-8 in 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).
The compound 62b used in the synthesis of the 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-carboxylic acid tert-butyl (Compound 62a)
From compound 11k obtained in Step 11-7 and 5-bromo-1- (2-methoxyethyl) indazole (Compound 56a), synthesis was conducted by the same procedure as in Step 1-11 of Example 1, using an appropriate reagent did.

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 Step 11-8 of Example 11, using an appropriate reagent.

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

(Step 63-1)
5-bromo-7-fluoro-N-methyl-N-phenyl-1H-indole-2-carboxamide (compound 63b)
The compound was synthesized from 5-bromo-7-fluoro-1H-indole-2-carboxylic acid (Compound 63a) by an operation similar to steps 1-10 of Example 1 using a suitable reagent.

(Step 63-2)
5-bromo-1- (cyanomethyl) -7-fluoro-N-methyl-N-phenylindole-2-carboxamide (compound 63c)
It synthesize | combined by the operation similar to the process 9-1 of Example 9 from the compound 63b obtained at the process 63-1 using the suitable reagent.

LC / MS mass spectrometry: m / z 386 ([M + H] ^< +>).
LC / MS retention time: 3.17 minutes (analysis conditions: SMD-FA 10-long).
(Step 63-3)
5-bromo-1-[(1S, 2S) -1-cyano-2-methylcyclopropyl] -7-fluoro-N-methyl-N-phenylindole-2-carboxamide (compound 63d)
The compound 63c obtained in Step 63-2 was synthesized by the same procedure as Step 1-6 in Example 1 using a suitable reagent.

LC / MS mass spectrometry: m / z 426 ([M + H] &lt; ⁺ &gt;).
LC / MS retention time: 1.36 minutes (analysis conditions: SMD-FA05-1).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.75 (1 H, s), 7.43-7.30 (6 H, m), 6.08 (1 H, brs), 3.44 (3 H, 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- (oxane-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), using a suitable reagent, in the same manner as in Step 8-1 of Example 8. Were synthesized by

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 Step 1-8 in Example 1 using a suitable reagent.

LC / MS mass spectrometry: m / z 491 ([M + H] &lt; ⁺ &gt;).
LC / MS retention time: 1.21 minutes (analytical 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- (oxane-4) -Yl) indole-2-carboxylic acid (compound 63 g)
It synthesize | combined by the operation similar to the process 6-4 of Example 6 from the compound 63f obtained at the process 63-5 using the suitable reagent.

LC / MS mass spectrometry: m / z 402 ([M + H] ^< +>).
LC / MS retention time: 0.97 minutes (analysis conditions: SMD-FA05-1).
The compound 64b used in the synthesis of the 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) -oxolane-3-yl] indazole-5- [Il] imidazol-1-yl] -6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carboxylate tert-butyl (compound 64a)
Using the appropriate reagent from compound 11k obtained in step 11-7 and compound 8f obtained in step 8-4, the compound was synthesized by the same procedure as step 1-11 in Example 1.

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 Step 11-8 of Example 11, using a suitable reagent.

LC / MS mass spectrometry: m / z 528 ([M + H] ^< +>).
LC / MS retention time: 0.78 minutes (analysis conditions: SMD-FA05-1).
The compound 65c used in the synthesis of the 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-carboxylic acid tert-butyl (Compound 65b)
It was synthesized from Compound 42e obtained in Step 42-4 and 5-bromo-4-fluoro-1-methylindazole (Compound 65a) by an operation similar to Step 1-11 in Example 1 using a suitable 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)
The compound was synthesized in the same manner as in step 11-8 of Example 11, using a suitable reagent from compound 65b obtained in step 65-1.

LC / MS mass spectrometry: m / z 506 ([M + H] ^< +>).
LC / MS retention time: 0.86 minutes (analysis conditions: SMD-FA05-1).
The compound 67b used in the synthesis of the 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-carboxylic acid tert-butyl (compound 67a)
It was synthesized from Compound 11k obtained in Step 11-7 and 5-bromo-4-fluoro-1-methylindazole (Compound 65a) by the same procedure as in Step 1-11 of Example 1 using an appropriate reagent. .

LC / MS mass spectrometry: m / 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)
It synthesize | combined by the operation similar to the process 11-8 of Example 11 from the compound compound 67a obtained at the process 67-1 using the suitable reagent.

LC / MS mass spectrometry: m / z 490 ([M + H] ^< +>).
LC / MS retention time: 0.80 minutes (analysis conditions: SMD-FA05-1).
The compound 68c used in the synthesis of the example compound 68 was synthesized as follows.

(Step 68-1)
(4S) -3- [3- (4-chloro-1-methylindazol-5-yl) -2-oxoimidazol-1-yl] -2- (4-fluoro-3,5-dimethylphenyl) -4 -Methyl-6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl (compound 68b)
It was synthesized from Compound 11k obtained in Step 11-7 and 5-bromo-4-chloro-1-methylindazole (Compound 68a) by an operation similar to Step 1-11 in 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)
The compound 68b obtained in Step 68-1 was synthesized by the same procedure as Step 11-8 of Example 11, using an appropriate reagent.

LC / MS mass spectrometry: m / z 506 ([M + H] ^< +>).
LC / MS retention time: 0.83 minutes (analysis conditions: SMD-FA05-1).
The compound 69b used in the synthesis of the 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)
It was synthesized from Compound 46d obtained in Step 46-3 and 5-bromo-4-fluoro-1-methylindazole (Compound 65a) by an operation similar to Step 1-11 in Example 1 using an appropriate reagent. .

LC / MS mass spectrometry: m / z 576 ([M + H] &lt; ⁺ &gt;).
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-tetrahydrofuran Pyrazolo [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 Step 11-8 of Example 11, using a suitable reagent.

LC / MS mass spectrometry: m / z 476 ([M + H] ⁺ ).
LC / MS retention time: 0.77 minutes (analysis conditions: SMD-FA05-1).
The compound 70c used in the synthesis of the 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)
It was synthesized from Compound 11k obtained in Step 11-7 and 5-bromo-6-fluoro-1-methylindazole (Compound 70a) by the same procedure as in Step 1-11 of Example 1 using an appropriate reagent. .

