AZABENZIMIDAZOLE COMPOUND AND MEDICINE

Abstract

The purpose of the present invention is to provide a compound having PAM M3 activity. Examples of the present invention include azabenzimidazole compounds represented by the following formula [1] and pharmaceutically acceptable salts thereof. (see Formula) [1] The compounds of the present invention have PAM M3 activity. Furthermore, since the compounds of the present invention have PAM M3 activity, the compounds of the present invention are useful as preventive or therapeutic agents for micturition disorders and urine accumulation disorders in underactive bladder, hypotonic bladder, acontractile bladder, detrusor hypoactivity, and neurogenic bladder.

Description

Azabenzimidazole compounds and pharmaceuticals

[0001] The present invention relates to a pharmaceutical composition containing, as an active ingredient, a novel azabenzimidazole compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0002] Acetylcholine (ACh) is a neurotransmitter that is released from the terminals of parasympathetic and motor nerves and transmits nerve impulses by binding to acetylcholine receptors (AChRs). Acetylcholine receptors are broadly classified into G protein-coupled muscarinic receptors and ionotropic nicotinic receptors. Muscarinic receptors are classified into five subtypes, M1 to M5. Subtype M3 muscarinic receptors (hereinafter sometimes referred to as "M3 receptors") are mainly expressed in the bladder, digestive tract, pupil, salivary glands, lacrimal glands, etc., and have been reported to be involved in bladder, digestive tract, and pupil contraction, saliva and tear secretion, etc. (see Non-Patent Documents 1 and 2).

[0003] Compounds that have the effect of enhancing M3 receptor signaling are expected to be useful as preventive or therapeutic agents for diseases of the bladder and urinary tract, gastrointestinal diseases, oral diseases, eye diseases, and the like (see Non-Patent Documents 3 to 6).

[0004] Pharmaceutical Reviews, 1998, Vol. 50, No. 2, p. 279-290 British Journal of Pharmacology, 2006, Vol. 148, No. 5, p. 565-578 Arabian Journal of Urology, 2013, Vol. 11, No. 4, p. 319-330 Clinics in Colon and Rectal Surgery., 2012, Vol. 25, p. 12-19Expert Opinion on Pharmacotherapy, 2009, Vol. 10, No. 16, p. 2663-2677Journal of Inflammation, 2017, Nov 21, 14:26Trends in Pharmacological Sciences, 2017, Vol. 38, No. 9, p. 837-847Nature, 2012, Vol. 482, p. 552-556

[0005] In G protein-coupled receptors, many allosteric site structures different from the orthosteric site to which endogenous agonists bind have been reported, and in recent years, these allosteric sites have attracted considerable attention (see Non-Patent Document 7). Depending on the ligand that binds to the allosteric site, it changes the structure of the receptor and increases the binding strength between the endogenous agonist and the receptor. This can enhance the signal level dependent on endogenous agonist stimulation for the receptor. In this specification, a ligand that enhances the receptor signal level caused by an endogenous agonist by binding to the allosteric site in this way is referred to as a positive allosteric modulator (PAM). In other words, a positive allosteric modulator means a ligand that enhances the agonist signal by binding to an allosteric site different from the orthosteric site to which endogenous agonists bind.

[0006] Recently, an allosteric site different from the orthosteric site to which endogenous agonists (acetylcholine, muscarine) bind has also been reported for the M3 receptor (see Non-Patent Document 8). It is believed that M3 receptor PAM (hereinafter referred to as "M3 PAM") can enhance the signal level dependent on endogenous agonist stimulation for the M3 receptor. Therefore, M3 PAM can enhance the signal level of the M3 receptor under more physiological conditions, and is expected to be promising for the treatment of diseases involving the M3 receptor.

[0007] An object of the present invention is to provide compounds that have M3 PAM activity.

[0008] As a result of extensive research, the present inventors have found that an azabenzimidazole compound represented by the following formula [1] or a pharmaceutically acceptable salt thereof, or a solvate thereof (hereinafter, sometimes referred to as the "compound of the present invention") has M3 PAM activity, and have completed the present invention.

[0009] That is, the present invention can include the following (Item 1) to (Item 8). (Item 1) A compound represented by the following formula [1]: [In the formula, R １ is a hydrogen atom or alkyl, or two R １ may be taken together with adjacent carbon atoms to form a 3- to 7-membered cycloalkyl or oxygen-containing non-aromatic heterocycle, ２ is a hydrogen atom, alkyl, cycloalkyl, alkyl substituted with cycloalkyl, or alkoxyalkyl; R ３ is a hydrogen atom, alkyl, or alkoxyalkyl; R ４is pyridyl optionally substituted with one or two groups selected from the group consisting of alkyl, trihaloalkyl, alkoxy, cyano, and cycloalkyl, or phenyl optionally substituted with one to three groups selected from the group consisting of trihaloalkyl, halogen, alkoxy, and cycloalkyl; Ar is an aromatic carbocyclic group or an aromatic heterocyclic group; the aromatic carbocyclic group and aromatic heterocyclic group of Ar may be substituted with a group selected from the group consisting of the following (1) to (3): (1) halogen; (2) alkyl; (3) alkoxy; L １ is a bond, (C1-C6) alkylene, (C1-C6) haloalkylene, (C1-C6) alkylene-N(Ra)-, (C1-C6) alkylene-O-, or -C(O)-, where Ra is a hydrogen atom or alkyl, X is a cycloalkyl, alkyl, or non-aromatic carboheterocyclic group optionally substituted with halogen, or a bond, L ２ represents a bond, (C1-C6) alkylene, —O—(C1-C6) alkylene, or —N(Rb)—(C1-C6) alkylene, where Rb is a hydrogen atom or alkyl, and Y is OH, NHSO ２ (alkyl), NHSO ２ (cycloalkyl), NHSO ２ (haloalkyl), NHSO ２ (monoalkylamino), NHSO ２ (dialkylamino), NHSO ２ (Item 2) An azabenzimidazole compound represented by the formula: R (alkoxy), NH (alkoxy), or NH (alkyl), or a pharmaceutically acceptable salt thereof, or a solvate thereof. １ is alkyl, or two R １ together with the adjacent carbon atom is a 3- to 7-membered cycloalkyl; R ２ is alkyl, and R ３ is alkyl, and R ４Item 3. The azabenzimidazole compound according to Item 1, wherein R is pyridyl optionally substituted with one or two groups selected from the group consisting of trihaloalkyl, alkoxy, and cycloalkyl, or phenyl optionally substituted with one to three groups selected from the group consisting of trihaloalkyl and cycloalkyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof. １ But two R １ together with the adjacent carbon atoms of R to form a 3- to 7-membered cycloalkyl; ２ is alkyl, and R ３ is alkyl, and R ４ is a trihaloalkyl, and pyridyl substituted with one group selected from the group consisting of: (1) alkoxy; (2) cycloalkyl; Ar is an aromatic heterocyclic group; L １ is a bond, (C1-C6) alkylene, (C1-C6) alkylene-N(Ra)-, where Ra is alkyl, X is a bond, L ２(Item 4) The azabenzimidazole compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, according to any one of Items 1 to 3, wherein the azabenzimidazole compound is a compound according to any one of the following (1) to (14): (1) 3-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoic acid, (2) 3-[6-({5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoic acid, (3) 3-[6-({5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoic acid, (4) 3-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]-2-methylpropanoic acid, (5) 2-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carboxylic acid, (6) 2-({[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,(5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]methyl}(methyl)amino)acetic acid, (7) 4-[4-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1H-imidazol-1-yl]butanoic acid, (8) 4-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoic acid, (9) 3-[6-({5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]propanoic acid, (10) 3-[6-({5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]propanoic acid, (11) 4-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoic acid, (12) 4-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoic acid, (13) 3-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino)-1H-imidazo[4,(14) 4-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoic acid. (Item 5) A pharmaceutical composition comprising, as an active ingredient, the azabenzimidazole compound or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of Items 1 to 4. (Item 6) An M3 positive allosteric modulator (PAM) comprising, as an active ingredient, the azabenzimidazole compound or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of Items 1 to 4. (Item 7) A preventive or therapeutic agent for dysuria or urinary storage disorder in bladder / urinary tract diseases involving M3 receptors, glaucoma, or diabetes, comprising as an active ingredient the azabenzimidazole compound or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of Items 1 to 4. (Item 8) The preventive or therapeutic agent according to any one of Items 1 to 4, wherein the dysuria or urinary storage disorder in bladder / urinary tract diseases involving M3 receptors is caused by underactive bladder, hypotonic bladder, acontractile bladder, detrusor underactivity, neurogenic bladder, urethral relaxation failure, or detrusor-external urethral sphincter dyssynergia.

[0010] According to the present invention, it is possible to provide an azabenzimidazole compound having M3 PAM activity.

[0011] The meaning of each term used in this specification is explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms.

[0012] "Halogen" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0013] Examples of "alkyl" include straight-chain or branched-chain alkyls having 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 1,2-dimethylpropyl, tert-pentyl, 2-methylbutyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, 1-ethylbutyl, isohexyl, neohexyl, 1,1-dimethylbutyl, thexyl, 2-ethylbutyl, 1,2,2-trimethylpropyl, 2,2-dimethylbutyl, n-heptyl, isoheptyl, n-octyl, and isooctyl.

[0014] The term "trihaloalkyl" refers to the above "alkyl" substituted with three of the above "halogens." Specific examples include trifluoromethyl, trichloromethyl, and trifluoroethyl.

[0015] "Alkoxy" refers to a group in which the above-mentioned "alkyl" is bonded to an oxygen atom. For example, there can be mentioned a straight-chain or branched alkoxy having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, and n-octyloxy.

[0016] The alkoxy moiety of "alkoxyalkyl" can be the same as "alkoxy" as defined above.

[0017] The term "alkylene" includes alkylene having a straight or branched divalent hydrocarbon group having 1 to 6 carbon atoms. Specific examples include methylene, ethylene, and propylene.

