Polycyclic Compounds that Inhibit H-PGDS

Abstract

The present invention provides a compound having hematopoietic organ-type prostaglandin D synthase (H-PGDS) inhibitory activity and useful for the prevention and treatment of diseases involving the aforementioned enzyme, and a pharmaceutical composition comprising the compound. Specifically, there is provided a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof. In formula (I), R 1 represents a hydrogen atom or the like, R 2 represents a hydrogen atom or the like, R 3 represents a hydrogen atom or the like, R 4 represents a hydrogen atom or the like, R 5 represents a hydrogen atom or the like, W represents an oxygen atom or the like, X represents C 1‑6 alkyl or the like.

Description

Technical Field

[0001] The present invention relates to polycyclic compounds that inhibit H-PGDS and are useful in the pharmaceutical field. Specifically, the present invention relates to polycyclic compounds having hematopoietic organ-type prostaglandin D synthase inhibitory activity, which are useful for the prevention and treatment of diseases involving the aforementioned enzyme, a pharmaceutical composition containing the compound, and an inhibitor of the aforementioned enzyme. Background Art

[0002] Prostaglandin D synthase is an enzyme that converts prostaglandin H2, a common intermediate of various prostaglandins, into prostaglandin D2.

[0003] Among prostaglandin D synthases, hematopoietic organ-type prostaglandin D synthase (H-PGDS), which is known to be distributed in mast cells, Th2 lymphocytes, etc., is involved in various diseases (e.g., allergic diseases, inflammatory diseases, neuromuscular-related diseases, or ischemic diseases, etc.) through the production of prostaglandin D2.

[0004] Therefore, attempts have been made to develop pharmaceutical compounds for treating the aforementioned various diseases by inhibiting H-PGDS (Patent Documents 1 to 23 and Non-Patent Documents 1 to 3).

[0005] Prior Art Documents

[0006] Patent Documents

[0007] Patent Document 1: International Publication No. WO2019 / 203296

[0008] Patent Document 2: Japanese Unexamined Patent Application Publication No. 2013-14520

[0009] Patent Document 3: International Publication No. WO2012 / 033069

[0010] Patent Document 4: International Publication No. WO2011 / 090062

[0011] Patent Document 5: International Publication No. WO2010 / 104024

[0012] Patent Document 6: International Publication No. WO2007 / 007778

[0013] Patent Document 7: Japanese Unexamined Patent Application Publication No. 2007-51121

[0014] Patent Document 8: International Publication No. WO2020 / 095215

[0015] Patent Document 9: International Publication No. WO2019 / 116256

[0016] Patent Document 10: International Publication No. WO2018 / 229629

[0017] Patent Document 11: International Publication No. WO2018 / 069863

[0018] Patent Document 12: International Publication No. WO2017 / 103851

[0019] Patent Document 13: International Publication No. WO2011 / 044307

[0020] Patent Document 14: International Publication No. WO2008 / 121670

[0021] Patent Document 15: International Publication No. WO2007 / 041634

[0022] Patent Document 16: International Publication No. WO2011 / 150457

[0023] Patent Document 17: International Publication No. WO2010 / 033977

[0024] Patent Document 18: International Publication No. WO2009 / 153721

[0025] Patent Document 19: International Publication No. WO2009 / 153720

[0026] Patent Document 20: International Publication No. WO2008 / 104869

[0027] Patent Document 21: International Publication No. WO2008 / 075172

[0028] Patent Document 22: International Publication No. WO2005 / 094805

[0029] Patent Document 23: International Publication No. WO2017 / 209272

[0030] Non-Patent Document

[0031] Non-Patent Document 1: Bioorg. Med. Chem. Lett. 2012, 22, 3795 - 3799

[0032] Non-Patent Document 2: J. Med. Chem. 2010, 53, 5536 - 5548

[0033] Non-Patent Document 3: Bioorg. Med. Chem. Lett. 2021, 34, 127759. Summary of the Invention

[0034] Problems to be Solved by the Invention

[0035] An object of the present invention is to provide a novel polycyclic compound having excellent H-PGDS inhibitory activity and useful for the treatment and prevention of diseases involving H-PGDS.

[0036] Means for Solving the Problem

[0037] To solve the above problems, the present inventors synthesized a wide variety of novel compounds and conducted studies. As a result, it was found that the polycyclic compound represented by the following formula (I) has excellent H-PGDS inhibitory activity, and thus the present invention was completed.

[0038] Accordingly, the present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof (hereinafter, also referred to as "the compound of the present invention"),

[0039]

[0040] In formula (I),

[0041] R 1 represents a hydrogen atom, a halogen atom or a C 1-6 alkyl group;

[0042] R 2 represents a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a carbamoyl group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a hydroxy C 1-6 alkyl group or a C 1-6 alkoxy group;

[0043] R 3 represents a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an amino group, a carbamoyl group, a sulfamoyl group, a carboxyl group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a halogenated C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 2-7 alkanoyl group, a C 1-6 alkylsulfonyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a C 1-6 alkylsulfonyloxy group, a halogenated C 1-6 alkylsulfonyloxy group, a mono-C 1-6 alkylamino group, a di-C 1-6 alkylamino group, a mono-C 2-7 alkanoylamino group, a (C 2-7 alkanoyl)C 1-6 alkylamino group, a di-C 2-7 alkanoylamino group, a mono-C 1-6 alkylsulfonylamino group, a mono-C 1-6 alkylcarbamoyl group, a di-C 1-6alkylcarbamoyl, mono-C 1-6 alkylsulfamoyl, di-C 1-6 alkylsulfamoyl, C 3-6 cycloalkyl, cyclic ether group, cyclic amino group or halogenated cyclic amino group;

[0044] R 4 represents a hydrogen atom, halogen atom, cyano group, hydroxyl group, amino group, carbamoyl group, sulfamoyl group, carboxyl group, C 1-6 alkyl, C 2-6 alkenyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, mono-C 1-6 alkylamino or di-C 1-6 alkylamino;

[0045] R 5 represents a hydrogen atom, halogen atom, cyano group, hydroxyl group, C 1-6 alkyl, halogenated C 1-6 alkyl or hydroxy C 1-6 alkyl;

[0046] W represents an oxygen atom, sulfur atom or a group represented by the general formula: -N(R 6 )-;

[0047] R 6 represents a hydrogen atom or C 1-6 alkyl;

[0048] X represents C 1-6 alkyl, C 2-6 alkenyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl, (halogenated C 1-6 alkoxy)C 1-6 alkyl, amino C 1-6 alkyl, (mono-C 1-6 alkylamino)C 1-6 alkyl, (di-C 1-6 alkylamino)C 1-6 alkyl, carbamoyl C 1-6 alkyl, (mono-C 1-6 alkylcarbamoyl)C 1-6 alkyl, (di-C 1-6 alkylcarbamoyl)C 1-6 alkyl, sulfamoyl C 1-6 alkyl, (mono-C 1-6 alkylsulfamoyl)C 1-6 alkyl, (di-C1-6 (alkylaminosulfonyl)C 1-6 alkyl, or,

[0049] a group represented by the general formula (II),

[0050]

[0051] wherein,

[0052] the wavy line represents the bonding point to the nitrogen atom,

[0053] L 1 represents a single bond, C 1-6 alkanediyl or hydroxyC 1-6 alkanediyl;

[0054] ring Y represents C 6-10 aryl, heteroaryl, C 3-10 cycloalkyl or a 4- to 10-membered heterocyclic group (wherein, the aforementioned C 3-10 cycloalkyl and 4- to 10-membered heterocyclic group may be fused with a benzene ring or a heteroaryl ring to form a fused ring group, or may also form a bicyclic group or a spiro ring group);

[0055] R 7 each independently represents a halogen atom, cyano group, hydroxyl group, thioalkyl group, amino group, carbamoyl group, aminosulfonyl group, carboxyl group, formyl group, imino group, azide group, hydrazino group, nitro group, C 1-6 alkyl, C 2-6 alkenyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl, C 2-7 alkanoyl, C 1-6 alkylsulfonyl, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6 alkoxy, C 1-6 alkylthio, monoC 1-6 alkylamino, diC 1-6 alkylamino, mono(haloC 1-6 alkyl)amino, C 2-7 alkoxycarbonyl, monoC 1-6 alkylcarbamoyl, diC 1-6 alkylcarbamoyl, C 1-6 alkylsulfonyloxy, haloC 1-6 alkylsulfonyloxy, monoC 1-6 alkylaminosulfonyl, diC 1-6 alkylaminosulfonyl, monoC 2-7 alkanoylamino, (C 2-7 alkanoyl)C1-6 alkylamino, di-C 2-7 alkanoylamino, mono-C 1-6 alkylsulfonylamino, mono(C 2-7 alkoxycarbonyl)amino, C 3-6 cycloalkyl, cyclic ether group, cyclic amino group, halogenated cyclic amino group or oxo group;

[0056] L 2 represents a single bond, C 1-6 alkanediyl, hydroxy-C 1-6 alkanediyl, carbonyl or sulfonyl;

[0057] Ring Z represents phenyl, heteroaryl or a 4- to 10-membered heterocyclic group (the aforementioned 4- to 10-membered heterocyclic group may be fused with a benzene ring or a heteroaryl ring to form a fused ring group, or may also form a bicyclic group or a spiro ring group);

[0058] R 8 each independently represents a halogen atom, cyano group, hydroxy group, thioalkyl group, amino group, carbamoyl group, sulfamoyl group, carboxyl group, C 1-6 alkyl, C 2-6 alkenyl, halogenated C 1-6 alkyl, hydroxy-C 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl, C 2-7 alkanoyl, C 1-6 alkylsulfonyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, mono-C 1-6 alkylamino, di-C 1-6 alkylamino, C 2-7 alkoxycarbonyl, mono-C 1-6 alkylcarbamoyl, di-C 1-6 alkylcarbamoyl, C 1-6 alkylsulfonyloxy, halogenated C 1-6 alkylsulfonyloxy, mono-C 1-6 alkylsulfamoyl, di-C 1-6 alkylsulfamoyl, mono-C 2-7 alkanoylamino, (C 2-7 alkanoyl)C 1-6 alkylamino, di-C 2-7 alkanoylamino, mono-C 1-6 alkylsulfonylamino, mono(C 2-7 alkoxycarbonyl)amino, C 3-6 cycloalkyl, cyclic ether group, cyclic amino group, halogenated cyclic amino group or oxo group;

[0059] m represents 0, 1, 2 or 3;

[0060] n represents 0, 1 or 2;

[0061] p represents 0 or 1.

[0062] Furthermore, the compound of the present invention further comprises, in formula (I), R 7 being oxetanyl amino, hydroxyhalo C 1-6 alkyl, halo C 2-7 alkanoyl, hydroxy C 2-7 alkanoyl, hydroxy C 3-6 cycloalkyl, (hydroxy C 3-6 cycloalkyl)C 1-6 alkoxy or C 3-6 cycloalkylcarbonyl, and R 8 being a compound of morpholinocarbonyl.

[0063] Furthermore, the present invention also relates to a pharmaceutical composition containing the compound of the present invention, particularly a pharmaceutical composition used for the treatment or prevention of diseases involved in H-PGDS.

[0064] Furthermore, the present invention also relates to an H-PGDS inhibitor containing the compound of the present invention.

[0065] Advantages of the Invention

[0066] Since the compound of the present invention has excellent H-PGDS inhibitory activity as shown in the following examples, it is useful as a therapeutic or prophylactic agent for diseases involved in H-PGDS. Detailed Embodiments

[0067] Hereinafter, the definitions of the terms used in the definition of the compound of the present invention will be described.

[0068] As the "halogen atom" in formula (I) (including formula (II) and formula (III) in formula (I); the same applies hereinafter), fluorine atom, chlorine atom, bromine atom and iodine atom can be mentioned.

[0069] The "C 1-6 alkyl" in formula (I) means a linear or branched alkyl having 1-6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1,1-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl and 1,2,2-trimethylpropyl, etc.

[0070] The "halo C1-6 "Alkyl" means a "C" in which any substitutable position is substituted by one or more, preferably 1-5, identical or different of the aforementioned "halogen atoms". 1-6 Examples of "alkyl" include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, chloromethyl, 2-chloroethyl, 1,2-dichloroethyl, bromomethyl, and iodomethyl, etc.

[0071] "Hydroxy C 1-6 alkyl" in formula (I) means a "C" in which any substitutable position is substituted by one or more, preferably 1 or 2, hydroxy groups. 1-6 Examples of "alkyl" include hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-1-methylethyl, 1-hydroxy-1-methylethyl, 1,2-dihydroxyethyl, and 3-hydroxypropyl, etc.

[0072] "Hydroxyhalo C 1-6 alkyl" in formula (I) means a "halo C" in which any substitutable position is substituted by one or more, preferably 1 or 2, hydroxy groups. 1-6 Examples of "alkyl" include 2,2,2-trifluoro-1-hydroxyethyl and 2-hydroxy-1,1-difluoroethyl, etc.

[0073] "C 1-6 alkoxy" in formula (I) means a group formed by substituting the hydrogen atom of a hydroxy group with the aforementioned "C 1-6 alkyl". Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, and isohexyloxy, etc.

[0074] "C 2-6 alkenyl" in formula (I) means a straight-chain or branched alkenyl having 2-6 carbon atoms. Examples include vinyl, 1-propenyl, allyl, isopropenyl, 3-butenyl, 2-butenyl, 1-butenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 1-ethyl-1-ethenyl, 2-methyl-2-propenyl, 2-methyl-1-propenyl, 3-methyl-2-butenyl, and 4-pentenyl, etc.

[0075] "C 2-7 alkanoyl" in formula (I) means a group formed by combining the aforementioned "C 1-6 alkyl" with a carbonyl group, i.e., an alkanoyl having 2-7 carbon atoms. Examples include acetyl, propionyl, butyryl, 2-methylpropionyl, valeryl, 3-methylbutyryl, and 2,2-dimethylpropionyl, etc.

[0076] "Halogenated C 2-7 alkanoyl" in formula (I) means the aforementioned "C 2-7 alkanoyl" in which any substitutable position is substituted by one or more, preferably 1-5, identical or different of the aforementioned "halogen atoms", and examples thereof include 3,3,3-trifluoropropionyl and the like.

[0077] "Hydroxy C 2-7 alkanoyl" in formula (I) means the aforementioned "C 2-7 alkanoyl" in which any substitutable position is substituted by one or more, preferably 1 or 2, hydroxy groups, and examples thereof include 2-hydroxy-2-methylpropionyl and the like.

[0078] "C 1-6 alkylsulfonyl" in formula (I) means a group formed by the combination of the aforementioned "C 1-6 alkyl" and sulfonyl, and examples thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, hexylsulfonyl, and isohexylsulfonyl and the like.

[0079] "Halogenated C 1-6 alkoxy" in formula (I) means a group in which the hydrogen atom of the hydroxy group is substituted by the aforementioned "halogenated C 1-6 alkyl", and examples thereof include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1,2-difluoroethoxy, 2,2,2-trifluoroethoxy, chloromethoxy, 2-chloroethoxy, 1,2-dichloroethoxy, bromomethoxy, and iodomethoxy and the like.

[0080] "C 1-6 alkylsulfonyloxy" in formula (I) means a group in which the hydrogen atom of the hydroxy group is substituted by the aforementioned "C 1-6 alkylsulfonyl", and examples thereof include methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, and isopropylsulfonyloxy and the like.

[0081] "Halogenated C 1-6 alkylsulfonyloxy" in formula (I) means the aforementioned "C 1-6 alkylsulfonyloxy" in which any substitutable position is substituted by one or more, preferably 1-3, identical or different of the aforementioned "halogen atoms", and examples thereof include fluoromethylsulfonyloxy, difluoromethylsulfonyloxy, trifluoromethylsulfonyloxy, and 2,2,2-trifluoroethylsulfonyloxy and the like.

[0082] "Mono-C 1-6 alkylamino" in formula (I) means a group in which one hydrogen atom of the amino group is substituted by the aforementioned "C 1-6Groups formed by substituting "alkyl" can include, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, and tert-butylamino, etc.

[0083] "DiC 1-6 alkylamino" in formula (I) means a group formed by substituting 2 hydrogen atoms of the amino group with the same or different aforementioned "C 1-6 alkyl", and examples can include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, dipentylamino, dihexylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-butyl-N-methylamino, N-methyl-N-pentylamino, and N-hexyl-N-methylamino, etc.

[0084] "MonoC 2-7 alkanoylamino" in formula (I) means a group formed by substituting 1 hydrogen atom of the amino group with the aforementioned "C 2-7 alkanoyl", and examples can include acetylamino, propionylamino, butyrylamino, 2-methylpropionylamino, valerylamino, 3-methylbutyrylamino, and 2,2-dimethylpropionylamino, etc.

[0085] "(C 2-7 alkanoyl)C 1-6 alkylamino" in formula (I) means a group formed by substituting the hydrogen atom bonded to the nitrogen atom of the aforementioned "monoC 1-6 alkylamino" with the aforementioned "C 2-7 alkanoyl", and examples can include N-acetyl-N-methylamino, N-methyl-N-propionylamino, N-butyryl-N-methylamino, N-methyl-N-valerylamino, N-acetyl-N-ethylamino, and N-acetyl-N-propylamino, etc.

[0086] "DiC 2-7 alkanoylamino" in formula (I) means a group formed by substituting 2 hydrogen atoms of the amino group with the same or different aforementioned "C 2-7 alkanoyl", and examples can include diacetylamino, dipropionylamino, and N-acetyl-N-propionylamino, etc.

[0087] "MonoC 1-6 alkylsulfonylamino" in formula (I) means a group formed by substituting 1 hydrogen atom of the amino group with the aforementioned "C 1-6 alkylsulfonyl", and examples can include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, sec-butylsulfonylamino, and tert-butylsulfonylamino, etc.

[0088] "MonoC 1-6"Alkylcarbamoyl" means a group in which one hydrogen atom of carbamoyl is replaced by the aforementioned "C" 1-6 "alkyl", and examples thereof include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, sec-butylcarbamoyl, and tert-butylcarbamoyl.

[0089] In formula (I), "di-C" 1-6 "alkylcarbamoyl" means a group in which two hydrogen atoms of carbamoyl are replaced by the same or different aforementioned "C" 1-6 "alkyl", and examples thereof include dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl, and N-ethyl-N-methylcarbamoyl.

[0090] In formula (I), "mono-C" 1-6 "alkylsulfamoyl" means a group in which one hydrogen atom of sulfamoyl is replaced by the aforementioned "C" 1-6 "alkyl", and examples thereof include methylsulfamoyl, ethylsulfamoyl, propylsulfamoyl, isopropylsulfamoyl, butylsulfamoyl, sec-butylsulfamoyl, and tert-butylsulfamoyl.

[0091] In formula (I), "di-C" 1-6 "alkylsulfamoyl" means a group in which two hydrogen atoms of sulfamoyl are replaced by the same or different aforementioned "C" 1-6 "alkyl", and examples thereof include dimethylsulfamoyl, diethylsulfamoyl, dipropylsulfamoyl, diisopropylsulfamoyl, and N-ethyl-N-methylsulfamoyl.

[0092] In formula (I), "C" 3-6 "cycloalkyl" means an aliphatic cyclic group having 3 to 6 members, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0093] In formula (I), "hydroxy-C" 3-6 "cycloalkyl" means the aforementioned "C" 3-6 "cycloalkyl" which is substituted at any substitutable position with one or more, preferably one or two hydroxy groups, and examples thereof include 1-hydroxycyclopropyl, 2-hydroxycyclopropyl, and 1-hydroxycyclobutyl.

[0094] In formula (I), "(hydroxy-C" 3-6 "cycloalkyl)C" 1-6 "alkoxy" means the aforementioned "C" 3-6 "alkoxy" which is substituted at any substitutable position with one or more, preferably one of the aforementioned "hydroxy-C" 1-6"Alkoxy", examples thereof include (1-hydroxycyclopropyl)methoxy, (2-hydroxycyclopropyl)methoxy, and (1-hydroxycyclobutyl)methoxy, etc.

[0095] "C" in formula (I) 3-6 "Cycloalkylcarbonyl" means a group formed by the combination of the aforementioned "C" 3-6 "Cycloalkyl" and carbonyl, examples thereof include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl, etc.

[0096] "Cyclic ether group" in formula (I) means a group in which one or two carbon atoms constituting the ring of the aforementioned "C" 3-6 "Cycloalkyl" are replaced by one or two oxygen atoms, examples thereof include oxiranyl, oxetanyl, oxolanyl, dioxolanyl, oxanyl, and dioxanyl, etc.

[0097] "Cyclic amino group" in formula (I) means a group in which one or two carbon atoms constituting the ring of the aforementioned "C" 3-6 "Cycloalkyl" are replaced by one or two nitrogen atoms and a bonding bond is present on the nitrogen atom, examples thereof include azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, and piperazin-1-yl, etc.

[0098] "Halogenated cyclic amino group" in formula (I) means the aforementioned "cyclic amino group" in which one or more, preferably 1-5, identical or different aforementioned "halogen atoms" are substituted at any substitutable position, examples thereof include 3-fluoroazetidin-1-yl, 3,3-difluoroazetidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 3,3,4,4-tetrafluoropyrrolidin-1-yl, and 3,3-difluoropiperidin-1-yl, etc.

[0099] "(C" in formula (I) 1-6 "Alkoxy)C" 1-6 "Alkyl" means the aforementioned "C" 1-6 "Alkyl" substituted at any substitutable position by one or more, preferably one or two, identical or different aforementioned "C" 1-6 "Alkoxy", examples thereof include methoxymethyl, ethoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 1-methoxy-1-methylethyl, 1,2-dimethoxyethyl, and 3-methoxypropyl, etc.

[0100] "(Halogenated C" in formula (I) 1-6 "Alkoxy)C" 1-6 "Alkyl" means the aforementioned "C" 1-6 "Alkyl" substituted at any substitutable position by one or more, preferably one or two, identical or different aforementioned "halogenated C" 1-6"Alkyl" examples include fluoromethoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, 1-(fluoromethoxy)ethyl, 1-(difluoromethoxy)ethyl, 1-(trifluoromethoxy)ethyl, 2-(fluoromethoxy)ethyl, 2-(difluoromethoxy)ethyl, 2-(trifluoromethoxy)ethyl, chloromethoxymethyl, and bromomethoxymethyl, etc.

[0101] "Amino C 1-6 alkyl" in formula (I) means the aforementioned "C 1-6 alkyl" which is substituted at any substitutable position by one or more, preferably one or two amino groups, and examples include aminomethyl, 1-aminoethyl, 1-aminopropyl, 2-aminoethyl, 2-aminopropyl, 2-amino-1-methylethyl, 1-amino-1-methylethyl, 1,2-diaminoethyl, and 3-aminopropyl, etc.

[0102] "(Mono C 1-6 alkylamino)C 1-6 alkyl" in formula (I) means the aforementioned "C 1-6 alkyl" which is substituted at any substitutable position by one or more, preferably one of the aforementioned "mono C 1-6 alkylamino", and examples include methylaminomethyl, ethylaminomethyl, propylaminomethyl, isopropylaminomethyl, 1-(methylamino)ethyl, 2-(methylamino)ethyl, and 2-(isopropylamino)ethyl, etc.

[0103] "(Di C 1-6 alkylamino)C 1-6 alkyl" in formula (I) means the aforementioned "C 1-6 alkyl" which is substituted at any substitutable position by one or more, preferably one of the aforementioned "di C 1-6 alkylamino", and examples include dimethylaminomethyl, diethylaminomethyl, dipropylaminomethyl, diisopropylaminomethyl, 1-(diisopropylamino)ethyl, 2-(diisopropylamino)ethyl, (N-ethyl-N-methylamino)methyl, 1-(N-ethyl-N-methylamino)ethyl, and 2-(N-ethyl-N-methylamino)ethyl, etc.

[0104] "Carbamoyl C 1-6 alkyl" in formula (I) means the aforementioned "C 1-6 alkyl" which is substituted at any substitutable position by one or more, preferably one carbamoyl group, and examples include carbamoylmethyl, 1-carbamoylethyl, 1-carbamoylpropyl, 2-carbamoylethyl, 2-carbamoylpropyl, 2-carbamoyl-1-methylethyl, 1-carbamoyl-1-methylethyl, and 3-carbamoylpropyl, etc.

[0105] "(mono-C 1-6 alkylcarbamoyl)C 1-6 alkyl" means the foregoing "C 1-6 alkyl" which is substituted at any substitutable position by one or more, preferably one, of the foregoing "mono-C 1-6 alkylcarbamoyl)", examples of which include methylcarbamoylmethyl, ethylcarbamoylmethyl, propylcarbamoylmethyl, isopropylcarbamoylmethyl, 1-(methylcarbamoyl)ethyl, 2-(methylcarbamoyl)ethyl, 1-(ethylcarbamoyl)ethyl, and 2-(ethylcarbamoyl)ethyl.

[0106] "(di-C 1-6 alkylcarbamoyl)C 1-6 alkyl" means the foregoing "C 1-6 alkyl" which is substituted at any substitutable position by one or more, preferably one, of the foregoing "di-C 1-6 alkylcarbamoyl)", examples of which include dimethylcarbamoylmethyl, diethylcarbamoylmethyl, dipropylcarbamoylmethyl, diisopropylcarbamoylmethyl, 1-(dimethylcarbamoyl)ethyl, 2-(dimethylcarbamoyl)ethyl, (N-ethyl-N-methylcarbamoyl)methyl, 1-(N-ethyl-N-methylcarbamoyl)ethyl, and 2-(N-ethyl-N-methylcarbamoyl)ethyl.

[0107] "sulfamoyl-C 1-6 alkyl" means the foregoing "C 1-6 alkyl" which is substituted at any substitutable position by one or more, preferably one, sulfamoyl group, examples of which include sulfamoylmethyl, 1-sulfamoylethyl, 1-sulfamoylpropyl, 2-sulfamoylethyl, 2-sulfamoylpropyl, 2-sulfamoyl-1-methylethyl, 1-sulfamoyl-1-methylethyl, and 3-sulfamoylpropyl.

[0108] "(mono-C 1-6 alkylsulfamoyl)C 1-6 alkyl" means the foregoing "C 1-6 alkyl" which is substituted at any substitutable position by one or more, preferably one, of the foregoing "mono-C 1-6 alkylsulfamoyl)", examples of which include methylsulfamoylmethyl, ethylsulfamoylmethyl, propylsulfamoylmethyl, isopropylsulfamoylmethyl, 1-(methylsulfamoyl)ethyl, 2-(methylsulfamoyl)ethyl, 1-(ethylsulfamoyl)ethyl, and 2-(ethylsulfamoyl)ethyl.

[0109] "(di-C1-6 (alkylaminosulfonyl) 1-6 "Alkyl" means that any position which may be substituted is replaced by one or more, preferably one, of the aforementioned "diC 1-6 The aforementioned "C 1-6 The “alkyl group” includes, for example, dimethylaminosulfonylmethyl, diethylaminosulfonylmethyl, dipropylaminosulfonylmethyl, diisopropylaminosulfonylmethyl, 1-(dimethylaminosulfonyl)ethyl, 2-(dimethylaminosulfonyl)ethyl, (N-ethyl-N-methylaminosulfonyl)methyl, 1-(N-ethyl-N-methylaminosulfonyl)ethyl and 2-(N-ethyl-N-methylaminosulfonyl)ethyl.

[0110] In formula (I), “C 1-6 "Alkanediyl" means the radical derived from the aforementioned "C 1-6 The term "alkyl" refers to a divalent group obtained by removing one hydrogen atom from an "alkyl" group, and examples thereof include a methylene group, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,2-diyl, propane-2,2-diyl and propane-1,3-diyl.

[0111] The "hydroxyl C 1-6 "Alkanediyl" means the aforementioned "C 1-6 The "alkanediyl group" includes, for example, hydroxymethylene, 1-hydroxyethane-1,1-diyl, 2-hydroxyethane-1,1-diyl, 1-hydroxyethane-1,2-diyl, 2-hydroxyethane-1,2-diyl, 1,2-dihydroxyethane-1,1-diyl and 1,2-dihydroxyethane-1,2-diyl.

[0112] In formula (I), “C 6-10 The term "aryl" refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms, and examples thereof include phenyl and naphthyl.

[0113] "Heteroaryl" in formula (I) means a 5- or 6-membered monocyclic ring containing 1 or more, preferably 1-4, identical or different heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom, or a bicyclic ring formed by the condensation of the monocyclic ring with a benzene ring or a pyridine ring. Examples thereof include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, imidazopyridyl, purinyl, quinolinyl, quinazolinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, and pyrido[3,2-b]pyridyl, etc.

[0114] "C 3-10 Cycloalkyl" in formula (I) means an aliphatic cyclic group having 3 to 10 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, etc.

[0115] "C 3-10 Cycloalkyl" may be condensed with a benzene ring or a heteroaryl ring to form a fused ring group. Examples of such a fused ring group include indan-1-yl, indan-2-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, and 1,2,3,4-tetrahydronaphthalen-2-yl, etc.

[0116] Furthermore, "C 3-10 Cycloalkyl" may form a bicyclic group or a spirocyclic group. Examples of such a cyclic group include bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, spiro[2.3]hexyl, spiro[3.3]heptyl, spiro[2.5]octyl, and spiro[3.4]octyl, etc.

[0117] "4- to 10-membered heterocyclic group" in formula (I) means an aliphatic cyclic group having 4 to 10 ring atoms and containing 1 or more, preferably 1-3, identical or different heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Examples thereof include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, oxetanyl, oxolanyl, oxanyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dioxanyl, morpholinyl, piperazinyl, and thiomorpholinyl, etc.

[0118] The "4- to 10-membered heterocyclic group" may be fused with a benzene ring or a heteroaryl ring to form a fused ring group. Examples of such fused ring groups include groups represented by the following formula (wherein the wavy line indicates the bonding point), etc.

[0119]

[0120] Furthermore, the "4- to 10-membered heterocyclic group" may form a bicyclic group or a spirocyclic group. Examples of such cyclic groups include 2-azabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.2]octyl, 2-azaspiro[3.3]heptyl, 2-azaspiro[3.4]octyl, and 2-oxaspiro[3.5]nonyl, etc.

[0121] The "4- to 10-membered nitrogen-containing heterocyclic group" in general formula (III) means that among the atoms constituting the ring in the aforementioned "4- to 10-membered heterocyclic group", there is one or more, preferably one nitrogen atom, and it is bonded to L in formula (I) through this nitrogen atom. The aliphatic cyclic group thus formed includes, for example, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, and 2-azaspiro[3.3]heptyl, etc. 2 The aliphatic cyclic group thus formed includes, for example, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, and 2-azaspiro[3.3]heptyl, etc.

[0122] The "hydroxy C 1-6 alkoxy" in formula (I) means the aforementioned "C 1-6 alkoxy" in which one or more, preferably one or two hydroxy groups are substituted at any substitutable position. Examples thereof include 2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy, and 2-hydroxy-2-methylpropoxy, etc.

[0123] The "C 1-6 alkylthio" in formula (I) means a group in which a hydrogen atom of thioalkyl is substituted by the aforementioned "C 1-6 alkyl". Examples thereof include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, isobutylthio, tert-butylthio, pentylthio, isopentylthio, hexylthio, and isohexylthio, etc.

[0124] The "mono(halo C 1-6 alkyl)amino" in formula (I) means a group in which one hydrogen atom of amino is substituted by the aforementioned "halo C 1-6 alkyl". Examples thereof include 2-fluoroethylamino, 2,2-difluoroethylamino, 2,2,2-trifluoroethylamino, and 2,2,3,3,3-pentafluoropropylamino, etc.

[0125] The "C 2-7 alkoxycarbonyl" in formula (I) means the aforementioned "C 1-6A group formed by combining an "alkoxy group" with a carbonyl group, that is, an alkoxycarbonyl group having 2 to 7 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, and pentyloxycarbonyl, etc. can be cited.

[0126] The "mono(C 2-7 alkoxycarbonyl)amino" in formula (I) means a group in which one hydrogen atom of the amino group is replaced by the aforementioned "C 2-7 alkoxycarbonyl", such as methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino, and pentyloxycarbonylamino, etc. can be cited.

[0127] The "oxo group" in formula (I) means an oxygen atom (=O) bonded by a double bond. Therefore, when the oxo group binds to a carbon atom, it forms a carbonyl group together with the carbon atom. When one oxo group binds to a sulfur atom, it forms a sulfinyl group together with the sulfur atom. When two oxo groups bind to a sulfur atom, it forms a sulfonyl group together with the sulfur atom. As examples of the cyclic group formed by the oxo group binding to a carbon atom constituting the ring, 2-oxopyrrolidin-3-yl, 2-oxopiperidin-4-yl, 6-oxo-1,6-dihydropyridin-2-yl, 1-methyl-6-oxo-1,6-dihydropyridin-2-yl, 6-oxo-1,6-dihydropyrimidin-2-yl, and 1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl, etc. can be cited. As examples of the cyclic group formed by the oxo group binding to a sulfur atom constituting the ring, 1,1-dioxoisothiazolidin-5-yl and 1,1-dioxothiomorpholin-4-yl, etc. can be cited.

[0128] "Any substitutable position" means the site of a hydrogen atom substitutable on a carbon atom, a nitrogen atom, an oxygen atom, and / or a sulfur atom, where the substitution of the hydrogen atom is chemically acceptable and the substitution results in a stable compound.

[0129] Next, each group constituting formula (I) will be described in detail.

[0130] R in formula (I) 1 represents a hydrogen atom, a halogen atom, or a C 1-6 alkyl group, preferably a hydrogen atom.

[0131] As the halogen atom of R 1 is preferably a fluorine atom or a chlorine atom.

[0132] As the C 1 alkyl group of R 1-6 is preferably a methyl group or an ethyl group.

[0133] R in formula (I) 2represents a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a carbamoyl group, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl or C 1-6 alkoxy, preferably a hydrogen atom, a halogen atom or C 1-6 alkyl.

[0134] As R 2 the halogen atom, preferably a fluorine atom, a chlorine atom.

[0135] As R 2 the C 1-6 alkyl, preferably methyl, ethyl.

[0136] As R 2 the halo C 1-6 alkyl, preferably trifluoromethyl, 2,2,2-trifluoroethyl.

[0137] As R 2 the hydroxy C 1-6 alkyl, preferably hydroxymethyl, 1-hydroxyethyl.

[0138] As R 2 the C 1-6 alkoxy, preferably methoxy, ethoxy.

[0139] R in formula (I) 3 represents a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an amino group, a carbamoyl group, a sulfamoyl group, a carboxyl group, C 1-6 alkyl, C 2-6 alkenyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 2-7 alkanoyl, C 1-6 alkylsulfonyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkylsulfonyloxy, halo C 1-6 alkylsulfonyloxy, mono C 1-6 alkylamino, di C 1-6 alkylamino, mono C 2-7 alkanoylamino, (C 2-7 alkanoyl)C 1-6 alkylamino, di C 2-7 alkanoylamino, mono C 1-6 alkylsulfonylamino, mono C 1-6 alkylcarbamoyl, di C 1-6 alkylcarbamoyl, mono C 1-6 alkylsulfamoyl, di C 1-6 alkylsulfamoyl, C3-6 A cycloalkyl group, a cyclic ether group, a cyclic amino group or a halogenated cyclic amino group, preferably a hydrogen atom, a halogen atom or a C 1-6 alkyl group.

[0140] As R 3 The C 1-6 alkyl group, preferably a methyl group or an ethyl group.

[0141] As R 3 The C 2-6 alkenyl group, preferably a vinyl group or an allyl group.

[0142] As R 3 The halogenated C 1-6 alkyl group, preferably a trifluoromethyl group or a 2,2,2-trifluoroethyl group.

[0143] As R 3 The hydroxy C 1-6 alkyl group, preferably a hydroxymethyl group or a 1-hydroxyethyl group.

[0144] As R 3 The C 2-7 alkanoyl group, preferably an acetyl group or a propionyl group.

[0145] As R 3 The C 1-6 alkylsulfonyl group, preferably a methylsulfonyl group or an ethylsulfonyl group.

[0146] As R 3 The C 1-6 alkoxy group, preferably a methoxy group or an ethoxy group.

[0147] As R 3 The halogenated C 1-6 alkoxy group, preferably a difluoromethoxy group or a trifluoromethoxy group.

[0148] As R 3 The C 1-6 alkylsulfonyloxy group, preferably a methylsulfonyloxy group or an ethylsulfonyloxy group.