LC / MS mass spectrometry: m / 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)
Using the appropriate reagent from compound 70b obtained in Process 70-1, Process 11 of Example 11
It synthesize | combined by the operation similar to -8.

LC / MS mass spectrometry: m / z 490 ([M + H] ^< +>).
LC / MS retention time: 0.81 minutes (analysis conditions: SMD-FA05-1).
The compound 71b used in the synthesis of the example compound 71 was synthesized as follows.

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

LC / MS mass spectrometry: m / z 273 ([M + H] &lt; ⁺ &gt;).
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 -Yl] tert-Butyl (compound 71c) of 4-methyl-6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carboxylate
The compound 11k obtained in Step 11-7 and the compound 71b obtained in Step 71-1 were synthesized by the same procedure as in Step 1-11 of Example 1 using an appropriate reagent.

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)
The compound 71c obtained in Step 71-2 was synthesized by the same procedure as Step 11-8 of Example 11, using a suitable reagent.

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- Synthesis of c] 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 obtained in Step 1-9 (26.8 mg, 0.064 mmol) HATU (26.6 mg, 0.070 mmol) and N, N-diisopropylethylamine (18.1 mg, 0.14 mmol) were added to a solution of (1.5 mL) in DMF, and the mixture was 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 give a residue which is 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 condition column: YMC Actus ODS-A, 20 × 100 mm, 5 μm
Solvent: 0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution = 40/60 (homogeneous system)
Flow rate: 20 mL / min, room temperature
Entity A
LC / MS mass spectrometry: m / z 872 ([M + H] &lt; ⁺ &gt;).

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] &lt; ⁺ &gt;).

LC / MS retention time: 1.01 minutes (analysis conditions: SMD-FA05-3).
EXAMPLE 74 3-[(1S, 2S) -1- [6-Fluoro-2-[(4S) -2- (4-fluoro-3,5-dimethylphenyl) -4-methyl-3- [3 3- (1-Methylindazol-5-yl) -2-oxoimidazol-1-yl] -6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carbonyl] -5- (2 Synthesis of -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) by an operation similar to steps 1-10 of Example 1 using a suitable reagent.

LC / MS mass spectrometry: m / z 347 ([M + H] ^< +>).
LC / MS retention time: 1.06 minutes (analytical conditions: SMD-TFA 05-4).
(Step 74-2)
5-bromo-1- (cyanomethyl) -6-fluoro-N-methyl-N-phenylindole-2-carboxamide (compound 74c)
The compound 74b obtained in Step 74-1 was synthesized by the same procedure as Step 9-1 of Example 9 using an appropriate reagent.

LC / MS mass spectrometry: m / z 386 ([M + H] ^< +>).
LC / MS retention time: 1.06 minutes (analytical conditions: SMD-TFA 50-4).
(Step 74-3)
5-bromo-1-[(1S, 2S) -1-cyano-2-methylcyclopropyl] -6-fluoro-N-methyl-N-phenylindole-2-carboxamide (compound 74d)
Using the appropriate reagent from compound 74c obtained in step 74-2 and (4R) -4-methyl-1,3,2-dioxathiolane 2,2-dioxide (compound 1k), step 1- of Example 1 It synthesize | combined by the operation similar to 6.

LC / MS mass spectrometry: m / z 426 ([M + H] &lt; ⁺ &gt;).
LC / MS retention time: 1.04 minutes (analysis conditions: SMD-FA 10-5).
(Step 74-4)
5-bromo-6-fluoro-N-methyl-1-[(1S, 2S) -2-methyl-1- (5-oxo-4H-1,2,4-oxadiazol-3-yl) cyclopropyl ] -N-phenylindole-2-carboxamide (compound 74e)
The compound 74d obtained in Step 74-3 was synthesized by the same procedure as Step 1-8 in Example 1 using a suitable reagent.

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)
The compound 74e obtained in Step 74-4 was synthesized by the same procedure as Step 6-4 of Example 6, using an appropriate reagent.

LC / MS mass spectrometry: m / z 396 ([M + H] &lt; ⁺ &gt;).
LC / MS retention time: 0.80 minutes (analytical 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 74 g)
The compound 74f obtained in Step 74-5 and Compound 61b obtained in Step 61-2 were synthesized by the same procedure as in Step 1-10 of Example 1, using an appropriate reagent.

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- (1-S)] Methylindazol-5-yl) -2-oxoimidazol-1-yl] -6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carbonyl] -5- (2-methoxy-3-yl) Methylpyridin-4-yl) indol-1-yl] -2-methylcyclopropyl] -4H-1,2,4-oxadiazol-5-one (Compound 74)
The compound was synthesized by the same procedure as in Step 6-5 of Example 6, using 74 g of the compound obtained in Step 74-6 and 4-iodo-2-methoxy-3-methylpyridine (Compound 6 g), and an appropriate reagent. did.

LC / MS mass spectrometry: m / z 892 ([M + H] &lt; ⁺ &gt;).
LC / MS retention time: 1.48 minutes (analytical conditions: SMD-TFA 05-1).
<Examples 75 to 77>
The same procedures as in step 8-1 of Example 8 are carried out using an indole bromide compound and an iodo (oxane-4-yl) zinc derivative, and an appropriate reagent, and the examples shown in Table 2-6 by the following reactions Compounds 75-77 were obtained.

The compound 75b used in the synthesis of the example compound 75 was synthesized as follows.
(Step 75-1)
Iodo (6-oxaspiro [4.5] decan-9-yl) zinc (compound 75b)

Using 9-iodo-6-oxaspiro [4.5] decane (Compound 75a), and using an appropriate reagent, it was synthesized by the same procedure as step 41-1 of Example 41.
This compound was used directly in the next step.

  The compound 76a used in the synthesis of the 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)
The compound 56b obtained in Step 56-1 and the compound 6f obtained in Step 6-4 were synthesized by the same procedure as Step 1-10 in Example 1 using an appropriate reagent.