[0018] The cycloalkyl moiety of the "alkyl substituted with cycloalkyl" includes the "cycloalkyl" described below.

[0019] Examples of "non-aromatic heterocyclic groups containing oxygen" include 3- to 8-membered non-aromatic heterocyclic groups, more preferably 5- to 7-membered non-aromatic heterocyclic groups, which contain an oxygen atom as a ring-constituting atom other than carbon atoms. Specific examples include oxolanyl (1-oxolanyl, 2-oxolanyl), oxanyl (1-oxanyl, 2-oxanyl, 3-oxanyl), and oxepanyl (1-oxepanyl, 2-oxepanyl, 3-oxepanyl).

[0020] Examples of the "aromatic carbocyclic group" include monocyclic to tricyclic aromatic hydrocarbon groups having 6 to 14 carbon atoms. Specific examples include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, and 10-phenanthryl. Of these, phenyl is preferred.

[0021] The term "cycloalkyl" refers to a monocyclic to tricyclic non-aromatic hydrocarbon group, specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0022] The above "cycloalkyl" may be a bridged hydrocarbon group. Examples of such bridged hydrocarbon groups include: bicyclo[2.2.1]heptanyl (e.g., bicyclo[2.2.1]heptan-1-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]heptan-7-yl), bicyclo[1.1.1]pentanyl (e.g., bicyclo[1.1.1]pentan-1-yl, bicyclo[1.1.1]pentan-2-yl), bicyclo[4.1.0]heptanyl (e.g., bicyclo[4.1.0]heptan-1-yl, bicyclo[4.1.0]heptan-2-yl, bicyclo[4.1.0]heptan-3-yl, bicyclo[4.1.0]heptan-7-yl), Mention may be made of bicyclo[2.2.2]octanyl (for example, bicyclo[2.2.2]octan-1-yl, bicyclo[2.2.2]octan-2-yl), bicyclo[3.1.1]heptanyl (for example, bicyclo[3.1.1]heptan-1-yl, bicyclo[3.1.1]heptan-2-yl, bicyclo[3.1.1]heptan-3-yl, bicyclo[3.1.1]heptan-6-yl), or cuban-1-yl.

[0023] The above "cycloalkyl" may be a spirocyclic group. Such spirocyclic groups may include, for example, spiro[3.3]heptanyl (e.g., spiro[3.3]heptan-1-yl, spiro[3.3]heptan-2-yl), spiro[4.4]nonanyl (e.g., spiro[4.4]nonan-1-yl, spiro[4.4]nonan-2-yl), spiro[5.5]undecanyl (e.g., spiro[5.5]undecan-1-yl, spiro[5.5]undecan-2-yl, spiro[5.5]undecan-3-yl), or spiro[2.5]octanyl (e.g., spiro[2.5]octan-1-yl, spiro[2.5]octan-4-yl, spiro[2.5]octan-5-yl, spiro[2.5]octan-6-yl).

[0024] Examples of "heteroaryl" include monocyclic to tricyclic aromatic rings having 1 to 3 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, and having 6 to 14 carbon atoms. Specific examples include: furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), - isoxazolyl (for example, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), - oxadiazolyl (for example, 1,3,4-oxadiazol-2-yl), - thiazolyl (for example, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), - thiadiazolyl (for example, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl), - isothiazolyl (for example, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), - pyridyl (for example, 2-pyridyl, 3-pyridyl, 4-pyridyl), - pyridazinyl (for example, 3-pyridazinyl, 4-pyridazinyl), - pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), - pyrazinyl (for example, 2-pyrazinyl), Benzothiadiazolyl (for example, 1,2,3-benzothiadiazol-4-yl, 1,2,3-benzothiadiazol-5-yl, 2,1,3-benzothiadiazol-4-yl, 2,1,3-benzothiadiazol-5-yl), benzothiazolyl (for example, benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzothiazol-7-yl), indolyl (for example, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl), benzothiophenyl (for example, 1-benzothiophen-2-yl, 1-benzothiophen-3-yl, 1-benzothiophen-4-yl, 1-benzothiophen-5-yl, 1-benzothiophen-6-yl, 1-benzothiophen-7-yl), 1,1-dioxo-1-benzothiophenyl (for example, 1,1-dioxo-1-benzothiophen-2-yl, 1,1-dioxo-1-benzothiophen-3-yl, 1,1-dioxo-1-benzothiophen-4-yl, 1,1-dioxo-1-benzothiophen-5-yl, 1,1-dioxo-1-benzothiophen-6-yl, 1,1-dioxo-1-benzothiophen-7-yl), quinolyl (quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl), or 1,3-benzoxazol-2-yl.

[0025] The term "non-aromatic heterocyclic group" refers to a monocyclic or bicyclic or more cyclic non-aromatic group having one or more identical or different heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms in the ring. Specific examples include: oxetanyl (e.g., 2-oxetanyl, 3-oxetanyl), azetidinyl (e.g., 2-azetidinyl, 3-azetidinyl), tetrahydropyranyl (e.g., 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), 1,4-dioxanyl (e.g., 1,4-dioxan-2-yl), 1,3-dioxanyl (e.g., 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), Examples of suitable alkyl groups include piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl, 3-piperazinyl), azepanyl (e.g., 1-azepanyl, 2-azepanyl, 3-azepanyl, 4-azepanyl), azocanyl (e.g., 1-azocanyl, 2-azocanyl, 3-azocanyl, 4-azocanyl, 5-azocanyl), homopiperidinyl (e.g., 2-homopiperidinyl, 3-homopiperidinyl, 4-homopiperidinyl), morpholinyl (e.g., 2-morpholinyl, 3-morpholinyl, 4-morpholinyl), thiomorpholinyl (e.g., 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl), and tetrahydrofuryl (2-tetrahydrofuryl, 3-tetrahydrofuryl).

[0026] The above-mentioned "non-aromatic heterocyclic group" may be a bridged cyclic group. Examples of such bridged cyclic groups include: 3-azabicyclo[3.2.1]octanyl (e.g., 3-azabicyclo[3.2.1]octan-1-yl, 3-azabicyclo[3.2.1]octan-2-yl, 3-azabicyclo[3.2.1]octan-3-yl, 3-azabicyclo[3.2.1]octan-6-yl, 3-azabicyclo[3.2.1]octan-8-yl), 3-azabicyclo[3.1.0]hexanyl (e.g., 3-azabicyclo[3.1.0]hexan-1-yl, 3-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexan-6-yl), quinuclidinyl (e.g., quinuclidin-2-yl, quinuclidin-3-yl, quinuclidin-4-yl), or 6-oxa-3-azabicyclo[3.1.1]heptanyl (e.g., 6-oxa-3-azabicyclo[3.1.1]heptan-1-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-2-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-7-yl).

[0027] The above-mentioned "non-aromatic heterocyclic group" may be a spirocyclic group. Examples of such spirocyclic groups include: 6-azaspiro[2.5]octan-1-yl (e.g., 6-azaspiro[2.5]octan-1-yl, 6-azaspiro[2.5]octan-4-yl, 6-azaspiro[2.5]octan-5-yl), 3,9-diazaspiro[5.5]undecan-1-yl (e.g., 3,9-diazaspiro[5.5]undecan-1-yl, 3,9-diazaspiro[5.5]undecan-2-yl, 3,9-diazaspiro[5.5]undecan-3-yl), 2,7-diazaspiro[3.5]nonan-1-yl (e.g. 2,7-diazaspiro[3.5]nonan-1-yl, 2,7-diazaspiro[3.5]nonan-2-yl, 2,7-diazaspiro[3.5]nonan-5-yl, 2,7-diazaspiro[3.5]nonan-6-yl, 2,7-diazaspiro[3.5]nonan-7-yl), 7-azaspiro[3.5]nonanyl (7-azaspiro[3.5]nonan-1-yl, 7-azaspiro[3.5]nonan-2-yl, 7-azaspiro[3.5]nonan-5-yl, 7-azaspiro[3.5]nonan-6-yl), or 2,5-diazabicyclo[2.2.1]heptanyl (2,5-diazabicyclo[2.2.1]heptan-1-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2,5-diazabicyclo[2.2.1]heptan-3-yl, 2,5-diazabicyclo[2.2.1]heptan-7-yl).

[0028] Each symbol in formula [1] will be explained below. R in formula [1] １ is a hydrogen atom or alkyl, or two R １ may be taken together with adjacent carbon atoms to form a 3- to 7-membered cycloalkyl or oxygen-containing non-aromatic heterocycle.

[0029] R １ As the "alkyl", methyl, ethyl, n-propyl and n-butyl are preferred, and methyl and ethyl are more preferred.

[0030] R １ Two R's １When taken together with the adjacent carbon atom, the 3- to 7-membered cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, more preferably cyclobutyl, cyclopentyl or cyclohexyl.

[0031] R in formula [1] ２ is a hydrogen atom, alkyl, cycloalkyl, alkyl substituted with cycloalkyl, or alkoxyalkyl.

[0032] R ２ As the "alkyl" in the above, methyl, ethyl, n-propyl, n-butyl and n-pentyl are preferred, and methyl, ethyl, n-propyl and n-butyl are more preferred.

[0033] R in formula [1] ３ is a hydrogen atom, alkyl, cycloalkyl, alkyl substituted with cycloalkyl, or alkoxyalkyl.

[0034] R ３ As the "alkyl", methyl, ethyl and n-propyl are preferred, and methyl and ethyl are more preferred.

[0035] R in formula [1] ４ is pyridyl optionally substituted with one or two groups selected from the group consisting of alkyl, trihaloalkyl, alkoxy, cyano, and cycloalkyl, or phenyl optionally substituted with one to three groups selected from the group consisting of trihaloalkyl, halogen, alkoxy, and cycloalkyl.

[0036] R ４ As the "trihaloalkyl" in the pyridyl which may be substituted with one or two alkyl groups, trifluoromethyl is preferred.