[0149] As R 3 The halogenated C 1-6 alkylsulfonyloxy group, preferably a trifluoromethylsulfonyloxy group or a 2,2,2-trifluoroethylsulfonyloxy group.

[0150] As R 3 The mono-C 1-6 alkylamino group, preferably a methylamino group or an ethylamino group.

[0151] As R 3 The di-C 1-6 alkylamino group, preferably a dimethylamino group or an N-ethyl-N-methylamino group.

[0152] As R 3 mono-C 2-7 alkanoylamino, preferably acetylamino, propionylamino.

[0153] As R 3 (C 2-7 alkanoyl)C 1-6 alkylamino, preferably N-acetyl-N-methylamino, N-acetyl-N-ethylamino.

[0154] As R 3 di-C 2-7 alkanoylamino, preferably diacetylamino, dipropionylamino.

[0155] As R 3 mono-C 1-6 alkylsulfonylamino, preferably methylsulfonylamino, ethylsulfonylamino.

[0156] As R 3 mono-C 1-6 alkylaminocarbonyl, preferably methylaminocarbonyl, ethylaminocarbonyl.

[0157] As R 3 di-C 1-6 alkylaminocarbonyl, preferably dimethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl.

[0158] As R 3 mono-C 1-6 alkylaminosulfonyl, preferably methylaminosulfonyl, ethylaminosulfonyl.

[0159] As R 3 di-C 1-6 alkylaminosulfonyl, preferably dimethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl.

[0160] As R 3 C 3-6 cycloalkyl, preferably cyclopropyl, cyclobutyl.

[0161] As R 3 cyclic ether group, preferably oxetanyl, oxolanyl.

[0162] As R 3 cyclic amino group, preferably azetidin-1-yl, pyrrolidin-1-yl.

[0163] As R 3 halogenated cyclic amino group, preferably 3,3-difluoroazetidin-1-yl, 3,3-difluoropyrrolidin-1-yl.

[0164] R of formula (I) 4 represents a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an amino group, a carbamoyl group, a sulfamoyl group, a carboxyl group, C 1-6 alkyl, C 2-6 alkenyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, mono C 1-6 alkylamino or di C 1-6 alkylamino, preferably a hydrogen atom, a halogen atom or C 1-6 alkyl.

[0165] As R 4 of C 1-6 alkyl, preferably methyl, ethyl.

[0166] As R 4 of C 2-6 alkenyl, preferably vinyl, allyl.

[0167] As R 4 of halo C 1-6 alkyl, preferably trifluoromethyl, 2,2,2-trifluoroethyl.

[0168] As R 4 of hydroxy C 1-6 alkyl, preferably hydroxymethyl, 1-hydroxyethyl.

[0169] As R 4 of C 1-6 alkoxy, preferably methoxy, ethoxy.

[0170] As R 4 of halo C 1-6 alkoxy, preferably difluoromethoxy, trifluoromethoxy.

[0171] As R 4 of mono C 1-6 alkylamino, preferably methylamino, ethylamino.

[0172] As R 4 of di C 1-6 alkylamino, preferably dimethylamino, N-ethyl-N-methylamino.

[0173] R of formula (I) 5 represents a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, C 1-6 alkyl, halo C 1-6 alkyl or hydroxy C 1-6 alkyl, preferably a hydrogen atom or a fluorine atom.

[0174] As R 5 's halogen atom, it is preferably a fluorine atom or a chlorine atom.

[0175] As R 5 's C 1-6 alkyl group, it is preferably a methyl group or an ethyl group.

[0176] As R 5 's halo C 1-6 alkyl group, it is preferably a trifluoromethyl group or a 2,2,2-trifluoroethyl group.

[0177] As R 5 's hydroxy C 1-6 alkyl group, it is preferably a hydroxymethyl group or a 1-hydroxyethyl group.

[0178] W in formula (I) represents an oxygen atom, a sulfur atom or a general formula: -N(R 6 )-(R 6 represents a hydrogen atom or a C 1-6 alkyl group), preferably an oxygen atom or a general formula: -N(R 6 )-(wherein, R 6 has the same meaning as described above), more preferably an oxygen atom or -NH-.

[0179] As R 6 's C 1-6 alkyl group, it is preferably a methyl group or an ethyl group.

[0180] X in formula (I) is a C 1-6 alkyl group, a C 2-6 alkenyl group, a halo C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a (C 1-6 alkoxy)C 1-6 alkyl group, a (halo C 1-6 alkoxy)C 1-6 alkyl group, an amino C 1-6 alkyl group, a (mono C 1-6 alkylamino)C 1-6 alkyl group, a (di C 1-6 alkylamino)C 1-6 alkyl group, a carbamoyl C 1-6 alkyl group, a (mono C 1-6 alkylcarbamoyl)C 1-6 alkyl group, a (di C 1-6 alkylcarbamoyl)C 1-6 alkyl group, an aminosulfonyl C 1-6 alkyl group, a (mono C 1-6 alkylaminosulfonyl)C 1-6 alkyl group, a (di C 1-6 alkylaminosulfonyl)C1-6 alkyl, or

[0181] a group represented by the general formula (II),

[0182]

[0183] wherein,

[0184] the wavy line represents the bonding point to the nitrogen atom,

[0185] L 1 represents a single bond, C 1-6 alkanediyl or hydroxy C 1-6 alkanediyl;

[0186] ring Y represents C 6-10 aryl, heteroaryl, C 3-10 cycloalkyl (the aforementioned C 3-10 cycloalkyl may be fused with a benzene ring or a heteroaryl ring to form a fused ring group, or may also form a bicyclic group or a spiro ring group) or a 4- to 10-membered heterocyclic group (the aforementioned 4- to 10-membered heterocyclic group may be fused with a benzene ring or a heteroaryl ring to form a fused ring group, or may also form a bicyclic group or a spiro ring group);

[0187] R 7 each independently represents a halogen atom, cyano group, hydroxy group, thioalkyl group, amino group, carbamoyl group, sulfamoyl group, carboxyl group, formyl group, imino group, azide group, hydrazino group, nitro group, C 1-6 alkyl, C 2-6 alkenyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl, C 2-7 alkanoyl, C 1-6 alkylsulfonyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1-6 alkylthio, mono C 1-6 alkylamino, di C 1-6 alkylamino, mono(halo C 1-6 alkyl)amino, C 2-7 alkoxycarbonyl, mono C 1-6 alkylcarbamoyl, di C 1-6 alkylcarbamoyl, C 1-6 alkylsulfonyloxy, halo C 1-6 alkylsulfonyloxy, mono C 1-6 alkylaminosulfonyl, di C 1-6 alkylaminosulfonyl, mono C 2-7 alkanoylamino, (C 2-7alkanoyl)C 1-6 alkylamino, di-C 2-7 alkanoylamino, mono-C 1-6 alkylsulfonylamino, mono(C 2-7 alkoxycarbonyl)amino, C 3-6 cycloalkyl, cyclic ether group, cyclic amino group, halogenated cyclic amino group or oxo group;

[0188] L 2 represents a single bond, C 1-6 alkanediyl, hydroxy-C 1-6 alkanediyl, carbonyl or sulfonyl;

[0189] Ring Z represents phenyl, heteroaryl or a 4- to 10-membered heterocyclic group (the aforementioned 4- to 10-membered heterocyclic group may be fused with a benzene ring or a heteroaryl ring to form a fused ring group, or may also form a bicyclic group or a spiro ring group);

[0190] R 8 each independently represents a halogen atom, cyano group, hydroxy group, thioalkyl group, amino group, carbamoyl group, sulfamoyl group, carboxyl group, C 1-6 alkyl, C 2-6 alkenyl, halogenated C 1-6 alkyl, hydroxy-C 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl, C 2-7 alkanoyl, C 1-6 alkylsulfonyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, mono-C 1-6 alkylamino, di-C 1-6 alkylamino, C 2-7 alkoxycarbonyl, mono-C 1-6 alkylcarbamoyl, di-C 1-6 alkylcarbamoyl, C 1-6 alkylsulfonyloxy, halogenated C 1-6 alkylsulfonyloxy, mono-C 1-6 alkylaminosulfonyl, di-C 1-6 alkylaminosulfonyl, mono-C 2-7 alkanoylamino, mono-C 1-6 alkylsulfonylamino, mono(C 2-7 alkoxycarbonyl)amino, C 3-6 cycloalkyl, cyclic ether group, cyclic amino group, halogenated cyclic amino group or oxo group;

[0191] m represents 0, 1, 2 or 3;

[0192] n represents 0, 1 or 2;

[0193] p represents 0 or 1.

[0194] C as X 1-6 Alkyl, preferably butyl, hexyl.

[0195] C as X 2-6 Alkenyl, preferably vinyl, allyl.

[0196] Halogenated C as X 1-6 Alkyl, preferably 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl.

[0197] Hydroxy C as X 1-6 Alkyl, preferably 3-hydroxypropyl, 2-hydroxypropyl.

[0198] (C 1-6 Alkoxy)C 1-6 Alkyl, preferably 3-methoxypropyl, 2-ethoxyethyl.

[0199] (Halogenated C 1-6 Alkoxy)C 1-6 Alkyl, preferably 2-(difluoromethoxy)ethyl, 2-(trifluoromethoxy)ethyl.

[0200] Amino C as X 1-6 Alkyl, preferably 2-aminoethyl, 2-aminopropyl.

[0201] (Mono C 1-6 Alkylamino)C 1-6 Alkyl, preferably 2-(methylamino)ethyl, 2-(isopropylamino)ethyl.

[0202] (Di C 1-6 Alkylamino)C 1-6 Alkyl, preferably 2-(diisopropylamino)ethyl, 2-(N-ethyl-N-methylamino)ethyl.

[0203] Carbamoyl C as X 1-6 Alkyl, preferably 2-carbamoylethyl, 2-carbamoylpropyl.

[0204] (Mono C 1-6 Alkylcarbamoyl)C 1-6 Alkyl, preferably 2-(methylcarbamoyl)ethyl, 2-(ethylcarbamoyl)ethyl.

[0205] (Di C 1-6 Alkylcarbamoyl)C 1-6 Alkyl, preferably 2-(dimethylcarbamoyl)ethyl, 2-(N-ethyl-N-methylcarbamoyl)ethyl.

[0206] As the aminosulfonyl C of X 1-6 alkyl group, preferably 2-aminosulfonylethyl, 2-aminosulfonylpropyl.

[0207] As the (mono-C 1-6 alkylaminosulfonyl)C 1-6 alkyl group, preferably 2-(methylaminosulfonyl)ethyl, 2-(ethylaminosulfonyl)ethyl.

[0208] As the (di-C 1-6 alkylaminosulfonyl)C 1-6 alkyl group, preferably 2-(dimethylaminosulfonyl)ethyl, 2-(N-ethyl-N-methylaminosulfonyl)ethyl.

[0209] As L 1 of C 1-6 alkanediyl group, preferably methylene, propane-1,3-diyl.

[0210] As L 1 of hydroxy-C 1-6 alkanediyl group, preferably 2-hydroxyethane-1,1-diyl, 2-hydroxyethane-1,2-diyl.

[0211] As L 1 , preferably a single bond or methylene.

[0212] As the C 6-10 aryl group of ring Y, preferably phenyl, naphthyl.

[0213] As the heteroaryl group of ring Y, preferably pyrazolyl, pyridyl.

[0214] As the C 3-10 cycloalkyl group of ring Y, preferably cyclohexyl, indan-1-yl, spiro[3.3]heptyl.

[0215] As the 4- to 10-membered heterocyclic group of ring Y, preferably a 4- to 10-membered nitrogen-containing heterocyclic group, a fused heterocyclic group formed by the fusion of a 4- to 10-membered heterocyclic group with a benzene ring or a heteroaryl ring.

[0216] Ring Y is preferably a group represented by the general formula (III):

[0217]

[0218] In the formula,

[0219] The wavy line represents the bonding point to L 1 ,

[0220] * represents the bonding point to L 2 ,

[0221] R 7n and m have the same meanings as described above,

[0222] Ring A is a 4- to 10-membered nitrogen-containing heterocyclic group;

[0223] Ring Y is more preferably a group represented by the following general formula,

[0224]

[0225] In the formula,

[0226] The wavy line represents the bonding point with L 1 ;

[0227] * represents the bonding point with L 2 ;

[0228] R 7 and m have the same meanings as described above.

[0229] As a preferred Ring Y, a fused heterocyclic group formed by fusing a 4- to 10-membered heterocyclic group with a benzene ring or a heteroaryl ring can also be mentioned;

[0230] As a more preferred Ring Y, a group represented by the following general formula can be mentioned,

[0231]

[0232] In the formula,

[0233] The wavy line represents the bonding point with L 1 ;

[0234] R 7 and m have the same meanings as described above.

[0235] As the halogen atom of R 7 , a fluorine atom and a chlorine atom are preferred.

[0236] As the C 7 alkyl of R 1-6 , methyl and ethyl are preferred.

[0237] As the C 7 alkenyl of R 2-6 , vinyl and allyl are preferred.

[0238] As the halo C 7 alkyl of R 1-6 , trifluoromethyl and 2,2,2-trifluoroethyl are preferred.

[0239] As the hydroxy C 7 alkyl of R 1-6 , hydroxymethyl and 1-hydroxy-1-methylethyl are preferred.

[0240] As the (C 7 of R1-6 (alkoxy)C 1-6 alkyl, preferably 2-methoxyethyl, 2-ethoxyethyl.

[0241] As R 7 the C 2-7 alkanoyl, preferably acetyl, propionyl.

[0242] As R 7 the C 1-6 alkylsulfonyl, preferably methylsulfonyl, ethylsulfonyl.

[0243] As R 7 the C 1-6 alkoxy, preferably methoxy, ethoxy.

[0244] As R 7 the halo C 1-6 alkoxy, preferably difluoromethoxy, trifluoromethoxy.

[0245] As R 7 the hydroxy C 1-6 alkoxy, preferably 2-hydroxyethoxy, 2-hydroxy-2-methylpropoxy.

[0246] As R 7 the C 1-6 alkylthio, preferably methylthio, ethylthio.

[0247] As R 7 the mono C 1-6 alkylamino, preferably methylamino, ethylamino.

[0248] As R 7 the di C 1-6 alkylamino, preferably dimethylamino, N-ethyl-N-methylamino.

[0249] As R 7 the mono(halo C 1-6 alkyl)amino, preferably 2,2-difluoroethylamino, 2,2,2-trifluoroethylamino.

[0250] As R 7 the C 2-7 alkoxycarbonyl, preferably methoxycarbonyl, ethoxycarbonyl.

[0251] As R 7 the mono C 1-6 alkylaminocarbonyl, preferably methylaminocarbonyl, ethylaminocarbonyl.

[0252] As R 7 the di C 1-6Alkylcarbamoyl, preferably dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl.

[0253] As R 7 of C 1-6 Alkylsulfonyloxy, preferably methylsulfonyloxy, ethylsulfonyloxy.

[0254] As R 7 of halo C 1-6 Alkylsulfonyloxy, preferably trifluoromethylsulfonyloxy, 2,2,2-trifluoroethylsulfonyloxy.

[0255] As R 7 of mono C 1-6 Alkylaminosulfonyl, preferably methylaminosulfonyl, ethylaminosulfonyl.

[0256] As R 7 of di C 1-6 Alkylaminosulfonyl, preferably dimethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl.

[0257] As R 7 of mono C 2-7 Alkanoylamino, preferably acetylamino, propionylamino.

[0258] As R 7 of (C 2-7 alkanoyl)C 1-6 Alkylamino, preferably N-acetyl-N-methylamino, N-acetyl-N-ethylamino.

[0259] As R 7 of di C 2-7 Alkanoylamino, preferably diacetylamino, dipropionylamino.

[0260] As R 7 of mono C 1-6 Alkylsulfonylamino, preferably methylsulfonylamino, ethylsulfonylamino.

[0261] As R 7 of mono (C 2-7 alkoxycarbonyl)amino, preferably methoxycarbonylamino, tert-butoxycarbonylamino.

[0262] As R 7 of C 3-6 Cycloalkyl, preferably cyclopropyl, cyclobutyl.

[0263] As R 7 Cyclic ether group, preferably oxetanyl, oxolanyl.

[0264] As R7 The cyclic amino group, preferably azetidin-1-yl, pyrrolidin-1-yl.

[0265] As R 7 The halogenated cyclic amino group, preferably 3,3-difluoroazetidin-1-yl, 3,3-difluoropyrrolidin-1-yl.

[0266] As R 7 The cyclic group formed by the oxo group bonding to the carbon atom constituting the ring, preferably 2-oxopyrrolidin-3-yl, 2-oxopiperidin-4-yl.

[0267] As R 7 The cyclic group formed by the oxo group bonding to the sulfur atom constituting the ring, preferably 1,1-dioxoisothiazolidin-5-yl, 1,1-dioxothiomorpholin-4-yl.

[0268] As L 2 The C of 1-6 alkanediyl, preferably methylene, ethane-1,2-diyl.

[0269] As L 2 The hydroxy C of 1-6 alkanediyl, preferably hydroxymethylene, 1-hydroxyethane-1,1-diyl.

[0270] The heteroaryl group as ring Z, preferably tetrazolyl, pyrimidinyl.

[0271] The 4- to 10-membered heterocyclic group as ring Z, preferably pyrrolidinyl, isothiazolidinyl.

[0272] Ring Z is preferably phenyl or heteroaryl (preferably a 5- or 6-membered nitrogen-containing heteroaryl), more preferably the group represented by the following general formula,

[0273]

[0274] In the formula,

[0275] The wavy line represents the bonding point with L 2 and

[0276] R 8 and n have the same meanings as described above,

[0277] R 9 is C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl or C 3-6 cycloalkyl.

[0278] As R 8The halogen atom is preferably a fluorine atom or a chlorine atom.

[0279] As R 8 the C 1-6 alkyl group is preferably a methyl group or an ethyl group.

[0280] As R 8 the C 2-6 alkenyl group is preferably a vinyl group or an allyl group.

[0281] As R 8 the halo C 1-6 alkyl group is preferably a trifluoromethyl group or a 2,2,2-trifluoroethyl group.

[0282] As R 8 the hydroxy C 1-6 alkyl group is preferably a hydroxymethyl group or a 1-hydroxy-1-methylethyl group.

[0283] As R 8 the (C 1-6 alkoxy)C 1-6 alkyl group is preferably a methoxymethyl group or an ethoxymethyl group.

[0284] As R 8 the C 2-7 alkanoyl group is preferably an acetyl group or a propionyl group.

[0285] As R 8 the C 1-6 alkylsulfonyl group is preferably a methylsulfonyl group or an ethylsulfonyl group.

[0286] As R 8 the C 1-6 alkoxy group is preferably a methoxy group or an ethoxy group.

[0287] As R 8 the halo C 1-6 alkoxy group is preferably a difluoromethoxy group or a trifluoromethoxy group.

[0288] As R 8 the mono C 1-6 alkylamino group is preferably a methylamino group or an ethylamino group.

[0289] As R 8 the di C 1-6 alkylamino group is preferably a dimethylamino group or an N-ethyl-N-methylamino group.

[0290] As R 8 the C 2-7 alkoxycarbonyl group is preferably a methoxycarbonyl group or an ethoxycarbonyl group.

[0291] As R 8 the mono C1-6 Alkylcarbamoyl, preferably methylcarbamoyl, ethylcarbamoyl.

[0292] As R 8 Di-C 1-6 alkylcarbamoyl, preferably dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl.

[0293] As R 8 C 1-6 alkylsulfonyloxy, preferably methylsulfonyloxy, ethylsulfonyloxy.

[0294] As R 8 Halogenated C 1-6 alkylsulfonyloxy, preferably trifluoromethylsulfonyloxy, 2,2,2-trifluoroethylsulfonyloxy.

[0295] As R 8 Mono-C 1-6 alkylaminosulfonyl, preferably methylaminosulfonyl, ethylaminosulfonyl.

[0296] As R 8 Di-C 1-6 alkylaminosulfonyl, preferably dimethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl.

[0297] As R 8 Mono-C 2-7 alkanoylamino, preferably acetylamino, propionylamino.

[0298] As R 8 (C 2-7 alkanoyl)C 1-6 alkylamino, preferably N-acetyl-N-methylamino, N-acetyl-N-ethylamino.

[0299] As R 8 Di-C 2-7 alkanoylamino, preferably diacetylamino, dipropionylamino.

[0300] As R 8 Mono-C 1-6 alkylsulfonylamino, preferably methylsulfonylamino, ethylsulfonylamino.

[0301] As R 8 Mono-(C 2-7 alkoxycarbonyl)amino, preferably methoxycarbonylamino, tert-butoxycarbonylamino.

[0302] As R 8 C 3-6 cycloalkyl, preferably cyclopropyl, cyclobutyl.

[0303] As R 8 's cyclic ether group, it is preferably an oxetanyl group or an oxolanyl group.

[0304] As R 8 's cyclic amino group, it is preferably an azetidin-1-yl group or a pyrrolidin-1-yl group.

[0305] As R 8 's halogenated cyclic amino group, it is preferably a 3,3-difluoroazetidin-1-yl group or a 3,3-difluoropyrrolidin-1-yl group.

[0306] As m, when p is 1, it is preferably 0, and when p is 0, it is preferably 1 or 2.

[0307] As n, it is preferably 0 or 1.

[0308] In one aspect of the present invention, X is preferably a group represented by the general formula (II).

[0309] In one aspect of the present invention, for the group represented by the general formula (II), it is preferred that p is 1 and the ring Y is of the general formula (III):

[0310]

[0311] (In the formula,

[0312] The wavy line indicates the bonding point to L 1 ,

[0313] * indicates the bonding point to L 2 ,

[0314] R 7 and m have the same meanings as described above,

[0315] and the ring A is a 4- to 10-membered nitrogen-containing heterocyclic group) as those shown.

[0316] More preferably, further, those in which m is 0 or L 2 is a single bond.

[0317] In one aspect of the present invention, for the group represented by the general formula (II), it is preferred that p is 1 and the ring Y is of the general formula:

[0318]

[0319] (In the formula,

[0320] The wavy line indicates the bonding point to L 1 ,

[0321] * indicates the bonding point to L 2 ,

[0322] R7 and m are the same as defined above), more preferably, m is 0 or L 2 Those which are single bonds

[0323] In one embodiment of the present invention, the group represented by the general formula (II) preferably includes those where p is 1 and ring Z is phenyl or heteroaryl

[0324] In one embodiment of the present invention, the group represented by the general formula (II) preferably includes those where p is 1 and ring Z is phenyl or a 5- or 6-membered nitrogen-containing heteroaryl

[0325] In one embodiment of the present invention, the group represented by the general formula (II) preferably includes those where p is 1 and ring Z has the general formula:

[0326]

[0327] (wherein

[0328] The wavy line represents the bonding point with L 2 of

[0329] R 8 and n are the same as defined above,

[0330] R 9 is C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl or C 3-6 cycloalkyl) as described. Additionally, R 9 is an alternative of R 8 when bonded through the nitrogen atom constituting ring Z 8 of R

[0331] As the C 9 alkyl of R 1-6 it is preferably methyl, ethyl

[0332] As the halo C 9 alkyl of R 1-6 it is preferably 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl

[0333] As the hydroxy C 9 alkyl of R 1-6 it is preferably 2-hydroxyethyl, 3-hydroxypropyl

[0334] As the (C 9 alkoxy)C 1-6 alkyl of R 1-6 it is preferably 2-methoxyethyl, 2-ethoxyethyl

[0335] As R 9 of C 3-6 cycloalkyl group, preferably cyclopropyl or cyclobutyl.

[0336] In one embodiment of the present invention, in the group represented by the general formula (II), it is preferred that p is 0 and ring Y is C 3-10 cycloalkyl group (the aforementioned C 3-10 cycloalkyl group may be fused with a benzene ring or a heteroaryl ring to form a fused ring group, or may also form a bicyclic group or a spiro ring group) or a 4- to 10-membered heterocyclic group (the aforementioned 4- to 10-membered heterocyclic group may be fused with a benzene ring or a heteroaryl ring to form a fused ring group, or may also form a bicyclic group or a spiro ring group).

[0337] In one embodiment of the present invention, in the group represented by the general formula (II), it is preferred that p is 0 and ring Y is C 3-10 cycloalkyl group (the aforementioned C 3-10 cycloalkyl group may be fused with a benzene ring or a heteroaryl ring to form a fused ring group, or may also form a bicyclic group or a spiro ring group).

[0338] In one embodiment of the present invention, in the group represented by the general formula (II), it is preferred that p is 0 and ring Y is a fused heterocyclic group formed by fusing a 4- to 10-membered heterocyclic group with a benzene ring or a heteroaryl ring.

[0339] In one embodiment of the present invention, in the group represented by the general formula (II), it is preferred that p is 0 and ring Y is of the general formula:

[0340]

[0341] (wherein,

[0342] the wavy line represents the bonding point to L 1 ,

[0343] R 7 and m have the same meanings as described above).

[0344] In one embodiment of the present invention, in the group represented by the general formula (II), it is preferred that L 1 is methylene, p is 0, and ring Y is of the general formula:

[0345]

[0346] (wherein,

[0347] the wavy line represents the bonding point to L 1 ,

[0348] R 7 and m have the same meanings as described above).

[0349] In addition, in one embodiment of the present invention, in the group represented by the general formula (II), p is preferably 0 and the ring Y is represented by the general formula:

[0350]

[0351] (wherein,

[0352] the wavy line represents the bonding point with L 1 ,

[0353] R 7 and m have the same meanings as described above) and those of the group represented by the formula.

[0354] As specific examples of the compounds of the present invention, those described in the examples can be cited, and among them, the following compounds (1) to (49) are preferred.

[0355] (1) N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide;

[0356] (2) N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(thieno[3,2-c]pyridin-4-yl)benzamide;

[0357] (3) 4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]benzamide;

[0358] (4) 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(1-methyl-1H-tetrazol-5-yl)piperidin-4-yl]benzamide;

[0359] (5) 4-(furo[3,2-c]pyridin-4-yl)-N-{trans-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}benzamide;

[0360] (6) 4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide;

[0361] (7) 3-fluoro-4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide;

[0362] (8) N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(6-methylfuro[3,2-c]pyridin-4-yl)benzamide;

[0363] (9) N-[trans-4-(2-Hydroxypropan-2-yl)cyclohexyl]-4-(7-methylfuro[3,2-c]pyridin-4-yl)benzamide;

[0364] (10) 4-(Furo[3,2-c]pyridin-4-yl)-N-[1-(pyrimidin-2-yl)piperidin-4-yl]benzamide;

[0365] (11) 4-(Furo[3,2-c]pyridin-4-yl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]benzamide;

[0366] (12) (S)-4-(Furo[3,2-c]pyridin-4-yl)-N-[1-(pyrimidin-2-yl)pyrrolidin-3-yl]benzamide;

[0367] (13) (S)-4-(Furo[3,2-c]pyridin-4-yl)-N-{1-[5-(hydroxymethyl)pyrimidin-2-yl]pyrrolidin-3-yl}benzamide;

[0368] (14) N-(Chroman-3-ylmethyl)-4-(furo[3,2-c]pyridin-4-yl)benzamide;

[0369] (15) 4-(Furo[3,2-c]pyridin-4-yl)-N-(1-propionylpiperidin-4-yl)benzamide;

[0370] (16) N-[1-(Cyclopropanecarbonyl)piperidin-4-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide;

[0371] (17) 4-(Furo[3,2-c]pyridin-4-yl)-N-[1-(oxetan-3-yl)piperidin-4-yl]benzamide;

[0372] (18) N-[1-(1,3,4-Thiadiazol-2-yl)piperidin-4-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide;

[0373] (19) 4-(Furo[3,2-c]pyridin-4-yl)-N-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]benzamide;

[0374] (20) 4-(Furo[3,2-c]pyridin-4-yl)-N-(trans-4-hydroxycyclohexyl)benzamide;

[0375] (21) 4-(Furo[3,2-c]pyridin-4-yl)-N-[trans-4-(1-hydroxycyclopropyl)cyclohexyl]benzamide;

[0376] (22) 4-(Furo[3,2-c]pyridin-4-yl)-N-{trans-4-[(1-hydroxycyclopropyl)methoxy]cyclohexyl}benzamide;

[0377] (23) 4-(Furo[3,2-c]pyridin-4-yl)-N-(trans-4-hydroxy-4-methylcyclohexyl)benzamide;

[0378] (24) 4-(Furo[3,2-c]pyridin-4-yl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)benzamide;

[0379] (25) 4-(Furo[3,2-c]pyridin-4-yl)-N-[trans-4-(methoxy-d3)cyclohexyl]benzamide;

[0380] (26) 4-(Furo[3,2-c]pyridin-4-yl)-N-(trans-4-isopropoxycyclohexyl)benzamide;

[0381] (27) N-{trans-4-[(2,2-difluoroethyl)amino]cyclohexyl}-4-(furo[3,2-c]pyridin-4-yl)benzamide;

[0382] (28) 4-(Furo[3,2-c]pyridin-4-yl)-N-[trans-4-(oxetan-3-ylamino)cyclohexyl]benzamide;

[0383] (29) 4-[6-(Hydroxymethyl)furo[3,2-c]pyridin-4-yl]-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide;

[0384] (30) 4-[6-(Hydroxymethyl-d2)furo[3,2-c]pyridin-4-yl]-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide;

[0385] (31) 3-Fluoro-4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]benzamide;

[0386] (32) N-[trans-4-(1-hydroxycyclopropyl)cyclohexyl]-4-(6-methylfuro[3,2-c]pyridin-4-yl)benzamide;

[0387] (33) N-[1-(Pyrimidin-2-yl)piperidin-4-yl]-4-(1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide;

[0388] (34) N-(trans-4-Hydroxycyclohexyl)-4-(1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide;

[0389] (35) N-[trans-4-(2-Hydroxypropan-2-yl)cyclohexyl]-4-(6-methyl-1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide;

[0390] (36) N-[trans-4-(2-Hydroxypropan-2-yl)cyclohexyl]-4-(7-methyl-1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide;

[0391] (37) 3-Fluoro-N-[trans-4-(2-Hydroxypropan-2-yl)cyclohexyl]-4-(1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide;

[0392] (38) N-[trans-4-(2-Hydroxy-2-methylpropoxy)cyclohexyl]-4-(6-methylfuro[3,2-c]pyridin-4-yl)benzamide;

[0393] (39) N-(4-Hydroxybicyclo[2.2.2]octan-1-yl)-4-(6-methylfuro[3,2-c]pyridin-4-yl)benzamide;

[0394] (40) N-(trans-4-Hydroxy-4-methylcyclohexyl)-4-(6-methylfuro[3,2-c]pyridin-4-yl)benzamide;

[0395] (41) 3-Fluoro-4-(furo[3,2-c]pyridin-4-yl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)benzamide;

[0396] (42) 3-Fluoro-4-(furo[3,2-c]pyridin-4-yl)-N-(trans-4-hydroxy-4-methylcyclohexyl)benzamide;

[0397] (43) 3-Fluoro-4-(furo[3,2-c]pyridin-4-yl)-N-{trans-4-[(1-hydroxycyclopropyl)methoxy]cyclohexyl}benzamide;

[0398] (44) 4-(furo[3,2-c]pyridin-4-yl)-N-[cis-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]benzamide;

[0399] (45) 4-(furo[3,2-c]pyridin-4-yl)-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)benzamide;

[0400] (46) N-(4-cyanobicyclo[2.2.2]octan-1-yl)-4-(furo[3,2-c]pyridin-4-yl)benzamide;

[0401] (47) 4-[4-(furo[3,2-c]pyridin-4-yl)benzamido]bicyclo[2.2.2]octane-1-carboxamide;

[0402] (48) 4-(furo[3,2-c]pyridin-4-yl)-N-{cis-4-[(1-hydroxycyclopropyl)methoxy]cyclohexyl}benzamide; and

[0403] (49) 4-(furo[3,2-c]pyridin-4-yl)-N-[cis-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[0404] The compounds of formula (I) may have asymmetric centers, chiral axes and chiral planes.

[0405] The compounds of formula (I) may exist as racemates, as racemic mixtures and as individual diastereoisomers.

[0406] The compounds of formula (I) include all possible isomers, including optical isomers, and mixtures thereof.

[0407] The compounds of formula (I) may exist as tautomers. Even if only one tautomeric structure is described in the present specification, both tautomeric forms are included in the present invention.

[0408] The compounds of formula (I) include isotopomers in which one or more atoms within the molecule are replaced by their isotopes. In the present specification, an isotope means an atom having the same atomic number but a different mass number. Thus, "replaced by an isotope" in the present specification means replacement by an atom having the same atomic number but a different mass number from those normally present in nature.

[0409] For example, the hydrogen atoms constituting the compounds of formula (I) may be replaced by 2 H(D) or 3 H(T), and similarly, the carbon atoms constituting the compounds of formula (I) may be replaced by 11 C, 13 C or 14 C. Isotopomers replaced by stable isotopes such as 2 H(D) are useful because they sometimes exhibit therapeutic advantages due to higher metabolic stability. On the other hand, those replaced by 3 H(T), 14Isotopologues substituted with radioactive isotopes such as C are useful in the tissue distribution study of drugs and / or substrates. In addition, these isotopologues can be prepared by the methods disclosed in this specification or methods similar thereto using appropriate reagents containing the corresponding isotopes.

[0410] The "pharmaceutically acceptable salts" of the compounds of formula (I) are not particularly limited as long as they are pharmaceutically acceptable. For example, when the compound of formula (I) has a carboxyl group, a hydroxyl group or an acidic heteroaryl group (such as a tetrazolyl group), the base addition salts of the carboxyl group, the hydroxyl group or the acidic heteroaryl group, and when the compound of formula (I) has an amino group or a basic heteroaryl group, the acid addition salts of the amino group or the basic heteroaryl group, etc.

[0411] Examples of the base addition salts include alkali metal salts (such as sodium salt, potassium salt); alkaline earth metal salts (such as calcium salt, magnesium salt); ammonium salts; organic amine salts (such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt, N,N'-dibenzylethylenediamine salt), etc.

[0412] Examples of the acid addition salts include inorganic acid salts (such as hydrochloride, sulfate, nitrate, phosphate, perchlorate); organic acid salts (such as maleate, fumarate, tartrate, citrate, ascorbate, trifluoroacetate, etc.); sulfonate salts (such as methanesulfonate, hydroxyethanesulfonate, benzenesulfonate, p-toluenesulfonate), etc.

[0413] The "pharmaceutically acceptable salts" can be manufactured according to the methods used in the field of organic synthesis. For example, they can be manufactured by neutralizing and titrating a solution of the free form of the compound of formula (I) with an alkali solution or an acidic solution.

[0414] The "pharmaceutically acceptable salts" also include solvates with pharmaceutically acceptable solvents such as water or ethanol.

[0415] Next, the preparation method of the compounds of the present invention will be specifically described, but the preparation method is not limited thereto. The reaction sequence can be appropriately changed, and the implementation can start from a reasonable step.

[0416] Steps for converting substituents (conversion or further modification of substituents) can be inserted between each step.

[0417] When a reactive functional group is present, protection and deprotection can be carried out. As protecting groups and methods of protection and deprotection, those used in the field of organic synthesis can be used. For example, methods described in the literature [Protective Groups in Organic Synthesis, 3rd Edition, by T.W. Greene, published by John Wiley & Sons (1999)] or methods based thereon can be suitably used. Protection and deprotection can be carried out any number of times at any step as needed.

[0418] Unless otherwise specified, free compounds are used for convenience in the following production methods, but salts of free compounds can also be used for production.

[0419] In order to promote the progress of the reaction, reagents other than the exemplified reagents can also be suitably used. Heating in each reaction can utilize microwave irradiation as needed.

[0420] Starting material compounds not described in the production method are commercially available or can be easily prepared by combining known synthetic reactions.

[0421] The compounds obtained in each step can be separated and purified according to conventional methods (crystallization, recrystallization, column chromatography, preparative HPLC, etc.), or can be carried on to the subsequent step without separation and purification.

[0422] Production Method 1: Method for producing the compound of formula (I) (Part 1)

[0423]

[0424] (In the formula,

[0425] R 1 、R 2 、R 3 、R 4 、R 5 、W and X have the same meanings as described above,

[0426] M is boric acid, borate ester, trifluoroborate or cyclic triol borate, etc.,

[0427] LG represents a leaving group such as a halogen atom or trifluoromethanesulfonyloxy group.)

[0428] Step 1:

[0429] React the compound of formula (1) (hereinafter, also referred to as "compound (1)") with the compound of formula (2) (hereinafter, also referred to as "compound (2)") in the presence of a condensing agent to obtain the compound of formula (3) (hereinafter, also referred to as "compound (3)").