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

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

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

  anti δ: 4.87 to 4.84 (1 H, m), 3.90 to 3.82 (2 H, m), 3.70 to 3.64 (1 H, m), 2.37 to 1. 38 ( 6H, m), 0.94 (3H, t, J = 7.6 Hz).

(Step 77-2)
(2-Ethyloxan-4-yl) -iodo zinc (compound 77c)
To a solution of zinc (102 mg, 1.56 mmol) in DMA (0.25 mL) under a nitrogen atmosphere, chloro (trimethyl) silane (0.017 mL, 0.137 mmol) and 1,2-dibromoethane (0.012 mL, 0. 1). The mixture of 137 mmol) was slowly dropped to keep the temperature at 65 ° C. or less, and 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) is slowly added dropwise so as to keep the temperature at 65 ° C. or lower. The mixture was stirred for 30 minutes to obtain a DMA solution (0.86 M) of a diastereomeric mixture of the title compound 77c.

(Step 77-3)
3-[(1S, 2S) -1- [5- (2-ethyloxane-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 acetate (II) (2.20 mg, 0.00978 mmol), 2- (2-dicyclohexyl) in a solution of compound 51d (40.0 mg, 0.049 mmol) obtained in step 51-4 in DMA (0.163 mL) Add phosphanylphenyl) -1-N, 1-N, 3-N, 3-N-tetramethylbenzene-1,3-diamine (8.54 mg, 0.020 mmol), vacuum degassing, and then replace with nitrogen And stirred for 5 minutes at room temperature. Subsequently, a solution of compound 77c obtained in Step 77-2 in DMA (0.86 M, 0.398 mL, 0.342 mmol) was added, and stirred at room temperature for 1.5 hours. Formic acid was added to the reaction mixture and purification was conducted by reverse phase silica gel chromatography (acetonitrile / water, 0.1% formic acid) to obtain a syn isomer diastereomer mixture. The syn isomer diastereomer mixture is separated into stereoisomers by reverse phase HPLC, and the white amorphous Entity A (17.4 mg, yield 41%) and the white amorphous title compound 77, Entity B ( 14.9 mg (yield 37%) was obtained.

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

HPLC retention time: 4.99 minutes (preparation 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 (preparation 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- (oxane-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)
From compound 51c obtained in step 51-3 and 5-bromo-1- (cyanomethyl) indole-2-carboxylic acid (compound 6a), the same procedure as in step 1-10 of Example 1 using a suitable reagent Synthesized by

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)
Analogously to Step 8-1 of Example 8 using a suitable reagent from compound 78a obtained in Step 78-1 and (tetrahydro-2H-pyran-4-yl) zinc (II) iodide (Compound 8a) Were synthesized by

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- (oxane-4-yl) indol-1-yl] cyclopropane-1 Carbonitrile (Compound 78d)
It synthesize | combined by operation similar to the process 1-6 of Example 1 from the compound 78b obtained at the process 78-2 using the suitable reagent.

LC / MS mass spectrometry: m / z 778 ([M + H] &lt; ⁺ &gt;).
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- (oxane-4-yl) indol-1-yl] cyclopropyl ] -4H-1,2,4-oxadiazol-5-one (Compound 78)
The compound 78d obtained in Step 78-2 was synthesized by the same procedure as Step 1-8 in Example 1 using a suitable reagent.

LC / MS mass spectrometry: m / z 837 ([M + H] ⁺ ).
LC / MS retention time: 1.39 minutes (analytical conditions: SMD-TFA 05-2).
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- (oxane-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 6 using a suitable reagent from compound 6c obtained in step 6-1 and (4R) -4- (phenylmethoxymethyl) -1,3,2-dioxathiolane 2,2-dioxide (compound 79a) It synthesize | combined by the operation similar to process 1-6 of 5.

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- (oxane-4-yl) -N-phenylindole-2-carboxamide (Compound 79c)
The compound 79b obtained in Step 79-1 and (tetrahydro-2H-pyran-4-yl) zinc (II) iodide (Compound 8a) are used in the same manner as in Step 8-1 of Example 8 using an appropriate reagent. Were synthesized by

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- (2) Phenylmethoxymethyl) cyclopropyl] -N-phenylindole-2-carboxamide (79d)
The compound 79c obtained in Step 79-2 was synthesized by the same procedure as Step 1-8 in Example 1 using a suitable reagent.

LC / MS mass spectrometry: m / z 579 ([M + H] &lt; ⁺ &gt;).
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)
It synthesize | combined by the operation similar to the process 6-4 of Example 6 from the compound 79d obtained at the process 79-3 using the suitable reagent.

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 79 f)
The compound 79e obtained in Step 79-4 and the compound 51c obtained in Step 51-3 were synthesized by the same procedure as Step 1-10 in Example 1 using an appropriate reagent.

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) is cooled to 0 ° C., and a hexane solution of 1 M boron trichloride (0.191 mL, 0.191 mmol) Was added slowly. The reaction solution was warmed to room temperature and stirred for 105 minutes, then a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with 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 give the title compound (18.5 mg, yield 50%) .

LC / MS mass spectrometry: m / z 839 ([M + H] ⁺ ).
LC / MS retention time: 1.20 minutes (analytical conditions: SMD-TFA 05-1).
Example 80 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- (oxane Synthesis of 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) in a solution of (3S) -3-aminobutane nitrile (compound 80b, 7.0 g, 83.2 mmol) and iodine (2.12 g, 8.35 mmol) in acetonitrile (50 mL) , 99.9 mmol) was added and stirred at room temperature for 4 hours. The reaction mixture is concentrated under reduced pressure, the solvent is evaporated, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1: 0 to 3: 2) to give the title compound 80c (9.5 g, yield 58%) as a yellow oil.