[0037] R ４ As the "alkoxy" in the pyridyl which may be substituted by one or two alkoxy groups, methoxy, ethoxy, n-propoxy and n-butoxy are preferred, and ethoxy is more preferred.

[0038] R ４As the "cycloalkyl" in the pyridyl which may be substituted by one or two cycloalkyl groups, cyclopropyl and cyclobutyl are preferred, and cyclopropyl is more preferred.

[0039] R ４ As the "trihaloalkyl" in the phenyl optionally substituted with 1 to 3 trihaloalkyl, trifluoromethyl is preferred.

[0040] R ４ As the "cycloalkyl" which may be substituted on phenyl, cyclopropyl and cyclobutyl are preferred, and cyclopropyl is more preferred.

[0041] R ４ As the aryl group, one group selected from the group consisting of alkyl, trihaloalkyl, alkoxy, cyano, and cycloalkyl, as well as pyridyl substituted with trihaloalkyl are preferred.

[0042] Ar is an aromatic carbocyclic group or an aromatic heterocyclic group, preferably an aromatic heterocyclic group, and more preferably pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridyl, 1,2,3,4-tetrahydro-2,7-naphthyridine, 5,6,7,8-tetrahydro-1,6-naphthyridine, 4,5,6,7-tetrahydropyrazolo[1,2-a]pyridyl, 5,6,7,8-tetrahydroisoquinoline, or pyridazinyl.

[0043] L １ is a bond, (C1-C6) alkylene, (C1-C6) alkylene-N(Ra)-, (C1-C6) alkylene-O-, or -C(O)-. A bond or (C1-C6) alkylene is preferred, and (C1-C6) alkylene is more preferred.

[0044] X is a bond, a cycloalkyl, or a non-aromatic carboheterocyclic group, preferably a bond or a non-aromatic carboheterocyclic group.

[0045] L ２is a bond, (C1-C6) alkylene, —O—(C1-C6) alkylene, or —N(Rb)—(C1-C6) alkylene. A bond or (C1-C6) alkylene is preferred, and a bond is more preferred.

[0046] Y is OH, NHSO ２ (alkyl), NHSO ２ (cycloalkyl), NHSO ２ (haloalkyl), NHSO ２ (monoalkylamino), NHSO ２ (dialkylamino), NHSO ２ (alkoxy), NH(alkoxy), or NH(alkyl). OH is more preferred.

[0047] The compound of the present invention can be produced from a known compound or an easily synthesized intermediate, for example, by the method described below, the Examples described later, or a known method. In producing the compound of the present invention, if the raw material has a substituent that affects the reaction, the raw material is generally protected with an appropriate protecting group by a known method beforehand, and then the reaction is carried out. The protecting group can be removed by a known method after the reaction.

[0048] The azabenzimidazole compounds of the present invention can be used as pharmaceuticals as they are, or can be used in the form of a pharmaceutically acceptable salt, solvate, or solvate of a salt by known methods. Examples of pharmaceutically acceptable salts include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; salts of organic acids such as acetic acid, malic acid, lactic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid; salts of alkali metals such as lithium, potassium, and sodium; salts of alkaline earth metals such as magnesium and calcium; and salts of organic bases such as ammonium salts. These salts can be formed by commonly used methods.

[0049] For example, when the compound of the present invention is a hydrochloride salt, the azabenzimidazole compound of the present invention can be obtained by dissolving the compound in an alcohol solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a cyclopentyl methyl ether solution of hydrogen chloride, or a diethyl ether solution of hydrogen chloride.

[0050] Of the compounds of the present invention, those having an asymmetric carbon atom include all stereoisomers and mixtures thereof. Stereoisomers can be produced, for example, by optical resolution of a racemate using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) by a known method, taking advantage of its basicity, or by using a pre-prepared optically active compound as a starting material. Alternatively, stereoisomers can also be produced by optical resolution using a chiral column or asymmetric synthesis.

[0051] The formula [1] in the present invention is not limited to a specific isomer, but includes all possible isomers and racemates, including, for example, the tautomer [1Eq] and stereoisomers shown below. (wherein each symbol has the same meaning as defined above) (Method for producing the compound of the present invention)

[0052] The compound [1] of the present invention and its salts can be produced from known compounds or intermediates that can be easily prepared from known compounds, for example, by the following methods, the examples described below, or known methods.

[0053] When the solvents, reagents, and raw materials used in each step in the following production methods are commercially available, the commercially available products can be used as they are. Furthermore, the compounds obtained in each step in the production methods described below and the raw materials used may form salts, which can be converted into other types of salts or free forms by known methods. Conversely, when the compounds obtained in each step in the following production methods and the raw materials used are in free forms, they can be converted into the desired salts by known methods. Examples of such salts include the same salts as those used for the compounds of the present invention described above.

[0054] The compound represented by formula [1] of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (e.g., a hydrate, etc.) and / or a crystalline polymorph, and the present invention also encompasses such various solvates and crystalline polymorphs. A "solvate" may be coordinated with the compound represented by formula [1] with any number of solvent molecules (e.g., water molecules, etc.). When the compound represented by formula [1] or a pharmaceutically acceptable salt thereof is left in the atmosphere, it may absorb moisture, resulting in the adhesion of adsorbed water or the formation of a hydrate. Furthermore, when the compound represented by formula [1] or a pharmaceutically acceptable salt thereof is recrystallized, a crystalline polymorph thereof may be formed.

[0055] In the production of the compound of the present invention, when a raw material has a substituent that may affect the reaction, a protecting group may be introduced into the substituent in advance by a known method, and the target compound can be obtained by removing the protecting group after the reaction, as necessary. The introduction and removal of such a protecting group may be carried out by appropriately selecting and using conditions described, for example, in "Greene's Protective Groups in Organic Synthesis," 4th Edition, John Wiley & Sons Inc., 2006, or "Protecting Groups," 3rd Edition, Thieme, 2005, by Wuts and Greene.

[0056] The compounds obtained in each step of the following production methods can be isolated or purified in accordance with a conventional method, such as solvent extraction, concentration, distillation, sublimation, recrystallization, reprecipitation, or chromatography, or can be used in the next step in the form of a reaction mixture or a crude product.

[0057] Unless otherwise specified, the reactions in each step in the following production methods are carried out according to known methods, for example, those described in "Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition" by R.C. Larock, John Wiley & Sons Inc. , 1999, "Experimental Chemistry Lectures" edited by the Chemical Society of Japan, 4th edition, Maruzen, 1992, "Strategies in Organic Synthesis Learned from Named Reactions" by L. Kuerti and B. Czako, translated and supervised by Tomioka Kiyoshi, Kagaku Dojin, 2006, "Latest Organic Synthesis Methods: Design and Strategy" by G. S. Zweifel and M. H. Nantz, translated by Hiyama Tamijiro, Kagaku Dojin, 2009, or the methods described in the examples can be suitably modified or combined for use.

[0058] Production method 1: Among the compounds [1], compound [1A] (when Y is OH) and compound [1B] (when Y is NHSO ２ (alkyl), NHSO ２ (cycloalkyl), NHSO ２ (haloalkyl), NHSO ２ (monoalkylamino), NHSO ２ (wherein the group is selected from dialkylamino, NH(alkoxy), or NH(alkyl))

[0059] (In the formula, R １ , R ２ , R ３ , R ４ , Ar, L １ , X, L ２ has the same meaning as above. Y' represents alkoxy, for example, methoxy or ethoxy. YA represents a hydroxyl group in the Y, and YB represents NHSO in the Y. ２ (alkyl), NHSO ２ (cycloalkyl), NHSO ２ (haloalkyl), NHSO ２ (monoalkylamino), NHSO２ (dialkylamino), NH(alkoxy), or NH(alkyl), where the appropriate alkyl, haloalkyl, cycloalkyl, and alkoxy are as defined above.

[0060] Step 1 This reaction is an amidation reaction for producing compound [4] by condensing compound [2] with compound [3], which is commercially available or can be produced according to a known method, or a salt thereof, and can be carried out according to a known method.

[0061] Examples of salts of compound [3] include salts with suitable acids, such as hydrochloride and trifluoroacetate.

[0062] The amount of compound [2] used in this reaction is suitably within the range of 0.5 to 2 molar equivalents relative to compound [3].

[0063] This reaction is carried out in the presence of a condensing agent, such as O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as "HBTU"), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as "HATU"), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (hereinafter referred to as "TBTU"), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (hereinafter referred to as "EEDQ"), chloro-N,N,N',N'-tetramethylformamidinium Examples of suitable methyl methyl hexafluorophosphate include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafter referred to as "EDCI"), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (hereinafter referred to as "DMT-MM"), N-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino(morpholino)]uronium hexafluorophosphate (hereinafter referred to as "COMU"), and N,N'-carbonyldiimidazole (hereinafter referred to as "CDI").

[0064] The amount of the condensing agent is suitably within the range of 1 to 4 molar equivalents relative to the compound [2].

[0065] In this reaction, a base can be used as needed. Examples of the base that can be used include organic bases such as triethylamine, N,N-diisopropylethylamine (hereinafter referred to as "DIPEA"), 1,8-diazabicyclo[5.4.0]-7-undecene (hereinafter referred to as "DBU"), pyridine, and N-methylmorpholine, and inorganic bases such as potassium carbonate, cesium carbonate, and sodium carbonate.

[0066] The amount of the base used is, for example, within the range of 1 to 10 molar equivalents relative to the compound [2].

[0067] In this reaction, additives such as 1-hydroxybenzotriazole (hereinafter referred to as "HOBt"), N-hydroxysuccinimide, 1-hydroxy-7-azabenzotriazole (hereinafter referred to as "HOAt"), 4-dimethylaminopyridine (hereinafter referred to as "DMAP"), etc. can also be added as necessary.

[0068] When the above-mentioned additives are used in this reaction, the amount of each additive used is suitably within the range of 1 to 3 molar equivalents relative to compound [2].