[0430] As the compound (1), for example, boric acid (1a), borate ester (1b), trifluoroborate (1c), cyclic triol borate (1d), etc. shown below can be cited.

[0431]

[0432] The compound (2) can be a commercially available product, or can be produced as appropriate by combining known methods, the methods described in the examples, or methods based thereon as needed.

[0433] Examples of the condensing agent include N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), N,N'-carbonyldiimidazole (CDI), diphenyl azidophosphate (DPPA), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbonium hexafluorophosphate (COMU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), etc.

[0434] In Step 1, a base can be used as needed. Examples of the base include N,N-diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, tripotassium phosphate, potassium fluoride, cesium fluoride, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc., and N,N-diisopropylethylamine and triethylamine are particularly preferred.

[0435] The reaction solvent is not particularly limited as long as it has no influence on the reaction, and examples thereof include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, dimethyl sulfoxide, acetonitrile, ethyl acetate, toluene, methanol, ethanol, water, etc., and N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, and chloroform are particularly preferred.

[0436] The usage amount of the compound (2) is usually 1-3 moles, preferably 1-2 moles, relative to 1 mole of the compound (1).

[0437] The usage amount of the base is usually 1-10 moles, preferably 1-3 moles, relative to 1 mole of the compound (1).

[0438] The reaction temperature is usually 0°C - 100°C, preferably 0°C - 60°C.

[0439] The reaction time is usually 10 minutes - 24 hours, preferably 30 minutes - 5 hours.

[0440] Step 2:

[0441] Compound (3) and a compound of formula (4) (hereinafter also referred to as “compound (4)”) are subjected to a coupling reaction in the presence of a palladium catalyst and a base to obtain a compound of formula (I).

[0442] Compound (4) may be a commercially available product, or may be produced by appropriately combining known methods or methods described in Examples or methods based thereon as necessary.

[0443] Examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium(0), palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]chloro[3-phenylallyl]palladium(II), and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II).

[0444] In step 2, a phosphine ligand may be used as needed. Examples of the phosphine ligand include triphenylphosphine, tri(2-methylphenyl)phosphine, tri(2-furyl)phosphine, tri-tert-butylphosphine, (4-dimethylaminophenyl)di-tert-butylphosphine (Amphos), 2-[di(tert-butyl)phosphino]-1,1'-biphenyl (JohnPhos), 2-[di(tert-butyl)phosphino]-2'-N,N-dimethylamino-1,1'-biphenyl (tBuDavePhos), 2-(dicyclohexylphosphino)- 1,1'-biphenyl (CyJohnPhos), 2-(dicyclohexylphosphino)-2'-N,N-dimethylamino-1,1'-biphenyl (DavePhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), etc.

[0445] Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, tripotassium phosphate, potassium fluoride, cesium fluoride, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, N,N-diisopropylethylamine, triethylamine and the like.

[0446] The reaction solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, methanol, ethanol, acetonitrile, water and the like.

[0447] The reaction solvent may be a single solvent or a mixed solvent of two or more solvents.

[0448] Examples of the mixed solvent include combinations of methanol and water, ethanol and water, toluene and water, 1,4-dioxane and water, etc.

[0449] The usage amount of compound (3) is generally 1 - 3 moles, preferably 1 - 2 moles, relative to 1 mole of compound (4).

[0450] The usage amount of the palladium catalyst is generally 0.01 - 0.5 moles, preferably 0.03 - 0.2 moles, relative to 1 mole of compound (4).

[0451] The usage amount of the base is generally 1 - 10 moles, preferably 1 - 3 moles, relative to 1 mole of compound (4).

[0452] The reaction temperature is generally 20°C - 160°C, preferably 20°C - 120°C.

[0453] The reaction time is generally 10 minutes - 24 hours, preferably 30 minutes - 5 hours.

[0454] Production Method 2: Production Method of the Compound of Formula (I) (The Second One)

[0455]

[0456] In the formula,

[0457] R 1 、R 2 、R 3 、R 4 、R 5 、W and X have the same meanings as described above,

[0458] M is boric acid, borate ester, trifluoroborate, cyclic triol borate, etc.,

[0459] LG is a leaving group such as a halogen atom or trifluoromethanesulfonyloxy group,

[0460] R a represents C 1-6 alkyl.

[0461] Step 3:

[0462] The compound of formula (5) (hereinafter, also referred to as "compound (5)") is subjected to a coupling reaction with compound (4) in the presence of a palladium catalyst and a base to obtain the compound of formula (6) (hereinafter, also referred to as "compound (6)").

[0463] Examples of compound (5) include, for example, boric acid (5a), borate ester (5b), trifluoroborate (5c), cyclic triol borate (5d), etc. shown below.

[0464]

[0465] Compound (4) may be a commercially available product, or may be produced by appropriately combining known methods or methods described in Examples or methods based thereon as necessary.

[0466] Examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium(0), palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]chloro[3-phenylallyl]palladium(II), and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II).

[0467] In step 3, a phosphine ligand may be used as needed. Examples of the phosphine ligand include triphenylphosphine, tri(2-methylphenyl)phosphine, tri(2-furyl)phosphine, tri-tert-butylphosphine, (4-dimethylaminophenyl)di-tert-butylphosphine (Amphos), 2-[di(tert-butyl)phosphino]-1,1'-biphenyl (JohnPhos), 2-[di(tert-butyl)phosphino]-2'-N,N-dimethylamino-1,1'-biphenyl (tBuDavePhos), 2-(dicyclohexylphosphino)- 1,1'-biphenyl (CyJohnPhos), 2-(dicyclohexylphosphino)-2'-N,N-dimethylamino-1,1'-biphenyl (DavePhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), etc.

[0468] Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, tripotassium phosphate, potassium fluoride, cesium fluoride, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, N,N-diisopropylethylamine, triethylamine and the like.

[0469] The reaction solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, methanol, ethanol, acetonitrile, water and the like.

[0470] The reaction solvent may be a single solvent or a mixed solvent of two or more solvents.

[0471] Examples of the mixed solvent include a combination of methanol and water, a combination of ethanol and water, a combination of toluene and water, and a combination of 1,4-dioxane and water.

[0472] The usage amount of compound (5) is generally 1 - 3 moles, preferably 1 - 2 moles, relative to 1 mole of compound (4).

[0473] The usage amount of the palladium catalyst is generally 0.01 - 0.5 moles, preferably 0.03 - 0.2 moles, relative to 1 mole of compound (4).

[0474] The usage amount of the base is generally 1 - 10 moles, preferably 1 - 3 moles, relative to 1 mole of compound (4).

[0475] The reaction temperature is generally 20°C - 160°C, preferably 20°C - 120°C.

[0476] The reaction time is generally 10 minutes - 24 hours, preferably 30 minutes - 5 hours.

[0477] Step 4:

[0478] Compound (6) is amidated with compound (2) in the presence of a base catalyst to obtain the compound of formula (I).

[0479] Compound (2) can be a commercially available product, or can be prepared as appropriate by combining known methods or the methods described in the examples or methods based thereon as needed.

[0480] Examples of the base catalyst include 1,5,7 - triazabicyclo[4.4.0]dec - 5 - ene, 1,8 - diazabicyclo[5.4.0]-7 - undecene (DBU), sodium methoxide, etc.

[0481] The reaction solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include toluene, 2 - methyltetrahydrofuran, tetrahydrofuran, 1,2 - dimethoxyethane, 1,4 - dioxane, dichloromethane, chloroform, ethyl acetate, acetonitrile, dimethyl sulfoxide, etc., and toluene, 2 - methyltetrahydrofuran, and tetrahydrofuran are particularly preferred.

[0482] The usage amount of compound (2) is generally 1 - 20 moles, preferably 1 - 10 moles, relative to 1 mole of compound (6).

[0483] The usage amount of the base catalyst is generally 0.01 - 1 mole, preferably 0.1 - 0.6 mole, relative to 1 mole of compound (6).

[0484] The reaction temperature is generally 20°C - 160°C, preferably 40°C - 110°C.

[0485] The reaction time is generally 1 hour - 48 hours, preferably 5 hours - 48 hours.

[0486] Production method 3: Production method of the compound of formula (I) (its 3)

[0487]

[0488] wherein

[0489] R 1 、R 2 、R 3 、R 4 、R 5 、W and X have the same meanings as described above,

[0490] M is boric acid, borate ester, trifluoroborate or cyclic triol borate, etc.,

[0491] LG represents a leaving group such as a halogen atom or trifluoromethanesulfonyloxy group.

[0492] Step 5:

[0493] According to the method of Step 2 based on Manufacturing Method 1, the compound (1) and the compound (4) are subjected to a coupling reaction in the presence of a palladium catalyst and a base to obtain the compound of formula (7) (hereinafter, also referred to as "compound (7)").

[0494] Step 6:

[0495] According to the method of Step 1 based on Manufacturing Method 1, the compound (7) and the compound (2) are reacted in the presence of a condensing agent to obtain the compound of formula (I).

[0496] Manufacturing Method 4: Method for manufacturing the compound of formula (7)

[0497]

[0498] wherein

[0499] R 1 、R 2 、R 3 、R 4 、R 5 and W have the same meanings as described above,

[0500] R a represents C 1-6 alkyl.

[0501] Step 7:

[0502] The compound (6) is hydrolyzed in the presence of a base to obtain the compound (7).

[0503] Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.

[0504] The reaction solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, water, etc., and methanol, ethanol, and water are preferred.

[0505] The reaction solvent may be a single solvent or a mixed solvent composed of two or more solvents combined.

[0506] Examples of the mixed solvent include the combination of methanol and water, the combination of ethanol and water, etc.

[0507] The amount of the base used is usually 1 mole to a large excess relative to 1 mole of the compound (6).

[0508] The reaction temperature is usually 0°C - 160°C, preferably 0°C - 130°C.

[0509] The reaction time is usually 0.5 hours - 48 hours, preferably 10 minutes - 5 hours.

[0510] Production method 5: Method for producing the compound of formula (12)

[0511] The compound of formula (12) corresponds to the compound in formula (I) where X is a group of formula (II) (in formula (II), L 1 is a single bond, ring Y is a group of formula (III), L 2 is a single bond, and p is 1).

[0512]

[0513] In the formula,

[0514] R 1 、R 2 、R 3 、R 4 、R 5 、R 7 、R 8 、ring A, ring Z, m and n have the same meanings as described above,

[0515] PG is a protecting group for the amine,

[0516] LG represents a leaving group such as a halogen atom or trifluoromethanesulfonyloxy group.

[0517] Step 8:

[0518] According to the method of Step 1 based on Production method 1, the compound (7) is reacted with the compound of formula (8) (hereinafter, also referred to as "compound (8)") in the presence of a condensing agent to obtain the compound of formula (9) (hereinafter, also referred to as "compound (9)").

[0519] As the compound (8), for example, azetidine (8a), pyrrolidine (8b-1), pyrrolidine (8b-2), piperidine (8c), etc. shown below can be mentioned.

[0520]

[0521] As PG (the protecting group of the amine), as long as it has its function, there is no particular limitation, and for example, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, trityl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc. can be mentioned. Particularly preferably, tert-butoxycarbonyl and 4-methoxybenzyl.

[0522] Step 9:

[0523] The compound (9) is deprotected under acidic conditions or hydrogenation conditions to obtain the compound of formula (10) (hereinafter, also referred to as "compound (10)").

[0524] Deprotection under acidic conditions

[0525] As the acid used under acidic conditions, for example, hydrogen chloride, hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, formic acid, p-toluenesulfonic acid, methanesulfonic acid, pyridinium p-toluenesulfonate, etc. can be mentioned.

[0526] The reaction solvent is not particularly limited as long as it does not affect the reaction, and for example, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, acetonitrile, ethyl acetate, toluene, water, etc. can be mentioned.

[0527] The usage amount of the acid is usually 0.01 mole to a large excess relative to 1 mole of the compound (9).

[0528] The reaction temperature is usually 0°C - 100°C, preferably 0°C - 40°C.

[0529] The reaction time is usually 10 minutes - 24 hours, preferably 10 minutes - 5 hours.

[0530] Deprotection under hydrogenation conditions

[0531] A catalyst is used under hydrogenation conditions. As the catalyst, for example, 5% palladium-on-activated carbon, 10% palladium-on-activated carbon, 20% palladium hydroxide-on-activated carbon, Raney nickel, platinum, platinum oxide, etc. can be mentioned.

[0532] The reaction solvent is not particularly limited as long as it does not affect the reaction, and for example, methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, toluene, ethyl acetate, etc. can be mentioned.

[0533] The amount of the catalyst used is generally 0.01 - 1 mole, preferably 0.05 - 0.2 mole, relative to 1 mole of the compound (9).

[0534] The reaction temperature is generally 0°C - 100°C, preferably 10°C - 40°C.

[0535] The reaction time is generally 10 minutes - 24 hours, preferably 30 minutes - 5 hours.

[0536] Step 10:

[0537] React the compound (10) with the compound of formula (11) (hereinafter, also referred to as "compound (11)") in the presence of a base to obtain the compound (12).

[0538] Examples of the compound (11) include pyridine (11a), pyridine (11b), pyrimidine (11c), pyrazine (11d), pyrimidine (11e), pyridazine (11f), thiazole (11g), thiadiazole (11h), oxazole (11i), pyrazole (11j), imidazole (11k), imidazole (11l), tetrazole (11m), pyrazole (11n), tetrazole (11o), etc. shown below.

[0539]

[0540] Examples of the base include N,N - diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, tripotassium phosphate, potassium fluoride, cesium fluoride, sodium tert - butoxide, potassium tert - butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, etc.

[0541] The reaction solvent is not particularly limited as long as it does not affect the reaction. Examples include N,N - dimethylformamide, N,N - dimethylacetamide, N - methylpyrrolidone, tetrahydrofuran, 1,4 - dioxane, dichloromethane, chloroform, dimethyl sulfoxide, acetonitrile, ethyl acetate, toluene, methanol, ethanol, water, etc. Particularly preferred are N,N - dimethylformamide, N,N - dimethylacetamide, N - methylpyrrolidone, and dimethyl sulfoxide.

[0542] The amount of the compound (11) used is generally 1 - 3 moles, preferably 1 - 2 moles, relative to 1 mole of the compound (10).

[0543] The amount of the base used is generally 1 - 10 moles, preferably 1 - 3 moles, relative to 1 mole of the compound (10).

[0544] The reaction temperature is generally 0°C - 200°C, preferably 0°C - 160°C.

[0545] The reaction time is generally 10 minutes - 24 hours, preferably 30 minutes - 10 hours.

[0546] Production method 6: Production method of the compound of formula (14)

[0547] The compound of formula (14) corresponds to the group of formula (II) for X in formula (I) (in formula (II), L 1 is a single bond, ring Y is a group of formula (III), L 2 is a single bond, and p is 1).

[0548]

[0549] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 9 , ring A, and m have the same meanings as described above.

[0550] Step 11: After reacting the thiourea intermediate formed by reacting the compound (10) with the compound of formula (13) (hereinafter, also referred to as "compound (13)") with an alkylating agent to form an S-alkylisothiourea intermediate, reacting with sodium azide to obtain the compound of formula (14) (hereinafter, also referred to as "compound (14)").

[0551] The compound (13) can be a commercially available product or can be produced by a known method or a method based thereon.

[0552] Examples of the alkylating agent include 1,3-propane sultone, 1,4-butane sultone, methyl iodide, ethyl iodide, dimethyl sulfate, diethyl sulfate, etc., and 1,3-propane sultone is particularly preferred. In addition, when using 1,3-propane sultone as the alkylating agent, it is preferred to inactivate the excess 1,3-propane sultone by adding a base and then carry out the reaction with sodium azide.

[0553] Examples of the base include triethylamine, N,N-diisopropylethylamine, pyridine, etc., and triethylamine is particularly preferred.

[0554] The alkylating agent and the base can be added simultaneously.

[0555] The reaction solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, ethyl acetate, toluene, etc., and acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone are particularly preferred.

[0556] The usage amount of compound (13) is generally 1 - 3 moles, preferably 1 - 2 moles, relative to 1 mole of compound (10).

[0557] The usage amount of the alkylating agent is generally 1 - 5 moles, preferably 1 - 3 moles, relative to 1 mole of compound (10).

[0558] The usage amount of the base is generally 1 - 10 moles, preferably 1 - 6 moles, relative to 1 mole of compound (10).

[0559] The usage amount of sodium azide is generally 1 - 20 moles, preferably 1 - 12 moles, relative to 1 mole of compound (10).

[0560] The reaction temperature is generally 20°C - 160°C, preferably 100°C, after the addition of compound (13), generally 20°C - 160°C, preferably 100°C, after the addition of the alkylating agent, generally 20°C - 160°C, preferably 100°C, after the addition of the base, and generally 20°C - 160°C, preferably 50°C - 100°C, after the addition of sodium azide.

[0561] The reaction time is generally 10 minutes - 24 hours, preferably 30 minutes - 8 hours, after the addition of compound (13), generally 10 minutes - 72 hours, preferably 1 hour - 16 hours, after the addition of the alkylating agent, generally 5 minutes - 1 hour, preferably 30 minutes - 1 hour, after the addition of the base, and generally 10 minutes - 72 hours, preferably 1 hour - 12 hours, after the addition of sodium azide.

[0562] Next, the pharmaceutical composition containing the compound of the present invention and the H - PGDS inhibitor will be described.

[0563] "H - PGDS" refers to hematopoietic PGD synthase.

[0564] "Inhibiting H - PGDS" means making the activity of H - PGDS as a prostaglandin D synthase disappear or weaken, for example, inhibiting the activity of H - PGDS under the conditions described in Example 222 below.

[0565] "H - PGDS inhibitor" refers to an agent for inhibiting H - PGDS.

[0566] "A pharmaceutical composition for treating or preventing diseases involving H - PGDS" refers to a pharmaceutical composition for treating or preventing diseases involving H - PGDS by inhibiting H - PGDS.

[0567] Examples of "diseases involving H-PGDS" include asthma, chronic obstructive pulmonary disease, allergic rhinitis, sinusitis, eosinophilic pneumonia, atherosclerosis, rheumatoid arthritis, cystic fibrosis, actinic keratosis, chronic urticaria, dermatitis, muscular dystrophy, sarcopenia, disuse muscle atrophy, muscle injury, wound, dermatomyositis, amyotrophic lateral sclerosis, cerebral infarction, myocardial infarction, ischemic enteropathy, ischemic nephropathy, ischemic gastropathy, ischemic hepatopathy, diabetic limb ischemia, Buerger's disease, etc.

[0568] The pharmaceutical compositions and inhibitors of the present invention can be provided as preparations.

[0569] The "preparation" can contain both a pharmaceutically acceptable carrier and a compound of the present invention.

[0570] The preparation can be manufactured using formulation techniques commonly used in the pharmaceutical field.

[0571] Examples of "pharmaceutically acceptable carriers" include solvents (e.g., pure water, ethanol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil), excipients (e.g., lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid), disintegrants (e.g., starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, L-hydroxypropyl cellulose), binders (e.g., crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose), lubricants (e.g., magnesium stearate, calcium stearate, talc, colloidal silica), wetting agents (e.g., propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, polyoxyethylene lauryl ether), antioxidants (e.g., sodium sulfite, potassium sulfite, ascorbic acid, α-tocopherol), suspending agents (stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxy methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose), preservatives (e.g., ethyl p-hydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, potassium sorbate), buffers (e.g., sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate), solubilizing aids (e.g., propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate), etc.

[0572] The preparation can exist in various dosage forms according to its use. The preparation can be solid or liquid. Additionally, the preparation can be an oral preparation or a topical preparation. Examples of the preparation include tablets, capsules, powders, granules, liquids, suppositories, ointments, injections, infusions, etc.

[0573] The content of the compound of the present invention in the preparation can be appropriately selected according to its use. For example, in the case of an oral preparation, 0.1 to 100% by mass, preferably 5 to 98% by mass, of the compound of the present invention can be formulated as an active ingredient relative to the total mass of the preparation.

[0574] The preparation can also contain a medicament other than the compound of the present invention (hereinafter, also referred to as "concomitant medicament"). The concomitant medicament can be appropriately selected according to its use.

[0575] "Concomitant use" means using a combination of multiple active ingredients. Examples of concomitant use include use as a formulation agent, use as a kit, and a method of separately administering each active ingredient through the same or different administration routes. Examples

[0576] Examples are listed below to further specifically illustrate the present invention, but the present invention is not limited by these examples.

[0577] Commercially available products are used for various reagents used in the examples unless otherwise specified.

[0578] In the examples, room temperature means 1°C - 40°C.

[0579] In silica gel column chromatography, unless otherwise specified, Biotage (registered trademark) SNAP Ultra Silica Cartridge or SNAP KP-Sil Cartridge manufactured by Biotage, or CHROMATOREX (registered trademark) Q-PACK SI, Q-PACK NH, or Q-PACK CO2H manufactured by Fuji Silysia Chemical Ltd. is used as the column, and ethyl acetate / n-hexane, methanol / chloroform, or methanol / ethyl acetate is used as the mobile phase.

[0580] In reverse-phase silica gel column chromatography, Biotage (registered trademark) SNAP Ultra C18 Cartridge manufactured by Biotage is used as the column, and 0.1% aqueous trifluoroacetic acid solution and 0.1% trifluoroacetic acid acetonitrile solution are used as the mobile phase.

[0581] In reverse-phase preparative liquid chromatography, YMC-Actus Triart C18 manufactured by YMC is used as the column, and 0.1% aqueous trifluoroacetic acid solution and 0.1% trifluoroacetic acid acetonitrile solution are used as the mobile phase.

[0582] In the preparation of thin-layer chromatography, PLC Silica gel 60 F254 manufactured by Merck was used as the TLC (silica gel plate).

[0583] 1 1H-NMR was measured using ECZ400S (400 MHz) manufactured by JEOL Ltd. The chemical shifts of the NMR data are based on the residual protons in the deuterated solvents used and are expressed in parts per million (ppm, δ).

[0584] Mass spectrometry was measured using ACQUITY (registered trademark) SQD manufactured by Waters through electrospray ionization (ESI). The ESI-MS data are recorded as the measured values (found). In the case of salts, the molecular ion peaks of the free forms are usually observed.

[0585] The microwave reaction was carried out using Initiator (registered trademark) manufactured by Biotage.

[0586] The meanings of the abbreviations are as follows.

[0587] s: singlet

[0588] d: doublet

[0589] t: triplet

[0590] q: quartet

[0591] dd: doublet of doublets

[0592] m: multiplet

[0593] br: broad peak

[0594] CDCl3: deuterochloroform

[0595] CD3OD: deuterated methanol

[0596] DMSO-d6: deuterated dimethyl sulfoxide

[0597] DIPEA: N,N-diisopropylethylamine

[0598] DMF: N,N-dimethylformamide

[0599] DMSO: dimethyl sulfoxide

[0600] EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0601] NMP: N-methylpyrrolidone

[0602] PdCl2(dppf): Dichloropalladium(II) [1,1'-bis(diphenylphosphino)ferrocene]

[0603] PdCl2(dppf)·CH2Cl2: Dichloropalladium(II) [1,1'-bis(diphenylphosphino)ferrocene] dichloromethane complex

[0604] Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0)

[0605] THF: Tetrahydrofuran.

[0606] Example 1

[0607] Synthesis of N-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide [1] (hereinafter referred to as compound [1])

[0608]

[0609] To a solution of 4-chloro-1H-pyrrolo[3,2-c]pyridine (76 mg) in ethanol (1.0 mL) / water (1.0 mL) was added N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (116 mg), potassium carbonate (90 mg) and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (13 mg) at room temperature. The mixture was stirred at 80 °C for 3 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (78 mg) as a white solid.

[0610] 1 1H-NMR (400 MHz, DMSO-d6) δ: 11.70 (br, 1H), 8.59 - 8.45 (m, 1H), 8.28 (d, J = 5.9 Hz, 1H), 8.08 (d, J = 8.7 Hz, 2H), 7.97 (d, J = 8.2 Hz, 2H), 7.56 - 7.54 (m, 1H), 7.41 (dd, J = 5.9, 0.9 Hz, 1H), 6.81 - 6.79 (m, 1H), 2.81 (d, J = 4.6 Hz, 3H).

[0611] ESI-MS: 252.2 [M + H] + .

[0612] Example 2

[0613] Synthesis of N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide [2] (hereinafter referred to as Compound [2])

[0614]

[0615] (1) Synthesis of N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [2-1] (hereinafter referred to as Compound [2-1])

[0616]

[0617] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2.44 g) in DMF (33 mL) was added DIPEA (1.84 mL) and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (4.63 g) at room temperature, and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added 2-(trans-4-aminocyclohexyl)propan-2-ol (2.01 g) at room temperature, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was suspended in ethyl acetate / n-hexane, and the solid was filtered to obtain the title compound (2.54 g) as a white solid.

[0618] 1 1H-NMR (400 MHz, CDCl3) δ: 7.85 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 7.8 Hz, 2H), 5.92 (d, J = 8.2 Hz, 1H), 4.01 - 3.84 (m, 1H), 2.27 - 2.09 (m, 2H), 2.03 - 1.84 (m, 2H), 1.45 - 1.11 (m, 23H).

[0619] ESI-MS: 388.5 [M + H] + .

[0620] (2) Synthesis of N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide [2]

[0621] To a solution of 4-chloro-1H-pyrrolo[3,2-c]pyridine (770 mg) in ethanol (12.5 mL) / water (12.5 mL) at room temperature, compound [2-1] (2.54 g), potassium carbonate (906 mg), and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (163 mg) were added, and the mixture was stirred at 100 °C for 2 hours under an argon atmosphere. Water was added to the reaction mixture, and the resulting solid was filtered. The obtained solid was dissolved in a chloroform (400 mL) / methanol (200 mL) solution and injected into a column packed with strongly acidic cation exchange resin (H form) (DOWEX TM 50WX2, 50 - 100 mesh). The column was washed with a chloroform / methanol (volume ratio 2 / 1) solution and eluted with a 2M ammonia / methanol solution. The eluate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (984 mg) as a white solid.

[0622] 1 1H-NMR (400 MHz, DMSO-d6) δ: 11.70 (br, 1H), 8.36 - 8.20 (m, 2H), 8.07 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 3.2 Hz, 1H), 7.41 (d, J = 5.5 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 4.04 (s, 1H), 3.81 - 3.65 (m, 1H), 2.00 - 1.74 (m, 4H), 1.41 - 1.25 (m, 2H), 1.24 - 0.96 (m, 9H).

[0623] ESI-MS: 378.4 [M + H] + 。

[0624] Example 3

[0625] Synthesis of N-[trans-4-(hydroxymethyl)cyclohexyl]-4-(1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide [3] (hereinafter referred to as compound [3])

[0626]

[0627] Based on the method of Example 2, the title compound was synthesized.

[0628] 1H-NMR (400 MHz, DMSO-d6) δ: 11.69 (br, 1H), 8.37 - 8.21 (m, 2H), 8.06 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 7.8 Hz, 2H), 7.57 - 7.54 (m, 1H), 7.41 (d, J = 6.4 Hz, 1H), 6.86 - 6.72 (m, 1H), 4.40 (t, J = 5.3 Hz, 1H), 3.84 - 3.67 (m, 1H), 3.23 (dd, J = 5.7, 5.7 Hz, 2H), 1.95 - 1.69 (m, 4H), 1.44 - 1.19 (m, 3H), 1.08 - 0.88 (m, 2H).

[0629] ESI-MS: 350.3 [M + H] + 。

[0630] Example 4

[0631] Synthesis of N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(1-methyl-1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide [4] (hereinafter referred to as compound [4])

[0632]

[0633] To a solution of 4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine (14 mg) in 1,4-dioxane (1.3 mL) / water (0.30 mL) at room temperature, compound [2-1] (30 mg), tripotassium phosphate (33 mg), and PdCl2(dppf) (5.7 mg) were added, and the mixture was stirred for 30 minutes at 130 °C using a microwave reactor. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (9.0 mg) as a white solid.

[0634] 1 H-NMR (400 MHz, DMSO-d6) δ: 8.34 (d, J = 5.5 Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.97 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 3.7 Hz, 1H), 7.51 (d, J = 5.9 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 4.04 (s, 1H), 3.85 (s, 3H), 3.79 - 3.64 (m, 1H), 1.96 - 1.74 (m, 4H), 1.41 - 1.25 (m, 2H), 1.24 - 0.95 (m, 9H).

[0635] ESI-MS: 392.2 [M+H] + 。

[0636] Example 5

[0637] Synthesis of N-cyclohexyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide [5] (hereinafter referred to as Compound [5])

[0638]

[0639] (1) Synthesis of ethyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)benzoate [5-1] (hereinafter referred to as Compound [5-1])

[0640]

[0641] To a solution of 4-chloro-1H-pyrrolo[3,2-c]pyridine (839 mg) in ethanol (5.5 mL) / water (5.5 mL) at room temperature, 4-(ethoxycarbonyl)phenylboronic acid (1.39 g), potassium carbonate (988 mg) and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (143 mg) were added. Under an argon atmosphere, the mixture was stirred at 100 °C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.19 g) as a white solid.

[0642] 1 1H-NMR (400 MHz, CDCl3) δ: 9.14 (br, 1H), 8.45 (d, J = 5.9 Hz, 1H), 8.20 (d, J = 8.2 Hz, 2H), 8.08 (d, J = 7.8 Hz, 2H), 7.39 - 7.28 (m, 2H), 6.91 - 6.77 (m, 1H), 4.42 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H).

[0643] ESI-MS: 267.3 [M+H] + 。

[0644] (2) Synthesis of N-cyclohexyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide [5]

[0645] ​​​​​​​To a solution of compound [5-1] (40 mg) in toluene (0.30 mL) at room temperature, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (6.3 mg) and cyclohexylamine (86 μL) were added, and the mixture was stirred at 80 °C for 31 hours. Chloroform was added to the reaction mixture, and the mixture was purified by silica gel column chromatography to obtain the title compound (9.4 mg) as a white solid.

[0646] 1 1H-NMR (400 MHz, DMSO-d6) δ: 11.71 (br, 1H), 8.37 - 8.20 (m, 2H), 8.06 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 2.7 Hz, 1H), 7.41 (d, J = 5.5 Hz, 1H), 6.79 (d, J = 3.2 Hz, 1H), 3.87 - 3.71 (m, 1H), 1.93 - 1.66 (m, 4H), 1.65 - 1.57 (m, 1H), 1.42 - 1.06 (m, 5H).

[0647] ESI-MS: 320.4 [M + H] + 。

[0648] Examples 6 - 58

[0649] Based on the method shown in step (2) of Example 5, the compounds of Examples 6 - 58 shown in the following table were synthesized. The structures, names, and ESI-MS of the compounds of each example are shown in the following table.

[0650] [Table 1-1]

[0651]

[0652] [Table 1-2]

[0653]

[0654] [Table 1-3]

[0655]

[0656] [Table 1-4]

[0657]

[0658] [Table 1-5]

[0659]

[0660] [Table 1-6]

[0661]

[0662] [Table 1-7]

[0663]

[0664] [Table 1-8]

[0665]

[0666] [Table 1-9]

[0667]

[0668] [Table 1-10]

[0669]

[0670] [Table 1-11]

[0671]

[0672] Example 59

[0673] Synthesis of N-benzyl-4-(thieno[3,2-c]pyridin-4-yl)benzamide

[59] (hereinafter referred to as compound

[59] )

[0674]

[0675] (1) Synthesis of ethyl 4-(thieno[3,2-c]pyridin-4-yl)benzoate [59-1] (hereinafter referred to as compound [59-1])

[0676]

[0677] To a solution of 4-chlorothieno[3,2-c]pyridine (509 mg) in ethanol (3.0 mL) / water (3.0 mL) at room temperature, 4-(ethoxycarbonyl)phenylboronic acid (757 mg), potassium carbonate (539 mg), and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (78.0 mg) were added, and the mixture was stirred at 100 °C for 2 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (741 mg) as a yellowish-white solid.

[0678] 11H-NMR (400 MHz, CDCl3) δ: 8.58 (d, J = 5.5 Hz, 1H), 8.21 (d, J = 8.7 Hz, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.84 (dd, J = 5.5, 0.9 Hz, 1H), 7.59 (dd, J = 5.5, 0.9 Hz, 1H), 7.54 (d, J = 5.5 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H).

[0679] ESI-MS: 284.5 [M+H] + 。

[0680] (2) Synthesis of N-benzyl-4-(thieno[3,2-c]pyridin-4-yl)benzamide

[59]

[0681] To a solution of compound [59-1] (28 mg) in toluene (0.20 mL) at room temperature, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (4.2 mg) and benzylamine (55 μL) were added, and the mixture was stirred at 80 °C for 21 h. Ethyl acetate was added to the reaction mixture, and the mixture was purified by silica gel column chromatography to give the title compound (31 mg) as a white solid.

[0682] 1 1H-NMR (400 MHz, DMSO-d6) δ: 9.19 (t, J = 5.9 Hz, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.12 (d, J = 5.5 Hz, 1H), 8.07 (d, J = 8.2 Hz, 2H), 8.01 - 7.85 (m, 3H), 7.66 (d, J = 5.0 Hz, 1H), 7.42 - 7.29 (m, 4H), 7.29 - 7.18 (m, 1H), 4.52 (d, J = 5.9 Hz, 2H).

[0683] ESI-MS: 345.2 [M+H] + 。

[0684] Example 60

[0685] Synthesis of N-(pyridin-4-ylmethyl)-4-(thieno[3,2-c]pyridin-4-yl)benzamide

[60] (hereinafter referred to as compound

[60] )

[0686]

[0687] To a solution of compound [59-1] (28 mg) in toluene (0.20 mL) at room temperature, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (4.2 mg) and 4-methylpyridinamine (51 μL) were added, and the mixture was stirred at 80 °C for 21 hours. Ethyl acetate was added to the reaction mixture, and the mixture was purified by silica gel column chromatography to obtain the title compound (31 mg) as a white solid.

[0688] ESI-MS: 346.2 [M+H] + 。

[0689] Example 61

[0690] Synthesis of N-(2-hydroxypropyl)-4-(thieno[3,2-c]pyridin-4-yl)benzamide

[61] (hereinafter referred to as compound

[61] )

[0691]

[0692] To a solution of compound [59-1] (28 mg) in toluene (0.20 mL) at room temperature, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (4.2 mg) and 1-amino-2-propanol (39 μL) were added, and the mixture was stirred at 80 °C for 21 hours. Ethyl acetate was added to the reaction mixture, and the mixture was purified by silica gel column chromatography to obtain the title compound (24 mg) as a white solid.

[0693] ESI-MS: 313.2 [M+H] + 。

[0694] Example 62

[0695] Synthesis of N-[2-(diisopropylamino)ethyl]-4-(thieno[3,2-c]pyridin-4-yl)benzamide dihydrochloride

[62] (hereinafter referred to as compound

[62] )

[0696]

[0697] To a solution of compound [59-1] (28 mg) in toluene (0.20 mL) at room temperature, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (4.2 mg) and N,N-diisopropylethylenediamine (87 μL) were added, and the mixture was stirred at 80 °C for 21 hours. Ethyl acetate was added to the reaction mixture, and the mixture was purified by silica gel column chromatography. A 4M solution of hydrogen chloride in ethyl acetate was added to the resulting oil, and the precipitated solid was filtered to obtain the title compound (20 mg) as a white solid.

[0698] ESI-MS: 382.3 [M+H] + 。

[0699] Example 63

[0700] Synthesis of N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(thieno[3,2-c]pyridin-4-yl)benzamide

[63] (hereinafter referred to as Compound

[63] )

[0701]

[0702] To a solution of 4-chlorothieno[3,2-c]pyridine (58.0 mg) in ethanol (0.8 mL) / water (0.8 mL) at room temperature, Compound [2-1] (120 mg), potassium carbonate (56.0 mg) and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (10.0 mg) were added, and the mixture was stirred at 80 °C for 1 hour under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (105 mg) as a white solid.

[0703] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.54 (d, J = 5.5 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.12 (dd, J = 5.5, 0.9 Hz, 1H), 8.01 (d, J = 8.2 Hz, 2H), 7.96 (d, J = 5.5 Hz, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.70 - 7.61 (m, 1H), 4.04 (s, 1H), 3.85 - 3.65 (m, 1H), 1.96 - 1.72 (m, 4H), 1.42 - 1.25 (m, 2H), 1.24 - 0.93 (m, 9H).