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 solution of compound 80c (10 g, 51.0 mmol) obtained in Step 80-1 and sodium triacetoxyborohydride (43.3 g, 204 mmol) in dichloromethane (200 mL) and stirred at room temperature for 16 hours . Water and acetic acid were added to the reaction solution to adjust to pH 5, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1: 0 to 1: 4) to give 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-FA 10-4).
(Step 80-3)
(6S) -1-formyl-4-hydroxy-2,6-dimethyl-3,6-dihydro-2H-pyridine-5-carbonitrile (compound 80e)
A solution of compound 80d (1.0 g, 5.04 mmol) obtained in Step 80-2 in toluene (5 mL) was slowly added dropwise to a solution of potassium tert butoxide (680 mg, 6.06 mmol) in toluene (10 mL) at 80 ° C. did. After stirring for 1 hour at 80 ° C., the solution was cooled to room temperature to obtain a toluene solution of (6S) -4-hydroxy-2,6-dimethyl-1,2,3,6-tetrahydropyridine-5-carbonitrile .

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

(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-carba Rudede (compound 80f)
Ethanol (30 mL) of the compound 80e (1.30 g, 7.21 mmol) obtained in Step 80-3 and the hydrochloride salt of (4-fluoro-3,5-dimethylphenyl) hydrazine (Compound 2c, 690 mg, 3.62 mmol) The solution was warmed to 75 ° C. and stirred for 16 hours. Cool to room temperature and concentrate the reaction under reduced pressure. The residue is purified by silica gel column chromatography (dichloromethane / methanol = 1: 0 to 9: 1) to give the title compound 80f (step 8).
Two steps from 0-3, 800 mg (35% yield) were obtained as a yellow solid.

LC / MS mass spectrometry: m / z 317 ([M + H] &lt; ⁺ &gt;).
LC / MS retention time: 0.79 minutes (analysis conditions: SMD-FA 10-3).
(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 80 g)
To a solution of N, N'-carbodiimidazole (1.63 g, 10.1 mmol) in DMA (50 mL) at 0 ° C is added 2,2-dimethoxyethane-1-amine (1.14 g, 10.8 mmol) Stir for 30 minutes. To the solution was sequentially added potassium tert-butoxide (5.62 g, 50.1 mmol) and compound 80f (2.64 g, 8.34 mmol) obtained in Step 80-4. After stirring at room temperature for 6 hours, water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 80 g (2.80 g, yield 75%) of the title compound as a brown oil.

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

LC / MS mass spectrometry: m / z 384 ([M + H] &lt; ⁺ &gt;).
LC / MS retention time: 1.64 minutes (analytical conditions: SMD-TFA 05-6).
Title compound (Compound 80h: (4S, 6R) -2- (4-fluoro-3,5-dimethylphenyl) -4,6-dimethyl-3- (2-oxo-1H-imidazol-3-yl) -6 A diastereomeric mixture (480 mg, 5.59 mmol) containing 1,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carbaldehyde) is separated into stereoisomers by SFC to give the title compound 80h. Entity A (155 mg, 7.0% yield) and Entity B (270 mg, 12% yield) were obtained.

SFC Preparation Conditions Column: CHIRALPAK AD-H, 50 × 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 minutes.

LC / MS mass spectrometry: m / z 384 ([M + H] &lt; ⁺ &gt;).
LC / MS retention time: 2.15 minutes (analysis conditions: SMD-FA1060-1).
¹ H-NMR (300 MHz, DMSO-D ₆ ) δ: 10.35 (1 H, s), 8.24 (1 H, s), 7.11 (2 H, d, J = 6.3 Hz), 6.60 −6.58 (2 H, m), 5.21-5. 14 (1 H, m), 4.46 to 4.21 (1 H, m), 2.96 to 2.89 (1 H, m), 2 .74-2.68 (1 H, m), 2.20 (6 H, s), 1.27-1.13 (6 H, m).

In addition, it was determined from 2D-NOESY that the compound 80h is a 6R isomer from the fact that the configuration is cis.
Entity B
SFC retention time: 5.60 minutes.

LC / MS mass spectrometry: m / z 384 ([M + H] &lt; ⁺ &gt;).
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 = 6.9 Hz), 3.89-3.84 (1H, m), 2.90 (1H, dd, J = 3. 3, 15.6 Hz), 2.59-2.51 (1 H, m), 2. 20 (6 H, d, J = 2.1 Hz), 1.55 (3 H, d, J = 6.6 Hz), 1.18 (3 H, d, J = 6.6 Hz).

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

LC / MS mass spectrometry: m / z 356 ([M + H] &lt; ⁺ &gt;).
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] pyridine- 3-yl] -3- (1-methylindazol-5-yl) imidazol-2-one (Compound 80j)
Compound 80i (15 mg, 0.042 mmol) obtained in Step 80-7, 5-bromo-1-methylindazole (Compound 1 q, 10.7 mg, 0.051 mmol), (1S, 2S) -1-N, 2 I-iodination of N-dimethylcyclohexane-1,2-diamine (6.00 mg, 0.042 mmol), and a suspension of potassium carbonate (17.5 mg, 0.127 mmol) in N-methyl piperazine (0.188 mL) Copper (I) (4.02 mg, 0.021 mmol) was added at room temperature and the mixture was stirred at 130 ° C. for 90 minutes under a nitrogen atmosphere. The reaction mixture was purified by reverse phase silica gel chromatography (acetonitrile / water, 0.1% formic acid) and concentrated in vacuo. To the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to give the title compound 80j (17.4 mg, yield 85%).

LC / MS mass spectrometry: m / z 486 ([M + H] ^< +>).
LC / MS retention time: 0.51 minutes (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)
55 wt% sodium hydride (34.1 mg, 0.782 mmol) and 2- (trimethylsilyl) ethoxymethyl chloride (100 mg, 0.261 mmol) in DMF (2.6 mL) solution obtained in step 8-1 0.116 mL, 0.652 mmol) was added, and stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution is added, and the mixture is extracted with ethyl acetate, concentrated, and the obtained residue is purified by normal phase column chromatography (ethyl acetate / hexane) to give the title compound 80k (147 mg, yield 88) as a yellow gum. %) Got.
LC / MS retention time: 1.21 minutes (Analytical 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 (80 l)
Magnesium bromide diethyl ether complex (295 mg, 1.14 mmol) is added to a solution of compound 80k (147 mg, 0.228 mmol) obtained in Steps 80-9 in dichloromethane (2.3 mL), Stir for 5 hours. The mixture is warmed to room temperature and stirred for 30 minutes, saturated aqueous ammonium chloride solution is added, extraction is performed with ethyl acetate, and after concentration, the residue is diluted with DMSO and water, and reverse phase chromatography (acetonitrile / water, 0.1% formic acid) The title compound 801 (60 mg, 51% yield) was synthesized.