[0069] The solvent used in this reaction is not particularly limited as long as it is not involved in the reaction, and examples thereof include hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as 1,4-dioxane, tetrahydrofuran (hereinafter referred to as "THF"), and ethylene glycol dimethyl ether (hereinafter referred to as "DME"); amides such as dimethylformamide (hereinafter referred to as "DMF"), dimethylacetamide (hereinafter referred to as "DMA"), and N-methylpyrrolidone (hereinafter referred to as "NMP"); alcohols such as ethanol and isopropanol; dimethyl sulfoxide (hereinafter referred to as "DMSO"), acetonitrile, water, and mixed solvents thereof.

[0070] The reaction temperature can be within the range of 0° C. to 200° C., preferably 0° C. to 70° C. If necessary, a microwave reaction apparatus (for example, a microwave synthesis system "Initiator" (manufactured by Biotage Japan)) may be used.

[0071] The reaction time varies depending on the types of raw materials used and the reaction temperature, but is usually within the range of 0.5 to 72 hours.

[0072] Step 2 This step is a step in which compound [1A] is obtained by hydrolyzing compound [4] in the presence of an appropriate acid or base in an appropriate solvent.

[0073] In this reaction, examples of the acid to be used include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid (hereinafter referred to as "TFA"), methanesulfonic acid, and toluenesulfonic acid. Examples of the base to be used include inorganic bases such as sodium hydroxide, potassium hydroxide, and lithium hydroxide.

[0074] In this reaction, the amount of acid or base used is suitably 1 to 50 molar equivalents relative to compound [4].

[0075] The solvent to be used is not particularly limited as long as it is not involved in the reaction, and examples thereof include alcohols such as methanol, ethanol, and isopropanol; ethers such as THF, diethyl ether, 1,4-dioxane, and DME; nitriles such as acetonitrile and propionitrile; ketones such as acetone; water; and mixed solvents thereof.

[0076] The reaction temperature ranges from −10° C. to 200° C., preferably from 0° C. to 70° C. If necessary, a microwave reaction apparatus may be used.

[0077] The reaction time varies depending on the types of raw materials used and the reaction temperature, but is usually within the range of 0.5 hours to 4 days.

[0078] Step 3 This step is a step for producing compound [1B] by a condensation reaction between compound [1A] and compound [5], which is commercially available or can be produced according to a known method, or a salt thereof, and can be carried out according to a known method.

[0079] Examples of salts of compound [5] include salts with suitable acids, such as hydrochloride and trifluoroacetate.

[0080] The amount of compound [5] used in this reaction is suitably within the range of 1 to 10 molar equivalents relative to compound [1A].

[0081] This reaction is carried out in the presence of a condensing agent, such as HBTU, HATU, TBTU, EEDQ, TCFH, EDC, DMT-MM, COMU, or CDI.

[0082] The amount of the condensing agent is suitably within the range of 1 to 4 molar equivalents relative to compound [1A].

[0083] In this reaction, a base can be used as needed. Examples of the base that can be used include organic bases such as triethylamine, DIPEA, DBU, pyridine, and N-methylmorpholine, and inorganic bases such as potassium carbonate, cesium carbonate, and sodium carbonate.

[0084] The amount of the base used is, for example, suitably within the range of 1 to 10 molar equivalents relative to compound [1A].

[0085] In this reaction, additives such as HOBt, N-hydroxysuccinimide, HOAt, DMAP, etc. may be added as needed.

[0086] When the above-mentioned additives are used in this reaction, the amount of each additive is suitably within the range of 1 to 3 molar equivalents relative to compound [1A].

[0087] The solvent used in this reaction is not particularly limited as long as it is not involved in the reaction, and examples thereof include hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as 1,4-dioxane, THF, and DME, amides such as DMF, DMA, and NMP, alcohols such as ethanol and isopropanol, DMSO, acetonitrile, water, and mixed solvents thereof.

[0088] The reaction temperature can be within the range of 0° C. to 200° C., preferably 0° C. to 70° C. If necessary, a microwave reaction apparatus can be used.

[0089] The reaction time varies depending on the types of raw materials used and the reaction temperature, but is usually within the range of 0.5 hours to 4 days.

[0090] Preparation of Compound [2] Compound [2] can be prepared, for example, according to the following preparation method.

[0091] (In the formula, R １ , R ２ , R ３ , and R ４ has the same meaning as above. ５ａ , and R ５ｂ represents a hydroxy group, or R ５ａ and R ５ｂ Together, they form -O-C(CH ３ ) ２ -C(CH ３ ) ２ -O-, -O-(CH ２ ) ３ —O— or O—CH ２ -C(CH ３ ) ２ -CH ２ -O-. １ , Lg ２ is a leaving group, Lg １ , Lg ２ Examples of the atom include a chlorine atom and a bromine atom.

[0092] Step 1 This step is a step of reacting compound [6] with a boron compound [7], which is commercially available or can be produced by a known method, in the presence of a palladium catalyst and a base, to obtain compound [8], i.e., a cross-coupling reaction.

[0093] The amount of compound [7] used is suitably within the range of 1 to 3 molar equivalents relative to compound [6].

[0094] Examples of the palladium catalyst to be used include tris(dibenzylideneacetone)bispalladium chloroform adduct (hereinafter referred to as "Pd2(dba)3.CHCl3"), tris(dibenzylideneacetone)bispalladium (hereinafter referred to as "Pd2(dba)3"), tetrakistriphenylphosphinepalladium (hereinafter referred to as "Pd(PPh3)4"), and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane adduct (hereinafter referred to as "Pd(dppf)Cl2"). bis(triphenylphosphine)palladium(II) dichloride (hereinafter referred to as "PdCl(PPh)"), [1,1'-bis(di-tert-butylphosphino)ferrocene]-dichloropalladium(II) (hereinafter referred to as "Pd(dtbpf)Cl"), bis(tricyclohexylphosphine)palladium(II) dichloride (hereinafter referred to as "PdCl(PCy)"), palladium(II) acetate (hereinafter referred to as "Pd(OAc)"), and the like can be mentioned.

[0095] The amount of the palladium catalyst used is suitably within the range of, for example, 0.01 to 0.3 molar equivalents relative to the compound [6].

[0096] Examples of the base to be used include inorganic bases such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium acetate, potassium acetate, trisodium phosphate, and tripotassium phosphate.

[0097] The amount of the base used is suitably within the range of, for example, 1 to 4 molar equivalents relative to the compound [6].

[0098] In this step, an appropriate ligand may be used as needed. Examples of usable ligands include 1,1'-bis(diphenylphosphino)ferrocene (hereinafter referred to as "dppf"), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (hereinafter referred to as "Xantphos"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (hereinafter referred to as "XPhos"), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos"), triphenylphosphine (hereinafter referred to as "PPh3"), and tricyclohexylphosphine (hereinafter referred to as "PCy3").

[0099] The amount of the ligand to be used is suitably within the range of, for example, 1 to 5 molar equivalents relative to the palladium catalyst.

[0100] The solvent used in this step is not particularly limited as long as it is not involved in the reaction, and examples thereof include hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, THF, and DME; amides such as DMF, DMA, and NMP; alcohols such as ethanol, 2-propanol, and tert-butanol; water; and mixed solvents thereof.

[0101] The reaction temperature varies depending on the types of raw materials and reagents used, but is usually within the range of 20° C. to 200° C. If necessary, a microwave reaction apparatus may be used.

[0102] The reaction time varies depending on the types of raw materials used and the reaction temperature, but is usually within the range of 0.1 to 24 hours.

[0103] Alternatively, compound [8] can be produced via the following Steps 5 and 6.

[0104] (In the formula, R ４ , R ５ａ , R ５ｂ , Lg１ , and Lg ２ has the same meaning as above.)

[0105] Step 5 This step is a cross-coupling reaction of compound

[14] with compound [7] using a palladium catalyst, and can be carried out under the same reaction conditions as in Step 1 of the above-mentioned production method of compound [2].

[0106] Step 6 This step is a step in which compound

[15] is nitrated in the presence of a suitable nitrating agent to obtain compound [8], and can be carried out in accordance with a known method for nitration reaction.

[0107] Examples of the nitrating agent that can be used include nitric acid, fuming nitric acid, copper nitrate, sodium nitrate, and potassium nitrate.

[0108] The amount of the nitrating agent used is suitably within the range of 1 to 1.1 molar equivalents relative to the compound

[15] .

[0109] In this step, the solvent used is selected according to the type of reagent used, and examples thereof include concentrated sulfuric acid and concentrated hydrochloric acid.

[0110] The reaction temperature varies depending on the types of raw materials and reagents used, but is usually within the range of 0°C to 40°C, more preferably within the range of 5°C to 15°C.

[0111] The reaction time varies depending on the types of raw materials and reagents used and the reaction temperature, but is usually within the range of 0.5 to 12 hours, more preferably within the range of 1 to 3 hours.

[0112] Step 2 This step is a step in which the compound [8] is reacted with a compound [9] that is commercially available or can be prepared according to a known method to obtain an aromatic amino compound

[10] .

[0113] Compound [9] may be used in the form of a salt with an appropriate acid, such as hydrochloride, trifluoroacetate, etc.

[0114] The amount of compound [9] used is suitably within the range of 0.5 to 1.5 molar equivalents relative to compound [8].

[0115] In this step, a base can be used as needed. Examples of the base that can be used include organic bases such as triethylamine, DIPEA, and DBU, and inorganic bases such as potassium carbonate, cesium carbonate, and sodium carbonate.

[0116] The amount of the base used is, for example, within the range of 1 to 10 molar equivalents relative to the compound [8].

[0117] The solvent to be used is not particularly limited as long as it is not involved in the reaction, and examples thereof include hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, THF, and DME; amides such as DMF and DMA; nitriles such as acetonitrile and propionitrile; alcohols such as 2-propanol and tert-butanol; DMSO; water; and mixed solvents thereof.

[0118] The reaction temperature varies depending on the types of raw materials and reagents used, but is usually within the range of 20° C. to 200° C. If necessary, a microwave reaction apparatus may be used.