[0704] ESI-MS: 395.3 [M + H] + .

[0705] Example 64

[0706] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]benzamide

[64] (hereinafter referred to as Compound

[64] )

[0707]

[0708] (1) Synthesis of trans-4-(dibenzylamino)cyclohexan-1-ol [64-1] (hereinafter referred to as Compound [64-1])

[0709]

[0710] To a solution of trans-4-aminocyclohexan-1-ol (3.00 g) in ethanol (50.0 mL) at room temperature, benzyl bromide (6.80 mL) and sodium bicarbonate (8.75 g) were added, and the mixture was stirred at 80 °C for 45 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2.00 g) as a white solid.

[0711] 1 1H-NMR (400 MHz, CDCl3) δ: 7.37 - 7.35 (m, 4H), 7.30 - 7.26 (m, 4H), 7.22 - 7.18 (m, 2H), 3.64 (s, 4H), 3.57 - 3.52 (m, 1H), 2.56 - 2.48 (m, 1H), 2.14 - 1.97 (m, 2H), 1.94 - 1.88 (m, 2H), 1.48 - 1.38 (m, 2H), 1.23 - 1.14 (m, 2H).

[0712] ESI-MS: 296.3 [M + H] + 。

[0713] (2) Synthesis of tert-butyl 2-{[trans-4-(dibenzylamino)cyclohexyl]oxy}acetate [64 - 2] (hereinafter referred to as compound [64 - 2])

[0714]

[0715] To a solution of compound [64 - 1] (2.0 g) in DMF (13 mL) at room temperature, 60% sodium hydride (320 mg) and tert-butyl bromoacetate (1.5 mL) were added, and the mixture was stirred at 55 °C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (700 mg) as a yellow oil.

[0716] 1 1H-NMR (400 MHz, CDCl3) δ: 7.36 - 7.34 (m, 4H), 7.30 - 7.26 (m, 4H), 7.21 - 7.18 (m, 2H), 3.96 (s, 2H), 3.60 (s, 4H), 3.27 - 3.20 (m, 1H), 2.56 - 2.49 (m, 1H), 2.10 - 2.07 (m, 2H), 1.93 - 1.90 (m, 2H), 1.46 - 1.43 (m, 13H).

[0717] ESI-MS: 410.4 [M+H] + 。

[0718] (3) Synthesis of 1-{[trans-4-(dibenzylamino)cyclohexyl]oxy}-2-methylpropan-2-ol [64-3] (hereinafter referred to as Compound [64-3])

[0719]

[0720] To a solution of Compound [64-2] (700 mg) in THF (3.40 mL) at 0 °C was added a diethyl ether solution of 33 M methylmagnesium bromide (1.70 mL), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (285 mg) as a yellow oil.

[0721] 1 H-NMR (400 MHz, CDCl3) δ: 7.37 - 7.35 (m, 4H), 7.31 - 7.27 (m, 4H), 7.22 - 7.19 (m, 2H), 3.61 (s, 4H), 3.24 (s, 2H), 3.22 - 3.15 (m, 1H), 2.56 - 2.50 (m, 1H), 2.08 - 2.04 (m, 2H), 1.93 - 1.90 (m, 2H), 1.40 - 1.31 (m, 2H), 1.20 - 1.10 (m, 8H).

[0722] ESI-MS: 368.4 [M+H] + 。

[0723] (4) Synthesis of 1-[(trans-4-aminocyclohexyl)oxy]-2-methylpropan-2-ol [64-4] (hereinafter referred to as Compound [64-4])

[0724]

[0725] To a solution of Compound [64-3] (285 mg) in ethanol (1.50 mL) at room temperature was added 20% palladium hydroxide on activated carbon (21.0 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the title compound (140 mg) as a black oil.

[0726] 11H-NMR (400 MHz, CDCl3) δ: 3.27 - 3.21 (m, 3H), 2.74 - 2.68 (m, 1H), 2.03 - 1.99 (m, 2H), 1.89 - 1.86 (m, 2H), 1.34 - 1.08 (m, 10H).

[0727] ESI-MS: 188.3 [M + H] + 。

[0728] (5) Synthesis of ethyl 4-(furo[3,2-c]pyridin-4-yl)benzoate [64 - 5] (hereinafter referred to as Compound [64 - 5])

[0729]

[0730] To a solution of 4-chlorofuro[3,2-c]pyridine (2.00 g) in ethanol (13.0 mL) / water (13.0 mL) at room temperature, 4-(ethoxycarbonyl)phenylboronic acid (2.65 g), potassium carbonate (2.36 g) and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (84.0 mg) were added, and the mixture was stirred at 100 °C for 3 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (3.20 g) as a white solid.

[0731] 1 1H-NMR (400 MHz, CDCl3) δ: 8.62 (d, J = 5.5 Hz, 1H), 8.24 - 8.18 (m, 2H), 8.05 - 8.03 (m, 2H), 7.74 (d, J = 2.3 Hz, 1H), 7.48 (dd, J = 5.9, 0.9 Hz, 1H), 7.08 - 7.07 (m, 1H), 4.43 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H).

[0732] ESI-MS: 268.3 [M + H] + 。

[0733] (6) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]benzamide

[64]

[0734] To a solution of compound [64-5] (20 mg) in toluene (150 μL) at room temperature, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (3.2 mg) and compound [64-4] (71 mg) were added, and the mixture was stirred at 80 °C for 24 hours. Chloroform was added to the reaction mixture, and the mixture was purified by silica gel column chromatography to obtain the title compound (4.2 mg) as a brown solid.

[0735] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.59 (d, J = 5.5 Hz, 1H), 8.33 (d, J = 7.8 Hz, 1H), 8.24 (d, J = 2.7 Hz, 1H), 8.08 (dd, J = 6.9, 1.8 Hz, 2H), 8.03 - 7.98 (m, 2H), 7.73 (d, J = 5.5 Hz, 1H), 7.37 - 7.36 (m, 1H), 3.86 - 3.72 (m, 1H), 3.16 - 3.11 (m, 3H), 2.03 - 2.01 (m, 2H), 1.90 - 1.87 (m, 2H), 1.46 - 1.34 (m, 2H), 1.31 - 1.20 (m, 2H), 1.06 (s, 6H).

[0736] ESI-MS: 409.4 [M + H] + 。

[0737] Examples 65 to 97

[0738] Based on the method shown in step (6) of Example 64, the compounds of Examples 65 to 97 shown in the following table were synthesized. The structures, names, and ESI-MS of the compounds of each example are shown in the following table.

[0739] [Table 2-1]

[0740]

[0741] [Table 2-2]

[0742]

[0743] [Table 2-3]

[0744]

[0745] [Table 2-4]

[0746]

[0747] [Table 2-5]

[0748]

[0749] [Table 2-6]

[0750]

[0751] [Table 2-7]

[0752]

[0753] Example 98

[0754] Synthesis of N-[2-(diisopropylamino)ethyl]-4-(furo[3,2-c]pyridin-4-yl)benzamide dihydrochloride

[98] (hereinafter referred to as Compound

[98] )

[0755]

[0756] To a solution of Compound [64-5] (150 mg) in toluene (1.12 mL) at room temperature were added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (23.4 mg) and N,N-diisopropylethylenediamine (488 μL), and the mixture was stirred at 80 °C for 24 hours. Chloroform was added to the reaction mixture, and the mixture was purified by silica gel column chromatography. To the resulting oil was added an ethyl acetate solution of 4M hydrogen chloride, and the precipitated solid was collected by filtration to give the title compound (154 mg) as a yellow solid.

[0757] ESI-MS: 366.3 [M+H] + .

[0758] Example 99

[0759] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(1-methyl-1H-tetrazol-5-yl)piperidin-4-yl]benzamide

[99] (hereinafter referred to as Compound

[99] )

[0760]

[0761] (1) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)benzoic acid [99-1] (hereinafter referred to as Compound [99-1])

[0762]

[0763] To a solution of Compound [64-5] (3.50 g) in methanol (44.0 mL) at room temperature was added 2M aqueous sodium hydroxide solution (33.0 mL), and the mixture was stirred at 100 °C for 10 minutes. 2M hydrochloric acid (33.0 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration and dried under reduced pressure at 40 °C to give the title compound (3.42 g) as a gray solid.

[0764] 1 H-NMR (400 MHz, DMSO-d6) δ: 8.72 - 8.66 (m, 1H), 8.43 - 8.36 (m, 1H), 8.17 - 8.12 (m, 4H), 8.02 - 7.91 (m, 1H), 7.49 - 7.45 (m, 1H).

[0765] ESI-MS: 240.3 [M+H] + 。

[0766] (2) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(1-methyl-1H-tetrazol-5-yl)piperidin-4-yl]benzamide

[99]

[0767] To a solution of compound [99-1] (10.0 mg) in DMF (150 μL) at room temperature, DIPEA (8.00 μL), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (20.0 mg), and 1-(1-methyl-1H-1,2,3,4-tetrazol-5-yl)piperidin-4-amine dihydrochloride (14.0 mg) were added, and the mixture was stirred at room temperature for 22 h. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (13.0 mg) as a peach-colored solid.

[0768] 1 H-NMR (400 MHz, CD3OD) δ: 8.53 (d, J = 5.5 Hz, 1H), 8.04 - 7.99 (m, 5H), 7.63 (d, J = 5.9 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 4.22 - 4.14 (m, 1H), 3.94 (s, 3H), 3.76 - 3.73 (m, 2H), 3.25 - 3.18 (m, 2H), 2.13 - 2.09 (m, 2H), 1.92 - 1.82 (m, 2H).

[0769] ESI-MS: 404.4 [M+H] + 。

[0770] Examples 100 - 117

[0771] Based on the method shown in step (2) of Example 99, the compounds of Examples 100 - 117 shown in the following table were synthesized. The structures, names, and ESI-MS of the compounds of each example are shown in the following table.

[0772] [Table 3-1]

[0773]

[0774] [Table 3-2]

[0775]

[0776] [Table 3-3]

[0777]

[0778] [Table 3-4]

[0779]

[0780] Example 118

[0781] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(pyridin-2-yl)piperidin-4-yl]benzamide

[118] (hereinafter referred to as Compound

[118] )

[0782]

[0783] To a solution of Compound [99-1] (20.0 mg) in DMF (300 μL) at room temperature were added DIPEA (16.0 μL), (1-cyano-2-ethoxy-2-oxoethylaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (40.0 mg), and 1-(pyridin-2-yl)piperidin-4-amine (19.4 mg), and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (13.0 mg) as a yellow solid.

[0784] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.55 (d, J = 5.5 Hz, 1H), 8.39 (d, J = 8.2 Hz, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.10 - 8.03 (m, 3H), 7.99 (dd, J = 6.9, 1.8 Hz, 2H), 7.69 (dd, J = 5.9, 0.9 Hz, 1H), 7.57 - 7.43 (m, 1H), 7.34 - 7.33 (m, 1H), 6.85 (d, J = 8.7 Hz, 1H), 6.57 (dd, J = 6.6, 4.8 Hz, 1H), 4.31 - 4.28 (m, 2H), 4.16 - 4.07 (m, 1H), 2.95 - 2.89 (m, 2H), 1.85 - 1.83 (m, 2H), 1.58 - 1.49 (m, 2H).

[0785] ESI-MS: 399.4 [M + H] + 。

[0786] Example 119

[0787] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{trans-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}benzamide

[119] (hereinafter referred to as Compound

[119] )

[0788]

[0789] (1) Synthesis of benzyl {trans-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}carbamate [119-1] (hereinafter referred to as Compound [119-1])

[0790]

[0791] To a solution of trans-1,4-cyclohexanediamine (228 mg) in water (2.00 mL) / 1,4-dioxane (18.0 mL) at 0 °C, potassium carbonate (553 mg) and benzyl chloroformate (284 μL) were added, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the resulting residue in 1,4-dioxane (6.30 mL) at room temperature, DIPEA (220 μL) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (91.0 μL) were added, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (132 mg) as a white solid.

[0792] 1 H-NMR (400 MHz, CDCl3) δ: 7.36 - 7.30 (m, 5H), 5.08 (s, 2H), 4.58 - 4.57 (m, 1H), 3.48 - 3.47 (m, 1H), 3.19 (q, J = 9.6 Hz, 2H), 2.04 - 1.94 (m, 4H), 1.29 - 1.10 (m, 4H).

[0793] ESI-MS: 331.3 [M + H] + 。

[0794] (2) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{trans-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}benzamide [

[119] ]

[0795] To a solution of compound [[119-1]] (117 mg) in ethanol (1.20 mL) at room temperature was added 10% palladium-on-carbon (19.0 mg), and the mixture was stirred for 23 hours under a hydrogen atmosphere at room temperature. The reaction mixture was filtered and concentrated under reduced pressure. To a solution of the resulting residue in DMF (300 μL) at room temperature were added DIPEA (16.0 μL), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (40.0 mg), and compound [[99-1]] (20.0 mg), and the mixture was stirred for 21 hours at room temperature. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (4.50 mg) as a peach-colored solid.

[0796] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.58 (d, J = 5.5 Hz, 1H), 8.33 (d, J = 8.2 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.08 (dd, J = 6.9, 1.8 Hz, 2H), 8.04 - 7.94 (m, 2H), 7.72 (dd, J = 5.7, 1.1 Hz, 1H), 7.36 - 7.35 (m, 1H), 3.86 - 3.68 (m, 1H), 3.29 - 3.19 (m, 2H), 2.41 - 2.39 (m, 1H), 2.23 - 2.18 (m, 1H), 1.94 - 1.84 (m, 4H), 1.42 - 1.32 (m, 2H), 1.16 - 1.06 (m, 2H).

[0797] ESI-MS: 418.4 [M + H] + 。

[0798] Example 120

[0799] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(hydroxymethyl)cyclohexyl]benzamide [

[120] ] (hereinafter referred to as compound [

[120] ])

[0800]

[0801] To a solution of compound [99-1] (191 mg) in DMF (3.20 mL) at room temperature, DIPEA (150 μL), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (377 mg), and (trans-4-aminocyclohexyl)methanol (134 mg) were added, and the mixture was stirred at room temperature for 17 h. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (280 mg) as a yellow solid.

[0802] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.59 (d, J = 5.5 Hz, 1H), 8.34 (d, J = 7.8 Hz, 1H), 8.25 (d, J = 2.3 Hz, 1H), 8.08 (dd, J = 6.4, 1.8 Hz, 2H), 8.02 - 8.00 (m, 2H), 7.74 (d, J = 5.9 Hz, 1H), 7.37 - 7.36 (m, 1H), 3.79 - 3.71 (m, 1H), 3.24 - 3.22 (m, 2H), 1.89 - 1.87 (m, 2H), 1.80 - 1.77 (m, 2H), 1.40 - 1.31 (m, 3H), 1.03 - 0.94 (m, 2H).

[0803] ESI-MS: 351.3 [M + H] + 。

[0804] Example 121

[0805] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(1-hydroxyethyl)cyclohexyl]benzamide

[121] (hereinafter referred to as compound

[121] )

[0806]

[0807] To a solution of compound

[120] (250 mg) in dichloromethane (2.40 mL) at room temperature, Dess-Martin periodinane (394 mg) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the resulting residue in THF (3.00 mL) at 0 °C, a diethyl ether solution of 3 M methylmagnesium bromide (880 μL) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (47.0 mg) as a peach-colored solid.

[0808] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.56 (d, J = 5.9 Hz, 1H), 8.33 - 8.27 (m, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.09 - 8.03 (m, 2H), 8.01 - 7.95 (m, 2H), 7.69 (dd, J = 5.8, 1.0 Hz, 1H), 7.34 - 7.33 (m, 1H), 4.28 - 4.27 (m, 1H), 3.75 - 3.66 (m, 1H), 3.35 - 3.33 (m, 1H), 1.90 - 1.67 (m, 4H), 1.36 - 1.02 (m, 8H).

[0809] ESI-MS: 365.3 [M + H] + 。

[0810] Example 122

[0811] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[6-(2-hydroxypropan-2-yl)spiro[3.3]heptan-2-yl]benzamide

[122] (hereinafter referred to as compound

[122] )

[0812]

[0813] (1) Synthesis of methyl 6-(dibenzylamino)spiro[3.3]heptane-2-carboxylate [122-1] (hereinafter referred to as compound [122-1])

[0814]

[0815] To a solution of methyl 6-oxospiro[3.3]heptane-2-carboxylate (1.00 g) in THF (50.0 mL) at room temperature was added dibenzylamine (1.17 mL), and the mixture was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (1.90 g) and acetic acid (34.0 μL) were added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 19 h. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained residue was purified by silica gel column chromatography to give the title compound (530 mg) as a yellow oil.

[0816] ESI-MS: 351.3 [M+H] + 。

[0817] (2) Synthesis of 2-[6-(dibenzylamino)spiro[3.3]heptan-2-yl]propan-2-ol [122-2] (hereinafter referred to as compound [122-2])

[0818]

[0819] To a solution of compound [122-1] (530 mg) in diethyl ether (20.0 mL) at 0 °C was added a diethyl ether solution of 3 M methylmagnesium bromide (6.06 mL), and the mixture was stirred at room temperature for 3 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (306 mg) as a white solid.

[0820] ESI-MS: 351.4 [M+H] + 。

[0821] (3) Synthesis of 2-(6-aminospiro[3.3]heptan-2-yl)propan-2-ol [122-3] (hereinafter referred to as compound [122-3])

[0822]

[0823] To a solution of compound [122-2] (306 mg) in ethanol (2.00 mL) at room temperature was added 20% palladium hydroxide on carbon (30.0 mg), and the mixture was stirred at room temperature for 5 h under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (142 mg) as a brown oil.

[0824] ESI-MS: 170.3 [M+H] + 。

[0825] Synthesis of 4-(Furo[3,2-c]pyridin-4-yl)-N-[6-(2-hydroxypropan-2-yl)spiro[3.3]heptan-2-yl]benzamide

[122]

[0826] To a solution of compound [99-1] (20 mg) in DMF (0.30 mL) at room temperature, DIPEA (16 μL), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (40 mg) and compound [122-3] (18 mg) were added, and the mixture was stirred at room temperature for 22 h. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (8.2 mg) as a yellow solid.

[0827] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.64 (d, J = 5.9 Hz, 1H), 8.56 - 8.51 (m, 1H), 8.22 - 8.20 (m, 1H), 8.11 - 8.02 (m, 2H), 8.01 - 7.94 (m, 2H), 7.70 - 7.69 (m, 1H), 7.34 - 7.33 (m, 1H), 4.32 - 4.26 (m, 1H), 3.96 (s, 1H), 2.42 - 2.37 (m, 1H), 2.12 - 2.06 (m, 4H), 1.99 - 1.88 (m, 4H), 0.94 (s, 3H), 0.92 (s, 3H).

[0828] ESI-MS: 391.4 [M + H] + .

[0829] Example 123

[0830] Synthesis of 4-(Furo[3,2-c]pyridin-4-yl)-N-[1-(pyridin-4-yl)piperidin-4-yl]benzamide

[123] (hereinafter referred to as compound

[123] )

[0831]

[0832] To a solution of compound [99-1] (35 mg) in DMF (0.50 mL) at room temperature, DIPEA (85 μL), (1-cyano-2-ethoxy-2-oxoethylaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (56 mg), and 4-amino-1-(pyridin-4-yl)piperidine dihydrochloride (20 mg) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (10 mg) as a yellow solid.

[0833] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.55 (d, J = 5.5 Hz, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.11 (d, J = 6.4 Hz, 2H), 8.06 (d, J = 8.7 Hz, 2H), 7.99 (d, J = 8.2 Hz, 2H), 7.73 - 7.65 (m, 1H), 7.33 (d, J = 1.1 Hz, 1H), 6.82 (d, J = 6.9 Hz, 2H), 4.13 - 4.03 (m, 1H), 3.99 - 3.96 (m, 2H), 3.00 - 2.94 (m, 2H), 1.91 - 1.78 (m, 2H), 1.60 - 1.51 (m, 2H).

[0834] ESI-MS: 399.3 [M + H] + 。

[0835] Example 124

[0836] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[124] (hereinafter referred to as compound

[124] )

[0837]

[0838] To a solution of 4-chlorofuro[3,2-c]pyridine (336 mg) in ethanol (5.20 mL) / water (5.20 mL) at room temperature, compound [2-1] (808 mg), potassium carbonate (375 mg), and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (54.2 mg) were added, and the mixture was stirred at 80 °C for 6 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (588 mg) as a white solid.

[0839] 1 H-NMR (400 MHz, DMSO-d6) δ: 8.58 (d, J = 5.5 Hz, 1H), 8.32 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.08 (d, J = 8.7 Hz, 2H), 8.01 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 5.5 Hz, 1H), 7.39 - 7.33 (m, 1H), 4.04 (s, 1H), 3.81 - 3.66 (m, 1H), 2.00 - 1.70 (m, 4H), 1.47 - 1.25 (m, 2H), 1.24 - 0.92 (m, 9H).

[0840] ESI-MS: 379.4 [M + H] + 。

[0841] Example 125

[0842] Synthesis of 3-fluoro-4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[125] (hereinafter referred to as Compound

[125] )

[0843]

[0844] (1) Synthesis of methyl 3-fluoro-4-(furo[3,2-c]pyridin-4-yl)benzoate [125-1] (hereinafter referred to as Compound [125-1])

[0845]

[0846] To a solution of 4-chlorofuro[3,2-c]pyridine (154 mg) in methanol (1.65 mL) / water (1.65 mL) at room temperature, 2-fluoro-4-(methoxycarbonyl)phenylboronic acid (257 mg), potassium carbonate (180 mg), and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (26.0 mg) were added, and the mixture was stirred at 80 °C for 1 hour under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (242 mg) as a pale yellow solid.

[0847] 11H-NMR (400 MHz, CDCl3) δ: 8.64 (d, J = 5.5 Hz, 1H), 7.99 (dd, J = 8.0, 1.6 Hz, 1H), 7.94 - 7.85 (m, 2H), 7.71 (d, J = 2.3 Hz, 1H), 7.52 (dd, J = 5.9, 0.9 Hz, 1H), 6.89 - 6.80 (m, 1H), 3.98 (s, 3H).

[0848] ESI-MS: 272.2 [M + H] + 。

[0849] (2) Synthesis of 3-fluoro-4-(furo[3,2-c]pyridin-4-yl)benzoic acid [125-2] (hereinafter referred to as compound [125-2])

[0850]

[0851] To a solution of compound [125-1] (242 mg) in methanol (8.8 mL) at room temperature was added 2 M aqueous sodium hydroxide solution (4.4 mL), and the mixture was stirred at 60 °C for 20 minutes. The reaction mixture was concentrated under reduced pressure, and 2 M hydrochloric acid was added. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (191 mg) as a gray solid.

[0852] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.62 (d, J = 5.5 Hz, 1H), 8.19 (d, J = 2.3 Hz, 1H), 7.93 (dd, J = 8.2, 1.4 Hz, 1H), 7.90 - 7.81 (m, 2H), 7.79 (dd, J = 5.9, 0.9 Hz, 1H), 7.08 - 6.94 (m, 1H).

[0853] ESI-MS: 258.2 [M + H] + 。

[0854] (3) Synthesis of 3-fluoro-4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[125]

[0855] To a solution of compound [125-2] (51 mg) in DMF (1.0 mL) at room temperature, DIPEA (37 μL) and (1-cyano-2-ethoxy-2-oxoethylaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (94 mg) were added, and the mixture was stirred at room temperature for 5 minutes. 2-(trans-4-Aminocyclohexyl)propan-2-ol (41 mg) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 22 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (65 mg) as a white solid.

[0856] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.61 (d, J = 5.5 Hz, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.18 (d, J = 2.3 Hz, 1H), 7.91 - 7.75 (m, 4H), 7.01 - 6.90 (m, 1H), 4.03 (s, 1H), 3.85 - 3.64 (m, 1H), 1.99 - 1.73 (m, 4H), 1.40 - 1.24 (m, 2H), 1.25 - 0.92 (m, 9H).

[0857] ESI-MS: 397.4 [M + H] + 。

[0858] Example 126

[0859] Synthesis of 2-fluoro-4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[126] (hereinafter referred to as compound

[126] )

[0860]

[0861] (1) Synthesis of methyl 2-fluoro-4-(furo[3,2-c]pyridin-4-yl)benzoate [126-1] (hereinafter referred to as compound [126-1])

[0862]

[0863] To a solution of 4-chlorofuro[3,2-c]pyridine (154 mg) in methanol (1.65 mL) / water (1.65 mL) at room temperature, 3-fluoro-4-(methoxycarbonyl)phenylboronic acid (257 mg), potassium carbonate (180 mg), and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (26.0 mg) were added, and the mixture was stirred at 80 °C for 2 h under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (208 mg) as a pale yellow solid.

[0864] ESI-MS: 272.2 [M+H] + 。

[0865] (2) Synthesis of 2-fluoro-4-(furo[3,2-c]pyridin-4-yl)benzoic acid [126-2] (hereinafter referred to as compound [126-2])

[0866]

[0867] To a solution of compound [126-1] (208 mg) in methanol (7.6 mL) at room temperature, 2 M aqueous sodium hydroxide solution (3.8 mL) was added, and the mixture was stirred at 60 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and 2 M hydrochloric acid was added. The resulting solid was filtered, washed with water, and dried under reduced pressure to give the title compound (111 mg) as a gray solid.

[0868] ESI-MS: 258.2 [M+H] + 。

[0869] (3) Synthesis of 2-fluoro-4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[126]

[0870] To a solution of compound [126-2] (51 mg) in DMF (1.0 mL) at room temperature, DIPEA (37 μL) and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (94 mg) were added, and the mixture was stirred at room temperature for 5 min. To the reaction mixture at room temperature, 2-(trans-4-aminocyclohexyl)propan-2-ol (41 mg) was added, and the mixture was stirred at room temperature for 22 h. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (74 mg) as a yellow solid.

[0871] 1 H-NMR (400 MHz, DMSO-d6) δ: 8.59 (d, J = 5.5 Hz, 1H), 8.31 - 8.20 (m, 2H), 7.91 (dd, J = 8.0, 1.6 Hz, 1H), 7.84 (dd, J = 11.4, 1.4 Hz, 1H), 7.75 (dd, J = 5.5, 0.9 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.45 - 7.35 (m, 1H), 4.03 (s, 1H), 3.75 - 3.61 (m, 1H), 2.00 - 1.73 (m, 4H), 1.36 - 0.93 (m, 11H).

[0872] ESI-MS: 397.4 [M + H] + 。

[0873] Example 127

[0874] Synthesis of N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(6-methylfuro[3,2-c]pyridin-4-yl)benzamide

[127] (hereinafter referred to as compound

[127] )

[0875]

[0876] (1) Synthesis of 3-hydroxy-6-methyl-3,5-dihydrofuro[3,2-c]pyridin-4(2H)-one [127-1] (hereinafter referred to as compound [127-1])

[0877]

[0878] To a solution of 2,4-dihydroxy-6-methylpyridine (528 mg) in acetone (42 mL) at room temperature, potassium carbonate (1.75 g) was added, and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture at room temperature, 40% aqueous chloroacetaldehyde solution (4.15 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and water was added. The resulting solid was filtered off and dried under reduced pressure to obtain the title compound (267 mg) as a brown solid.

[0879] 1 H-NMR (400 MHz, DMSO-d6) δ: 11.10 (br, 1H), 5.81 (s, 1H), 5.28 (d, J = 5.9 Hz, 1H), 5.06 - 5.01 (m, 1H), 4.44 (dd, J = 10.5, 6.4 Hz, 1H), 4.23 (dd, J = 10.3, 2.1 Hz, 1H), 2.13 (s, 3H).

[0880] ESI-MS: 168.2 [M+H] + 。

[0881] (2) Synthesis of 4-chloro-6-methylfuro[3,2-c]pyridine [127-2] (hereinafter referred to as Compound [127-2])

[0882]

[0883] To Compound [127-1] (266 mg) at room temperature, phosphorus oxychloride (4.00 mL) was added and stirred at room temperature for 30 minutes. Subsequently, the reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was poured into ice-cold saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (152 mg) as a pale yellow solid.

[0884] 1 H-NMR (400 MHz, CDCl3) δ: 7.61 (d, J = 2.3 Hz, 1H), 7.23 (s, 1H), 6.83 (dd, J = 2.3, 0.9 Hz, 1H), 2.63 (s, 3H).

[0885] ESI-MS: 168.1 [M+H] + 。

[0886] (3) Synthesis of N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(6-methylfuro[3,2-c]pyridin-4-yl)benzamide

[127]

[0887] To a solution of Compound [127-2] (37 mg) in ethanol (1.0 mL) / water (1.0 mL) at room temperature, Compound [2-1] (78 mg), potassium carbonate (36 mg) and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (6.5 mg) were added and stirred at 80 °C for 3 hours under an argon atmosphere. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (60 mg) as a white solid.

[0888] 11H-NMR (400 MHz, DMSO-d6) δ: 8.31 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 2.3 Hz, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 8.7 Hz, 2H), 7.56 (s, 1H), 7.28 (d, J = 1.4 Hz, 1H), 4.04 (s, 1H), 3.80 - 3.65 (m, 1H), 2.64 (s, 3H), 1.95 - 1.76 (m, 4H), 1.41 - 1.26 (m, 2H), 1.23 - 0.95 (m, 9H).

[0889] ESI-MS: 393.4 [M + H] + 。

[0890] Example 128

[0891] Synthesis of N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(2-methylfuro[3,2-c]pyridin-4-yl)benzamide

[128] (hereinafter referred to as Compound

[128] )

[0892]

[0893] To a solution of 4-chloro-2-methylfuro[3,2-c]pyridine (37 mg) in ethanol (1.0 mL) / water (1.0 mL) at room temperature, Compound [2-1] (78 mg), potassium carbonate (36 mg) and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (6.5 mg) were added, and the mixture was stirred at 80 °C for 2 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (55 mg) as a white solid.

[0894] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.50 (d, J = 5.5 Hz, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 8.2 Hz, 2H), 7.60 (dd, J = 5.5, 0.9 Hz, 1H), 7.04 - 6.96 (m, 1H), 4.04 (s, 1H), 3.81 - 3.64 (m, 1H), 2.52 (d, J = 0.9 Hz, 3H), 1.96 - 1.75 (m, 4H), 1.40 - 1.25 (m, 2H), 1.24 - 0.92 (m, 9H).

[0895] ESI-MS: 393.4 [M+H] + 。

[0896] Example 129

[0897] Synthesis of N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(7-methylfuro[3,2-c]pyridin-4-yl)benzamide

[129] (hereinafter referred to as Compound

[129] )

[0898]

[0899] (1) Synthesis of 4-chloro-7-methylfuro[3,2-c]pyridine [129-1] (hereinafter referred to as Compound [129-1])

[0900]

[0901] To a solution of 7-bromo-4-chlorofuro[3,2-c]pyridine (116 mg) in 1,4-dioxane (2.0 mL) at room temperature, cesium carbonate (163 mg), PdCl2(dppf) (36.6 mg) and 2,4,6-trimethylcyclotriboroxane (70.0 μL) were added, and the mixture was stirred at 100 °C for 3 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (40.2 mg) as a white solid.

[0902] 1 1H-NMR (400 MHz, CDCl3) δ: 8.07 (s, 1H), 7.69 (d, J = 2.3 Hz, 1H), 6.87 (d, J = 2.3 Hz, 1H), 2.49 (s, 3H).

[0903] ESI-MS: 168.2 [M+H] + 。

[0904] (2) Synthesis of N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(7-methylfuro[3,2-c]pyridin-4-yl)benzamide

[129]

[0905] To a solution of compound [129-1] (37 mg) in ethanol (1.0 mL) / water (1.0 mL) at room temperature, compound [2-1] (78 mg), potassium carbonate (36 mg), and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (6.5 mg) were added, and the mixture was stirred at 80 °C for 1 hour under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (48 mg) as a white solid.

[0906] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.42 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.05 (d, J = 8.7 Hz, 2H), 7.99 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 2.3 Hz, 1H), 4.04 (s, 1H), 3.82 - 3.59 (m, 1H), 2.51 (s, 3H), 2.01 - 1.64 (m, 4H), 1.45 - 1.25 (m, 2H), 1.25 - 0.93 (m, 9H).

[0907] ESI-MS: 393.4 [M + H] + 。

[0908] Example 130

[0909] Synthesis of N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(3-methylfuro[3,2-c]pyridin-4-yl)benzamide

[130] (hereinafter referred to as compound

[130] )

[0910]

[0911] (1) Synthesis of 4-chloro-3-methylfuro[3,2-c]pyridine [130-1] (hereinafter referred to as compound [130-1])

[0912]

[0913] To a solution of 3-bromo-4-chlorofuro[3,2-c]pyridine (41.6 mg) in 1,4-dioxane (3.6 mL) at room temperature, cesium carbonate (70.0 mg), PdCl2(dppf)·CH2Cl2 (14.6 mg) and 2,4,6-trimethylcyclotriboroxane (30.0 μL) were added. Under an argon atmosphere, the mixture was stirred at 100 °C for 2 h. PdCl2(dppf)·CH2Cl2 (7.3 mg) and 2,4,6-trimethylcyclotriboroxane (30.0 μL) were added at room temperature, and the mixture was stirred at 100 °C for 4 h under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (14.1 mg) as a yellow solid.

[0914] ESI-MS: 168.2 [M+H] + 。

[0915] (2) Synthesis of N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(3-methylfuro[3,2-c]pyridin-4-yl)benzamide

[130]

[0916] To a solution of compound [130-1] (20 mg) in ethanol (0.60 mL) / water (0.60 mL) at room temperature, compound [2-1] (45 mg), potassium carbonate (21 mg) and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (4.9 mg) were added. Under an argon atmosphere, the mixture was stirred at 80 °C for 1 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (18 mg) as a white solid.

[0917] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.51 (d, J = 5.5 Hz, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.03 - 7.91 (m, 3H), 7.75 - 7.60 (m, 3H), 4.02 (s, 1H), 3.80 - 3.66 (m, 1H), 1.96 - 1.76 (m, 7H), 1.41 - 1.25 (m, 2H), 1.24 - 0.96 (m, 9H).

[0918] ESI-MS: 393.5 [M+H] + 。

[0919] Example 131

[0920] Synthesis of 3-chloro-4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[131] (hereinafter referred to as Compound

[131] )

[0921]

[0922] (1) Synthesis of methyl 3-chloro-4-(furo[3,2-c]pyridin-4-yl)benzoate [131-1] (hereinafter referred to as Compound [131-1])

[0923]

[0924] To a solution of 4-chlorofuro[3,2-c]pyridine (154 mg) in 1,4-dioxane (4.0 mL) / water (1.0 mL) at room temperature, 2-chloro-4-(methoxycarbonyl)phenylboronic acid (279 mg), tripotassium phosphate (425 mg) and PdCl2(dppf) (73.2 mg) were added, and the mixture was stirred at 100 °C for 30 minutes under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography to obtain the title compound (103 mg) as a white solid.

[0925] ESI-MS: 288.2 [M+H] + 。

[0926] (2) Synthesis of 3-chloro-4-(furo[3,2-c]pyridin-4-yl)benzoic acid [131-2] (hereinafter referred to as Compound [131-2])

[0927]

[0928] To a solution of Compound [131-1] (31 mg) in methanol (2.2 mL) at room temperature, 2M aqueous sodium hydroxide solution (1.1 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and 1M hydrochloric acid was added. The resulting solid was filtered, washed with water, and dried under reduced pressure to obtain the title compound (28 mg) as a white solid.

[0929] ESI-MS: 274.2 [M+H] + 。

[0930] (3) Synthesis of 3-chloro-4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[131]

[0931] To a solution of compound [131-2] (28 mg) in DMF (1.0 mL) at room temperature, DIPEA (19 μL) and (1-cyano-2-ethoxy-2-oxoethylaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (47 mg) were added, and the mixture was stirred at room temperature for 5 minutes. 2-(trans-4-Aminocyclohexyl)propan-2-ol (21 mg) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (31 mg) as a white solid.

[0932] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.58 (d, J = 5.9 Hz, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.16 (d, J = 2.3 Hz, 1H), 8.08 (d, J = 1.8 Hz, 1H), 7.95 (dd, J = 7.8, 1.8 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.63 (d, J = 7.8 Hz, 1H), 6.85 - 6.79 (m, 1H), 4.04 (s, 1H), 3.79 - 3.66 (m, 1H), 2.03 - 1.74 (m, 4H), 1.39 - 1.25 (m, 2H), 1.24 - 0.94 (m, 9H).