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)
A solution of the compound 80l (18 mg, 0.036 mmol) obtained in Step 80-10 in acetonitrile (0.36 mL) was treated with 1-chloro-N, N, 2-trimethylprop-1-en-1-amine (0. 1). 0057 mL, 0.043 mmol) was added, and the mixture was stirred at room temperature for 2 hours and concentrated to give a crude product of 80 m of the title compound. 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- (1) Methylindazol-5-yl) -2-oxoimidazol-1-yl] -6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carbonyl] -5- (oxane-4-yl) Indol-1-yl] -2-methylcyclopropyl] -4- (2-trimethylsilylethoxymethyl) -1,2,4-oxadiazol-5-one (Compound 80n)
The compound 80m obtained in Step 80-11 is dissolved in THF (0.717 mL), and the compound 80j (19.1 mg, 0.036 mmol) obtained in Step 80-8 and N, N-diisopropylethylamine (0. 1) are dissolved. 0188 mL (0.108 mmol) was added, and 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-FA 50-1).
(Step 80-13)
3-[(1S, 2S) -1- [2-[(4S, 6R) -2- (4-fluoro-3,5-dimethylphenyl) -4,6-dimethyl-3- [3- (1- (1) Methylindazol-5-yl) -2-oxoimidazol-1-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 80)
In a solution of compound 80n (32 mg, 0.033 mmol) obtained in steps 80-12 in THF (0.326 mL), acetic acid (0.0019 mL, 0.033 mmol) and 1 M tetrabutylammonium fluoride in THF (0. 065 mL, 0.065 mmol) was added and stirred at 80 ° C. for 66 hours. Acetic acid (0.0019 mL, 0.033 mmol) and 1 M tetrabutylammonium fluoride in THF (0.065 mL, 0.065 mmol) are added and stirred for 23.5 hours, and a solution of 1 M tetrabutylammonium fluoride in THF ( 0.065 mL, 0.065 mmol) was added, and after stirring for 7 hours, formic acid was added. After concentration, it was diluted with DMSO and water, and purified by reverse phase column chromatography (acetonitrile / water, 0.1% formic acid) to synthesize the title compound 80 (18 mg, yield 65%).

LC / MS mass spectrometry: m / z 851 ([M + H] &lt; ⁺ &gt;).
LC / MS retention time: 1.42 minutes (analytical conditions: SMD-TFA 05-1).
Moreover, similarly to 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 Crystal of Compound 1 3-[(1S, 2S) -1- [2- [2- (3,5-dimethylphenyl) -3 obtained in Example 1] -[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 Acetonitrile (3.02 mL) was added to) and dissolved at room temperature. To this solution were added 5 M aqueous sodium hydroxide solution (0.495 mL) and seed crystals of Compound 1 sodium hydrate, and the mixture was stirred at room temperature for 2 hours. Further, after adding tert-butyl methyl ether (3.02 mL) and stirring at room temperature for 1 hour, tert-butyl methyl ether (9.05 mL) is added, and stirring is carried out at room temperature for 2 hours. Crystals (1007.0 mg) were obtained as powdery crystals (Sample 160a). The seed crystals were obtained by the following method.

  Compound 1 (26.9 mg) was added with DMSO (0.244 mL) and 2 M aqueous solution of sodium hydroxide (0.032 mL). The lysate (0.030 mL) was lyophilized at -20.degree. C. for 2 days. Acetonitrile (0.015 mL) is added to the obtained lyophilizate, and after shaking and stirring at room temperature for 2 days, tert-butyl methyl ether (0.015 mL) is added, and shaking is performed at room temperature for 12 days. Sodium salt hydrate crystals of Compound 1 were obtained as powdery crystals (Sample 160b).

<Example 161> Crystal Preparation of Example Compound 66 3-[(1S, 2S) -1- [5-[(4S) -2,2-dimethylan-4-yl] -2-[(4S) -2- (4-fluoro-3,5-dimethylphenyl) -4-methyl-3- [3- (1-methylindazol-5-yl) -2-oxoimidazol-1-yl] -6,7- Dihydro-4H-pyrazolo [4,3-c] pyridine-5-carbonyl] indol-1-yl] -2-methylcyclopropyl] -4H-1,2,4-oxadiazol-5-one (Example Compound 66 (400.3 mg) was suspended in ethanol (8.00 mL), seed crystals of Example Compound 66 were added, and the mixture was stirred at 70 ° C. for 5 minutes. The suspension was stirred at 50 ° C. for 1 hour, and then stirred at room temperature for 17 hours to obtain crystals of Example Compound 66 (381.1 mg) as powdery crystals (Sample 161a). The seed crystals were obtained by the following method.

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

Example 162 Preparation of 1⁄2 Calcium Salt Hydrate Crystal of Example Compound 67 3-[(1S, 2S) -1- [5-[(4S) -2,2-dimethylan -4-yl ] -2-[(4S) -2- (4-Fluoro-3,5-dimethylphenyl) -3- [3- (4-fluoro-1-methylindazol-5-yl) -2-oxoimidazole-1 -Yl] -4-methyl-6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carbonyl] indol-1-yl] -2-methylcyclopropyl] -4H-1,2, Ethanol (5.60 mL) and 2 M aqueous solution of sodium hydroxide (0.75 mL) were added to 4-oxadiazol-5-one (Example compound 67, 1120 mg), and dissolved at room temperature. To this solution were added 1.26 M calcium acetate aqueous solution (0.68 mL), a seed crystal of calcium hydrate of Example Compound 67, and water (0.68 mL), and the mixture was stirred at room temperature for 3 hours. Further, water (1.2 mL) was added, and after stirring for 1 hour at room temperature, water (2.3 mL) was added, and calcium salt hydrate crystals of Example Compound 67 (973.0 mg) by stirring for 1 hour at room temperature Were obtained as powdery 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. The lysate (0.015 mL) was lyophilized at -20.degree. C. for 2 days. A water-acetonitrile mixed solution (3: 1, 0.015 mL) is added to the obtained lyophilizate, and calcium salt hydrate crystals of Example Compound 67 are converted to powdery crystals by shaking at room temperature for 7 days. Sample (Sample 162b).