[0119] The reaction time varies depending on the types of raw materials used and the reaction temperature, but is usually within the range of 0.5 to 24 hours.

[0120] Furthermore, when compound

[10] is produced using compound [6] as a starting material, compound

[10] can be obtained by switching the order of Step 1 and Step 2. In this case, the reaction conditions are the same as those of Step 1 and Step 2 in the above-mentioned production method of compound [2].

[0121] Step 3: This step is a step of reducing the nitro group of compound

[10] to obtain aromatic diamine compound

[13] , and can be carried out according to a method known per se. This reduction reaction can be achieved, for example, by iron reduction using reduced iron and ammonium chloride in an appropriate solvent, or zinc reduction using zinc powder and ammonium chloride or acetic acid.

[0122] Examples of reducing agents that can be used in this reduction reaction include reduced iron, zinc powder, and tin(II) chloride.

[0123] In this step, the amount of the reducing agent used is suitably within the range of 1 to 10 molar equivalents relative to the compound

[10] .

[0124] When the above-mentioned metal reagent is used in this reduction reaction, an acid is usually used, such as hydrochloric acid, acetic acid, or ammonium chloride.

[0125] In this step, the amount of the acid used is suitably within the range of 1 to 10 molar equivalents relative to the compound

[10] .

[0126] The solvent used in this step is not particularly limited as long as it is not involved in the reaction, and examples thereof include hydrocarbons such as toluene and 1,4-dioxane, ethers such as THF and DME, esters such as ethyl acetate, ketones such as acetone, nitriles such as acetonitrile, amides such as DMF, alcohols such as methanol, ethanol, 2-propanol, and tert-butanol, water, and mixed solvents thereof.

[0127] The reaction temperature varies depending on the types of raw materials and reagents used, but is usually within the range of 0°C to 200°C.

[0128] The reaction time varies depending on the types of raw materials and reagents used and the reaction temperature, but is usually within the range of 1 to 24 hours. Step 4 This step is a ring-closure reaction in which diamine compound

[13] is reacted with cyanogen bromide to obtain compound [2], which can be produced, for example, according to the method described in WO 2005 / 082901.

[0129] In this step, the amount of cyanogen bromide used is suitably within the range of 2 to 10 molar equivalents relative to the compound

[13] .

[0130] The solvent used in this step is not particularly limited as long as it is not involved in the reaction, and examples thereof include alcohols such as methanol, ethanol, 2-propanol, and tert-butanol.

[0131] The reaction temperature varies depending on the raw materials used, but is usually within the range of 20°C to 70°C.

[0132] The reaction time varies depending on the types of raw materials and reagents used and the reaction temperature, but is usually within the range of 1 to 72 hours.

[0133] Urine storage and urination are regulated by the functions of the bladder and urethra. Urinary continence is maintained and urine is stored by relaxation of the bladder smooth muscle (detrusor muscle) and contraction of the urethral sphincter. On the other hand, urination is carried out by contraction of the bladder smooth muscle and relaxation of the urethral smooth muscle. During urination, acetylcholine is released from the nerve endings of the pelvic nerve, a parasympathetic nerve that controls the bladder. The released acetylcholine binds to the M3 receptors of the bladder smooth muscle, causing the bladder smooth muscle to contract.

[0134] For example, when urinary storage disorders occur due to overactive bladder, urine cannot be retained during collection. Furthermore, when urinary disorders occur due to underactive bladder, urine cannot be sufficiently excreted during urination. Furthermore, urinary disorders may result in residual urine after urination. An increase in the amount of residual urine may cause symptoms such as frequent urination. In other words, urinary storage disorders and urinary disorders may occur together (see Current Urology Report, 2016, 17:17).

[0135] The compound of the present invention can be used for the prevention or treatment of diseases in which the M3 receptor is involved, particularly bladder / urinary tract diseases involving bladder contraction, digestive diseases involving gastrointestinal contraction, oral diseases involving saliva secretion, and eye diseases involving tear secretion or pupil constriction. The compound of the present invention is particularly useful for the prevention or treatment of dysuria and urine storage disorders in bladder / urinary tract diseases, glaucoma in eye diseases, and diabetes. Here, diabetes refers to diabetes in which insulin secretion in which the M3 receptor is involved (see Cell Metabolism, 2006, Vol. 3, pp. 449-461) is reduced.

[0136] Examples of dysuria and dysuria for which the prevention or treatment with the compound of the present invention is particularly useful include dysuria and dysuria caused by underactive bladder, hypotonic bladder, acontractile bladder, detrusor hypoactivity, neurogenic bladder, urethral relaxation insufficiency, detrusor-external urethral sphincter dyssynergia, overactive bladder, pollakiuria, nocturia, urinary incontinence, benign prostatic hyperplasia, interstitial cystitis, chronic prostatitis, urinary tract stones, etc.

[0137] The compound of the present invention is particularly useful for the prevention or treatment of dysuria and urinary storage disorder in underactive bladder, hypotonic bladder, acontractile bladder, detrusor underactivity, benign prostatic hyperplasia, and neurogenic bladder. For example, in underactive bladder, dysuria occurs due to a decrease in the contractile force of the bladder detrusor muscle during urination, but the compound of the present invention can improve the contractile force of the bladder detrusor muscle during urination and promote urination.

[0138] The compounds of the present invention are particularly useful for the prevention or treatment of underactive bladder, hypotonic bladder, acontractile bladder, and detrusor underactivity due to specific causes, such as neurological diseases (multiple system atrophy, Parkinson's disease, multiple sclerosis, spinal cord injury, lumbar disc herniation, etc.), diabetes, pelvic surgery, benign prostatic hyperplasia, and aging.

[0139] Acetylcholine contracts the ciliary muscle of the eye via M3 receptors in the ciliary muscle. Contraction of the ciliary muscle opens the Schlemm's canal, allowing aqueous humor to drain through the Schlemm's canal. This reduces intraocular pressure. Examples of glaucoma that can be particularly effectively prevented or treated with the compound of the present invention include primary open-angle glaucoma, normal-tension glaucoma, and primary angle-closure glaucoma.

[0140] When the compound of the present invention is administered as a pharmaceutical, it is administered to mammals, including humans, either as it is or as a pharmaceutical composition containing the compound of the present invention in a pharmaceutically acceptable, non-toxic and inert carrier, for example, in an amount of 0.001% to 99.5%, preferably 0.1% to 90%.

[0141] The carrier may be one or more solid, semi-solid, or liquid diluents, fillers, and other formulation auxiliary agents. The pharmaceutical composition of the present invention is preferably administered in a dosage unit form. The pharmaceutical composition may be administered intramuscularly, orally, intravenously, topically (transdermally, by eye drop, intraperitoneally, intrapleurally, etc.), or rectally. Of course, the pharmaceutical composition may be administered in a dosage form suitable for these administration methods.

[0142] The pharmaceutical dosage is desirably adjusted taking into consideration the patient's condition, such as age, body weight, type and severity of disease, the route of administration, the type of compound of the present invention, whether or not it is a salt, and the type of salt. However, in general, the amount of the active ingredient of the compound of the present invention or a pharmaceutically acceptable salt thereof for an adult, when administered orally, is within the range of 0.01 mg to 5 g per adult, preferably 1 mg to 500 mg per adult, per day. In some cases, a lower dose may be sufficient, or conversely, a higher dose may be required. Generally, the compound is administered once a day or in divided doses, or in the case of intravenous administration, it can be administered as a bolus or continuously for up to 24 hours.

[0143] One or more hydrogen, carbon and / or other atoms of the compounds of the present invention may be replaced with an isotope of the hydrogen, carbon and / or other atom, respectively. Examples of such isotopes include, but are not limited to, ２ H. ３ H. １１ C. １３ C. １４ C. １５ N. １８ O. １７ O. ３１ P. ３２ P. ３５ S. １８ F. １２３ I and ３６ The isotope-substituted compounds are useful as pharmaceuticals and include all radiolabeled compounds of the present invention.

[0144] The present invention will be explained in more detail below with reference to comparative examples, examples and test examples, but the present invention is not limited thereto.

[0145] The following abbreviations are used in the examples: TFA: trifluoroacetic acid, Pt—C: platinum on carbon, Pd—C: palladium on carbon, Pd(OH) ２ -C: Palladium (II) hydroxide-carbon Pd ２ (dba) ３ CHCl ３ : Tris(dibenzylideneacetone)bispalladium chloroform adduct Pd ２ (dba) ３ : Tris(dibenzylideneacetone)bispalladium Pd(dppf)Cl ２ ・CH ２ Cl ２ : [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-dichloromethane adduct Pd(OAc) ２ : Palladium(II) acetate dppf: 1,1'-bis(diphenylphosphino)ferrocene XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl RuPhos: 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl Dave-Phos: 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl SPhos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl PPh ３ : Triphenylphosphine Rh ２ (OAc) ４: Rhodium(II) acetate dimer Boc: tert-butoxycarbonyl Bn: Benzyl Ts: 4-toluenesulfonyl HBTU: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate TBTU: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate EEDQ: 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline TCFH: chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; COMU: N-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino(morpholino)]uronium hexafluorophosphate; CDI: N,N'-carbonyldiimidazole; HOBt: 1-hydroxybenzotriazole; HOAt: 1-hydroxy-7-azabenzotriazole; DMAP: 4-dimethylaminopyridine; DEAD: diethyl azodicarboxylate; DMA: dimethylacetamide; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; THF: tetrahydrofuran; NMP: N-methylpyrrolidone; DIPEA: N,N-diisopropylethylamine TEA: Triethylamine DBU: 1,8-diazabicyclo[5.4.0]-7-undecene CDCl ３ : deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide TLC: thin layer chromatography MS: mass spectrometry LCMS: high performance liquid chromatography mass spectrometry ESI: electron spray ionization M: molar concentration (mol / L)

[0146] MS was measured by LCMS. ESI was used as the ionization method. The observed mass spectrometry values ​​are expressed as m / z.