[0933] ESI-MS: 413.4 [M + H] + 。

[0934] Example 132

[0935] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-3-methylbenzamide

[132] (hereinafter referred to as compound

[132] )

[0936]

[0937] (1) Synthesis of methyl 4-(furo[3,2-c]pyridin-4-yl)-3-methylbenzoate [132-1] (hereinafter referred to as compound [132-1])

[0938]

[0939] To a solution of 4-chlorofuro[3,2-c]pyridine (154 mg) in methanol (2.5 mL) / water (2.5 mL) at room temperature, methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (359 mg), potassium carbonate (180 mg), and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (26.0 mg) were added, and the mixture was stirred at 80 °C for 1 h under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (272 mg) as a yellow solid.

[0940] ESI-MS: 268.1 [M+H] + 。

[0941] (2) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-3-methylbenzamide

[132]

[0942] The title compound was synthesized from compound [132-1] according to the methods of steps (2) and (3) of Example 131.

[0943] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.55 (d, J = 5.5 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 2.3 Hz, 1H), 7.84 (s, 1H), 7.78 (dd, J = 7.8, 1.4 Hz, 1H), 7.71 (dd, J = 5.9, 0.9 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 6.83 - 6.77 (m, 1H), 4.04 (s, 1H), 3.79 - 3.65 (m, 1H), 2.27 (s, 3H), 1.96 - 1.77 (m, 4H), 1.40 - 1.24 (m, 2H), 1.23 - 0.97 (m, 9H).

[0944] ESI-MS: 393.4 [M+H] + 。

[0945] Example 133

[0946] Synthesis of 3-cyano-4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[133] (hereinafter referred to as compound

[133] )

[0947]

[0948] (1) Synthesis of methyl 3-cyano-4-(furo[3,2-c]pyridin-4-yl)benzoate [133-1] (hereinafter referred to as compound [133-1])

[0949]

[0950] To a solution of 4-chlorofuro[3,2-c]pyridine (41 mg) in 1,2-dimethoxyethane (2.6 mL) at room temperature, methyl 3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (83 mg), cesium fluoride (88 mg) and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (9.3 mg) were added, and the mixture was stirred at 100 °C for 1 hour under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (34 mg) as a yellowish-white solid.

[0951] ESI-MS: 279.3 [M+H] + .

[0952] (2) Synthesis of 3-cyano-4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[133]

[0953] The title compound was synthesized from compound [133-1] according to the methods of steps (2) and (3) of Example 131.

[0954] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.64 (d, J = 5.5 Hz, 1H), 8.54 (d, J = 7.8 Hz, 1H), 8.47 (d, J = 1.8 Hz, 1H), 8.32 - 8.22 (m, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 5.5 Hz, 1H), 7.14 (d, J = 1.8 Hz, 1H), 4.05 (s, 1H), 3.80 - 3.66 (m, 1H), 2.03 - 1.76 (m, 4H), 1.39 - 1.25 (m, 2H), 1.24 - 0.93 (m, 9H).

[0955] ESI-MS: 404.4 [M+H] + .

[0956] Example 134

[0957] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-3-hydroxy-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[134] (hereinafter referred to as Compound

[134] )

[0958]

[0959] (1) Synthesis of methyl 4-(furo[3,2-c]pyridin-4-yl)-3-methoxybenzoate [134-1] (hereinafter referred to as Compound [134-1])

[0960]

[0961] To a solution of 4-chlorofuro[3,2-c]pyridine (76.8 mg) in methanol (1.25 mL) / water (1.25 mL) at room temperature, 2-methoxy-4-(methoxycarbonyl)phenylboronic acid (137 mg), potassium carbonate (89.8 mg) and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (13.0 mg) were added, and the mixture was stirred at 80 °C for 30 minutes under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (117 mg) as a yellowish-white solid.

[0962] ESI-MS: 284.3 [M+H] + 。

[0963] (2) Synthesis of methyl 4-(furo[3,2-c]pyridin-4-yl)-3-hydroxybenzoate [134-2] (hereinafter referred to as Compound [134-2])

[0964]

[0965] Under an argon atmosphere, to a solution of Compound [134-1] (56 mg) in dichloromethane (1.0 mL) at 0 °C, a 1 M solution of boron tribromide in dichloromethane (989 μL) was added, and the mixture was stirred at 0 °C for 3 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (10 mg) as a yellow solid.

[0966] ESI-MS: 270.3 [M+H] + 。

[0967] Synthesis of 4-(Furo[3,2-c]pyridin-4-yl)-3-hydroxy-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[134]

[0968] The title compound was synthesized from compound [134-2] according to the methods of steps (2) and (3) of Example 131.

[0969] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.57 (d, J = 5.9 Hz, 1H), 8.33 (d, J = 2.3 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.86 - 7.80 (m, 1H), 7.64 - 7.55 (m, 1H), 7.49 - 7.40 (m, 2H), 4.03 (s, 1H), 3.77 - 3.62 (m, 1H), 1.94 - 1.76 (m, 4H), 1.39 - 0.98 (m, 11H).

[0970] ESI-MS: 395.4 [M + H] + .

[0971] Example 135

[0972] Synthesis of 4-[7-(Hydroxymethyl)furo[3,2-c]pyridin-4-yl]-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[135] (hereinafter referred to as compound

[135] )

[0973]

[0974] (1) Synthesis of 4-Chlorofuro[3,2-c]pyridine-7-carbaldehyde [135-1] (hereinafter referred to as compound [135-1])

[0975]

[0976] Under an argon atmosphere, a solution of 7-bromo-4-chlorofuro[3,2-c]pyridine (233 mg) in THF (5.0 mL) was added to a THF solution (1.15 mL) of 1.3 M isopropylmagnesium chloride-lithium chloride complex at room temperature, and the mixture was stirred at room temperature for 20 minutes. Then, N-formylpiperidine (222 μL) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. After adding 1 M hydrochloric acid to the reaction mixture, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (155 mg) as a white solid.

[0977] 1 1H-NMR (400 MHz, CDCl3) δ: 10.40 (s, 1H), 8.75 (s, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.01 (d, J = 1.8 Hz, 1H).

[0978] ESI-MS: 182.2 [M+H] + 。

[0979] (2) Synthesis of 4-(7-formylfuro[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide [135-2] (hereinafter referred to as compound [135-2])

[0980]

[0981] To a solution of compound [135-1] (72.6 mg) in 1,4-dioxane (3.2 mL) / water (0.8 mL) at room temperature were added compound [2-1] (155 mg), tripotassium phosphate (170 mg), and PdCl2(dppf)·CH2Cl2(16.3 mg). The mixture was stirred at 100 °C for 15 minutes under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (139 mg) as a white solid.

[0982] 1 1H-NMR (400 MHz, DMSO-d6) δ: 10.37 (s, 1H), 9.08 (s, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.16 (d, J = 8.7 Hz, 2H), 8.04 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 2.3 Hz, 1H), 4.04 (s, 1H), 3.80 - 3.66 (m, 1H), 1.97 - 1.71 (m, 4H), 1.42 - 1.26 (m, 2H), 1.24 - 0.94 (m, 9H).

[0983] ESI-MS: 407.4 [M+H] + 。

[0984] (3) Synthesis of 4-[7-(hydroxymethyl)furo[3,2-c]pyridin-4-yl]-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[135]

[0985] To a solution of compound [135-2] (20 mg) in methanol (1.0 mL) at room temperature, sodium borohydride (5.7 mg) was added, and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (17 mg) as a white solid.

[0986] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.55 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.07 (d, J = 8.7 Hz, 2H), 8.00 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 2.3 Hz, 1H), 5.46 (br, 1H), 4.86 (d, J = 3.7 Hz, 2H), 4.04 (s, 1H), 3.79 - 3.65 (m, 1H), 1.96 - 1.75 (m, 4H), 1.43 - 1.24 (m, 2H), 1.24 - 0.96 (m, 9H).

[0987] ESI-MS: 409.4 [M + H] + 。

[0988] Example 136

[0989] Synthesis of 4-(7-fluorofuro[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[136] (hereinafter referred to as compound

[136] )

[0990]

[0991] (1) Synthesis of 4-chloro-7-fluorofuro[3,2-c]pyridine [136-1] (hereinafter referred to as compound [136-1])

[0992]

[0993] Under an argon atmosphere, to a solution of 7-bromo-4-chlorofuro[3,2-c]pyridine (47 mg) in THF (0.50 mL) at 0 °C was added a THF solution (0.23 mL) of 1.3 M isopropylmagnesium chloride-lithium chloride complex. The mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure, dichloromethane (0.50 mL) was added at room temperature, and the mixture was cooled to 0 °C. Then, a solution of N-fluorobenzenesulfonimide (95 mg) in dichloromethane (0.50 mL) was added at 0 °C, and the mixture was stirred at room temperature for 2 hours. Chloroform was added to the reaction mixture, and the mixture was purified by silica gel column chromatography to obtain the title compound (5.7 mg) as a white solid.

[0994] 1 1H-NMR (400 MHz, CDCl3) δ: 8.18 (d, J = 2.3 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 6.94 (dd, J = 2.5, 2.5 Hz, 1H).

[0995] (2) Synthesis of 4-(7-fluorofuro[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide [

[136] ]

[0996] To a solution of compound [136-1] (5.5 mg) in ethanol (0.50 mL) / water (0.50 mL) at room temperature were added compound [2-1] (12 mg), potassium carbonate (5.8 mg), and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (1.0 mg). The mixture was stirred at 80 °C for 1 hour under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7.4 mg) as a white solid.

[0997] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.64 (d, J = 1.8 Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.09 - 7.95 (m, 4H), 7.47 (dd, J = 2.5, 2.5 Hz, 1H), 4.04 (s, 1H), 3.79 - 3.66 (m, 1H), 1.96 - 1.76 (m, 4H), 1.43 - 1.25 (m, 2H), 1.24 - 0.92 (m, 9H).

[0998] ESI-MS: 397.4 [M + H] + 。

[0999] Example 137

[1000] Synthesis of N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(7-vinylfuro[3,2-c]pyridin-4-yl)benzamide

[137] (hereinafter referred to as Compound

[137] )

[1001]

[1002] To a solution of methyltriphenylphosphonium bromide (237 mg) in THF (2.7 mL) at room temperature was added potassium tert-butoxide (74.5 mg), and the mixture was stirred at room temperature for 5 minutes. Then, a solution of Compound [135-2] (54.0 mg) in THF (1.8 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (29.1 mg) as a white solid.

[1003] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.65 (s, 1H), 8.36 - 8.27 (m, 2H), 8.08 (d, J = 8.7 Hz, 2H), 8.00 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 2.3 Hz, 1H), 7.00 (dd, J = 17.8, 11.9 Hz, 1H), 6.38 (dd, J = 17.8, 0.9 Hz, 1H), 5.70 (dd, J = 11.4, 0.9 Hz, 1H), 4.04 (s, 1H), 3.79 - 3.66 (m, 1H), 1.95 - 1.76 (m, 4H), 1.39 - 1.26 (m, 2H), 1.23 - 0.99 (m, 9H).

[1004] ESI-MS: 405.3 [M + H] + .

[1005] Example 138

[1006] Synthesis of 4-(7-ethylfuro[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[138] (hereinafter referred to as Compound

[138] )

[1007]

[1008] To a solution of compound

[137] (15 mg) in methanol (1.0 mL) at room temperature was added 5% palladium-on-carbon (15 mg), and the mixture was stirred for 1 hour at room temperature under a hydrogen atmosphere. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography to give the title compound (7.2 mg) as a white solid.

[1009] 1 H-NMR (400 MHz, DMSO-d6) δ: 8.44 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 2.3 Hz, 1H), 4.04 (s, 1H), 3.83 - 3.65 (m, 1H), 2.94 (q, J = 7.6 Hz, 2H), 1.96 - 1.76 (m, 4H), 1.42 - 1.25 (m, 5H), 1.24 - 0.90 (m, 9H).

[1010] ESI-MS: 407.4 [M + H] + 。

[1011] Example 139

[1012] Synthesis of 4-(7-cyanofuro[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[139] (hereinafter referred to as compound

[139] )

[1013]

[1014] (1) Synthesis of 4-chlorofuro[3,2-c]pyridine-7-carbonitrile [139-1] (hereinafter referred to as compound [139-1])

[1015]

[1016] To a solution of [135-1] (54.5 mg) in DMF (1.0 mL) at room temperature were added hydroxylamine hydrochloride (31.3 mg) and triethylamine (62.7 μL), and the mixture was stirred for 5 minutes at room temperature. Then, a 1.7 M solution of propylphosphonic anhydride in ethyl acetate (265 μL) was added at room temperature, and the mixture was stirred at 100 °C for 7 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (45.9 mg) as a white solid.

[1017] ESI-MS: 179.2 [M+H] + 。

[1018] (2) Synthesis of 4-(7-cyanofuro[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[139]

[1019] To a solution of compound [139-1] (44.6 mg) in ethanol (1.25 mL) / water (1.25 mL) at room temperature, compound [2-1] (96.8 mg), potassium carbonate (44.9 mg) and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (8.1 mg) were added, and the mixture was stirred at 80 °C for 2 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (60.4 mg) as a white solid.

[1020] ESI-MS: 404.3 [M+H] + 。

[1021] Example 140

[1022] Synthesis of 4-(4-{[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]carbamoyl}phenyl)furo[3,2-c]pyridine-7-carboxamide

[140] (hereinafter referred to as compound

[140] )

[1023]

[1024] To a solution of compound

[139] (19.6 mg) in tert-butanol (972 μL) at room temperature, potassium tert-butoxide (81.8 mg) was added, and the mixture was stirred at 40 °C for 4 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, ethanol and water were added to the resulting residue. The solid was filtered, washed with water, and dried under reduced pressure to give the title compound (17.1 mg) as a white solid.

[1025] ESI-MS: 422.3 [M+H] + 。

[1026] Example 141

[1027] Synthesis of 4-[7-(1-hydroxyethyl)furo[3,2-c]pyridin-4-yl]-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[141] (hereinafter referred to as compound

[141] )

[1028]

[1029] (1) Synthesis of 1-(4-chlorofuro[3,2-c]pyridin-7-yl)ethan-1-ol [141-1] (hereinafter referred to as compound [141-1])

[1030]

[1031] Under an argon atmosphere, a solution of compound [135-1] (10.7 mg) in THF (1.2 mL) was cooled to 0 °C, and a THF solution of 3 M methylmagnesium chloride (39 μL) was added. The mixture was stirred at 0 °C for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound as a colorless oil (9.4 mg).

[1032] ESI-MS: 198.2 [M+H] + 。

[1033] (2) Synthesis of 4-[7-(1-hydroxyethyl)furo[3,2-c]pyridin-4-yl]-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide

[141]

[1034] To a solution of compound [141-1] (9.4 mg) in ethanol (0.48 mL) / water (0.48 mL) at room temperature were added compound [2-1] (18 mg), potassium carbonate (8.6 mg), and [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro[3-phenylallyl]palladium(II) (1.6 mg). The mixture was stirred under an argon atmosphere at 80 °C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound as a white solid (16 mg).

[1035] 11H-NMR (400 MHz, DMSO-d6) δ: 8.59 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.05 (d, J = 8.7 Hz, 2H), 7.99 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 2.3 Hz, 1H), 5.54 (d, J = 4.6 Hz, 1H), 5.31 - 5.19 (m, 1H), 4.03 (s, 1H), 3.80 - 3.65 (m, 1H), 1.96 - 1.77 (m, 4H), 1.54 (d, J = 6.4 Hz, 3H), 1.40 - 1.25 (m, 2H), 1.24 - 0.92 (m, 9H).

[1036] ESI-MS: 423.3 [M + H] + 。

[1037] Example 142

[1038] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-(piperidin-4-yl)benzamide

[142] (hereinafter referred to as Compound

[142] )

[1039]

[1040] To a solution of Compound [99-1] (500 mg) in DMF (7.00 mL) at room temperature were added DIPEA (392 μL), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (986 mg), and tert-butyl 4-aminopiperidine-1-carboxylate (461 mg), and the mixture was stirred at room temperature for 16 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the resulting residue in dichloromethane (20.0 mL) at room temperature was added trifluoroacetic acid (14.0 mL), and the mixture was stirred at room temperature for 30 minutes. 5M aqueous sodium hydroxide was added to the reaction mixture at 0 °C, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (420 mg) as a white solid.

[1041] 11H-NMR (400 MHz, DMSO-d6) δ: 8.59 (dd, J = 5.7, 2.1 Hz, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.24 - 8.23 (m, 1H), 8.12 - 8.05 (m, 2H), 8.04 - 7.98 (m, 2H), 7.72 (d, J = 5.9 Hz, 1H), 7.37 - 7.35 (m, 1H), 3.88 - 3.80 (m, 1H), 3.31 - 3.30 (m, 2H), 2.97 - 2.94 (m, 2H), 1.76 - 1.72 (m, 2H), 2.05 (br, 1H), 1.47 - 1.39 (m, 2H).

[1042] ESI-MS: 322.4 [M + H] + 。

[1043] Example 143

[1044] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(pyrimidin-2-yl)piperidin-4-yl]benzamide

[143] (hereinafter referred to as Compound

[143] )

[1045]

[1046] To a solution of Compound

[142] (20.0 mg) in NMP (300 μL) at room temperature, potassium carbonate (77.0 mg) and 2-chloropyrimidine (32.0 mg) were added, and the mixture was stirred at 140 °C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (14.0 mg) as a white solid.

[1047] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.58 (d, J = 5.5 Hz, 1H), 8.41 (d, J = 7.3 Hz, 1H), 8.36 (d, J = 5.0 Hz, 2H), 8.24 (d, J = 2.3 Hz, 1H), 8.09 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 8.2 Hz, 2H), 7.72 (dd, J = 5.5, 0.9 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 6.61 (t, J = 4.8 Hz, 1H), 4.67 - 4.64 (m, 2H), 4.19 - 4.11 (m, 1H), 3.06 - 3.00 (m, 2H), 1.91 - 1.87 (m, 2H), 1.55 - 1.46 (m, 2H).

[1048] ESI-MS: 400.4 [M+H] + 。

[1049] Examples 144 to 170

[1050] Based on the method shown in Example 143, the compounds of Examples 144 to 170 shown in the following table were synthesized. The structures, names, and ESI-MS of the compounds of each example are shown in the following table.

[1051] [Table 4-1]

[1052]

[1053] [Table 4-2]

[1054]

[1055] [Table 4-3]

[1056]

[1057] [Table 4-4]

[1058]

[1059] [Table 4-5]

[1060]

[1061] [Table 4-6]

[1062]

[1063] Example 171

[1064] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(pyrimidin-4-yl)piperidin-4-yl]benzamide

[171] (hereinafter, referred to as Compound

[171] )

[1065]

[1066] To a solution of Compound

[146] (20 mg) in ethanol (0.50 mL) at room temperature was added 10% palladium on activated carbon (2.0 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 23 hours. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (2.1 mg) as a white solid.

[1067] ESI-MS: 400.5 [M+H] + 。

[1068] Example 172

[1069] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(6-oxo-1,6-dihydropyridin-2-yl)piperidin-4-yl]benzamide

[172] (hereinafter referred to as compound

[172] )

[1070]

[1071] To a solution of compound

[147] (10 mg) in 1,4-dioxane (0.20 mL) at room temperature was added 5 M hydrochloric acid (0.20 mL), and the mixture was stirred at room temperature for 23 hours. 5 M aqueous sodium hydroxide was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (2.1 mg) as a white solid.

[1072] 1 1H-NMR (400 MHz, CD3OD) δ: 8.53 (d, J = 5.5 Hz, 1H), 8.01 - 7.99 (m, 5H), 7.63 (d, J = 5.9 Hz, 1H), 7.44 (t, J = 8.2 Hz, 1H), 7.19 - 7.18 (m, 1H), 5.90 - 5.88 (m, 2H), 4.18 - 4.14 (m, 1H), 3.92 - 3.89 (m, 2H), 3.06 - 3.01 (m, 2H), 2.18 - 2.06 (m, 2H), 1.79 - 1.74 (m, 2H).

[1073] ESI-MS: 415.4 [M + H] + .

[1074] Example 173

[1075] Synthesis of N-[1-(5-cyanopyrimidin-2-yl)piperidin-4-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide

[173] (hereinafter referred to as compound

[173] )

[1076]

[1077] To a solution of compound

[154] (13.4 mg) in DMF (0.60 mL) at room temperature were added zinc cyanide (6.6 mg) and Pd(PPh3)4 (6.5 mg). Under an argon atmosphere, using a microwave reaction apparatus, the mixture was stirred at 120 °C for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (5.6 mg) as a white solid.

[1078] ESI-MS: 425.4 [M+H] + 。

[1079] Example 174

[1080] Synthesis of 2-{4-[4-(Furo[3,2-c]pyridin-4-yl)benzamido]piperidin-1-yl}pyrimidine-5-carboxamide

[174] (hereinafter referred to as Compound

[174] )

[1081]

[1082] To a solution of Compound

[173] (14.6 mg) in tert-butanol (0.60 mL) at room temperature was added potassium tert-butoxide (93.0 mg), and the mixture was stirred at 80 °C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (5.5 mg) as a white solid.

[1083] ESI-MS: 443.4 [M+H] + 。

[1084] Example 175

[1085] Synthesis of 2-{4-[4-(Furo[3,2-c]pyridin-4-yl)benzamido]piperidin-1-yl}pyrimidine-4-carboxamide

[175] (hereinafter referred to as Compound

[175] )

[1086]

[1087] To a solution of Compound

[164] (10.6 mg) in tert-butanol (0.50 mL) at room temperature was added potassium tert-butoxide (67.0 mg), and the mixture was stirred at 80 °C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (3.8 mg) as a white solid.

[1088] ESI-MS: 443.4 [M+H] + 。

[1089] Example 176

[1090] Synthesis of 4-{4-[4-(Furo[3,2-c]pyridin-4-yl)benzamido]piperidin-1-yl}pyridinecarboxamide

[176] (hereinafter referred to as Compound

[176] )

[1091]

[1092] To a solution of compound

[166] (7.8 mg) in tert-butanol (0.40 mL) at room temperature, potassium tert-butoxide (50 mg) was added, and the mixture was stirred at 80 °C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (5.4 mg) as a white solid.

[1093] ESI-MS: 442.4 [M+H] + 。

[1094] Example 177

[1095] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(5-sulfamoylpyrimidin-2-yl)piperidin-4-yl]benzamide

[177] (hereinafter referred to as compound

[177] )

[1096]

[1097] (1) Synthesis of N-(1-{5-[N-(tert-butyl)sulfamoyl]pyrimidin-2-yl}piperidin-4-yl)-4-(furo[3,2-c]pyridin-4-yl)benzamide [177-1] (hereinafter referred to as compound [177-1])

[1098]

[1099] To a solution of 2-chloropyrimidine-5-sulfonyl chloride (100 mg) in THF (1.50 mL) at 0 °C, tert-butylamine (60.0 μL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To a solution of the resulting residue in DMSO (150 μL) at room temperature, potassium carbonate (10.0 mg) and compound

[142] (10.0 mg) were added, and the mixture was stirred at 140 °C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (9.6 mg) as a white solid.

[1100] ESI-MS: 535.3 [M+H] + 。

[1101] (2) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(5-sulfamoylpyrimidin-2-yl)piperidin-4-yl]benzamide

[177]

[1102] To a solution of compound [177-1] (9.60 mg) in ethyl acetate (200 μL) at room temperature, trifluoroacetic acid (200 μL) was added, and the mixture was stirred at 80 °C for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (0.73 mg) as a white solid.

[1103] ESI-MS: 479.4 [M + H] + 。

[1104] Example 178

[1105] Synthesis of N-{1-[4-(azetidin-1-yl)pyrimidin-2-yl]piperidin-4-yl}-4-(furo[3,2-c]pyridin-4-yl)benzamide

[178] (hereinafter referred to as compound

[178] )

[1106]

[1107] (1) Synthesis of 4-(azetidin-1-yl)-2-chloropyrimidine [178-1] (hereinafter referred to as compound [178-1])

[1108]

[1109] To a solution of 2,4-dichloropyrimidine (100 mg) in THF (1.00 mL) at room temperature, cesium carbonate (437 mg) and azetidine hydrochloride (69.0 mg) were added, and the mixture was stirred at 60 °C for 19 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (15.5 mg) as a white solid.

[1110] ESI-MS: 170.2 [M + H] + 。

[1111] (2) Synthesis of N-{1-[4-(azetidin-1-yl)pyrimidin-2-yl]piperidin-4-yl}-4-(furo[3,2-c]pyridin-4-yl)benzamide

[178]

[1112] To a solution of compound

[142] (27.0 mg) in NMP (300 μL) at room temperature, cesium carbonate (59.0 mg) and compound [178-1] (15.5 mg) were added, and the mixture was stirred at 140 °C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (12.2 mg) as a yellow solid.

[1113] ESI-MS: 455.4 [M + H] + 。

[1114] Example 179

[1115] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl]benzamide

[179] (hereinafter referred to as compound

[179] )

[1116]

[1117] (1) Synthesis of 2-chloropyrimidin-4(3H)-one [179-1] (hereinafter referred to as compound [179-1])

[1118]

[1119] To 2,4-dichloropyrimidine (1.00 g) at room temperature, 5 M aqueous sodium hydroxide solution (2.68 mL) was added, and the mixture was stirred at 80 °C for 4 hours. 5 M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (780 mg) as a yellow solid.

[1120] ESI-MS: 131.1 [M + H] + 。

[1121] (2) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl]benzamide

[179]

[1122] To a solution of compound

[142] (20 mg) in NMP (0.30 mL) at room temperature, potassium carbonate (56 mg) and compound [179-1] (23 mg) were added, and the mixture was stirred at 140 °C for 17 hours. 1 M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (7.5 mg) as a yellow solid.

[1123] ESI-MS: 416.4 [M+H] + 。

[1124] Example 180

[1125] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]benzamide

[180] (hereinafter referred to as Compound

[180] )

[1126]

[1127] To a solution of Compound

[142] (10 mg) in 1,4-dioxane (0.30 mL) at room temperature were added DIPEA (16 μL) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (5.4 μL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (8.5 mg) as a white solid.

[1128] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.59 (d, J = 5.5 Hz, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.14 - 8.06 (m, 2H), 8.01 (dd, J = 6.6, 2.1 Hz, 2H), 7.72 (dd, J = 5.5, 0.9 Hz, 1H), 7.37 - 7.36 (m, 1H), 3.84 - 3.77 (m, 1H), 3.17 (q, J = 10.2 Hz, 2H), 2.96 - 2.93 (m, 2H), 2.47 - 2.39 (m, 2H), 1.84 - 1.78 (m, 2H), 1.66 - 1.56 (m, 2H).

[1129] ESI-MS: 404.4 [M+H] + 。

[1130] Example 181

[1131] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl]benzamide

[181] (hereinafter referred to as Compound

[181] )

[1132]

[1133] (1) Synthesis of 2-chloro-6-methylpyrimidin-4(3H)-one trifluoroacetate [181-1] (hereinafter referred to as Compound [181-1])

[1134]

[1135] To 2,4-dichloro-6-methylpyrimidine (155 mg) at room temperature was added 5 M aqueous sodium hydroxide solution (536 μL), and the mixture was stirred at 80 °C for 4 h. The reaction mixture was purified by reverse-phase silica gel column chromatography to give the title compound as a yellow solid (89.3 mg).

[1136] ESI-MS: 145.3 [M+H] + 。

[1137] (2) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl]benzamide

[181]

[1138] To a solution of compound

[142] (20 mg) in NMP (0.3 mL) at room temperature was added potassium carbonate (25 mg) and compound [181-1] (18 mg), and the mixture was stirred at 140 °C for 4 h. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound as a white solid (7.8 mg).

[1139] ESI-MS: 430.4 [M+H] + 。

[1140] Example 182

[1141] Synthesis of N-[1-(5-bromo-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide

[182] (hereinafter referred to as compound

[182] )

[1142]

[1143] (1) Synthesis of 5-bromo-2-chloropyrimidin-4(3H)-one [182-1] (hereinafter referred to as compound [182-1])

[1144]

[1145] To 5-bromo-2,4-dichloropyrimidine (5.0 g) at room temperature was added 5 M aqueous sodium hydroxide solution (8.8 mL), and the mixture was stirred at 80 °C for 3 h. 1 M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was suspended in chloroform / n-hexane, and the solid was filtered off to give the title compound as a yellow solid (2.2 g).

[1146] ESI-MS: 209.1 [M+H] + 。

[1147] (2)Synthesis of N-[1-(5-bromo-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide

[182]

[1148] At room temperature, potassium carbonate (25 mg) and compound [182-1] (18 mg) were added to a solution of compound

[142] (20 mg) in NMP (0.30 mL), and the mixture was stirred at 140 °C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7.8 mg) as a white solid.

[1149] ESI-MS: 494.4 [M+H] + 。

[1150] Example 183

[1151] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl]benzamide

[183] (hereinafter referred to as compound

[183] )

[1152]

[1153] (1)Synthesis of 2-chloro-3-methylpyrimidin-4(3H)-one [183-1] (hereinafter referred to as compound [183-1])

[1154]

[1155] To a solution of compound [179-1] (680 mg) in 1,4-dioxane (11.0 mL) at room temperature, potassium tert-butoxide (1.14 g) was added, and the mixture was stirred at room temperature for 10 minutes. Methyl iodide (2.06 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at 80 °C for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (32.0 mg) as a white solid.

[1156] 1 1H-NMR (400 MHz, CDCl3) δ: 7.69 (d, J = 6.9 Hz, 1H), 6.37 (d, J = 6.4 Hz, 1H), 3.64 (s, 3H).

[1157] (2) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl]benzamide

[183]

[1158] To a solution of compound

[142] (59 mg) in NMP (0.6 mL) at room temperature, potassium carbonate (76 mg) and compound [183-1] (32 mg) were added, and the mixture was stirred at 120 °C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (62 mg) as a yellow solid.

[1159] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.59 (d, J = 5.9 Hz, 1H), 8.50 (d, J = 7.3 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 8.7 Hz, 2H), 8.04 (d, J = 8.7 Hz, 2H), 7.73 (d, J = 6.4 Hz, 2H), 7.37 - 7.36 (m, 1H), 6.00 (d, J = 6.4 Hz, 1H), 4.15 - 3.99 (m, 1H), 3.61 - 3.58 (m, 2H), 3.37 (s, 3H), 2.99 - 2.93 (m, 2H), 1.93 - 1.91 (m, 2H), 1.79 - 1.70 (m, 2H).

[1160] ESI-MS: 430.4 [M + H] + 。

[1161] Example 184

[1162] 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)piperidin-4-yl]benzamide

[1163] Synthesis of

[184] (hereinafter referred to as compound

[184] )

[1164]

[1165] To a solution of 2,6-difluoropyridine (1.00 g) in tert-butanol (29.0 mL) at room temperature was added potassium tert-butoxide (2.90 g), and the mixture was stirred at room temperature for 2 hours. Formic acid (992 μL) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product (340 mg). To a solution of the obtained crude product (100 mg) in 1,4-dioxane (3.00 mL) at room temperature was added potassium tert-butoxide (300 mg), and the mixture was stirred at room temperature for 20 minutes. Iodomethane (550 μL) was added to the reaction mixture at room temperature, and the mixture was stirred at 80 °C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the obtained residue in NMP (0.30 mL) at room temperature were added potassium carbonate (25.0 mg) and compound

[142] (20.0 mg), and the mixture was stirred at 120 °C for 3 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (3.2 mg) as a brown solid.

[1166] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.59 (d, J = 5.3 Hz, 1H), 8.51 (d, J = 7.8 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.15 - 8.08 (m, 2H), 8.04 (dd, J = 6.4, 1.8 Hz, 2H), 7.73 (dd, J = 5.9, 0.9 Hz, 1H), 7.42 - 7.30 (m, 2H), 6.09 (dd, J = 9.1, 0.9 Hz, 1H), 5.86 (dd, J = 7.3, 0.9 Hz, 1H), 4.04 - 4.00 (m, 1H), 3.40 (s, 3H), 3.21 - 3.19 (m, 2H), 2.78 - 2.72 (m, 2H), 1.98 - 1.94 (m, 2H), 1.85 - 1.68 (m, 2H).

[1167] ESI-MS: 429.4 [M + H] + 。

[1168] Example 185

[1169] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{1-[5-(2-hydroxypropan-2-yl)pyrimidin-2-yl]piperidin-4-yl}benzamide

[185] (hereinafter referred to as compound

[185] )

[1170]

[1171] Synthesis of 2-(2-chloropyrimidin-5-yl)propan-2-ol [185-1] (hereinafter referred to as compound [185-1])

[1172]

[1173] To a solution of ethyl 2-chloropyrimidine-5-carboxylate (100 mg) in THF (1.78 mL) at 0 °C, a diethyl ether solution of 3M methylmagnesium bromide (533 μL) was added, and the mixture was stirred at 40 °C for 2 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (25.4 mg) as a white solid.

[1174] ESI-MS: 173.2 [M+H] + .

[1175] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{1-[5-(2-hydroxypropan-2-yl)pyrimidin-2-yl]piperidin-4-yl}benzamide

[185]

[1176] To a solution of compound

[142] (19 mg) in NMP (0.30 mL) at room temperature, potassium carbonate (25 mg) and compound [185-1] (10 mg) were added, and the mixture was stirred at 120 °C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (8.2 mg) as a white solid.

[1177] ESI-MS: 458.5 [M+H] + .

[1178] Example 186

[1179] Synthesis of N-(1-acetylpiperidin-4-yl)-4-(furo[3,2-c]pyridin-4-yl)benzamide

[186] (hereinafter referred to as compound

[186] )

[1180]

[1181] To a solution of compound

[142] (20 mg) in NMP (0.30 mL) at room temperature, cesium carbonate (60 mg) and acetyl chloride (3.9 μL) were added, and the mixture was stirred at 120 °C for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (10 mg) as a white solid.

[1182] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.59 (dd, J = 5.5, 1.4 Hz, 1H), 8.50 - 8.38 (m, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 6.9 Hz, 2H), 8.06 - 7.98 (m, 2H), 7.73 (d, J = 5.5 Hz, 1H), 7.37 - 7.35 (m, 1H), 4.34 - 4.31 (m, 1H), 4.20 - 3.97 (m, 1H), 3.84 - 3.80 (m, 1H), 3.16 - 3.09 (m, 1H), 2.80 - 2.61 (m, 1H), 2.02 (s, 3H), 1.85 - 1.80 (m, 2H), 1.58 - 1.32 (m, 2H).

[1183] ESI-MS: 364.3 [M + H] + 。

[1184] Example 187

[1185] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{1-[4-(hydroxymethyl)pyrimidin-2-yl]piperidin-4-yl}benzamide

[187] (hereinafter referred to as compound

[187] )

[1186]

[1187] To a solution of compound

[167] (15 mg) in THF (0.40 mL) at 0 °C, sodium borohydride (12 mg) was added, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (10 mg) as a white solid.

[1188] ESI-MS: 430.3 [M + H] + 。

[1189] Example 188

[1190] Synthesis of N-{1-[5-(N-acetylacetamide)pyrimidin-2-yl]piperidin-4-yl}-4-(furo[3,2-c]pyridin-4-yl)benzamide

[188] (hereinafter referred to as compound

[188] )

[1191]

[1192] (1) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(5-nitropyrimidin-2-yl)piperidin-4-yl]benzamide [188-1] (hereinafter referred to as compound [188-1])

[1193]

[1194] To a solution of compound

[142] (40.0 mg) in NMP (370 μL) at room temperature, potassium carbonate (77.0 mg) and 2-chloro-5-nitropyrimidine (27.0 mg) were added, and the mixture was stirred at 120 °C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (28.6 mg) as a yellow solid.

[1195] ESI-MS: 445.3 [M+H] + 。

[1196] (2) Synthesis of N-{1-[5-(N-acetylacetamide)pyrimidin-2-yl]piperidin-4-yl}-4-(furo[3,2-c]pyridin-4-yl)benzamide

[188]

[1197] To a solution of compound [188-1] (24 mg) in ethanol (0.40 mL) / water (0.40 mL) at room temperature, iron (15 mg) and ammonium chloride (29 mg) were added, and the mixture was stirred at 80 °C for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a crude product (51 mg). To a solution of the resulting crude product (20 mg) in dichloromethane (0.50 mL) at room temperature, triethylamine (20 μL) and acetyl chloride (17 μL) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2.1 mg) as a white solid.