Example 163 Powder X-Ray Diffraction Measurement The sodium salt hydrate crystals of Compound 1 (Samples 160a and 160b) obtained in Example 160, the crystals of Example Compound 66 obtained in Example 161 (Samples 161a and 161b) The calcium salt hydrate crystals (Samples 162a and 162b) of Example Compound 67 obtained in Example 162 were subjected to powder X-ray diffraction measurement by the following measurement methods. The results are shown in FIGS.

Measuring device: D8 Discover with GADDS CS diffractometer (made by Bruker AXS)
Anticathode: Cu
Tube voltage: 40kV
Tube current: 40 mA
Scanning range: 5 to 25.3 °
Sampling width: 0.02 °
<Example 164> Thermogravimetric measurement / differential thermal analysis Sodium salt hydrate crystal of Compound 1 (Sample 160a) and calcium salt hydrate crystal of Example Compound 67 (Sample 162a) Used for differential thermal analysis. The results are shown in FIG. 7 and FIG. Sample 160a was dehydrated to about 110 ° C., and did not show a clear melting point. In addition, sample 162a was dehydrated to around 240 ° C. and did not show a clear melting point.

Measuring device: EXSTAR TG / DTA 6200R (Seiko Instruments (current name: Hitachi High-Tech Science) product)
Measurement range: 30 to 350 ° C
Heating rate: 10 ° C / min. Atmosphere: nitrogen
<Example 165> Karl Fischer moisture measurement Compound 1 sodium hydrate crystal (Sample 160a) and Example Compound 67 calcium hydrate crystal (Sample 162a) The moisture content contained in the coulometric Karl Fischer moisture meter ( It measured with Metrome 756 KF Coulometer. The results were 7.4% for sample 160a and 6.2% for sample 162a.

  From the results of Example 164 and Example 165, it was confirmed that the water contained in the sodium salt hydrate crystal of Compound 1 and the calcium salt hydrate 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 Laboratories, dissolved in phosphate buffered saline to 200 μM and stored at -80 ° C freezer.

(Cell culture)
Human GLP1R stably expressing cell line (hGLP1R-HEK293) was used for the experiment. Cells were prepared 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). The cells were cultured at 37 ° C. in a humidified atmosphere containing% CO ₂ .

(CAMP assay)
hGLP1R-HEK293 was seeded at 2.0 × 10 ⁴ cells / well in a 96-well plate and cultured overnight. On the next day, 50 μL of medium A for cell culture (DMEM, 20 mM HEPES, 0.05% BSA, 0.5 mM 3-isobutyl-1-meth)
ylxanthine) and incubated at 37.degree. C. for 30 minutes. Subsequently, 50 μL of medium B (DMEM, 20 mM HEPES, 0.05 containing GLP-1 or a compound
% BSA, 0.5 mM 3-isobutyl-1-methylxanthine) was added, and the mixture was further incubated at 37 ° C. for 30 minutes. Then, 100 μL of Assay
The lysis buffer (Applied Bioscience) was added and incubated at 37 ° C. for 30 minutes. cAMP concentrations were quantified using the cAMP HiRange kit (Cisbio Bioassays).

(Calculation of EC ₅₀ )
The cAMP concentration in each well was converted to the reaction rate (%), with the concentration of cAMP being 100% when treated with human GLP-1 (7-37) at a concentration of 1 nM. XLfit (ver 5.4.0
. Dose response curves of each example compound were prepared using 4-parameter logistic regression analysis according to 8), and 50% effect concentration (EC ₅₀ ) was calculated. The results are shown in Table 3.

<Test Example 2> Insulin Secretion Promoting Action and Hypoglycemic Action Under anesthesia in a male cynomolgus monkey, Example Compound 67 dissolved solution (solvent: PEG 400 (10 vol%): propylene glycol (10 vol%): 100 mM Glycine-NaO
H buffer solution, pH 9.0 (80 vol%) was continuously administered intravenously for 40 minutes, and the drug concentration in plasma was brought 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 similarly administered to bring the drug concentration in plasma to a steady state of 9.2 or 23.9 pmol / L. The solvent of the Example Compound 67 solution was administered to the solvent group. Next, a 50% glucose solution was intravenously administered at a glucose level of 0.5 g / kg, blood was collected at intervals of 5 minutes or 10 minutes, and plasma insulin concentration and glucose concentration were measured. The area under the curve was calculated from the time transition after drug administration time of each parameter, and insulin secretion promoting action and hypoglycemic action were evaluated.

  In the Example compound 67 administration group, a drug concentration-dependent increase in area under the insulin curve (FIG. 9) and a decrease in area under the plasma glucose curve were observed at steady-state plasma concentration of 0.94 to 4.8 nmol / L. Figure 10). A similar increase in the area under the insulin curve (Fig. 9) and a decrease in the area under the plasma glucose curve were also observed at steady-state plasma concentrations of 9.2 to 23.9 pmol / L after continuous intravenous administration of the control drug sexenatide It was done (Figure 10).

In addition, 9.2 pmol / L (38.5 pg / mL) of exenatide is the therapeutic concentration range (50-350 pg / mL) of exenatide concentration in human diabetic patients (Pharmaceutical interview form, byetta subcutaneous injection 5μg pen 300, byetta subcutaneous injection 10μg Pen 300,
It was a value close to the lower limit value of September 2016 (revised 9th edition). From the above, Example Compound 67 was shown to exhibit an insulin secretion promoting action and a hypoglycemic action equivalent to exenatide at a plasma concentration of 1.6 nmol / L or more.