[0147] The LCMS measurement conditions were as follows: Analytical equipment: ACQUITY UPLC MS / PDA system (Waters Corporation) Mass spectrometer: Waters 3100 MS detector Photodiode array detector: ACQUITY PDA detector (UV detection wavelength: 210 nm to 400 nm) Column: Acquity BEH C18, 1.7 μm, 2.1 × 50 mm Flow rate: 0.5 mL / min Column temperature: 40 °C Solvents: Solution A: 0.1% formic acid / H2O (v / v; the same applies hereinafter) Solution B: 0.1% formic acid / acetonitrile

[0148] 1H NMR spectra were measured using a JNM-ECS400 nuclear magnetic resonance spectrometer (manufactured by JEOL RESONANCE Co., Ltd.). The observed peaks are expressed as chemical shift values ​​δ (ppm) (s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet, dd = double doublet, dt = double triplet).

[0149] For microwave experiments, an Initiator 60 (Biotage) was used, which can achieve temperatures between 40° C. and 250° C. and pressures up to 20 bar.

[0150] The compound names in this specification were determined using naming software conforming to IUPAC rules, ACD / NAME (registered trademark, Advanced Chemistry Development Inc.), or ChemBioDraw (version 14.0, manufactured by Cambridge Soft), or were determined according to the IUPAC nomenclature.

[0151] The r and s (lower case) in the compound names indicate the stereochemistry of the pseudo-asymmetric carbon atom according to IUPAC rules.

[0152] Reference Example 1 1-[1-(ethoxymethyl)cyclopentyl]-N-methylmethanamine hydrochloride [Step 1] Preparation of 1-(ethoxymethyl)cyclopentane-1-carbonitrile To a solution of 1-(hydroxymethyl)cyclopentane-1-carbonitrile (43 g) in DMF (1150 mL), 60% sodium hydride (17 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Ethyl iodide (64 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature. After confirming the disappearance of the starting materials by TLC, water and ethyl acetate were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (48 g). [Step 2] Preparation of tert-butyl {[1-(ethoxymethyl)cyclopentyl]methyl}methylcarbamate Lithium aluminum hydride (11 g) was suspended in THF (800 mL), and a solution of 1-(ethoxymethyl)cyclopentane-1-carbonitrile (46 g) obtained in Step 1 in THF (200 mL) was added dropwise with ice-cooling and stirring. After the addition was complete, the mixture was stirred at room temperature for 2 hours. To the reaction mixture, water (11 mL), 15% aqueous sodium hydroxide solution (11 mL), and water (34 mL) were added dropwise, successively, with ice-cooling. The mixture was stirred at room temperature for 2 hours, and the insoluble matter was filtered off through Celite and washed three times with THF (220 mL). To the filtrate, TEA (46 mL) and di-tert-butyl dicarbonate (72 g) were added with stirring at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in DMF (600 mL), and 60% sodium hydride (14 g) was added under ice-cooling, followed by stirring at room temperature for 1 hour. Methyl iodide (23 mL) was added dropwise to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was ice-cooled, diluted with water, and then extracted with ethyl acetate-hexane (1:2). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (71 g).[Step 3] Preparation of 1-[1-(ethoxymethyl)cyclopentyl]-N-methylmethanamine hydrochloride. To a solution of tert-butyl {[1-(ethoxymethyl)cyclopentyl]methyl}methylcarbamate (71 g) obtained in Step 2 in ethyl acetate (53 mL) was added hydrogen chloride (4 M ethyl acetate solution, 328 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the precipitated solid was collected by filtration, washed with hexane, and then dried to obtain the title compound (50 g). Reference Example 2 1-[1-(methoxymethyl)cyclopentyl]-N-methylmethanamine hydrochloride [Step 1] Preparation of tert-butyl {[1-(hydroxymethyl)cyclopentyl]methyl}carbamate To a solution of [1-(aminomethyl)cyclopentyl]methanol (51 g) in THF (304 mL), TEA (60 mL) and a solution of di-tert-butyl dicarbonate (94 g) in THF (101 mL) were added dropwise under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate-hexane (1:9) (700 mL) and stirred at room temperature for 3 hours. The precipitate was collected by filtration, washed with hexane, and dried to obtain the title compound (49 g). The solvent was removed from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (16 g). [Step 2] Preparation of tert-butyl {[1-(methoxymethyl)cyclopentyl]methyl}methylcarbamate. To a solution of tert-butyl {[1-(hydroxymethyl)cyclopentyl]methyl}carbamate (58 g) obtained in Step 1 in DMF (505 mL) was added methyl iodide (47 mL) with stirring at room temperature. Subsequently, 60% sodium hydride (30 g) was added in several portions under ice cooling. The mixture was stirred for 30 minutes under ice cooling and then stirred overnight at room temperature. Water (800 mL) was added dropwise to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was then removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (68 g).[Step 3] Preparation of 1-[1-(methoxymethyl)cyclopentyl]-N-methylmethanamine hydrochloride By a method similar to Step 3 of Reference Example 1, except that tert-butyl {[1-(methoxymethyl)cyclopentyl]methyl}methylcarbamate obtained in Step 2 of Reference Example 2 was used instead of tert-butyl {[1-(ethoxymethyl)cyclopentyl]methyl}methylcarbamate, the title compound (52 g) was obtained. Reference Example 3 6-chloro-N. ４ -(3-methoxy-2,2-dimethylpropyl)-N ４ A mixture of 4,6-dichloro-3-nitropyridine-2,4-diamine (6.3 g), 3-methoxy-N,2,2-trimethylpropan-1-amine hydrochloride (6.6 g), DIPEA (16 mL), and 2-propanol (100 mL) was stirred at 60°C for 1 hour. Water (50 mL) was added at room temperature, and the precipitate was collected by filtration, washed with 2-propanol and water, and then dried to obtain the title compound (8.0 g). Reference Example 4 6'-cyclopropyl-N ４ -{[1-(methoxymethyl)cyclohexyl]methyl}-N ４ -methyl-5-nitro-5'-(trifluoromethyl)[2,3'-bipyridine]-4,6-diamine 6-chloro-N ４ -{[1-(methoxymethyl)cyclohexyl]methyl}-N ４ A mixture of 2.5 g of 2-methyl-3-nitropyridine-2,4-diamine, 2.7 g of 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridine, 3.0 g of potassium carbonate, 29 mL of 1,4-dioxane, and 11 mL of water was degassed and stirred at room temperature under an argon atmosphere to give Pd(dppf)Cl. ２ ・CH ２ Cl ２(0.24 g) was added and the mixture was stirred at 95°C for 2 hours. At room temperature, the reaction mixture was diluted with water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (3.5 g). Reference Example 5 2'-ethoxy-N ４ -{[1-(ethoxymethyl)cyclopentyl]methyl}-N ４ -methyl-6'-(trifluoromethyl)[2,4'-bipyridine]-4,5,6-triamine 6-chloro-N ４ -{[1-(ethoxymethyl)cyclopentyl]methyl}-N ４ -methyl-3-nitropyridine-2,4-diamine (0.70 g), 2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (0.78 g), potassium carbonate (0.85 g), Pd(dppf)Cl ２ ・CH ２ Cl ２ A mixture of (67 mg), 1,4-dioxane (8.2 mL), and water (3.1 mL) was degassed and stirred at 90°C for 2 hours under an argon atmosphere. The reaction mixture was diluted with water and ethyl acetate at room temperature, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2'-ethoxy-N ４ -{[1-(ethoxymethyl)cyclopentyl]methyl}-N ４ 5-Methyl-5-nitro-6'-(trifluoromethyl)[2,4'-bipyridine]-4,6-diamine was obtained. This was mixed with 2-propanol (6.8 mL), water (3.4 mL), ammonium chloride (0.33 g), and zinc powder (0.67 mg) and stirred at room temperature for 1 hour. Insoluble matter was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (0.83 g).

[0153] Reference Example 6 6'-ethoxy-N ４-{[1-(methoxymethyl)cyclohexyl]methyl}-N ４ -methyl-5'-(trifluoromethyl)[2,3'-bipyridine]-4,5,6-triamine 6'-ethoxy-N ４ -{[1-(methoxymethyl)cyclohexyl]methyl}-N ４ To a mixture of 5-methyl-5-nitro-5'-(trifluoromethyl)[2,3'-bipyridine]-4,6-diamine (510 mg), 2-propanol (7.5 mL), and water (2.5 mL), ammonium chloride (165 mg) and reduced iron (powder, 172 mg) were added at room temperature, and the mixture was stirred at 90°C overnight. The mixture was diluted with ethyl acetate and water at room temperature, and the insoluble matter was filtered off. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (429 mg). Reference Example 7: 6'-cyclopropyl-N ４ -{[1-(ethoxymethyl)cyclopentyl]methyl}-N ４ -methyl-5'-(trifluoromethyl)[2,3'-bipyridine]-4,5,6-triamine 6'-cyclopropyl-N ４ -{[1-(ethoxymethyl)cyclopentyl]methyl}-N ４ To a mixture of 5-methyl-5-nitro-5'-(trifluoromethyl)[2,3'-bipyridine]-4,6-diamine (5.8 g), ammonium chloride (1.9 g), 2-propanol (39 mL), and water (20 mL) was added zinc powder (3.9 g) while stirring at room temperature, and the mixture was stirred at 50°C for 4 hours. The reaction mixture was diluted with ethyl acetate at room temperature, and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (5.3 g). Reference Example 8 5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-N ７ -{[1-(methoxymethyl)cyclohexyl]methyl}-N ７ -methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine 6'-ethoxy-N ４ -{[1-(methoxymethyl)cyclohexyl]methyl}-N ４5-Methyl-5'-(trifluoromethyl)[2,3'-bipyridine]-4,5,6-triamine (0.39 g) was dissolved in methanol (4.2 mL), and cyanogen bromide (0.18 g) was added under ice-cooling. The mixture was stirred at room temperature for 10 minutes and then at 50°C for 6 hours. After cooling to room temperature, the mixture was diluted with water and saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (0.27 g). Reference Example 9 5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-N ７ -{[1-(methoxymethyl)cyclopentyl]methyl}-N ７ -methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine 6'-cyclopropyl-N ４ -{[1-(methoxymethyl)cyclopentyl]methyl}-N ４ 5-Methyl-5'-(trifluoromethyl)[2,3'-bipyridine]-4,5,6-triamine (0.42 g) was dissolved in methanol (4.6 mL), and cyanogen bromide (0.20 g) was added under ice-cooling. The mixture was stirred at room temperature for 10 minutes and then at 50°C for 6 hours. After cooling to room temperature, the mixture was diluted with water and saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (0.31 g). Reference Example 10 5-(2-ethoxy-2-oxoethyl)pyridine-2-carboxylic acid [Step 1] Preparation of benzyl 5-(2-ethoxy-2-oxoethyl)picolinate Ethyl 2-(6-bromopyridin-3-yl)acetate (100 mg), Pd(dppf)Cl ２ ・CH ２ Cl ２A mixture of 5-(2-ethoxy-2-oxoethyl)pyridine-2-carboxylic acid (34 mg), dppf (45 mg), TEA (0.57 mL), DMF (1 mL), and benzyl alcohol (1 mL) was degassed and replaced with argon. This was stirred overnight at 80°C under atmospheric pressure and a carbon monoxide atmosphere. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (105 mg). [Step 2] Preparation of 5-(2-ethoxy-2-oxoethyl)pyridine-2-carboxylic acid Benzyl 5-(2-ethoxy-2-oxoethyl)picolinate (105 mg) obtained in Step 1 was dissolved in isopropanol (1.5 mL) and diluted with 20% Pd(OH) ２ To the reaction mixture was added 20 mg of HCl (C). After degassing and replacing with argon, the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere at normal pressure. The insoluble matter in the reaction mixture was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the title compound (63 mg).