[1198] ESI-MS: 499.3 [M+H] + 。

[1199] Example 189

[1200] Synthesis of N-[1-(5-acetamidopyrimidin-2-yl)piperidin-4-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide

[189] (hereinafter referred to as Compound

[189] )

[1201]

[1202] To a solution of Compound [188-1] (24 mg) in ethanol (0.40 mL) / water (0.40 mL) at room temperature, iron (15 mg) and ammonium chloride (29 mg) were added, and the mixture was stirred at 80 °C for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a crude product (51 mg). To a solution of the obtained crude product (30 mg) in dichloromethane (0.30 mL) at room temperature, triethylamine (30 μL) and acetyl chloride (6.7 μL) were added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (6.4 mg) as a white solid.

[1203] ESI-MS: 457.3 [M+H] + 。

[1204] Example 190

[1205] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(pyridazin-3-yl)piperidin-4-yl]benzamide

[190] (hereinafter referred to as Compound

[190] )

[1206]

[1207] To a solution of Compound [99-1] (20 mg) in dichloromethane (0.30 mL) at room temperature, 4-dimethylaminopyridine (11 mg), EDC (17 mg) and 1-(pyridazin-3-yl)piperidin-4-amine (16 mg) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (12 mg) as a yellow solid.

[1208] 11H-NMR (400 MHz, DMSO-d6) δ: 8.58 (d, J = 5.5 Hz, 1H), 8.53 - 8.52 (m, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.12 - 8.06 (m, 2H), 8.05 - 7.99 (m, 2H), 7.72 (dd, J = 5.5, 0.9 Hz, 1H), 7.38 - 7.29 (m, 3H), 4.42 - 4.39 (m, 2H), 4.18 - 4.15 (m, 1H), 3.09 - 3.04 (m, 2H), 1.92 - 1.90 (m, 2H), 1.64 - 1.55 (m, 2H).

[1209] ESI-MS: 400.4 [M + H] + 。

[1210] Example 191

[1211] Synthesis of (S)-4-(Furo[3,2-c]pyridin-4-yl)-N-[1-(pyrimidin-2-yl)pyrrolidin-3-yl]benzamide

[191] (hereinafter referred to as Compound

[191] )

[1212]

[1213] (1) Synthesis of tert-Butyl (S)-3-[4-(furo[3,2-c]pyridin-4-yl)benzamido]pyrrolidine-1-carboxylate [191-1] (hereinafter referred to as Compound [191-1])

[1214]

[1215] To a solution of Compound [99-1] (520 mg) in dichloromethane (4.00 mL) at room temperature were added 4-dimethylaminopyridine (279 mg), EDC (437 mg), and (S)-tert-3-aminopyrrolidine-1-carboxylate (432 μL), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (810 mg) as a yellow oil.

[1216] 1H-NMR (400 MHz, DMSO-d6) δ: 8.67 - 8.65 (m, 1H), 8.60 - 8.58 (m, 1H), 8.25 - 8.23 (m, 1H), 8.10 (d, J = 4.6 Hz, 2H), 8.04 - 8.02 (m, 2H), 7.74 - 7.72 (m, 1H), 7.37 - 7.35 (m, 1H), 4.48 - 4.42 (m, 1H), 3.57 - 3.42 (m, 3H), 3.23 - 3.20 (m, 1H), 2.15 - 2.07 (m, 1H), 1.97 - 1.91 (m, 1H), 1.40 (s, 9H).

[1217] ESI-MS: 408.4 [M + H] + 。

[1218] (2) Synthesis of (S)-4-(furo[3,2-c]pyridin-4-yl)-N-(pyrrolidin-3-yl)benzamide dihydrochloride [191-2] (hereinafter referred to as Compound [191-2])

[1219]

[1220] To a solution of Compound [191-1] (794 mg) in ethyl acetate (3.25 mL) at room temperature was added a 4 M solution of hydrogen chloride in ethyl acetate (3.25 mL), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (540 mg) as a white solid.

[1221] 1 H-NMR (400 MHz, DMSO-d6) δ: 9.19 (br, 2H), 8.91 - 8.86 (m, 1H), 8.66 - 8.64 (m, 1H), 8.39 - 8.28 (m, 1H), 8.19 - 8.04 (m, 4H), 7.98 - 7.79 (m, 1H), 7.38 - 7.37 (m, 1H), 4.56 - 4.55 (m, 1H), 3.40 - 3.21 (m, 4H), 2.23 - 2.15 (m, 1H), 2.05 - 1.99 (m, 1H).

[1222] ESI-MS: 308.3 [M + H] + 。

[1223] (3) Synthesis of (S)-4-(furo[3,2-c]pyridin-4-yl)-N-[1-(pyrimidin-2-yl)pyrrolidin-3-yl]benzamide

[191]

[1224] To a solution of compound [191-2] (20.0 mg) in NMP (300 μL) at room temperature, potassium carbonate (26.0 mg) and 2-chloropyrimidine (11.0 mg) were added, and the mixture was stirred at 140 °C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (9.6 mg) as a yellow solid.

[1225] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.76 (d, J = 6.9 Hz, 1H), 8.59 (d, J = 5.5 Hz, 1H), 8.34 (d, J = 4.6 Hz, 2H), 8.24 (d, J = 2.5 Hz, 1H), 8.11 - 8.08 (m, 2H), 8.05 - 8.03 (m, 2H), 7.73 - 7.72 (m, 1H), 7.36 - 7.35 (m, 1H), 6.61 - 6.59 (m, 1H), 4.63 - 4.59 (m, 1H), 3.83 - 3.53 (m, 4H), 2.29 - 2.22 (m, 1H), 2.29 - 2.04 (m, 1H).

[1226] ESI-MS: 386.4 [M + H] + 。

[1227] Example 192

[1228] Synthesis of (R)-4-(furo[3,2-c]pyridin-4-yl)-N-[1-(pyrimidin-2-yl)pyrrolidin-3-yl]benzamide

[192] (hereinafter referred to as compound

[192] )

[1229]

[1230] (1) Synthesis of tert-butyl (R)-3-[4-(furo[3,2-c]pyridin-4-yl)benzamide]pyrrolidine-1-carboxylate [192-1] (hereinafter referred to as compound [192-1])

[1231]

[1232] To a solution of compound [99-1] (100 mg) in dichloromethane (0.80 mL) at room temperature, 4-dimethylaminopyridine (54 mg), EDC (84 mg) and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (83 μL) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (160 mg) as a yellow oil.

[1233] ESI-MS: 408.4 [M+H] + 。

[1234] (2) Synthesis of (R)-4-(furo[3,2-c]pyridin-4-yl)-N-[1-(pyrimidin-2-yl)pyrrolidin-3-yl]benzamide

[192]

[1235] The title compound (4.2 mg) was synthesized as a yellow solid from compound [192-1] according to the methods of steps (2) and (3) of Example 191.

[1236] ESI-MS: 386.4 [M+H] + 。

[1237] Example 193

[1238] Synthesis of (S)-4-(furo[3,2-c]pyridin-4-yl)-N-{1-[5-(hydroxymethyl)pyrimidin-2-yl]pyrrolidin-3-yl}benzamide

[193] (hereinafter referred to as compound

[193] )

[1239]

[1240] To a solution of compound [191-2] (13.5 mg) in NMP (150 μL) at room temperature, potassium carbonate (17.7 mg) and (2-chloropyrimidin-5-yl)methanol (11.0 mg) were added, and the mixture was stirred at 120 °C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (8.0 mg) as a yellow solid.

[1241] 11H-NMR (400 MHz, DMSO-d6) δ: 8.73 (d, J = 6.4 Hz, 1H), 8.56 (d, J = 5.5 Hz, 1H), 8.28 (d, J = 4.6 Hz, 2H), 8.21 (d, J = 2.3 Hz, 1H), 8.07 (d, J = 8.7 Hz, 2H), 8.01 (d, J = 8.2 Hz, 2H), 7.70 (dd, J = 5.5, 0.9 Hz, 1H), 7.35 - 7.34 (m, 1H), 5.01 (t, J = 5.5 Hz, 1H), 4.64 - 4.57 (m, 1H), 4.32 - 4.30 (m, 2H), 3.84 - 3.80 (m, 1H), 3.72 - 3.66 (m, 1H), 3.60 - 3.50 (m, 2H), 2.30 - 2.22 (m, 1H), 2.12 - 2.04 (m, 1H).

[1242] ESI-MS: 416.4 [M + H] + 。

[1243] Examples 194 - 197

[1244] Based on the method shown in Example 193, the compounds of Examples 194 - 197 shown in the following table were synthesized. The structures, names, and ESI-MS of the compounds of each example are shown in the following table.

[1245] [Table 5]

[1246]

[1247] Example 198

[1248] Synthesis of (S)-4-(furo[3,2-c]pyridin-4-yl)-N-{1-[5-(hydroxymethyl)pyrazin-2-yl]pyrrolidin-3-yl}benzamide

[198] (hereinafter referred to as Compound

[198] )

[1249]

[1250] To a solution of Compound [191-2] (20 mg) in NMP (0.50 mL) at room temperature, cesium carbonate (94 mg) and (5-chloropyrazin-2-yl)methanol (13 mg) were added, and the mixture was stirred at 120 °C for 23 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (5.2 mg) as a white solid.

[1251] ESI-MS: 416.4 [M + H] + 。

[1252] Example 199

[1253] Synthesis of (S)-4-(furo[3,2-c]pyridin-4-yl)-N-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]benzamide

[199] (hereinafter referred to as Compound

[199] )

[1254]

[1255] To a solution of Compound [191-2] (20 mg) in 1,4-dioxane (0.30 mL) at room temperature were added DIPEA (15 μL) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.3 μL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (2.1 mg) as a white solid.

[1256] ESI-MS: 390.3 [M+H] + .

[1257] Example 200

[1258] Synthesis of (S)-4-(furo[3,2-c]pyridin-4-yl)-N-{1-[5-(2-hydroxypropan-2-yl)pyrimidin-2-yl]pyrrolidin-3-yl}benzamide

[200] (hereinafter referred to as Compound

[200] )

[1259]

[1260] (1) Synthesis of ethyl (S)-2-{3-[4-(furo[3,2-c]pyridin-4-yl)benzamido]pyrrolidin-1-yl}pyrimidine-5-carboxylate [200-1] (hereinafter referred to as Compound [200-1])

[1261]

[1262] To a solution of Compound [191-2] (20 mg) in NMP (0.30 mL) at room temperature were added potassium carbonate (29 mg) and ethyl 2-chloropyrimidine-5-carboxylate (24 mg), and the mixture was stirred at 120 °C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (31 mg) as a yellow solid.

[1263] ESI-MS: 458.4 [M+H] + .

[1264] Synthesis of (2)(S)-4-(furo[3,2-c]pyridin-4-yl)-N-{1-[5-(2-hydroxypropan-2-yl)pyrimidin-2-yl]pyrrolidin-3-yl}benzamide

[200]

[1265] To a solution of compound [200-1] (10 mg) in THF (0.20 mL) at 0 °C was added a diethyl ether solution of 33 M methylmagnesium bromide (0.24 mL), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (3.8 mg) as a white solid.

[1266] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.71 (d, J = 6.9 Hz, 1H), 8.56 (d, J = 5.9 Hz, 1H), 8.39 (s, 2H), 8.28 - 8.18 (m, 1H), 8.07 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 5.5 Hz, 1H), 7.36 - 7.35 (m, 1H), 5.01 (s, 1H), 4.59 - 4.55 (m, 1H), 3.80 - 3.48 (m, 4H), 2.25 - 2.21 (m, 1H), 2.07 - 2.02 (m, 1H), 1.37 (s, 6H).

[1267] ESI-MS: 444.4 [M + H] + .

[1268] Example 201

[1269] Synthesis of (S)-N-[1-(5-cyanopyrimidin-2-yl)pyrrolidin-3-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide

[201] (hereinafter referred to as compound

[201] )

[1270]

[1271] (1) Synthesis of (S)-N-[1-(5-bromopyrimidin-2-yl)pyrrolidin-3-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide [201-1] (hereinafter referred to as compound [201-1])

[1272]

[1273] To a solution of compound [191-2] (30 mg) in NMP (0.30 mL) at room temperature, potassium carbonate (54 mg) and 5-bromo-2-chloropyrimidine (28 mg) were added, and the mixture was stirred at 120 °C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (15 mg) as a yellow solid.

[1274] ESI-MS: 464.5 [M+H] + 。

[1275] Synthesis of (S)-N-[1-(5-cyanopyrimidin-2-yl)pyrrolidin-3-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide

[201]

[1276] To a solution of compound [201-1] (13.4 mg) in DMF (0.60 mL) at room temperature, zinc cyanide (8.0 mg) and Pd(PPh3)4 (8.0 mg) were added. Under an argon atmosphere, using a microwave reaction apparatus, the mixture was stirred at 120 °C for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (8.0 mg) as a white solid.

[1277] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.81 - 8.76 (m, 3H), 8.59 (d, J = 5.5 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 8.2 Hz, 2H), 8.03 (d, J = 8.7 Hz, 2H), 7.72 (dd, J = 5.5, 0.9 Hz, 1H), 7.36 - 7.35 (m, 1H), 4.66 - 4.62 (m, 1H), 3.88 - 3.64 (m, 4H), 2.32 - 2.24 (m, 1H), 2.16 - 2.08 (m, 1H).

[1278] ESI-MS: 411.3 [M+H] + 。

[1279] Example 202

[1280] Synthesis of (S)-2-{3-[4-(furo[3,2-c]pyridin-4-yl)benzamido]pyrrolidin-1-yl}pyrimidine-5-carboxamide

[202] (hereinafter referred to as compound

[202] )

[1281]

[1282] To a solution of compound

[201] (5.1 mg) in tert-butanol (0.30 mL) at room temperature, potassium tert-butoxide (16 mg) was added, and the mixture was stirred at 80 °C for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.5 mg) as a white solid.

[1283] ESI-MS: 429.3 [M + H] + 。

[1284] Example 203

[1285] Synthesis of N-{(3R,4R)-4-fluoro-1-[5-(hydroxymethyl)pyrimidin-2-yl]pyrrolidin-3-yl}-4-(furo[3,2-c]pyridin-4-yl)benzamide

[203] (hereinafter referred to as compound

[203] )

[1286]

[1287] (1) Synthesis of tert-butyl (3R,4R)-3-fluoro-4-[4-(furo[3,2-c]pyridin-4-yl)benzamido]pyrrolidine-1-carboxylate [203-1] (hereinafter referred to as compound [203-1])

[1288]

[1289] To a solution of compound [99-1] (176 mg) in dichloromethane (2.10 mL) at room temperature, 4-dimethylaminopyridine (63.0 mg), EDC (98.0 mg), and tert-butyl (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (100 mg) were added, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (208 mg) as a yellow oil.

[1290] ESI-MS: 426.4 [M + H] + 。

[1291] (2) Synthesis of N-[(3R,4R)-4-fluoropyrrolidin-3-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide dihydrochloride [203-2] (hereinafter referred to as compound [203-2])

[1292]

[1293] To a solution of compound [203-1] (208 mg) in ethyl acetate (1.20 mL) at room temperature was added a solution of 4 M hydrogen chloride in ethyl acetate (1.20 mL), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (170 mg).

[1294] ESI-MS: 326.3 [M+H] + 。

[1295] (3) Synthesis of N-{ (3R,4R)-4-fluoro-1-[5-(hydroxymethyl)pyrimidin-2-yl]pyrrolidin-3-yl}-4-(furo[3,2-c]pyridin-4-yl)benzamide

[203]

[1296] To a solution of compound [203-2] (49.0 mg) in NMP (500 μL) at room temperature were added cesium carbonate (169 mg) and (2-chloropyrimidin-5-yl)methanol (15.0 mg), and the mixture was stirred at 120 °C for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound as a white solid (15.2 mg).

[1297] 1 1H-NMR (400 MHz, CD3OD) δ: 8.52 (d, J = 5.9 Hz, 1H), 8.38 (s, 2H), 8.03 - 7.98 (m, 5H), 7.63 (d, J = 5.9 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 5.38 - 5.32 (m, 1H), 4.84 - 4.77 (m, 1H), 4.48 (s, 2H), 4.05 - 3.98 (m, 2H), 3.90 - 3.88 (m, 2H).

[1298] ESI-MS: 434.4 [M+H] + 。

[1299] Example 204

[1300] Synthesis of N-{ (3R,4S)-4-fluoro-1-[5-(hydroxymethyl)pyrimidin-2-yl]pyrrolidin-3-yl}-4-(furo[3,2-c]pyridin-4-yl)benzamide

[204] (hereinafter referred to as compound

[204] )

[1301]

[1302] Synthesis of tert-butyl (3S,4R)-3-fluoro-4-[4-(furo[3,2-c]pyridin-4-yl)benzamido]pyrrolidine-1-carboxylate [204-1] (hereinafter referred to as Compound [204-1])

[1303]

[1304] To a solution of Compound [99-1] (176 mg) in dichloromethane (2.10 mL) at room temperature, 4-dimethylaminopyridine (63.0 mg), EDC (98.0 mg) and tert-butyl (3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (100 mg) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (188 mg) as a yellow oil.

[1305] ESI-MS: 426.4 [M+H] + 。

[1306] Synthesis of N-{(3R,4S)-4-fluoro-1-[5-(hydroxymethyl)pyrimidin-2-yl]pyrrolidin-3-yl}-4-(furo[3,2-c]pyridin-4-yl)benzamide

[204]

[1307] The title compound was synthesized from Compound [204-1] according to the methods of steps (2) and (3) of Example 203.

[1308] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.81 (d, J = 6.9 Hz, 1H), 8.57 (d, J = 5.5 Hz, 1H), 8.31 (s, 2H), 8.22 (d, J = 2.3 Hz, 1H), 8.15 - 8.09 (m, 4H), 7.71 (d, J = 5.9 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 5.44 - 5.26 (m, 1H), 5.05 (t, J = 5.5 Hz, 1H), 4.81 - 4.74 (m, 1H), 4.32 - 4.30 (m, 2H), 3.96 - 3.60 (m, 4H).

[1309] ESI-MS: 434.3 [M+H] + 。

[1310] Example 205

[1311] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{ (3R,4R)-1-[5-(hydroxymethyl)pyrimidin-2-yl]-4-methoxypyrrolidin-3-yl}benzamide

[205] (hereinafter referred to as compound

[205] )

[1312]

[1313] (1) Synthesis of tert-butyl (3R,4R)-3-[4-(furo[3,2-c]pyridin-4-yl)benzamido]-4-methoxypyrrolidine-1-carboxylate [205-1] (hereinafter referred to as compound [205-1])

[1314]

[1315] To a solution of compound [99-1] (102 mg) in dichloromethane (1.00 mL) at room temperature were added 4-dimethylaminopyridine (37.0 mg), EDC (58.0 mg) and tert-butyl (3R,4R)-3-amino-4-methoxypyrrolidine-1-carboxylate (62.0 mg), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (109 mg) as a colorless oil.

[1316] ESI-MS: 438.7 [M+H] + .

[1317] (2) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{ (3R,4R)-1-[5-(hydroxymethyl)pyrimidin-2-yl]-4-methoxypyrrolidin-3-yl}benzamide

[205]

[1318] The title compound was synthesized from compound [205-1] according to the methods of steps (2) and (3) of Example 203.

[1319] 1H-NMR (400 MHz, DMSO-d6) δ: 8.80 (d, J = 6.4 Hz, 1H), 8.59 - 8.58 (m, 1H), 8.31 (s, 2H), 8.24 - 8.23 (m, 1H), 8.09 (d, J = 8.7 Hz, 2H), 8.04 (d, J = 8.7 Hz, 2H), 7.73 - 7.71 (m, 1H), 7.36 - 7.35 (m, 1H), 5.05 (t, J = 5.7 Hz, 1H), 4.59 - 4.56 (m, 1H), 4.33 - 4.32 (m, 2H), 4.00 - 3.97 (m, 1H), 3.82 - 3.73 (m, 2H), 3.67 - 3.61 (m, 2H), 3.39 (s, 3H).

[1320] ESI-MS: 446.3 [M + H] + 。

[1321] Example 206

[1322] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{ (3R,4S)-1-[5-(hydroxymethyl)pyrimidin-2-yl]-4-methoxypyrrolidin-3-yl}benzamide

[206] (hereinafter referred to as Compound

[206] )

[1323]

[1324] (1) Synthesis of tert-butyl (3R,4S)-3-[4-(furo[3,2-c]pyridin-4-yl)benzamido]-4-methoxypyrrolidine-1-carboxylate [206-1] (hereinafter referred to as Compound [206-1])

[1325]

[1326] To a solution of Compound [99-1] (85 mg) in dichloromethane (1.0 mL) at room temperature, 4-dimethylaminopyridine (29 mg), EDC (46 mg), and tert-butyl (3R,4S)-3-amino-4-methoxypyrrolidine-1-carboxylate (50 mg) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (96 mg) as a yellow oil.

[1327] ESI-MS: 438.4 [M + H] + 。

[1328] (2) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{[(3R,4S)-1-(5-(hydroxymethyl)pyrimidin-2-yl)-4-methoxypyrrolidin-3-yl]benzamide

[206]

[1329] From compound [206-1], the title compound was synthesized based on the methods of steps (2) and (3) of Example 203.

[1330] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.68 - 8.52 (m, 2H), 8.31 (s, 2H), 8.24 (d, J = 2.3 Hz, 1H), 8.12 - 8.07 (m, 4H), 7.73 (dd, J = 5.5, 0.9 Hz, 1H), 7.39 - 7.38 (m, 1H), 5.05 (t, J = 5.5 Hz, 1H), 4.75 - 4.72 (m, 1H), 4.33 - 4.31 (m, 2H), 4.12 - 4.09 (m, 1H), 3.86 - 3.77 (m, 2H), 3.65 - 3.57 (m, 2H), 3.32 (s, 3H).

[1331] ESI-MS: 446.3 [M + H] + 。

[1332] Example 207

[1333] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{[(3R,4R)-4-hydroxy-1-(5-(hydroxymethyl)pyrimidin-2-yl)pyrrolidin-3-yl]benzamide

[207] (hereinafter referred to as compound

[207] )

[1334]

[1335] (1) Synthesis of tert-butyl (3R,4R)-3-[4-(furo[3,2-c]pyridin-4-yl)benzamide]-4-hydroxypyrrolidine-1-carboxylate [207-1] (hereinafter referred to as compound [207-1])

[1336]

[1337] To a solution of compound [99-1] (176 mg) in dichloromethane (2.00 mL) at room temperature, 4-dimethylaminopyridine (62.0 mg), EDC (98.0 mg), and tert-butyl (3R,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylate (100 mg) were added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (91.0 mg) as a pale brown oil.

[1338] ESI-MS: 424.3 [M+H] + 。

[1339] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{ (3R,4R)-4-hydroxy-1-[5-(hydroxymethyl)pyrimidin-2-yl]pyrrolidin-3-yl}benzamide

[207]

[1340] The title compound was synthesized from compound [207-1] according to the methods of steps (2) and (3) of Example 203.

[1341] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.68 (d, J = 5.9 Hz, 1H), 8.58 (d, J = 5.5 Hz, 1H), 8.30 (s, 2H), 8.24 (s, 1H), 8.09 (d, J = 6.9 Hz, 2H), 8.03 (d, J = 6.9 Hz, 2H), 7.72 (d, J = 5.5 Hz, 1H), 7.36 - 7.34 (m, 1H), 5.43 - 5.42 (m, 1H), 5.05 - 5.03 (m, 1H), 4.45 - 4.28 (m, 4H), 3.86 - 3.72 (m, 2H), 3.61 - 3.58 (m, 1H), 3.49 - 3.46 (m, 1H).

[1342] ESI-MS: 432.3 [M+H] + 。

[1343] Example 208

[1344] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{ (3R,4S)-4-hydroxy-1-[5-(hydroxymethyl)pyrimidin-2-yl]pyrrolidin-3-yl}benzamide

[208] (hereinafter referred to as compound

[208] )

[1345]

[1346] Synthesis of (3R,4S)-3-[4-(furo[3,2-c]pyridin-4-yl)benzamide]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester [208-1] (hereinafter referred to as Compound [208-1])

[1347]

[1348] To a solution of Compound [99-1] (177 mg) in dichloromethane (2.00 mL) at room temperature, 4-dimethylaminopyridine (63.0 mg), EDC (99.0 mg) and (3R,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (100 mg) were added, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (167 mg) as a colorless oil.

[1349] ESI-MS: 424.3 [M+H] + 。

[1350] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{ (3R,4S)-4-hydroxy-1-[5-(hydroxymethyl)pyrimidin-2-yl]pyrrolidin-3-yl}benzamide

[208]

[1351] The title compound was synthesized from Compound [208-1] based on the methods of steps (2) and (3) of Example 203.

[1352] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.60 (d, J = 5.5 Hz, 1H), 8.39 (d, J = 7.3 Hz, 1H), 8.30 (s, 2H), 8.25 (d, J = 2.3 Hz, 1H), 8.14 - 8.08 (m, 4H), 7.73 (dd, J = 5.7, 1.1 Hz, 1H), 7.39 - 7.38 (m, 1H), 5.36 - 5.34 (m, 1H), 5.03 (t, J = 5.5 Hz, 1H), 4.61 - 4.49 (m, 1H), 4.40 - 4.37 (m, 1H), 4.32 - 4.31 (m, 2H), 3.87 - 3.83 (m, 1H), 3.63 - 3.52 (m, 3H).

[1353] ESI-MS: 432.3 [M+H] + 。

[1354] Example 209

[1355] Synthesis of 4-(Furo[3,2-c]pyridin-4-yl)-N-(2-azaspiro[3.3]heptan-6-yl)benzamide

[209] (hereinafter referred to as Compound

[209] )

[1356]

[1357] (1) Synthesis of tert-Butyl 6-[4-(Furo[3,2-c]pyridin-4-yl)benzamido]-2-azaspiro[3.3]heptane-2-carboxylate [209-1] (hereinafter referred to as Compound [209-1])

[1358]

[1359] To a solution of Compound [99-1] (200 mg) in dichloromethane (3.00 mL) at room temperature, 4-dimethylaminopyridine (110 mg), EDC (170 mg), and tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (234 mg) were added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (317 mg) as a yellow solid.

[1360] ESI-MS: 434.5 [M+H] + 。

[1361] (2) Synthesis of 4-(Furo[3,2-c]pyridin-4-yl)-N-(2-azaspiro[3.3]heptan-6-yl)benzamide

[209]

[1362] To a solution of Compound [209-1] (317 mg) in dichloromethane (2.00 mL) at room temperature, trifluoroacetic acid (3.00 mL) was added, and the mixture was stirred at room temperature for 22 hours. 5M aqueous sodium hydroxide solution was added to the reaction mixture at 0 °C, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (100 mg) as a white solid.

[1363] ESI-MS: 334.4 [M+H] + 。

[1364] Example 210

[1365] Synthesis of 4-(Furo[3,2-c]pyridin-4-yl)-N-[2-(pyrimidin-2-yl)-2-azaspiro[3.3]heptan-6-yl]benzamide

[210] (hereinafter referred to as Compound

[210] )

[1366]

[1367] To a solution of compound

[209] (10 mg) in NMP (0.30 mL) at room temperature, potassium carbonate (12 mg) and 2-chloropyrimidine (4.5 mg) were added, and the mixture was stirred at 140 °C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (3.0 mg) as a brown solid.

[1368] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.76 (d, J = 7.3 Hz, 1H), 8.59 (d, J = 5.5 Hz, 1H), 8.33 - 8.30 (m, 2H), 8.24 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 8.7 Hz, 2H), 8.02 (d, J = 8.2 Hz, 2H), 7.76 - 7.68 (m, 1H), 7.38 - 7.37 (m, 1H), 6.64 (t, J = 4.8 Hz, 1H), 4.42 - 4.36 (m, 1H), 4.11 (s, 2H), 4.00 (s, 2H), 2.61 - 2.57 (m, 2H), 2.38 - 2.34 (m, 2H).

[1369] ESI-MS: 412.4 [M + H] + 。

[1370] Example 211

[1371] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[(3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]benzamide

[211] (hereinafter referred to as compound

[211] )

[1372]

[1373] To a solution of tert-butyl N-[(3R,6S)-6-(hydroxymethyl)oxiran-3-yl]carbamate (200 mg) in ethyl acetate (650 μL) at room temperature was added a solution of 4 M hydrogen chloride in ethyl acetate (650 μL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. To the resulting residue in dichloromethane (1.6 mL) at room temperature were added 4-dimethylaminopyridine (62 mg), EDC (97 mg), and compound [99-1] (120 mg), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (78 mg) as a white solid.

[1374] 1 H-NMR (400 MHz, DMSO-d6) δ: 8.60 - 8.57 (m, 1H), 8.34 (d, J = 5.9 Hz, 1H), 8.25 - 8.23 (m, 1H), 8.10 - 8.08 (m, 2H), 8.02 - 8.00 (m, 2H), 7.74 - 7.72 (m, 1H), 7.36 - 7.35 (m, 1H), 4.65 - 4.63 (m, 1H), 3.92 - 3.90 (m, 2H), 3.40 - 3.24 (m, 3H), 3.19 - 3.12 (m, 1H), 1.99 - 1.96 (m, 1H), 1.75 - 1.58 (m, 2H), 1.36 - 1.27 (m, 1H).

[1375] ESI-MS: 353.3 [M + H] + 。

[1376] Example 212

[1377] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[(3R,6S)-6-(1-hydroxyethyl)tetrahydro-2H-pyran-3-yl]benzamide

[212] (hereinafter referred to as compound

[212] )

[1378]

[1379] To a solution of compound

[211] (26.1 mg) in dichloromethane (600 μL) at room temperature, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane) (47.0 mg) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the resulting residue in THF (300 μL) at 0 °C, a diethyl ether solution of 3 M methylmagnesium bromide (114 μL) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (15.3 mg) as a white solid.

[1380] ESI-MS: 367.3 [M + H] + 。

[1381] Example 213

[1382] Synthesis of N-[(3R,6S)-6-acetyltetrahydro-2H-pyran-3-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide

[213] (hereinafter referred to as compound

[213] )

[1383]

[1384] To a solution of compound

[212] (11.0 mg) in dichloromethane (500 μL) at room temperature, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane) (19.0 mg) was added, and the mixture was stirred at room temperature for 4 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (10.2 mg) as a white solid.

[1385] ESI-MS: 365.4 [M + H] + 。

[1386] Example 214

[1387] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[(3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl]benzamide

[214] (hereinafter referred to as compound

[214] )

[1388]

[1389] To a solution of compound

[213] (9.0 mg) in THF (0.30 mL) at 0 °C was added a diethyl ether solution of 3 M methylmagnesium bromide (246 μL), and the mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography to give the title compound (1.6 mg) as a white solid.

[1390] 1 1H-NMR (400 MHz, CD3OD) δ: 8.51 (d, J = 5.5 Hz, 1H), 8.01 - 7.97 (m, 5H), 7.63 (d, J = 5.9 Hz, 1H), 7.19 - 7.18 (m, 1H), 4.10 - 4.04 (m, 2H), 3.25 - 3.09 (m, 2H), 2.18 - 2.00 (m, 2H), 1.67 - 1.46 (m, 2H), 1.18 (s, 3H), 1.16 (s, 3H).

[1391] ESI-MS: 381.3 [M + H] + 。

[1392] Example 215

[1393] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[(1R,3R)-3-(2-hydroxypropan-2-yl)cyclopentyl]benzamide

[215] (hereinafter referred to as compound

[215] )

[1394]

[1395] (1) Synthesis of methyl (1R,3R)-3-[4-(furo[3,2-c]pyridin-4-yl)benzamido]cyclopentane-1-carboxylate [215-1] (hereinafter referred to as compound [215-1])

[1396]

[1397] To a solution of compound [99-1] (185 mg) in dichloromethane (2.00 mL) at room temperature were added 4-dimethylaminopyridine (72.0 mg), EDC (113 mg), and (1R,3R)-3-aminocyclopentane-1-carboxylate hydrochloride (100 mg), and the mixture was stirred at room temperature for 22 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (114 mg) as a white solid.

[1398] ESI-MS: 365.3 [M+H] + 。

[1399] (2) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[(1R,3R)-3-(2-hydroxypropan-2-yl)cyclopentyl]benzamide

[215]

[1400] To a solution of compound [215-1] (20.0 mg) in THF (300 μL) at room temperature was added a diethyl ether solution of 3 M methylmagnesium bromide (367 μL), and the mixture was stirred at room temperature for 24 hours. Aqueous saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (7.4 mg) as a yellow solid.

[1401] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.59 - 8.58 (m, 1H), 8.35 (d, J = 7.3 Hz, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.10 - 8.03 (m, 2H), 8.02 - 8.00 (m, 2H), 7.69 (dd, J = 6.2, 5.3 Hz, 1H), 7.36 - 7.35 (m, 1H), 4.26 - 4.20 (m, 1H), 4.06 - 4.05 (m, 1H), 2.17 - 1.40 (m, 7H), 1.08 - 1.00 (m, 6H).

[1402] ESI-MS: 365.3 [M+H] + 。

[1403] Example 216

[1404] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[(1S,3S)-3-(2-hydroxypropan-2-yl)cyclopentyl]benzamide

[216] (hereinafter referred to as compound

[216] )

[1405]

[1406] (1) Synthesis of methyl (1S,3S)-3-[4-(furo[3,2-c]pyridin-4-yl)benzamido]cyclopentane-1-carboxylate [216-1] (hereinafter referred to as compound [216-1])

[1407]

[1408] To a solution of compound [99-1] (93 mg) in dichloromethane (1.0 mL) at room temperature, 4-dimethylaminopyridine (36 mg), EDC (57 mg), and methyl (1S,3S)-3-aminocyclopentane-1-carboxylate hydrochloride (50 mg) were added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (43 mg) as a white solid.

[1409] ESI-MS: 365.3 [M+H] + 。

[1410] (2) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[(1S,3S)-3-(2-hydroxypropan-2-yl)cyclopentyl]benzamide

[216]

[1411] The title compound was synthesized from compound [216-1] according to the method of step (2) of Example 215.

[1412] 1 1H-NMR (400 MHz, CDCl3) δ: 8.60 - 8.58 (m, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.91 - 7.89 (m, 2H), 7.72 (d, J = 1.8 Hz, 1H), 7.47 - 7.45 (m, 1H), 7.03 (d, J = 2.3 Hz, 1H), 6.24 (d, J = 7.3 Hz, 1H), 4.47 - 4.42 (m, 1H), 3.70 - 3.64 (m, 1H), 2.23 - 2.16 (m, 2H), 2.20 - 1.98 (m, 1H), 1.89 - 1.83 (m, 1H), 1.73 - 1.51 (m, 3H), 1.20 (s, 6H).

[1413] ESI-MS: 365.3 [M+H] + 。

[1414] Example 217

[1415] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(pyrimidin-2-yl)azetidin-3-yl]benzamide

[217] (hereinafter referred to as compound

[217] )

[1416]

[1417] To a solution of compound [99-1] (20 mg) in dichloromethane (0.30 mL) at room temperature, 4-dimethylaminopyridine (11 mg), EDC (17 mg) and 1-(pyrimidin-2-yl)azetidin-3-amine dihydrochloride (25 mg) were added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (14 mg) as a white solid.

[1418] 1 1H-NMR (400 MHz, DMSO-d6) δ: 9.19 (d, J = 7.3 Hz, 1H), 8.59 (d, J = 5.9 Hz, 1H), 8.37 (d, J = 4.6 Hz, 2H), 8.24 (d, J = 2.3 Hz, 1H), 8.12 (d, J = 8.2 Hz, 2H), 8.06 (d, J = 8.7 Hz, 2H), 7.73 (dd, J = 5.5, 0.9 Hz, 1H), 7.39 - 7.38 (m, 1H), 6.69 (t, J = 4.8 Hz, 1H), 4.94 - 4.84 (m, 1H), 4.38 - 4.34 (m, 2H), 4.07 (dd, J = 9.1, 5.5 Hz, 2H).

[1419] ESI-MS: 372.4 [M + H] + 。

[1420] Example 218

[1421] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[(trans-3-hydroxycyclobutyl)methyl]benzamide

[218] (hereinafter referred to as compound

[218] )

[1422]

[1423] Based on the method of Example 217, the title compound was obtained as a white solid.