Test Example 3 Feeding Inhibitory Action The compound Example 67 was orally administered to male cynomolgus monkeys for 5 consecutive days, and the influence on the food intake for 90 minutes from 3 hours after each day was examined. In addition, exenatide, which is a control drug, was administered subcutaneously for 5 consecutive days, and the influence on food intake from 30 minutes to 90 minutes after administration was examined. The solvent group includes solvents for oral administration of Example Compound 67 (DMSO (10 vol%): Cremophor
EL (10 vol%): PEG 400 (15 vol%): 100 mM Glycine-NaOH buffer pH 10 (65 vol%), 1 mL / kg) and solvent for subcutaneous administration of exenatide (0.05 w / v% Tween / PBS (-), 0 .1 mL / kg) both were administered. In combination with this, the Example Compound 67 administration group (administration drug concentration, 0.05 or 0.1 mg / mL), a solvent for subcutaneous administration, exenatide administration group (administration drug concentration, 3 or 6 μg / mL) For oral administration, a solvent for oral administration was additionally administered.

  Example Compound 67 dose-dependently suppressed food intake (FIG. 11A). The degree of inhibition was nearly equivalent to the control drug exenatide (FIG. 11B). The plasma drug concentration (mean value ± standard error) immediately after food intake measurement in each group is 8.0 ± 1.0 nM (0.05 mg / kg group) and 16.3 ± 2 in the Example Compound 67 administration group .3 nM (0.1 mg / kg group), 91 ± 8.5 pM (0.3 μg / kg group) and 199 ± 13.1 pM (0.6 μg / kg group) in the exenatide administration group.

Test Example 4 Pharmacokinetics of the Compound Example Suspension of calcium salt hydrate crystal of Example Compound 67 (Sample 162a) obtained in Example 162 (dose: 0.05, 0.15, 0.45 and After oral administration (gavage with a gastric catheter) of 1.35 mg / kg) to male cynomolgus monkeys (n = 2 for each dose), blood was collected from the vein over time to separate plasma. The drug concentration in plasma was quantified by liquid chromatography tandem mass spectrometry. The lower limit of quantification was 0.3 ng / mL. The drug concentration transition in plasma is shown in Figure 12, the maximum plasma drug concentration arrival time ( _Tmax ), the maximum plasma drug concentration ( _Cmax ) and the area under the plasma drug concentration-time curve up to 24 hours after administration (AUC _0-24h
Table 4 shows the results.

Plasma drug concentrations after oral administration decreased with a similar transition pattern after reaching _Cmax at 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 ( _Cmax ratio: 1 .0: 4.3: 6.7: 31, AUC _0-24h ratio: 1.0: 5.7: 8.8: 44). The substance was shown to be absorbed in the digestive tract in a dose-dependent manner and to disappear.

Claims (14)