[0154] Reference Example 11 5-(3-ethoxy-3-oxopropyl)pyridine-2-carboxylic acid [Step 1] Preparation of benzyl (E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)picolinate Benzyl 5-bromopicolinate (2.2 g), Pd(OAc) ２A mixture of 1,3-dimethyl-2,4-trimethyl-2,4-trimethyl-1,3-trimethyl-2,4-trimethyl-1,3-trimethyl-1 ... [Step 2] Preparation of 5-(3-ethoxy-3-oxopropyl)pyridine-2-carboxylic acid. Benzyl (E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)picolinate (1.9 g) obtained in Step 1 was dissolved in isopropanol (20 mL) and THF (5 mL), and 10% Pd—C (200 mg) was added. This mixture was degassed and purged with argon, and then stirred overnight at room temperature under a 0.4 MPa hydrogen atmosphere. Insoluble matter was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was suspended in hexane-ethyl acetate (10:1) (200 mL), and the precipitate was collected by filtration. This was washed with hexane and then dried to obtain the title compound (1.3 g). Reference Example 12 5-(3-ethoxy-3-oxopropyl)-4-methoxypyridine-2-carboxylic acid [Step 1] Preparation of benzyl 5-bromo-4-methoxypicolinate Benzyl bromide (0.38 mL) was added to a mixture of 5-bromo-4-methoxypicolinic acid (622 mg), potassium carbonate (741 mg), and DMF (5 mL), and the mixture was stirred at 80°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (779 mg). [Step 2] Preparation of benzyl (E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-4-methoxypicolinate Benzyl 5-bromo-4-methoxypicolinate (779 mg) obtained in Step 1 was reacted with Pd(OAc) ２(54 mg), tri-o-tolylphosphine (147 mg), DIPEA (0.84 mL), ethyl acrylate (1.1 mL), and DMF (4.8 mL). This mixture was degassed and replaced with argon, and then stirred at 110°C overnight. The reaction mixture was diluted with water and ethyl acetate at room temperature, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (496 mg). [Step 3] Preparation of 5-(3-ethoxy-3-oxopropyl)-4-methoxypyridine-2-carboxylic acid. Benzyl (E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-4-methoxypicolinate (496 mg) obtained in Step 2 was dissolved in isopropanol (5 mL), THF (5 mL), and ethanol (5 mL), and 10% Pd—C (100 mg) was added. This mixture was degassed and purged with argon, and then stirred overnight at room temperature under a 0.4 MPa hydrogen atmosphere. Insoluble matter was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was suspended in hexane-ethyl acetate (10:1) (50 mL), and the precipitate was collected by filtration. This was washed with hexane and then dried to obtain the title compound (297 mg). Reference Example 13 5-[2-(ethoxycarbonyl)cyclopropyl]pyridine-2-carboxylic acid hydrochloride [Step 1] Preparation of tert-butyl (E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)picolinate tert-Butyl 5-bromopicolinate (200 mg), Pd(OAc) ２A mixture of 5-[2-(ethoxycarbonyl)cyclopropyl]picolinate (35 mg), tri-o-tolylphosphine (94 mg), DIPEA (0.27 mL), ethyl acrylate (0.34 mL), and DMF (2 mL) was degassed and replaced with argon. This was stirred overnight at 110°C. At room temperature, the reaction mixture was diluted with water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (197 mg). [Step 2] Preparation of tert-butyl 5-[2-(ethoxycarbonyl)cyclopropyl]picolinate Sodium hydride (27 mg) was added to a mixture of trimethylsulfoxonium iodide (157 mg) and DMSO (1.8 mL), and the mixture was stirred at room temperature for 15 minutes. To this was added tert-butyl (E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)picolinate (147 mg) obtained in Step 1, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (79 mg). [Step 3] Preparation of 5-[2-(ethoxycarbonyl)cyclopropyl]pyridine-2-carboxylic acid hydrochloride Hydrogen chloride (4 M 1,4-dioxane solution, 0.87 mL) was added to tert-butyl 5-[2-(ethoxycarbonyl)cyclopropyl]picolinate (101 mg) obtained in Step 2, and the mixture was stirred overnight at room temperature. The mixture was then stirred at 50°C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in hexane-chloroform (10:1) (10 mL), and the precipitate was collected by filtration. This was washed with hexane and then dried to obtain the title compound (70 mg). Reference Example 14 6-(3-ethoxy-3-oxopropyl)pyridine-3-carboxylic acid [Step 1] Preparation of benzyl (E)-6-(3-ethoxy-3-oxoprop-1-en-1-yl)nicotinate A mixture of benzyl 6-methylnicotinate (200 mg), ethyl 2-oxoacetate (47% toluene solution, 440 mg), and acetic anhydride (0.80 mL) was stirred at 130°C for 72 hours.After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (267 mg). [Step 2] Preparation of 6-(3-ethoxy-3-oxopropyl)pyridine-3-carboxylic acid. Benzyl (E)-6-(3-ethoxy-3-oxoprop-1-en-1-yl)nicotinate (267 mg) obtained in Step 1 was dissolved in ethanol (10 mL), and 10% Pd—C (27 mg) was added. This mixture was degassed and replaced with argon, and then stirred overnight at room temperature under a 0.4 MPa hydrogen atmosphere. The insoluble matter was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was suspended in hexane-chloroform (10:1, 30 mL), and the precipitate was collected by filtration. This was washed with hexane and then dried to obtain the title compound (97 mg). Reference Example 15 5-(5-ethoxy-5-oxopentyl)pyridine-2-carboxylic acid [Step 1] Preparation of benzyl 5-(5-ethoxy-5-oxopent-1-yn-1-yl)picolinate Benzyl 5-bromopicolinate (200 mg), Pd(PPh3). ４A mixture of (158 mg), copper(I) iodide (26 mg), TEA (0.48 mL), and DMF (1.4 mL) was degassed and replaced with argon. This was stirred at 75°C for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at room temperature, diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (251 mg). [Step 2] Preparation of 5-(5-ethoxy-5-oxopentyl)pyridine-2-carboxylic acid Benzyl 5-(5-ethoxy-5-oxopent-1-yn-1-yl)picolinate (230 mg) obtained in Step 1 was dissolved in isopropanol (5 mL) and THF (2 mL), and 10% Pd—C (40 mg) was added. This mixture was degassed and purged with argon, and then stirred overnight at room temperature under a 0.4 MPa hydrogen atmosphere. Insoluble matter was filtered off through Celite and washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was suspended in hexane-chloroform (10:1, 20 mL), and the precipitate was collected by filtration. This was washed with hexane and then dried to obtain the title compound (139 mg).