[1424] 1H-NMR (400 MHz, DMSO-d6) δ: 8.62 - 8.58 (m, 2H), 8.24 (d, J = 2.3 Hz, 1H), 8.09 (dd, J = 6.6, 2.1 Hz, 2H), 8.02 - 7.99 (m, 2H), 7.72 (dd, J = 5.7, 1.1 Hz, 1H), 7.38 - 7.37 (m, 1H), 4.94 (d, J = 6.4 Hz, 1H), 4.27 - 4.18 (m, 1H), 3.35 - 3.33 (m, 2H), 2.38 - 2.31 (m, 1H), 2.08 - 2.02 (m, 2H), 1.93 - 1.86 (m, 2H).

[1425] ESI-MS: 323.3 [M + H] + 。

[1426] Example 219

[1427] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[(cis-3-hydroxycyclobutyl)methyl]benzamide

[219] (hereinafter referred to as Compound

[219] )

[1428]

[1429] Based on the method of Example 217, the title compound was obtained as a white solid.

[1430] 1 H-NMR (400 MHz, DMSO-d6) δ: 8.59 - 8.56 (m, 2H), 8.24 (d, J = 2.3 Hz, 1H), 8.09 (d, J = 8.7 Hz, 2H), 8.02 - 8.00 (m, 2H), 7.72 (dd, J = 5.5, 0.9 Hz, 1H), 7.37 (dd, J = 1.1, 1.1 Hz, 1H), 4.93 (d, J = 6.9 Hz, 1H), 3.93 - 3.84 (m, 1H), 3.29 - 3.27 (d, 2H), 2.27 - 2.21 (m, 2H), 1.99 - 1.90 (m, 1H), 1.58 - 1.51 (m, 2H).

[1431] ESI-MS: 323.4 [M + H] + 。

[1432] Example 220

[1433] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[2-hydroxy-1-(pyridin-2-yl)ethyl]benzamide

[220] (hereinafter referred to as Compound

[220] )

[1434]

[1435] Based on the method of Example 217, the title compound was obtained as a yellow solid.

[1436] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.81 (d, J = 8.0 Hz, 1H), 8.60 (d, J = 5.3 Hz, 1H), 8.54 (d, J = 4.6 Hz, 1H), 8.25 (d, J = 2.3 Hz, 1H), 8.18 - 8.06 (m, 4H), 7.80 - 7.70 (m, 2H), 7.44 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 1.1 Hz, 1H), 7.29 - 7.25 (m, 1H), 5.18 (dd, J = 12.8, 7.8 Hz, 1H), 4.96 (t, J = 5.9 Hz, 1H), 3.89 - 3.77 (m, 2H).

[1437] ESI-MS: 360.3 [M + H] + 。

[1438] Example 221

[1439] Synthesis of N-(chroman-3-ylmethyl)-4-(furo[3,2-c]pyridin-4-yl)benzamide

[221] (hereinafter referred to as Compound

[221] )

[1440]

[1441] To a solution of Compound [99 - 1] (358 mg) in dichloromethane (4.30 mL) at room temperature were added 4-dimethylaminopyridine (128 mg), EDC (201 mg), and chroman-3-ylmethanamine hydrochloride (200 mg), and the mixture was stirred at room temperature for 16 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (313 mg) as a white solid.

[1442] 11H-NMR (400 MHz, DMSO-d6) δ: 8.76 - 8.73 (m, 1H), 8.56 (d, J = 5.5 Hz, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.08 (d, J = 8.2 Hz, 2H), 8.02 (d, J = 8.7 Hz, 2H), 7.73 - 7.66 (m, 1H), 7.36 - 7.35 (m, 1H), 7.06 - 7.01 (m, 2H), 6.79 (t, J = 7.3 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 4.22 - 4.19 (m, 1H), 3.88 - 3.83 (m, 1H), 3.36 - 3.31 (m, 2H), 2.89 - 2.82 (m, 1H), 2.62 - 2.56 (m, 1H), 2.34 - 2.31 (m, 1H).

[1443] ESI-MS: 385.3 [M + H] + 。

[1444] Example 222

[1445] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{4-[4-(morpholine-4-carbonyl)piperidin-1-yl]phenyl}benzamide

[222] (hereinafter referred to as Compound

[222] )

[1446]

[1447] (1) Synthesis of 1-(4-nitrophenyl)piperidine-4-carboxylic acid [222-1] (hereinafter referred to as Compound [222-1])

[1448]

[1449] To a solution of 4-fluoronitrobenzene (3.95 g) in acetonitrile (40 mL) at room temperature, ethyl 4-piperidinecarboxylate (4.75 mL) and potassium carbonate (9.70 g) were added, and the mixture was stirred at 60 °C for 9 hours. Then, it was stirred at room temperature for 20 hours. After concentrating the reaction mixture under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the resulting residue in ethanol (70 mL) at room temperature, 2 M aqueous sodium hydroxide solution (28 mL) was added, and the mixture was stirred at room temperature for 41 hours. Then, 5 M aqueous sodium hydroxide solution (20 mL) was added at room temperature, and the mixture was stirred at 100 °C for 2 hours. After cooling the reaction mixture to 0 °C, concentrated hydrochloric acid was added, and the resulting solid was collected by filtration and dried under reduced pressure to obtain the title compound (6.78 g) as a yellow solid.

[1450] ESI-MS: 251.1 [M + H] + 。

[1451] (2) Synthesis of morpholino[1-(4-nitrophenyl)piperidin-4-yl]methanone [222-2] (hereinafter referred to as compound [222-2])

[1452]

[1453] To a solution of compound [222-1] (1.00 g) in DMF (15 mL) at 0 °C, morpholine (522 μL), DIPEA (1.39 mL), and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinium hexafluorophosphate (2.57 g) were added, and the mixture was stirred at 0 °C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was suspended in ethyl acetate / diethyl ether, and the solid was filtered off to obtain the title compound (954 mg) as a yellow solid.

[1454] ESI-MS: 320.2 [M+H] + .

[1455] (3) Synthesis of [1-(4-aminophenyl)piperidin-4-yl](morpholino)methanone dihydrochloride [222-3] (hereinafter referred to as compound [222-3])

[1456]

[1457] To a solution of compound [222-2] (954 mg) in THF (25 mL) / methanol (20 mL) at room temperature, 10% palladium-on-carbon (320 mg) was added, and the mixture was stirred at room temperature for 10 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the resulting residue in ethyl acetate (20 mL) at room temperature, a 4M hydrogen chloride solution in ethyl acetate (2.00 mL) was added, and the mixture was stirred at room temperature for 15 minutes. The resulting solid was filtered off and dried under reduced pressure to obtain the title compound (1.04 g) as a white solid.

[1458] ESI-MS: 290.2 [M+H] + .

[1459] (4) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{4-[4-(morpholine-4-carbonyl)piperidin-1-yl]phenyl}benzamide

[222]

[1460] To a solution of compound [99-1] (30 mg) in DMF (0.42 mL) at room temperature, DIPEA (85 μL), (1-cyano-2-ethoxy-2-oxoethylaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (59 mg), and compound [222-3] (59 mg) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (41 mg) as a yellow solid.

[1461] ESI-MS: 511.2 [M+H] + 。

[1462] Example 223

[1463] Synthesis of N-{3-fluoro-4-[4-(morpholine-4-carbonyl)piperidin-1-yl]phenyl}-4-(furo[3,2-c]pyridin-4-yl)benzamide

[223] (hereinafter referred to as compound

[223] )

[1464]

[1465] The title compound was synthesized from 3,4-difluoronitrobenzene by the method of steps (1), (2), (3) and (4) of Example 222.

[1466] ESI-MS: 529.2 [M+H] + 。

[1467] Example 224

[1468] Synthesis of (S)-4-(furo[3,2-c]pyridin-4-yl)-N-[4-(pyrimidin-2-yl)-1,4-oxazepan-6-yl]benzamide

[224] (hereinafter referred to as compound

[224] )

[1469]

[1470] (1) Synthesis of tert-butyl (S)-6-[4-(furo[3,2-c]pyridin-4-yl)benzamide]-1,4-oxazepane-4-carboxylate [224-1] (hereinafter referred to as compound [224-1])

[1471]

[1472] To a solution of compound [99-1] (100 mg) in dichloromethane (1.4 mL) at room temperature, 4-dimethylaminopyridine (56 mg), EDC (88 mg), and (S)-tert-butyl 6-amino-1,4-oxazepane-6-carboxylate (108 mg) were added, and the mixture was stirred at room temperature for 23 h. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (89 mg) as a colorless oil.

[1473] ESI-MS: 438.2 [M+H] + 。

[1474] (2) Synthesis of (S)-4-(furo[3,2-c]pyridin-4-yl)-N-(1,4-oxazepan-6-yl)benzamide dihydrochloride [224-2] (hereinafter referred to as compound [224-2])

[1475]

[1476] To a solution of compound [224-1] (89 mg) in ethyl acetate (0.5 mL) at room temperature, a 4 M solution of hydrogen chloride in ethyl acetate (0.4 mL) was added, and the mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure to give the title compound (82 mg) as a yellow solid.

[1477] ESI-MS: 338.2 [M+H] + 。

[1478] (3) Synthesis of (S)-4-(furo[3,2-c]pyridin-4-yl)-N-[4-(pyrimidin-2-yl)-1,4-oxazepan-6-yl]benzamide

[224]

[1479] To a solution of compound [224-2] (14.0 mg) in NMP (0.5 mL) at room temperature, cesium carbonate (139 mg) and 2-chloropyrimidine (15.0 mg) were added, and the mixture was stirred at 120 °C for 4 h. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (6.70 mg) as a yellow solid.

[1480] ESI-MS: 416.3 [M+H] + 。

[1481] Example 225

[1482] Synthesis of (R)-4-(furo[3,2-c]pyridin-4-yl)-N-[4-(pyrimidin-2-yl)-1,4-oxazepan-6-yl]benzamide

[225] (hereinafter referred to as compound

[225] )

[1483]

[1484] Based on the method of Example 224, (R)-tert-butyl 6-amino-1,4-oxazepane-6-carboxylate was used instead of (S)-tert-butyl 6-amino-1,4-oxazepane-6-carboxylate to synthesize the title compound.

[1485] ESI-MS: 416.3 [M+H] + 。

[1486] Example 226

[1487] Synthesis of (S)-N-[1-(6-fluoropyridin-2-yl)pyrrolidin-3-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide

[226] (hereinafter referred to as compound

[226] )

[1488]

[1489] Based on the method of Example 193, 2,6-difluoropyridine was used instead of (2-chloropyrimidin-5-yl)methanol to synthesize the title compound.

[1490] ESI-MS: 403.2 [M+H] + 。

[1491] Example 227

[1492] Synthesis of (S)-N-[1-(6-chloropyrimidin-4-yl)pyrrolidin-3-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide

[227] (hereinafter referred to as compound

[227] )

[1493]

[1494] Based on the method of Example 193, 4,6-dichloropyrimidine was used instead of (2-chloropyrimidin-5-yl)methanol to synthesize the title compound.

[1495] ESI-MS: 420.1 [M+H] + 。

[1496] Example 228

[1497] Synthesis of (S)-N-[1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide

[228] (hereinafter referred to as compound

[228] )

[1498]

[1499] Based on the method of Example 193, 3,6-dichloropyridazine was used in place of (2-chloropyrimidin-5-yl)methanol to synthesize the title compound.

[1500] ESI-MS: 420.2 [M+H] + .

[1501] Example 229

[1502] Synthesis of (S)-4-(furo[3,2-c]pyridin-4-yl)-N-[1-(pyrimidin-4-yl)pyrrolidin-3-yl]benzamide

[229] (hereinafter referred to as compound

[229] )

[1503]

[1504] To a solution of compound

[227] (5.0 mg) in THF (0.3 mL) at room temperature were added sodium borohydride (1.4 mg), N,N,N',N'-tetramethylethylenediamine (1.8 μL), and PdCl2(dppf) (9.0 mg). The mixture was stirred at room temperature for 4 hours under an argon atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (3.2 mg) as a white solid.

[1505] ESI-MS: 386.2 [M+H] + .

[1506] Example 230

[1507] Synthesis of (S)-4-(furo[3,2-c]pyridin-4-yl)-N-[1-(pyridazin-3-yl)pyrrolidin-3-yl]benzamide

[230] (hereinafter referred to as compound

[230] )

[1508]

[1509] From compound

[228] , based on the method of Example 229, the title compound was synthesized.

[1510] ESI-MS: 386.2 [M+H] + .

[1511] Example 231

[1512] Synthesis of (S)-4-(furo[3,2-c]pyridin-4-yl)-N-[1-(1-methyl-1H-tetrazol-5-yl)pyrrolidin-3-yl]benzamide

[231] (hereinafter referred to as Compound

[231] )

[1513]

[1514] To a solution of Compound [191-2] (40 mg) in acetonitrile (0.5 mL) at room temperature, methyl isothiocyanate (12 mg) and DIPEA (63 μL) were added. After sealing the container, the mixture was stirred at 100 °C for 30 minutes. Then, 1,3-propane sultone (22 μL) and triethylamine (53 μL) were added at 100 °C. After sealing the container, the mixture was stirred at 100 °C for 1 hour. Then, sodium azide (81 mg) was added at 100 °C. After sealing the container, the mixture was stirred at 100 °C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2.3 mg) as a white solid.

[1515] ESI-MS: 390.2 [M + H] + 。

[1516] Example 232

[1517] Synthesis of (S)-4-(furo[3,2-c]pyridin-4-yl)-N-[1-(1-ethyl-1H-tetrazol-5-yl)pyrrolidin-3-yl]benzamide

[232] (hereinafter referred to as Compound

[232] )

[1518]

[1519] Based on the method of Example 231, ethyl isothiocyanate was used instead of methyl isothiocyanate to synthesize the title compound.

[1520] ESI-MS: 404.2 [M + H] + 。

[1521] Example 233

[1522] Synthesis of (S)-4-(furo[3,2-c]pyridin-4-yl)-N-[1-(6-oxo-1,6-dihydropyridin-2-yl)pyrrolidin-3-yl]benzamide

[233] (hereinafter referred to as Compound

[233] )

[1523]

[1524] Synthesis of 2-[(2,4-dimethoxybenzyl)oxy]-6-fluoropyridine [233-1] (hereinafter referred to as Compound [233-1])

[1525]

[1526] To a solution of 2,4-dimethoxybenzyl alcohol (1.46 g) in DMF (29 mL) at room temperature, 60% sodium hydride (382 mg) and 2,6-difluoropyridine (1.00 g) were added, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2.08 g) as a white solid.

[1527] 1 1H-NMR (400 MHz, CDCl3) δ: 7.62 (dd, J = 8.1, 8.1 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 6.63 (dd, J = 8.2, 1.4 Hz, 1H), 6.49 - 6.48 (m, 3H), 5.30 (s, 2H), 3.83 (s, 3H), 3.81 (s, 3H).

[1528] Synthesis of (S)-4-(furo[3,2-c]pyridin-4-yl)-N-[1-(6-oxo-1,6-dihydropyridin-2-yl)pyrrolidin-3-yl]benzamide

[233]

[1529] To a solution of Compound [191-2] (20 mg) in NMP (0.5 mL) at room temperature, cesium carbonate (101 mg) and Compound [233-1] (33 mg) were added, and the mixture was stirred at 120 °C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the resulting residue at room temperature, 4M hydrogen chloride in ethyl acetate solution (4.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (5.2 mg) as a white solid.

[1530] ESI-MS: 401.2 [M + H] + .

[1531] Example 234

[1532] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-(1-propionylpiperidin-4-yl)benzamide

[234] (hereinafter referred to as Compound

[234] )

[1533]

[1534] To a solution of compound

[142] (30 mg) in DMF (0.5 mL) at room temperature, propionic acid (12 μL), DIPEA (78 μL), and (1-cyano-2-ethoxy-2-oxoethylaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (65 mg) were added, and the mixture was stirred at room temperature for 18 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (20 mg) as a peach-colored solid.

[1535] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.59 (d, J = 5.5 Hz, 1H), 8.42 (d, J = 7.8 Hz, 1H), 8.24 - 8.23 (m, 1H), 8.11 - 8.08 (m, 2H), 8.03 - 8.01 (m, 2H), 7.74 - 7.71 (m, 1H), 7.37 - 7.36 (m, 1H), 4.39 - 4.36 (m, 1H), 4.07 - 4.06 (m, 1H), 3.89 - 3.86 (m, 1H), 3.15 - 3.08 (m, 1H), 2.72 - 2.66 (m, 1H), 2.37 - 2.32 (m, 2H), 1.90 - 1.81 (m, 2H), 1.50 - 1.38 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).

[1536] ESI-MS: 378.2 [M + H] + 。

[1537] Example 235

[1538] Synthesis of N-[1-(cyclopropanecarbonyl)piperidin-4-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide

[235] (hereinafter referred to as compound

[235] )

[1539]

[1540] To a solution of compound

[142] (50 mg) in DMF (1.0 mL) at room temperature, cyclopropanecarboxylic acid (100 μL), DIPEA (100 μL), and (1-cyano-2-ethoxy-2-oxoethylaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (100 mg) were added, and the mixture was stirred at room temperature for 22 h. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (40 mg) as a white solid.

[1541] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.59 (d, J = 5.5 Hz, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.26 - 8.22 (m, 1H), 8.10 (d, J = 7.3 Hz, 2H), 8.02 (d, J = 7.3 Hz, 2H), 7.74 - 7.71 (m, 1H), 7.37 - 7.36 (m, 1H), 4.36 - 4.25 (m, 2H), 4.11 - 4.07 (m, 1H), 3.26 - 3.19 (m, 1H), 2.79 - 2.65 (m, 1H), 2.05 - 1.82 (m, 3H), 1.52 - 1.42 (m, 2H), 0.73 - 0.69 (m, 4H).

[1542] ESI-MS: 390.2 [M + H] + 。

[1543] Example 236

[1544] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(oxetan-3-yl)piperidin-4-yl]benzamide

[236] (hereinafter referred to as compound

[236] )

[1545]

[1546] To a solution of compound

[142] (60 mg) in THF (1.0 mL) / dichloromethane (1.5 mL) at room temperature, DIPEA (103 μL), sodium acetate (17 mg), 3-oxetanone (16 mg), and sodium cyanoborohydride (48 mg) were added, and the mixture was stirred at 60 °C for 5 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (18 mg) as a white solid.

[1547] 1H-NMR (400 MHz, DMSO-d6) δ: 8.59 (dd, J = 5.6, 3.6 Hz, 1H), 8.40 (d, J = 6.4 Hz, 1H), 8.24 (d, J = 3.2 Hz, 1H), 8.09 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 5.5 Hz, 1H), 7.37 - 7.36 (m, 1H), 4.53 (dd, J = 6.4, 6.2 Hz, 2H), 4.42 (dd, J = 6.4, 6.2 Hz, 2H), 3.88 - 3.75 (m, 1H), 3.41 - 3.35 (m, 1H), 2.73 - 2.65 (m, 2H), 1.89 - 1.80 (m, 4H), 1.64 - 1.54 (m, 2H).

[1548] ESI-MS: 378.2 [M + H] + 。

[1549] Example 237

[1550] Synthesis of N-[1-(1,3,4-thiadiazol-2-yl)piperidin-4-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide

[237] (hereinafter referred to as Compound

[237] )

[1551]

[1552] To a solution of Compound

[142] (30 mg) in NMP (0.5 mL) at room temperature, cesium carbonate (124 mg) and 2-chloro-1,3,4-thiadiazole (30 mg) were added, and the mixture was stirred at 90 °C for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (4.2 mg) as a white solid.

[1553] 1 H-NMR (400 MHz, DMSO-d6) δ: 8.81 (s, 1H), 8.59 (d, J = 5.5 Hz, 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.09 (d, J = 8.7 Hz, 2H), 8.02 (d, J = 8.7 Hz, 2H), 7.72 (dd, J = 5.7, 1.1 Hz, 1H), 7.37 - 7.36 (m, 1H), 4.17 - 4.09 (m, 1H), 3.93 - 3.89 (m, 2H), 3.30 - 3.27 (m, 2H), 2.02 - 1.92 (m, 2H), 1.74 - 1.64 (m, 2H).

[1554] ESI-MS: 406.1 [M+H]+ + 。

[1555] Example 238

[1556] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(imidazo[1,2-a]pyridin-5-yl)piperidin-4-yl]benzamide

[238] (hereinafter referred to as compound

[238] )

[1557]

[1558] Based on the method of Example 237, 5-chloroimidazo[1,2-a]pyridine was used instead of 2-chloro-1,3,4-thiadiazole to synthesize the title compound.

[1559] ESI-MS: 438.2 [M+H]+ + 。

[1560] Example 239

[1561] Synthesis of N-[1-(1-ethyl-1H-tetrazol-5-yl)piperidin-4-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide

[239] (hereinafter referred to as compound

[239] )

[1562]

[1563] To a solution of compound

[142] (100 mg) in acetonitrile (0.83 mL) at room temperature, ethyl isothiocyanate (28 μL) and DIPEA (127 μL) were added. After sealing the container, the mixture was stirred at 100 °C for 30 minutes. Then, 1,3-propane sultone (44 μL) and triethylamine (104 μL) were added at 100 °C. After sealing the container, the mixture was stirred at 100 °C for 1 hour. Then, sodium azide (163 mg) was added at 100 °C. After sealing the container, the mixture was stirred at 100 °C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (15 mg) as a white solid.

[1564] ESI-MS: 418.2 [M+H]+ + 。

[1565] Examples 240 to 243

[1566] Based on the method shown in Example 239, the compounds of Examples 240 to 243 shown in the following table were synthesized. The structures, names, and ESI-MS of the compounds of each example are shown in the following table.

[1567]

[1568] Example 244

[1569] Synthesis of N-[1-(3-chloro-4-methoxybenzyl)piperidin-4-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide

[244] (hereinafter referred to as Compound

[244] )

[1570]

[1571] To a solution of Compound

[142] (20 mg) in dichloromethane (0.5 mL) at room temperature were added 60% sodium hydride (3.0 mg) and 3-chloro-4-methoxybenzaldehyde (20 mg), and the mixture was stirred at room temperature for 10 minutes. Then, sodium triacetoxyborohydride (34 mg) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (4.9 mg) as a yellow solid.

[1572] ESI-MS: 476.2 [M+H] + 。

[1573] Example 245

[1574] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]benzamide

[245] (hereinafter referred to as Compound

[245] )

[1575]

[1576] To a solution of Compound

[142] (21 mg) in DMF (0.5 mL) at room temperature were added DIPEA (27 μL), 2-hydroxyisobutyric acid (7.5 mg), and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (31 mg), and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (8.2 mg) as a white solid.

[1577] 11H-NMR (400 MHz, DMSO-d6) δ: 8.56 (d, J = 5.5 Hz, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.06 (d, J = 8.7 Hz, 2H), 8.02 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 5.5 Hz, 1H), 7.37 - 7.36 (m, 1H), 5.35 (s, 1H), 4.84 - 4.34 (m, 2H), 4.12 - 4.04 (m, 1H), 3.20 - 2.66 (m, 2H), 1.87 - 1.84 (m, 2H), 1.52 - 1.44 (m, 2H), 1.33 (s, 6H).

[1578] ESI-MS: 408.2 [M + H] + 。

[1579] Example 246

[1580] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]benzamide

[246] (hereinafter referred to as Compound

[246] )

[1581]

[1582] Based on the method of Example 245, 3,3,3-trifluoropropionic acid was used instead of 2-hydroxyisobutyric acid to synthesize the title compound.

[1583] ESI-MS: 432.2 [M + H] + 。

[1584] Example 247

[1585] Synthesis of N-(1-cyanopiperidin-4-yl)-4-(furo[3,2-c]pyridin-4-yl)benzamide

[247] (hereinafter referred to as Compound

[247] )

[1586]

[1587] To a solution of Compound

[142] (100 mg) in dichloromethane (1.0 mL) at room temperature, DIPEA (255 μL) and cyanogen bromide (379 mg) were added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (92 mg) as a yellow solid.

[1588] ESI-MS: 347.1 [M + H] + 。

[1589] Example 248

[1590] Synthesis of N-[1-(1H-tetrazol-5-yl)piperidin-4-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide

[248] (hereinafter referred to as Compound

[248] )

[1591]

[1592] To a solution of Compound

[247] (87 mg) in DMF (2.0 mL) at room temperature were added sodium azide (253 mg) and triethylamine hydrochloride (253 mg), and the mixture was stirred at 100 °C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (21 mg) as a white solid.

[1593] ESI-MS: 390.2 [M+H] + .

[1594] Example 249

[1595] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(2-methyl-2H-tetrazol-5-yl)piperidin-4-yl]benzamide

[249] (hereinafter referred to as Compound

[249] )

[1596]

[1597] To a solution of Compound

[248] (19 mg) in DMF (0.5 mL) at room temperature were added potassium carbonate (20 mg) and iodomethane (5.0 μL), and the mixture was stirred at 60 °C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (11 mg) as a white solid.

[1598] ESI-MS: 404.2 [M+H] + .

[1599] Example 250

[1600] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(1-methyl-1H-pyrazol-5-yl)piperidin-4-yl]benzamide

[250] (hereinafter referred to as Compound

[250] )

[1601]

[1602] Synthesis of N-[1-(4-formyl-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide [250-1] (hereinafter referred to as Compound [250-1])

[1603]

[1604] To a solution of Compound

[142] (14 mg) in DMSO (0.2 mL) at room temperature were added DIPEA (12 μL), cesium carbonate (10 mg), and 5-chloro-1-methyl-1H-pyrazole-4-carbaldehyde (10 mg). Using a microwave reaction apparatus, the mixture was stirred at 150 °C for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2.5 mg) as a brown oil.

[1605] ESI-MS: 430.2 [M + H] + .

[1606] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(1-methyl-1H-pyrazol-5-yl)piperidin-4-yl]benzamide

[250]

[1607] To a solution of Compound [250-1] (2.5 mg) in methanol (0.2 mL) at room temperature was added p-toluenesulfonic acid monohydrate (0.1 mg). Using a microwave reaction apparatus, the mixture was stirred at 120 °C for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2.0 mg) as a brown solid.

[1608] ESI-MS: 402.2 [M + H] + .

[1609] Example 251

[1610] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(1-methyl-1H-imidazol-2-yl)piperidin-4-yl]benzamide

[251] (hereinafter referred to as Compound

[251] )

[1611]

[1612] Synthesis of 4-azido-1-(1-methyl-1H-imidazol-2-yl)piperidine [251-1] (hereinafter referred to as Compound [251-1])

[1613]

[1614] At room temperature, to a solution of 1-(1-methyl-1H-imidazol-2-yl)piperidin-4-ol (16 mg) in dichloromethane (0.5 mL) obtained by the method described in the literature (International Publication No. 2011 / 143645), triethylamine (23 μL) and methanesulfonyl chloride (33 μL) were added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. At room temperature, sodium azide (28 mg) was added to a solution of the resulting residue in DMF (0.3 mL) / THF (0.3 mL), and the mixture was stirred at 100 °C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (9.3 mg) as a yellow oil.

[1615] ESI-MS: 207.2 [M+H] + 。

[1616] (2) Synthesis of 1-(1-methyl-1H-imidazol-2-yl)piperidin-4-amine [251-2] (hereinafter referred to as compound [251-2])

[1617]

[1618] To a solution of compound [251-1] (9.3 mg) in ethanol (0.5 mL) at room temperature, 10% palladium on activated carbon (4.8 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (5.4 mg) as a colorless oil.

[1619] 1 1H-NMR (400 MHz, CDCl3) δ: 6.76 (d, J = 1.4 Hz, 1H), 6.65 (d, J = 1.4 Hz, 1H), 3.72 (s, 3H), 3.23 - 3.20 (m, 2H), 2.95 - 2.84 (m, 3H), 2.68 (br, 2H), 1.96 - 1.93 (m, 2H), 1.62 - 1.54 (m, 2H).

[1620] (3) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(1-methyl-1H-imidazol-2-yl)piperidin-4-yl]benzamide

[251]

[1621] The title compound was synthesized from compound [251-2] based on the method of step (2) of Example 99.

[1622] ESI-MS: 402.2 [M+H] + .

[1623] Example 252

[1624] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[1-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl]benzamide

[252] (hereinafter referred to as compound

[252] )

[1625]

[1626] To a solution of compound

[142] (113 mg) in DMSO (0.9 mL) at room temperature, 4-iodo-1-methylpyrazole (30.0 mg), DIPEA (98.0 μL), L-proline (13.0 mg), potassium carbonate (100 mg), and copper(I) iodide (11.0 mg) were added, and the mixture was stirred at 100 °C for 23 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (10.7 mg) as an orange solid.

[1627] ESI-MS: 402.2 [M+H] + .

[1628] Example 253

[1629] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{1-[4-(hydroxymethyl)-1-methyl-1H-imidazol-5-yl]piperidin-4-yl}benzamide

[253] (hereinafter referred to as compound

[253] )

[1630]

[1631] (1) Synthesis of N-[1-(4-formyl-1-methyl-1H-imidazol-5-yl)piperidin-4-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide [253-1] (hereinafter referred to as compound [253-1])

[1632]

[1633] Based on the method of step (1) of Example 250, 5-chloro-1-methyl-1H-imidazole-4-carbaldehyde obtained by the method described in the literature (International Publication No. 2010 / 132999) was used instead of 5-chloro-1-methyl-1H-pyrazole-4-carbaldehyde to synthesize the title compound.

[1634] ESI-MS: 430.2 [M+H] + 。

[1635] (2) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{1-[4-(hydroxymethyl)-1-methyl-1H-imidazol-5-yl]piperidin-4-yl}benzamide

[253]

[1636] To a solution of compound [253-1] (33 mg) in methanol (0.8 mL) at room temperature was added sodium borohydride (12 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound as a white solid (13 mg).

[1637] ESI-MS: 432.2 [M+H] + 。

[1638] Example 254

[1639] Synthesis of ethyl 2-{4-[4-(furo[3,2-c]pyridin-4-yl)benzamido]piperidin-1-yl}oxazole-5-carboxylate

[254] (hereinafter referred to as compound

[254] )

[1640]

[1641] To a solution of compound

[142] (53 mg) in acetonitrile (0.65 mL) at room temperature were added ethyl 2-chloro-1,3-oxazole-5-carboxylate (28 mg) and potassium carbonate (90 mg), and the mixture was stirred at 80 °C for 22 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound as a yellow solid (42 mg).

[1642] ESI-MS: 461.2 [M+H] + 。

[1643] Example 255

[1644] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{1-[5-(hydroxymethyl)oxazol-2-yl]piperidin-4-yl}benzamide

[255] (hereinafter referred to as compound

[255] )

[1645]

[1646] To a solution of compound

[254] (4.7 mg) in ethanol (0.3 mL) at room temperature, sodium borohydride (1.8 mg) and lithium chloride (2.2 mg) were added, and the mixture was stirred at 70 °C for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (1.9 mg) as a white solid.

[1647] ESI-MS: 419.2 [M+H] + 。

[1648] Example 256

[1649] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-(trans-4-hydroxycyclohexyl)benzamide

[256] (hereinafter referred to as compound

[256] )

[1650]

[1651] To a solution of compound [99-1] (239 mg) in DMF (3.3 mL) at room temperature, DIPEA (680 μL), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (471 mg), and trans-4-aminocyclohexanol (150 mg) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (206 mg) as a white solid.

[1652] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.58 (d, J = 5.9 Hz, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.08 (dd, J = 6.9, 1.8 Hz, 2H), 8.00 (dd, J = 6.6, 2.1 Hz, 2H), 7.72 (dd, J = 5.7, 1.1 Hz, 1H), 7.37 - 7.36 (m, 1H), 4.55 (d, J = 4.1 Hz, 1H), 3.77 - 3.73 (m, 1H), 3.43 - 3.31 (m, 1H), 1.87 - 1.82 (m, 4H), 1.45 - 1.33 (m, 2H), 1.30 - 1.19 (m, 2H).

[1653] ESI-MS: 337.2 [M+H] + 。

[1654] Example 257

[1655] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(1-hydroxycyclopropyl)cyclohexyl]benzamide

[257] (hereinafter referred to as Compound

[257] )

[1656]

[1657] (1) Synthesis of methyl trans-4-(dibenzylamino)cyclohexane-1-carboxylate [257-1] (hereinafter referred to as Compound [257-1])

[1658]

[1659] To a solution of methyl trans-4-aminocyclohexanecarboxylate hydrochloride (387 mg) in acetonitrile (6.7 mL) at room temperature, potassium carbonate (1.11 g) and benzyl bromide (598 μL) were added, and the mixture was stirred at 80 °C for 9 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography to obtain the title compound (344 mg) as a white solid.

[1660] 1 1H-NMR (400 MHz, CDCl3) δ: 7.36 - 7.35 (m, 4H), 7.30 - 7.26 (m, 4H), 7.22 - 7.18 (m, 2H), 3.63 - 3.62 (m, 7H), 2.55 - 2.49 (m, 1H), 2.23 - 2.17 (m, 1H), 2.02 - 1.95 (m, 4H), 1.43 - 1.30 (m, 4H).

[1661] ESI-MS: 338.6 [M+H] + .

[1662] (2) Synthesis of 1-[trans-4-(dibenzylamino)cyclohexyl]cyclopropan-1-ol [257-2] (hereinafter referred to as Compound [257-2])

[1663]

[1664] Under an argon atmosphere, to a solution of Compound [257-1] (238 mg) in THF (23.5 mL) at room temperature, tetraisopropoxytitanium (620 μL) was added. To this reaction mixture, a 1 M solution of ethylmagnesium bromide in THF (4.23 mL) was added dropwise over 5 minutes, and then the mixture was stirred at room temperature for 21 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (186 mg) as a white solid.

[1665] 1 1H-NMR (400 MHz, CDCl3) δ: 7.38 - 7.36 (m, 4H), 7.30 - 7.26 (m, 4H), 7.22 - 7.18 (m, 2H), 3.62 (s, 4H), 2.54 - 2.47 (m, 1H), 1.99 - 1.95 (m, 2H), 1.83 - 1.80 (m, 2H), 1.62 (s, 1H), 1.42 - 1.32 (m, 2H), 1.26 - 1.16 (m, 2H), 0.93 - 0.85 (m, 1H), 0.68 - 0.66 (m, 2H), 0.42 - 0.39 (m, 2H).

[1666] ESI-MS: 336.1 [M + H] + 。

[1667] (3) Synthesis of 1-(trans-4-aminocyclohexyl)cyclopropan-1-ol [257-3] (hereinafter referred to as compound [257-3])

[1668]

[1669] To a solution of compound [257-2] (185 mg) in ethanol (6.9 mL) at room temperature was added 20% palladium hydroxide on carbon (37.0 mg), and the mixture was stirred for 17 hours at room temperature under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (81.8 mg) as a white solid.

[1670] 1 1H-NMR (400 MHz, CDCl3) δ: 2.67 - 2.59 (m, 1H), 1.94 - 1.90 (m, 2H), 1.81 - 1.76 (m, 2H), 1.41 - 1.30 (m, 2H), 1.13 - 1.03 (m, 2H), 0.95 - 0.87 (m, 1H), 0.72 - 0.69 (m, 2H), 0.46 - 0.43 (m, 2H).

[1671] ESI-MS: 156.3 [M + H] + 。

[1672] (4) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(1-hydroxycyclopropyl)cyclohexyl]benzamide

[257]

[1673] To a solution of compound [99-1] (59 mg) in DMF (0.82 mL) at room temperature, DIPEA (209 μL), (1-cyano-2-ethoxy-2-oxoethylaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (137 mg) and compound [257-3] (38 mg) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (18 mg) as an orange solid.

[1674] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.58 (d, J = 5.9 Hz, 1H), 8.33 (d, J = 8.2 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.10 - 8.08 (m, 2H), 8.01 - 7.99 (m, 2H), 7.72 (dd, J = 5.5, 0.9 Hz, 1H), 7.37 - 7.36 (m, 1H), 4.87 (s, 1H), 3.74 - 3.72 (m, 1H), 1.93 - 1.88 (m, 2H), 1.75 - 1.70 (m, 2H), 1.36 - 1.31 (m, 4H), 0.94 - 0.89 (m, 1H), 0.50 - 0.47 (m, 2H), 0.36 - 0.33 (m, 2H).