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- to 10-membered heteroaryl, wherein C _6-10 aryl and 5- to 10-membered heteroaryl are each a halogen atom, C _1-6 alkyl (where C is _1-6 alkyl may be substituted by one to five substituents independently selected from one or more halogen atoms), and C _1-6 alkoxy;
Q ² represents 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl, wherein the 3 to 12 membered heterocyclyl and 5 to 10 membered heteroaryl are halogen atoms, C _1-6 alkyl (herein And C _1-6 alkyl may be substituted with one or more halogen atoms), C _1-6 alkoxy, and substituted with 1 to 3 substituents independently selected from -NR ^Qa R ^Qb Further, two C _1-6 alkyls may be taken together with the carbon atom to which they are attached to form a C _3-8 carbocyclic ring; R ^Qa and R ^Qb are independent Selected from hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl) carbonyl;
R ¹ , R ² and R ³ are each independently a hydrogen atom and C _1-6 alkyl (wherein C _1-6 alkyl is independently selected from a halogen atom, C _1-6 alkoxy and hydroxy Selected from one or more substituents);
R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen atom, halogen atom, and C _1-6 alkyl;
R ⁷ and R ⁸ independently represent a hydrogen atom or C _1-6 alkyl, wherein C _1-6 alkyl is one or more independently selected from a halogen atom and C _3-15 cycloalkyl It may be substituted by a substituent, 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, wherein C _1-6 alkyl is a halogen atom, hydroxy, R ^7a R ^7b , C _1-6 alkoxy, and one or more substituents independently selected from 3 to 12 membered heterocyclyl, and R ^7a and R ^7b are independently hydrogen atom, _1-6 is selected 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 is a group of the formulas (IIa), (IIb), (IIc), (IId):
R ^9a , R ^9b , R ^9c , R ^9d , and R ^9g are each independently a hydrogen atom, selected from the group represented by —CO ₂ R ^9f and —C (= O) —NR ^9g R ^9h ; , _{C 1-6} alkyl (wherein _{C 1-6} alkyl may be optionally substituted with one or more substituents independently selected from halogen atoms and _{C 1-6} alkoxy), and _{(C 1- 6} alkyl) is selected from ^{carbonyl, R 9e} represents a hydrogen atom or one or more _{C 1-6} alkyl optionally substituted by a halogen ^{atom,, 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) _{n 3} -R ⁹ⁱ ; n 3 represents an integer of 0 to 2, R ⁹ⁱ is, _{C 1} It represents _alkyl;
Z ¹ is any of the formulas (IIIa), (IIIb), (IIIc), (IIId), and (IIIe):
R ^z is selected from a hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl) carbonyl, and R ^zb and R ^zc are independently a hydrogen atom or C _{1 -6} alkyl, n4 represents an integer of 1 to 3, n5 and n6 each independently represent an integer of 0 to 10 (* represents a binding site to a pyrazolopyridine skeleton, and ** represents Each represents a binding site to Z ² );
Z ² _{is, C 1-6 alkyl, C 3-15} cycloalkyl, 3-12 membered _{heterocyclyl,} heteroaryl of _{C 6-10} aryl, and 5-10 membered, _{where, C 3-15} cycloalkyl Alkyl, 3- to 12-membered heterocyclyl, C _6-10 aryl, and 5- to 10-membered heteroaryl are groups A:
Group A: a) oxo,
b) halogen atom,
c) cyano,
d) -NR ^zd R ^ze ; wherein each of R ^zd and R ^ze is independently selected from hydrogen atom, C _1-6 alkyl and (C _1-6 alkyl) carbonyl, wherein C _1-6 alkyl Is optionally substituted with one or more substituents independently selected from hydroxy, a halogen atom, and C _1-6 alkoxy
e) —C (= O) —NR ^zf R ^zg ; wherein each of R ^zf and R ^zg is independently selected from hydrogen atom, C _1-6 alkyl and (C _1-6 alkyl) carbonyl, and _Wherein C _1-6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy, halogen atoms, and C _1-6 alkoxy
f) -S (= O) _n7 -R ^zh ; wherein 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; wherein C _1-6 alkyl is independently selected from a halogen atom, hydroxy, —NR ^zi R ^zj , C _1-6 alkoxy, and 3- to 12-membered heterocyclyl 1 The substituent may be substituted by the above substituent, wherein R ^zi and R ^zj independently represent a hydrogen atom or C _1-6 alkyl, and a 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; wherein C _1-6 alkoxy may be substituted with one or more substituents independently selected from hydroxy, a halogen atom, and C _1-6 alkoxy,
i) 3-12 membered heterocyclyl; heterocyclyl wherein 3 to 12 _members, optionally substituted by _{C 1-6} alkyl and _{(C 1-6} alkyl) 1 or more substituents independently selected from carbonyl Also,
j) C _6-10 aryl; wherein C _6-10 aryl may be substituted with one or more (C _1-6 alkyl) carbonyl, and k) 5-10 membered heteroaryl; The ^10- to 10-membered heteroaryl is substituted by one or more substituents independently selected from C _1-6 alkyl, C _1-6 alkoxy, -NR ^zk R ^zl , and ^{3- to} 12-membered heterocyclyl R ^zk and R ^zl are independently selected from hydrogen atom, C _1-6 alkyl, and (C _1-6 alkyl) carbonyl, and ^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,
And may be substituted with 1 to 5 substituents independently selected from
The pharmaceutical composition containing the compound represented by these, its salt, or the solvate of any one of them. The compound according to claim ¹ , wherein Q ¹ is phenyl or pyridyl, wherein phenyl and pyridyl are substituted with a halogen atom and 1 to 4 substituents independently selected from C _1-6 alkyl. Pharmaceutical composition. 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, where R ⁷ and R ⁸ together form a C _3-8 cyclo. alkane ring may be substituted with one to two _{C 1-6} alkyl, wherein _{C 1-6} alkyl is _hydroxy, independently from heterocyclyl _{C 1-6} alkoxy, and 3-12 membered The pharmaceutical composition according to claim 1 or 2, which is optionally substituted by one or more substituents selected. 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, wherein C _3-15 cycloalkyl , 3-12 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl are groups B:
Group B: a) oxo,
b) halogen atom,
c) -NR ^zd1 R ^ze1 ; wherein R ^zd1 and R ^ze1 are independently selected from hydrogen atom, C _1-6 alkyl and (C _1-6 alkyl) carbonyl, wherein C _1-6 alkyl And may be substituted with one or more C _1-6 alkoxy,
d) -S (= O) _n7 -R ^zh1 ; wherein n7 represents an integer of 0 to 2 and R ^zh1 represents a C _1-6 alkyl;
e) C _1-6 alkyl; wherein C _1-6 alkyl is independently selected from a halogen atom, hydroxy, —NR ^zi R ^zj , C _1-6 alkoxy, and 3- to 12-membered heterocyclyl 1 The substituent may be substituted by the above substituent, wherein R ^zi and R ^zj independently represent a hydrogen atom or C _1-6 alkyl, and a 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; wherein C _1-6 alkoxy may be substituted with one or more hydroxy,
g) 3 to 12 membered heterocyclyl; wherein the 3 to 12 membered heterocyclyl may be optionally substituted by one or more (C _1-6 alkyl) carbonyl, and h) 5 to 10 membered heteroaryl; And 5- to 10-membered heteroaryl may be substituted by C _1-6 alkyl, and one or more substituents independently selected from -NR ^zk1 R ^zl 1, wherein R ^zk1 and R ^{zl 1} Is independently selected from hydrogen atom and C _1-6 alkyl
The pharmaceutical composition according to any one of claims 1 to 3, which may be substituted with 1 to 4 substituents independently selected from   The pharmaceutical composition according to any one of claims 1 to 4, wherein Y is -C (= O)-. The pharmaceutical composition according to any one of claims 1 to 5, wherein R ¹ is a hydrogen atom.   The pharmaceutical composition according to any one of claims 1 to 6, wherein n1 and n2 are both zero. R ⁹ is a compound of formula (IIb):
R ^9b is a hydrogen atom, C _1-6 alkyl (wherein C _1-6 alkyl is a halogen atom and one or more substituents independently selected from C _1-6 alkoxy) in optionally substituted), and (C _1-6 alkyl) is selected from carbonyl, pharmaceutical composition according to any one of claims 1 to 7.   The pharmaceutical composition according to any one of claims 1 to 8, wherein X is -N =, -CH = or -CF =. Z ¹ is the formula (IIIa):
The pharmaceutical composition according to any one of claims 1 to 9, wherein * represents a binding site to a pyrazolopyridine skeleton, and ** represents a binding site to Z ^2. .   3-[(1S, 2S) -1- [5-[(4S) -2,2-dimethyl- oxane-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 ,. The compound of the present invention contains 3-c] pyridine-5-carbonyl] indol-1-yl] -2-methylcyclopropyl] -4H-1,2,4-oxadiazol-5-one, or a salt thereof. The pharmaceutical composition as described in any one of -10.   The pharmaceutical composition according to any one of claims 1 to 11, which contains the compound represented by the formula (I) or a salt thereof as a hydrate. Non-insulin dependent diabetes (type 2 diabetes), hyperglycemia, glucose intolerance, insulin dependent diabetes (type 1 diabetes), diabetic complications, obesity, hypertension, dyslipidemia, arteriosclerosis, coronary The pharmaceutical composition according to any one of claims 1 to 12 for use in the prevention or treatment of arterial heart disease, cerebral infarction, non-alcoholic steatohepatitis, Parkinson's disease or dementia. Pharmaceutical composition according to claim 13, for use in the prevention or treatment of non-insulin dependent diabetes mellitus (type 2 diabetes) or obesity.