[1675] ESI-MS: 377.2 [M + H] + 。

[1676] Example 258

[1677] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{trans-4-[(1-hydroxycyclopropyl)methoxy]cyclohexyl}benzamide

[258] (hereinafter referred to as compound

[258] )

[1678]

[1679] (1) Synthesis of 1-({[trans-4-(dibenzylamino)cyclohexyl]oxy}methyl)cyclopropan-1-ol [258-1] (hereinafter referred to as compound [258-1])

[1680]

[1681] To a solution of compound [64-1] (398 mg) in THF (32 mL) at room temperature, titanium(IV) isopropoxide (852 μL) and a 1 M solution of ethylmagnesium bromide in THF (5.82 mL) were added, and the mixture was stirred at room temperature for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (45.0 mg) as a white solid.

[1682] ESI-MS: 366.3 [M+H] + 。

[1683] (2) Synthesis of 1-{[(trans-4-aminocyclohexyl)oxy]methyl}cyclopropan-1-ol [258-2] (hereinafter referred to as compound [258-2])

[1684]

[1685] To a solution of compound [258-1] (45 mg) in ethanol (0.5 mL) at room temperature, 20% palladium hydroxide on carbon (20 mg) was added, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (25 mg) as a colorless oil.

[1686] 1 1H-NMR (400 MHz, CD3OD) δ: 3.51 (s, 2H), 3.39 - 3.32 (m, 1H), 2.77 - 2.72 (m, 1H), 2.09 - 2.06 (m, 2H), 1.94 - 1.91 (m, 2H), 1.33 - 1.21 (m, 4H), 0.71 - 0.68 (m, 2H), 0.57 - 0.50 (m, 2H).

[1687] ESI-MS: 186.2 [M+H] + 。

[1688] (3) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{trans-4-[(1-hydroxycyclopropyl)methoxy]cyclohexyl}benzamide

[258]

[1689] To a solution of compound [99-1] (13 mg) in DMF (0.5 mL) at room temperature, (1-cyano-2-ethoxy-2-oxoethylaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (23 mg), DIPEA (9.1 μL), and compound [258-2] (9.0 mg) were added, and the mixture was stirred at room temperature for 19 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (6.2 mg) as a white solid.

[1690] 1 1H-NMR (400 MHz, CD3OD) δ: 8.53 (d, J = 5.9 Hz, 1H), 7.99 - 7.98 (m, 5H), 7.63 (d, J = 5.5 Hz, 1H), 7.19 (d, J = 1.1 Hz, 1H), 3.94 - 3.88 (m, 1H), 3.54 (s, 2H), 3.47 - 3.43 (m, 1H), 2.17 - 2.14 (m, 2H), 2.07 - 2.04 (m, 2H), 1.52 - 1.35 (m, 4H), 0.71 - 0.68 (m, 2H), 0.59 - 0.56 (m, 2H).

[1691] ESI-MS: 407.3 [M + H] + 。

[1692] Example 259

[1693] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-(trans-4-hydroxy-4-methylcyclohexyl)benzamide

[259] (hereinafter referred to as compound

[259] )

[1694]

[1695] To a solution of compound [99-1] (50 mg) in DMF (1.0 mL) at room temperature, (1-cyano-2-ethoxy-2-oxoethylaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (116 mg), DIPEA (142 μL), and trans-4-amino-1-methylcyclohexanol (35 mg) were added, and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (30 mg) as a reddish-brown solid.

[1696] 1H-NMR (400 MHz, DMSO-d6) δ: 8.59 (d, J = 5.5 Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.08 (d, J = 8.2 Hz, 2H), 8.00 (d, J = 8.2 Hz, 2H), 7.73 - 7.71 (m, 1H), 7.37 - 7.36 (m, 1H), 4.29 (br, 1H), 3.87 - 3.79 (m, 1H), 1.78 - 1.75 (m, 2H), 1.62 - 1.58 (m, 2H), 1.54 - 1.41 (m, 4H), 1.16 (s, 3H).

[1697] ESI-MS: 351.2 [M + H] + 。

[1698] Example 260

[1699] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)benzamide

[260] (hereinafter referred to as Compound

[260] )

[1700]

[1701] To a solution of Compound [99-1] (30 mg) in DMF (1.0 mL) at room temperature, (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (160 mg), DIPEA (64 μL), and 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (49 mg) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (31 mg) as a yellow solid.

[1702] 1 H-NMR (400 MHz, DMSO-d6) δ: 8.58 (d, J = 5.9 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.04 (d, J = 8.2 Hz, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.74 - 7.72 (m, 2H), 7.34 - 7.33 (m, 1H), 3.51 (br, 1H), 2.07 - 2.03 (m, 6H), 1.64 - 1.60 (m, 6H).

[1703] ESI-MS: 363.2 [M + H] + 。

[1704] Examples 261 - 285

[1705] Based on the method of Example 260, the compounds of Examples 261 - 285 shown in the following table were synthesized. The structures, names, and ESI-MS of the compounds of each example are shown in the following table.

[1706]

[1707]

[1708]

[1709]

[1710]

[1711] Example 286

[1712] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(methoxy-d3)cyclohexyl]benzamide

[286] (hereinafter referred to as Compound

[286] )

[1713]

[1714] (1) Synthesis of trans-N,N-dibenzyl-4-(methoxy-d3)cyclohexan-1-amine [286-1] (hereinafter referred to as Compound [286-1])

[1715]

[1716] To a solution of Compound [64-1] (200 mg) in THF (3.4 mL) at 0 °C, 60% sodium hydride (82 mg) and iodomethane-d3 (60 μL) were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (199 mg) as a colorless oil.

[1717] 1 1H-NMR (400 MHz, CDCl3) δ: 7.37 - 7.18 (m, 10H), 3.61 (s, 4H), 3.10 - 3.00 (m, 1H), 2.58 - 2.47 (m, 1H), 2.09 - 2.03 (m, 2H), 1.96 - 1.90 (m, 2H), 1.41 - 1.37 (m, 2H), 1.13 - 1.02 (m, 2H).

[1718] ESI-MS: 313.3 [M + H]+ 。

[1719] (2) Synthesis of 4-(Furo[3,2-c]pyridin-4-yl)-N-[trans-4-(methoxy-d3)cyclohexyl]benzamide

[286]

[1720] The title compound was synthesized from compound [286-1] by the method based on steps (3) and (4) of Example 257.

[1721] 1 H-NMR (400 MHz, DMSO-d6) δ: 8.58 (d, J = 5.7 Hz, 1H), 8.34 (d, J = 7.8 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.08 (dd, J = 6.4, 1.8 Hz, 2H), 8.00 (dd, J = 6.9, 1.8 Hz, 2H), 7.72 (d, J = 5.5 Hz, 1H), 7.36 - 7.35 (m, 1H), 3.82 - 3.76 (m, 1H), 3.13 - 3.03 (m, 1H), 2.07 - 2.02 (m, 2H), 1.90 - 1.86 (m, 2H), 1.45 - 1.32 (m, 2H), 1.26 - 1.19 (m, 2H).

[1722] ESI-MS: 354.2 [M + H] + 。

[1723] Example 287

[1724] Synthesis of N-(trans-4-Ethoxycyclohexyl)-4-(furo[3,2-c]pyridin-4-yl)benzamide

[287] (hereinafter referred to as compound

[287] )

[1725]

[1726] (1) Synthesis of trans-N,N-Dibenzyl-4-ethoxycyclohexan-1-amine [287-1] (hereinafter referred to as compound [287-1])

[1727]

[1728] Based on the method of step (1) of Example 286, using iodoethane instead of iodomethane-d3, the title compound was synthesized.

[1729] ESI-MS: 324.3 [M + H] + 。

[1730] (2) Synthesis of N-(trans-4-Ethoxycyclohexyl)-4-(furo[3,2-c]pyridin-4-yl)benzamide

[287]

[1731] The title compound was synthesized from compound [287-1] by the method based on steps (3) and (4) of Example 257.

[1732] ESI-MS: 365.2 [M+H] + 。

[1733] Example 288

[1734] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-(trans-4-isopropoxycyclohexyl)benzamide

[288] (hereinafter referred to as compound

[288] )

[1735]

[1736] (1) Synthesis of trans-N,N-dibenzyl-4-isopropoxycyclohexan-1-amine [288-1] (hereinafter referred to as compound [288-1])

[1737]

[1738] The title compound was synthesized by the method based on step (1) of Example 286, using isopropyl iodide instead of iodomethane-d3.

[1739] ESI-MS: 338.3 [M+H] + 。

[1740] (2) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-(trans-4-isopropoxycyclohexyl)benzamide

[288]

[1741] The title compound was synthesized from compound [288-1] by the method based on steps (3) and (4) of Example 257.

[1742] 1 1H-NMR (400 MHz, CD3OD) δ: 8.51 (d, J = 5.9 Hz, 1H), 8.00 - 7.99 (m, 5H), 7.61 (dd, J = 5.9, 0.9 Hz, 1H), 7.18 (d, J = 0.9 Hz, 1H), 3.93 - 3.86 (m, 1H), 3.82 - 3.76 (m, 1H), 3.40 - 3.38 (m, 1H), 2.06 - 2.04 (m, 4H), 1.65 - 1.52 (m, 4H), 1.13 (d, J = 5.9 Hz, 6H).

[1743] ESI-MS: 379.3 [M+H] + 。

[1744] Example 289

[1745] Synthesis of N-(trans-4-ethyl-4-hydroxycyclohexyl)-4-(furo[3,2-c]pyridin-4-yl)benzamide

[289] (hereinafter referred to as Compound

[289] )

[1746]

[1747] (1) Synthesis of trans-4-(dibenzylamino)-1-ethylcyclohexan-1-ol [289-1-a] (hereinafter referred to as Compound [289-1-a]) and cis-4-(dibenzylamino)-1-ethylcyclohexan-1-ol [289-1-b] (hereinafter referred to as Compound [289-1-b])

[1748]

[1749] To a solution of 4-(dibenzylamino)cyclohexanone (1.0 g) in toluene (15 mL) at room temperature was added a toluene solution of 1.1 M triethylaluminum (6.8 mL), and the mixture was stirred at room temperature for 16 hours. 2 M aqueous sodium hydroxide solution (4.5 mL) was added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound [289-1-a] (96 mg) and the title compound [289-1-b] (102 mg) as white solids, respectively.

[1750] Compound [289-1-a]

[1751] 1 1H-NMR (400 MHz, CDCl3) δ: 7.35 - 7.17 (m, 10H), 3.63 (s, 4H), 2.57 - 2.53 (m, 1H), 1.77 - 1.75 (m, 4H), 1.54 (q, J = 7.5 Hz, 2H), 1.47 - 1.37 (m, 2H), 1.31 - 1.23 (m, 2H), 0.87 (t, J = 7.5 Hz, 3H).

[1752] ESI-MS: 324.2 [M + H] +

[1753] Compound [289-1-b]

[1754] 11H-NMR (400 MHz, CDCl3) δ: 7.38 - 7.18 (m, 10H), 3.66 (s, 4H), 2.48 - 2.44 (m, 1H), 1.80 - 1.58 (m, 6H), 1.39 (q, J = 7.5 Hz, 2H), 1.28 - 1.18 (m, 2H), 0.86 (t, J = 7.5 Hz, 3H).

[1755] ESI-MS: 324.2 [M + H] + 。

[1756] (2) Synthesis of N-(trans-4-ethyl-4-hydroxycyclohexyl)-4-(furo[3,2-c]pyridin-4-yl)benzamide

[289]

[1757] The title compound was synthesized from compound [289-1-a] based on the methods of steps (3) and (4) of Example 257.

[1758] ESI-MS: 365.2 [M + H] + 。

[1759] Example 290

[1760] Synthesis of N-(cis-4-ethyl-4-hydroxycyclohexyl)-4-(furo[3,2-c]pyridin-4-yl)benzamide

[290] (hereinafter referred to as compound

[290] )

[1761]

[1762] The title compound was synthesized from compound [289-1-b] based on the methods of steps (3) and (4) of Example 257.

[1763] ESI-MS: 365.2 [M + H] + 。

[1764] Example 291

[1765] Synthesis of N-(cis-4-cyclopropyl-4-hydroxycyclohexyl)-4-(furo[3,2-c]pyridin-4-yl)benzamide

[291] (hereinafter referred to as compound

[291] )

[1766]

[1767] (1) Synthesis of cis-1-cyclopropyl-4-(dibenzylamino)cyclohexan-1-ol [291-1] (hereinafter referred to as compound [291-1])

[1768]

[1769] To a solution of 4-(dibenzylamino)cyclohexanone (500 mg) in THF (57 mL) at room temperature, a THF solution of 0.7 M cyclopropylmagnesium bromide (14.6 mL) was added, and the mixture was stirred at room temperature for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (104 mg) as a white solid.

[1770] ESI-MS: 336.2 [M+H] + 。

[1771] (2) Synthesis of N-(cis-4-cyclopropyl-4-hydroxycyclohexyl)-4-(furo[3,2-c]pyridin-4-yl)benzamide

[291]

[1772] The title compound was synthesized from compound [291-1] according to the methods of steps (3) and (4) of Example 257.

[1773] ESI-MS: 377.3 [M+H] + 。

[1774] Example 292

[1775] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-(cis-4-hydroxy-4-isopropylcyclohexyl)benzamide

[292] (hereinafter referred to as compound

[292] )

[1776]

[1777] (1) Synthesis of cis-4-(dibenzylamino)-1-isopropylcyclohexan-1-ol [292-1] (hereinafter referred to as compound [292-1])

[1778]

[1779] The title compound was synthesized according to the method of step (1) of Example 291, using a 2 M THF solution of isopropylmagnesium chloride instead of the 0.7 M THF solution of cyclopropylmagnesium bromide.

[1780] ESI-MS: 338.3 [M+H] + 。

[1781] (2) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-(cis-4-hydroxy-4-isopropylcyclohexyl)benzamide

[292]

[1782] The title compound was synthesized from compound [292-1] by the method based on steps (3) and (4) of Example 257.

[1783] ESI-MS: 379.3 [M+H] + .

[1784] Example 293

[1785] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-(cis-4-hydroxycycloheptyl)benzamide

[293] (hereinafter referred to as compound

[293] )

[1786]

[1787] (1) Synthesis of cis-4-aminocycloheptan-1-ol hydrochloride [293-1] (hereinafter referred to as compound [293-1])

[1788]

[1789] To a solution of tert-butyl N-(4-oxocycloheptyl)carbamate (120 mg) in methanol (5.4 mL) at room temperature was added sodium borohydride (31 mg), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the resulting residue at room temperature was added a 4M hydrogen chloride solution in ethyl acetate (2.0 mL), and the mixture was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (85 mg) as a yellow oil.

[1790] ESI-MS: 130.2 [M+H] + .

[1791] (2) Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-(cis-4-hydroxycycloheptyl)benzamide

[293]

[1792] The title compound was synthesized from compound [293-1] by the method based on Example 190.

[1793] ESI-MS: 351.2 [M+H] + .

[1794] Example 294

[1795] Synthesis of N-{trans-4-[(2,2-difluoroethyl)amino]cyclohexyl}-4-(furo[3,2-c]pyridin-4-yl)benzamide

[294] (hereinafter referred to as compound

[294] )

[1796]

[1797] (1) Synthesis of N-(trans-4-aminocyclohexyl)-4-(furo[3,2-c]pyridin-4-yl)benzamide [294-1] (hereinafter referred to as Compound [294-1])

[1798]

[1799] To a solution of Compound [99-1] (50 mg) in methanol (2.0 mL) / toluene (1.0 mL) at room temperature, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (290 mg) and trans-1,4-cyclohexanediamine (150 mg) were added, and the mixture was stirred at 110 °C for 17 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (30 mg) as a white solid.

[1800] 1 1H-NMR (400 MHz, DMSO-d6) δ: 8.55 (d, J = 5.5 Hz, 1H), 8.29 - 8.28 (m, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.04 (d, J = 8.2 Hz, 2H), 7.97 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 5.5 Hz, 1H), 7.33 - 7.32 (m, 1H), 3.72 - 3.69 (m, 1H), 3.28 (br, 2H), 2.55 - 2.45 (m, 1H), 1.81 - 1.77 (m, 4H), 1.41 - 1.32 (m, 2H), 1.18 - 1.12 (m, 2H).

[1801] ESI-MS: 336.2 [M + H] + .

[1802] (2) Synthesis of N-{trans-4-[(2,2-difluoroethyl)amino]cyclohexyl}-4-(furo[3,2-c]pyridin-4-yl)benzamide

[294]

[1803] To a solution of Compound [294-1] (14 mg) in 1,4-dioxane (0.5 mL) at room temperature, DIPEA (15 μL) and 2,2-difluoroethyl trifluoromethanesulfonate (40 μL) were added, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (8.2 mg) as a white solid.

[1804] 11H-NMR (400 MHz, DMSO-d6) δ: 8.56 (d, J = 5.9 Hz, 1H), 8.32 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 1.8 Hz, 1H), 8.06 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 5.5 Hz, 1H), 7.37 - 7.36 (m, 1H), 5.96 (t, J = 63.0 Hz, 1H), 3.80 - 3.70 (m, 1H), 3.10 - 2.85 (m, 2H), 2.44 - 2.38 (m, 1H), 1.97 - 1.83 (m, 5H), 1.40 - 1.31 (m, 2H), 1.15 - 1.10 (m, 2H).

[1805] ESI-MS: 400.3 [M + H] + 。

[1806] Example 295

[1807] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(oxetan-3-ylamino)cyclohexyl]benzamide

[295] (hereinafter referred to as Compound

[295] )

[1808]

[1809] To a solution of Compound [294-1] (53 mg) in dichloromethane (1.6 mL) / DMF (1.0 mL) at room temperature were added sodium acetate (54 mg), 3-oxetanone (16 mg) and sodium cyanoborohydride (50 mg), and the mixture was stirred at 80 °C for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (22 mg) as a white solid.

[1810] 11H-NMR (400 MHz, DMSO-d6) δ: 8.58 (dd, J = 5.7, 2.1 Hz, 1H), 8.32 (d, J = 6.9 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.08 (d, J = 6.4 Hz, 2H), 8.00 (d, J = 6.4 Hz, 2H), 7.72 (d, J = 5.9 Hz, 1H), 7.37 - 7.36 (m, 1H), 4.62 (dd, J = 6.2, 5.9 Hz, 2H), 4.30 (dd, J = 6.2, 5.9 Hz, 2H), 3.97 - 3.94 (m, 1H), 3.76 - 3.68 (m, 1H), 3.46 - 3.40 (m, 1H), 2.40 - 2.36 (m, 1H), 1.89 - 1.75 (m, 4H), 1.40 - 1.31 (m, 2H), 1.15 - 1.06 (m, 2H).

[1811] ESI-MS: 392.2 [M + H] + 。

[1812] Example 296

[1813] Synthesis of N-(trans-4-acetamidocyclohexyl)-4-(furo[3,2-c]pyridin-4-yl)benzamide

[296] (hereinafter referred to as Compound

[296] )

[1814]

[1815] To a solution of Compound [294-1] (10 mg) in ethyl acetate (0.5 mL) at room temperature was added acetic anhydride (36 μL) and DIPEA (65 μL), and the mixture was stirred at room temperature for 90 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (5.4 mg) as a white solid.

[1816] ESI-MS: 378.2 [M + H] + 。

[1817] Example 297

[1818] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(5-methyl-1H-tetrazol-1-yl)cyclohexyl]benzamide

[297] (hereinafter referred to as Compound

[297] )

[1819]

[1820] To a solution of compound

[296] (10 mg) in pyridine (0.2 mL) at room temperature, diphenylphosphoryl azide (72 μL) was added, and the mixture was stirred at 115 °C for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (5.0 mg) as a yellow solid.

[1821] ESI-MS: 403.2 [M + H] + 。

[1822] Example 298

[1823] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-(trans-4-propionamidocyclohexyl)benzamide

[298] (hereinafter referred to as compound

[298] )

[1824]

[1825] To a solution of compound [294-1] (20 mg) in THF (0.6 mL) at 0 °C, pyridine (16 μL) and propionyl chloride (6.8 μL) were added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (5.2 mg) as a white solid.

[1826] ESI-MS: 392.2 [M + H] + 。

[1827] Example 299

[1828] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-oxopyrrolidin-1-yl)cyclohexyl]benzamide

[299] (hereinafter referred to as compound

[299] )

[1829]

[1830] To a solution of compound [294-1] (67 mg) in 1,4-dioxane (0.7 mL) at room temperature, 60% sodium hydride (21 mg) and 4-chlorobutyryl chloride (34 μL) were added, and the mixture was stirred at 80 °C for 48 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (15 mg) as a white solid.

[1831] ESI-MS: 404.3 [M + H] + 。

[1832] Example 300

[1833] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-oxopiperidin-1-yl)cyclohexyl]benzamide

[300] (hereinafter referred to as Compound

[300] )

[1834]

[1835] Based on the method of Example 299, 5-chlorovaleryl chloride was used instead of 4-chlorobutyryl chloride, and thus the title compound was synthesized.

[1836] ESI-MS: 418.3 [M+H] + .

[1837] Example 301

[1838] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-{trans-4-[(2-methoxyethyl)amino]cyclohexyl}benzamide

[301] (hereinafter referred to as Compound

[301] )

[1839]

[1840] To a solution of Compound [294-1] (35 mg) in 1,4-dioxane (1.0 mL) at room temperature, 2-bromoethyl methyl ether (12 μL) and potassium carbonate (43 mg) were added, and the mixture was stirred at 100 °C for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (3.2 mg) as a white solid.

[1841] ESI-MS: 394.2 [M+H] + .

[1842] Example 302

[1843] Synthesis of N-{trans-4-[(1,1-difluoropropan-2-yl)amino]cyclohexyl}-4-(furo[3,2-c]pyridin-4-yl)benzamide

[302] (hereinafter referred to as Compound

[302] )

[1844]

[1845] To a solution of compound [294-1] (17 mg) in dichloromethane (0.3 mL) at room temperature, 1,1-difluoroacetone (4.5 μL) and sodium cyanoborohydride (31 mg) were added, and the mixture was stirred at 80 °C for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (2.1 mg) as a white solid.

[1846] ESI-MS: 414.2 [M+H] + 。

[1847] Example 303

[1848] Synthesis of 4-(furo[3,2-c]pyridin-4-yl)-N-(4-oxocyclohexyl)benzamide

[303] (hereinafter referred to as compound

[303] )

[1849]

[1850] To a solution of compound

[256] (165 mg) in dichloromethane (5.0 mL) at room temperature, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane) (270 mg) was added, and the mixture was stirred for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (104 mg) as a yellow solid.

[1851] 1 H-NMR (400 MHz, DMSO-d6) δ: 8.59 (d, J = 5.9 Hz, 1H), 8.49 (d, J = 7.3 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 8.2 Hz, 2H), 8.03 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 5.5 Hz, 1H), 7.37 - 7.36 (m, 1H), 4.35 - 4.32 (m, 1H), 2.54 - 2.50 (m, 2H), 2.32 - 2.28 (m, 2H), 2.15 - 2.07 (m, 2H), 1.90 - 1.74 (m, 2H).

[1852] ESI-MS: 335.2 [M+H] + 。

[1853] Example 304

[1854] Synthesis of N-[trans-4-(3,3-difluoroazetidin-1-yl)cyclohexyl]-4-(furo[3,2-c]pyridin-4-yl)benzamide

[304] (hereinafter referred to as compound

[304] )

[1855]

[1856] To a solution of compound

[303] (6.1 mg) in dichloromethane (0.3 mL) at room temperature, 3,3-difluoroazetidine hydrochloride (3.2 mg) and sodium acetate (2.1 mg) were added, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (20 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under ...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, In formula (I), R 1 represents a hydrogen atom or C 1-6 alkyl; R 2 represents a hydrogen atom or C 1-6 alkyl; R 3 represents a hydrogen atom, a halogen atom, a cyano group, an amino group, a carbamoyl group, C 1-6 alkyl, C 2-6 alkenyl, or hydroxy C 1-6 alkyl; R 4 represents a hydrogen atom, a halogen atom, a cyano group, a carbamoyl group, C 1-6 alkyl, C 2-6 alkenyl, or hydroxy C 1-6 alkyl; R 5 represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, or C 1-6 alkyl; W represents an oxygen atom, a sulfur atom or a group represented by the general formula: -N(R 6 )-; R 6 represents a hydrogen atom or C 1-6 alkyl; X represents C 1-6 alkyl, hydroxy C 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl, (di-C 1-6 alkylamino)C 1-6 alkyl, or a group represented by formula (II), wherein, the wavy line represents the bonding point to the nitrogen atom, L 1 represents a single bond, C 1-6 alkanediyl or hydroxy C 1-6 alkanediyl; ring Y represents C 6-10 aryl, heteroaryl, C 3-10 cycloalkyl or a 4- to 10-membered heterocyclic group, wherein, The aforementioned C 3-10 The cycloalkyl group and the 4- to 10-membered heterocyclic group may be fused with a benzene ring or a heteroaryl ring to form a fused ring group, or may also form a bicyclic group or a spiro ring group; R 7 each independently represents a halogen atom, a cyano group, a hydroxyl group, a sulfamoyl group, an oxetanyl amino group, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a hydroxy halo C 1-6 alkyl group, a (C 1-6 alkoxy)C 1-6 alkyl group, a C 2-7 alkanoyl group, a halo C 2-7 alkanoyl group, a hydroxy C 2-7 alkanoyl group, a C 1-6 alkylsulfonyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a hydroxy C 1-6 alkoxy group, a mono(halo C 1-6 alkyl)amino group, a mono C 2-7 alkanoylamino group, a C 3-6 cycloalkyl group, a hydroxy C 3-6 cycloalkyl group, a (hydroxy C 3-6 cycloalkyl)C 1-6 alkoxy group, a C 3-6 cycloalkylcarbonyl group, a cyclic ether group, a cyclic amino group, a halo cyclic amino group or an oxo group; L 2 represents a single bond, or a C 1-6 alkanediyl; Ring Z represents phenyl, heteroaryl or a 4- to 10-membered heterocyclic group, wherein the aforementioned 4- to 10-membered heterocyclic group can be fused with a benzene ring or a heteroaryl ring to form a fused ring group, or can also form a bicyclic group or a spirocyclic group; R 8 each independently represents a halogen atom, a cyano group, a carbamoyl group, a sulfamoyl group, a morpholinocarbonyl group, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a di-C 1-6 alkylamino group, a C 2-7 alkoxycarbonyl group, a mono-C 2-7 alkanoylamino group, a di-C 2-7 alkanoylamino group, a C 3-6 cycloalkyl group, a cyclic amino group, or an oxo group; m represents 0, 1, 2 or 3; n represents 0, 1 or 2; p represents 0 or 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, X is a group represented by the general formula (II), wherein, the wavy line represents the bonding point with the nitrogen atom, L 1 , ring Y, R 7 , L 2 , ring Z, R 8 , m, n and p have the same meanings as described above.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, L 1 is a single bond or a methylene group.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, p is 1.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, Ring Y is a group represented by the general formula (III), wherein, The wavy line indicates the bonding point with L 1 ​ *Indicates the bonding point with L 2 and R 7 R and m have the same meanings as described above, ring A is a 4- to 10-membered nitrogen-containing heterocyclic group.

6. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, Ring Y is a group represented by the following general formula, wherein, The wavy line indicates the bonding point with L 1 ​ *Indicates the bonding point with L 2 ​ R 7 R and m have the same meanings as described above.

7. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, m is 0.

8. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, L 2 is a single bond.

9. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, Ring Z is phenyl or heteroaryl.

10. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, Ring Z is phenyl or a 5- or 6-membered nitrogen-containing heteroaryl.

11. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, Ring Z is a group represented by the following general formula, wherein, The wavy line indicates the bonding point with L 2 and R 8 where m and n are as defined above, R 9 is C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl or C 3-6 cycloalkyl.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, p is 0.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein, Ring Y is C 3-10 cycloalkyl, or a 4- to 10-membered heterocyclic group, said C 3-10 cycloalkyl may be fused with a benzene ring or a heteroaryl ring to form a fused ring group, or may also form a bicyclic group or a spirocyclic group, and said 4- to 10-membered heterocyclic group may be fused with a benzene ring or a heteroaryl ring to form a fused ring group, or may also form a bicyclic group or a spirocyclic group.

14. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein, Ring Y is C 3-10 cycloalkyl, and said C 3-10 cycloalkyl may be fused with a benzene ring or a heteroaryl ring to form a fused ring group, or may also form a bicyclic group or a spirocyclic group.

15. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein, Ring Y is a group represented by the following general formula, wherein, The wavy line indicates the bonding point with L 1 and R 7 and m have the same meanings as described above.

16. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein, Ring Y is a group represented by the following general formula, wherein, The wavy line indicates the bonding point with L 1 ​ R 7 and m have the same meanings as described above.

17. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein, Ring Y is a group represented by the following general formula, wherein, The wavy line indicates the bonding point with L 1 and R 7 Has the same meaning as described above.

18. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein, m is 1 or 2.

19. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, W is an oxygen atom or a group represented by the general formula: -N(R 6 ), where R 6 has the same meaning as defined above.

20. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, W is an oxygen atom.

21. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, W is a group represented by the general formula: -N(R 6 ), where R 6 has the same meaning as described above.

22. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, W is -NH-.

23. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 5 is a hydrogen atom or a fluorine atom.

24. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 1 and R 2 each independently represents a hydrogen atom, or a C 1-6 alkyl group, R 4 represents a hydrogen atom, a halogen atom or a C 1-6 alkyl group.

25. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 3 is a hydrogen atom, a halogen atom, C 1-6 alkyl or hydroxy C 1-6 alkyl.

26. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from the following (1) to (49), (1) N-[trans-4-(2-Hydroxypropan-2-yl)cyclohexyl]-4-(1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide; (2) N-[trans-4-(2-Hydroxypropan-2-yl)cyclohexyl]-4-(thieno[3,2-c]pyridin-4-yl)benzamide; (3) 4-(Furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]benzamide; (4) 4-(Furo[3,2-c]pyridin-4-yl)-N-[1-(1-methyl-1H-tetrazol-5-yl)piperidin-4-yl]benzamide; (5) 4-(Furo[3,2-c]pyridin-4-yl)-N-{trans-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}benzamide; (6) 4-(Furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide; (7) 3-Fluoro-4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide; (8) N-[trans-4-(2-Hydroxypropan-2-yl)cyclohexyl]-4-(6-methylfuro[3,2-c]pyridin-4-yl)benzamide; (9) N-[trans-4-(2-Hydroxypropan-2-yl)cyclohexyl]-4-(7-methylfuro[3,2-c]pyridin-4-yl)benzamide; (10) 4-(Furo[3,2-c]pyridin-4-yl)-N-[1-(pyrimidin-2-yl)piperidin-4-yl]benzamide; (11) 4-(Furo[3,2-c]pyridin-4-yl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]benzamide; (12) (S)-4-(Furo[3,2-c]pyridin-4-yl)-N-[1-(pyrimidin-2-yl)pyrrolidin-3-yl]benzamide; (13) (S)-4-(Furo[3,2-c]pyridin-4-yl)-N-{1-[5-(hydroxymethyl)pyrimidin-2-yl]pyrrolidin-3-yl}benzamide; (14) N-(Chroman-3-ylmethyl)-4-(furo[3,2-c]pyridin-4-yl)benzamide; (15) 4-(Furo[3,2-c]pyridin-4-yl)-N-(1-propionylpiperidin-4-yl)benzamide; (16) N-[1-(Cyclopropanecarbonyl)piperidin-4-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide; (17) 4-(Furo[3,2-c]pyridin-4-yl)-N-[1-(oxetan-3-yl)piperidin-4-yl]benzamide; (18) N-[1-(1,3,4-Thiadiazol-2-yl)piperidin-4-yl]-4-(furo[3,2-c]pyridin-4-yl)benzamide; (19) 4-(Furo[3,2-c]pyridin-4-yl)-N-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]benzamide; (20) 4-(Furo[3,2-c]pyridin-4-yl)-N-(trans-4-hydroxycyclohexyl)benzamide; (21) 4-(Furo[3,2-c]pyridin-4-yl)-N-[trans-4-(1-hydroxycyclopropyl)cyclohexyl]benzamide; (22) 4-(Furo[3,2-c]pyridin-4-yl)-N-{trans-4-[(1-hydroxycyclopropyl)methoxy]cyclohexyl}benzamide; (23) 4-(Furo[3,2-c]pyridin-4-yl)-N-(trans-4-hydroxy-4-methylcyclohexyl)benzamide; (24) 4-(Furo[3,2-c]pyridin-4-yl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)benzamide; (25) 4-(Furo[3,2-c]pyridin-4-yl)-N-[trans-4-(methoxy-d3)cyclohexyl]benzamide; (26) 4-(Furo[3,2-c]pyridin-4-yl)-N-(trans-4-isopropoxycyclohexyl)benzamide; (27) N-{trans-4-[(2,2-Difluoroethyl)amino]cyclohexyl}-4-(furo[3,2-c]pyridin-4-yl)benzamide; (28) 4-(Furo[3,2-c]pyridin-4-yl)-N-[trans-4-(oxetan-3-ylamino)cyclohexyl]benzamide; (29) 4-[6-(Hydroxymethyl)furo[3,2-c]pyridin-4-yl]-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide; (30) 4-[6-(Hydroxymethyl-d2)furo[3,2-c]pyridin-4-yl]-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide; (31) 3-Fluoro-4-(furo[3,2-c]pyridin-4-yl)-N-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]benzamide; (32) N-[trans-4-(1-hydroxycyclopropyl)cyclohexyl]-4-(6-methylfuro[3,2-c]pyridin-4-yl)benzamide; (33) N-[1-(pyrimidin-2-yl)piperidin-4-yl]-4-(1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide; (34) N-(trans-4-hydroxycyclohexyl)-4-(1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide; (35) N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(6-methyl-1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide; (36) N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(7-methyl-1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide; (37) 3-Fluoro-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]-4-(1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide; (38) N-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-4-(6-methylfuro[3,2-c]pyridin-4-yl)benzamide; (39) N-(4-hydroxybicyclo 2.2.2]octan-1-yl)-4-(6-methylfuro[3,2-c]pyridin-4-yl)benzamide; (40) N-(trans-4-hydroxy-4-methylcyclohexyl)-4-(6-methylfuro[3,2-c]pyridin-4-yl)benzamide; (41) 3-Fluoro-4-(furo[3,2-c]pyridin-4-yl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)benzamide; (42) 3-Fluoro-4-(furo[3,2-c]pyridin-4-yl)-N-(trans-4-hydroxy-4-methylcyclohexyl)benzamide; (43) 3-Fluoro-4-(furo[3,2-c]pyridin-4-yl)-N-{trans-4-[(1-hydroxycyclopropyl)methoxy]cyclohexyl}benzamide; (44) 4-(furo[3,2-c]pyridin-4-yl)-N-[cis-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]benzamide; (45) 4-(furo[3,2-c]pyridin-4-yl)-N-(4-hydroxybicyclo 2.2.1]heptan-1-yl)benzamide; (46) N-(4-cyanobicyclo[2.2.2]octan-1-yl)-4-(furo[3,2-c]pyridin-4-yl)benzamide; (47) 4-[4-(furo[3,2-c]pyridin-4-yl)benzamido]bicyclo[2.2.2]octane-1-carboxamide; (48) 4-(Furo[3,2-c]pyridin-4-yl)-N-{cis-4-[(1-hydroxycyclopropyl)methoxy]cyclohexyl}benzamide; and (49) 4-(Furo[3,2-c]pyridin-4-yl)-N-[cis-4-(2-hydroxypropan-2-yl)cyclohexyl]benzamide.

27. The following compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from N-(2-acetamidoethyl)-4-(1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide or N-(4-acetamidobutyl)-4-(1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide.

28. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof as claimed in claim 1.

29. A pharmaceutical composition for preventing or treating a disease involving H-PGDS, comprising the compound or a pharmaceutically acceptable salt thereof as claimed in claim 1.

30. The pharmaceutical composition according to claim 28, wherein, The diseases involved by H-PGDS are selected from asthma, chronic obstructive pulmonary disease, allergic rhinitis, sinusitis, eosinophilic pneumonia, atherosclerosis, rheumatoid arthritis, cystic fibrosis, actinic keratosis, chronic urticaria, dermatitis, muscular dystrophy, sarcopenia, disuse muscle atrophy, muscle injury, wound, dermatomyositis, amyotrophic lateral sclerosis, cerebral infarction, myocardial infarction, ischemic enteropathy, ischemic nephropathy, ischemic gastropathy, ischemic hepatopathy, diabetic limb ischemia and Buerger's disease.

31. An H-PGDS inhibitor comprising the compound or a pharmaceutically acceptable salt thereof as claimed in claim 1.

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