[0155] Reference Example 16 5-{[(1R,5S,6r)-6-(methoxycarbonyl)-3-azabicyclo[3.1.0]hexan-3-yl]methyl}pyridine-2-carboxylic acid dihydrochloride [Step 1] Preparation of methyl (1R,5S,6r)-3-{[6-(tert-butoxycarbonyl)pyridin-3-yl]methyl}-3-azabicyclo[3.1.0]hexane-6-carboxylate Methyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloride (78 mg) was added to a mixture of tert-butyl 5-(bromomethyl)picolinate (100 mg), potassium carbonate (152 mg), and acetonitrile (0.74 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (83 mg). [Step 2] Preparation of 5-{[(1R,5S,6r)-6-(methoxycarbonyl)-3-azabicyclo[3.1.0]hexan-3-yl]methyl}pyridine-2-carboxylic acid. To a solution of methyl (1R,5S,6r)-3-{[6-(tert-butoxycarbonyl)pyridin-3-yl]methyl}-3-azabicyclo[3.1.0]hexane-6-carboxylate (83 mg) obtained in Step 1 in 1,4-dioxane (1.5 mL) was added hydrogen chloride (4 M 1,4-dioxane solution, 5 mL), and the mixture was stirred at 50 °C overnight. The reaction mixture was concentrated under reduced pressure to obtain the title compound (75 mg). Reference Example 17 5-[(2-ethoxy-2-oxoethyl)(methyl)amino]pyridine-2-carboxylic acid [Step 1] Preparation of ethyl N-(6-bromopyridin-3-yl)-N-methylglycinate To a mixture of 6-bromo-N-methylpyridin-3-amine (622 mg), DIPEA (0.60 mL), and DMF (3.5 mL) was added ethyl 2-bromoacetate (0.29 mL) with stirring at room temperature, and the mixture was stirred at 110°C overnight. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure.The residue was purified by silica gel column chromatography to obtain the title compound (395 mg). [Step 2] Preparation of benzyl 5-[(2-ethoxy-2-oxoethyl)(methyl)amino]picolinate Ethyl N-(6-bromopyridin-3-yl)-N-methylglycinate (395 mg) obtained in Step 1 was treated with Pd(dppf)Cl. ２ ・CH ２ Cl ２ (118 mg), TEA (0.61 mL), DMF (1.5 mL), and benzyl alcohol (1.5 mL) were mixed. The mixture was degassed and purged with argon, and then stirred at 80°C under atmospheric pressure and a carbon monoxide atmosphere for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (512 mg). [Step 3] Preparation of 5-[(2-ethoxy-2-oxoethyl)(methyl)amino]pyridine-2-carboxylic acid Benzyl 5-[(2-ethoxy-2-oxoethyl)(methyl)amino]picolinate (512 mg) obtained in Step 2 was dissolved in isopropanol (10 mL), and 10% Pd—C (55 mg) was added. This mixture was degassed and replaced with argon, and then stirred overnight at room temperature under a 0.4 MPa hydrogen atmosphere. The insoluble matter in the reaction mixture was filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was suspended in hexane-ethyl acetate (10:1) (50 mL), and the precipitate was collected by filtration. This was washed with hexane and then dried to obtain the title compound (300 mg). Reference Example 18 5-[4-(ethoxycarbonyl)piperidin-1-yl]pyridine-2-carboxylic acid [Step 1] Preparation of benzyl 5-[4-(ethoxycarbonyl)piperidin-1-yl]picolinate Benzyl 5-bromopicolinate (150 mg), ethyl piperidine-4-carboxylate (0.12 mL), Pd(OAc) ２A mixture of 5-[4-(ethoxycarbonyl)piperidin-1-yl]pyridine-2-carboxylic acid (151 mg) was obtained in Step 1. Benzyl 5-[4-(ethoxycarbonyl)piperidin-1-yl]picolinate (151 mg) obtained in Step 1 was dissolved in isopropanol (4 mL) and THF (2 mL) and diluted with 20% Pd(OH). ２ To the mixture was added 20 mg of HCl. The mixture was degassed and purged with argon, and then stirred overnight at room temperature under a hydrogen atmosphere at normal pressure. The insoluble matter was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was suspended in hexane-ethyl acetate (10:1) (15 mL), and the precipitate was collected by filtration. This was washed with hexane and then dried to obtain the title compound (99 mg). Reference Example 19 5-[(3S)-3-(2-ethoxy-2-oxoethoxy)pyrrolidin-1-yl]pyridine-2-carboxylic acid hydrochloride [Step 1] Preparation of tert-butyl (S)-5-[3-(2-ethoxy-2-oxoethoxy)pyrrolidin-1-yl]picolinate tert-Butyl 5-bromopicolinate (100 mg), ethyl (S)-2-(pyrrolidin-3-yloxy)acetate hydrochloride (122 mg), Pd(OAc) ２A mixture of 1,4-dioxane (1.9 mL) (8.7 mg), RuPhos (36 mg), cesium carbonate (379 mg), and 1,4-dioxane (1.9 mL) was degassed and replaced with argon. This was stirred at 100°C overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (120 mg). [Step 2] Preparation of 5-[(3S)-3-(2-ethoxy-2-oxoethoxy)pyrrolidin-1-yl]pyridine-2-carboxylic acid hydrochloride To a solution of tert-butyl (S)-5-[3-(2-ethoxy-2-oxoethoxy)pyrrolidin-1-yl]picolinate (120 mg) obtained in Step 1 in 1,4-dioxane (0.50 mL) was added hydrogen chloride (4 M 1,4-dioxane solution, 1.7 mL), and the mixture was stirred for 5 hours at 50° C. The reaction mixture was concentrated under reduced pressure to obtain the title compound (89 mg). Reference Example 20 6-[(2-ethoxy-2-oxoethyl)(methyl)amino]pyrimidine-4-carboxylic acid [Step 1] Preparation of benzyl 6-[(2-ethoxy-2-oxoethyl)(methyl)amino]pyrimidine-4-carboxylate Ethyl 2-methylglycinate hydrochloride (37 mg) was added to a mixture of benzyl 6-chloropyrimidine-4-carboxylate (50 mg), TEA (0.084 mL), and acetonitrile (0.40 mL), and the mixture was stirred at 50°C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (74 mg). [Step 2] Preparation of 6-[(2-ethoxy-2-oxoethyl)(methyl)amino]pyrimidine-4-carboxylic acid Benzyl 6-[(2-ethoxy-2-oxoethyl)(methyl)amino]pyrimidine-4-carboxylate (102 mg) obtained in Step 1 was dissolved in isopropanol (1 mL) and added with 20% Pd(OH) ２To the mixture was added 11 mg of HCl. The mixture was degassed and purged with argon, and then stirred overnight at room temperature under a hydrogen atmosphere at normal pressure. The insoluble matter was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was suspended in hexane-chloroform (10:1) (10 mL), and the precipitate was collected by filtration. This was washed with hexane and then dried to obtain the title compound (64 mg).

[0156] Reference Example 21 5-[2-(methoxycarbonyl)pyrrolidine-1-carbonyl]pyridine-2-carboxylic acid [Step 1] Preparation of benzyl 5-[2-(methoxycarbonyl)pyrrolidine-1-carbonyl]picolinate HATU (233 mg) was added to a mixture of 6-[(benzyloxy)carbonyl]nicotinic acid hydrochloride (100 mg), DIPEA (0.30 mL), and DMF (1 mL), and the mixture was stirred at room temperature for 10 minutes. Methyl prolinate hydrochloride (85 mg) was added to the mixture, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (160 mg). [Step 2] Preparation of 5-[2-(methoxycarbonyl)pyrrolidine-1-carbonyl]pyridine-2-carboxylic acid Benzyl 5-[2-(methoxycarbonyl)pyrrolidine-1-carbonyl]picolinate (160 mg) obtained in Step 1 was dissolved in isopropanol (4 mL) and THF (2 mL), and the mixture was diluted with 20% Pd(OH) ２To this was added 5-[(2-ethoxy-2-oxoethoxy)methyl]pyridine-2-carboxylic acid hydrochloride [Step 1] Preparation of tert-butyl 5-[(2-ethoxy-2-oxoethoxy)methyl]picolinate. 60% Sodium hydride (17 mg) was added in portions to a solution of tert-butyl 5-(hydroxymethyl)picolinate (73 mg) in THF (0.70 mL) under ice-cooling. The mixture was stirred for 10 minutes under ice-cooling, and then ethyl 2-bromoacetate (0.050 mL) was added, followed by stirring at room temperature overnight. The insoluble matter was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure to obtain the title compound (134 mg). Reference Example 22 5-[(2-ethoxy-2-oxoethoxy)methyl]pyridine-2-carboxylic acid hydrochloride [Step 1] Preparation of tert-butyl 5-[(2-ethoxy-2-oxoethoxy)methyl]picolinate. 60% Sodium hydride (17 mg) was added in portions to a solution of tert-butyl 5-(hydroxymethyl)picolinate (73 mg) in THF (0.70 mL). After stirring for 10 minutes under ice-cooling, ethyl 2-bromoacetate (0.050 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (33 mg). [Step 2] Preparation of 5-[(2-ethoxy-2-oxoethoxy)methyl]pyridine-2-carboxylic acid hydrochloride. Hydrogen chloride (4 M 1,4-dioxane solution, 0.57 mL) was added to tert-butyl 5-[(2-ethoxy-2-oxoethoxy)methyl]picolinate (33 mg) obtained in Step 1, and the mixture was stirred at 50°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in hexane-chloroform (10:1) (3 mL), and the precipitate was collected by filtration. This was washed with hexane and then dried to obtain the title compound (26 mg). Reference Example 23 5-[2-(2-ethoxy-2-oxoethoxy)ethyl]pyridine-2-carboxylic acid [Step 1] Preparation of ethyl 2-[2-(6-chloropyridin-3-yl)ethoxy]acetate 2-(6-chloropyridin-3-yl)ethan-1-ol (435 mg), Rh ２ (OAc) ４ To a mixture of Rh (24 mg) and dichloromethane (10 mL) was added dropwise 15% ethyl diazoacetate (toluene solution, 2.9 mL) over 15 minutes while stirring at room temperature, and the mixture was stirred at room temperature overnight. ２ (OAc) ４After adding (24 mg), 15% ethyl diazoacetate (toluene solution, 2.9 mL) was added dropwise over 15 minutes, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (295 mg). [Step 2] Preparation of benzyl 5-[2-(2-ethoxy-2-oxoethoxy)ethyl]picolinate Ethyl 2-[2-(6-chloropyridin-3-yl)ethoxy]acetate (295 mg) obtained in Step 1 was added to Pd(dppf)Cl ２ ・CH ２ Cl ２ (198 mg), TEA (0.51 mL), DMF (1.2 mL), and benzyl alcohol (1.2 mL) were mixed. The mixture was degassed and purged with argon, and then stirred overnight at 80°C under atmospheric pressure and a carbon monoxide atmosphere. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (250 mg). [Step 3] Preparation of 5-[2-(2-ethoxy-2-oxoethoxy)ethyl]pyridine-2-carboxylic acid Benzyl 5-[2-(2-ethoxy-2-oxoethoxy)ethyl]picolinate (250 mg) obtained in Step 2 was dissolved in isopropanol (5 mL) and THF (1 mL), and the mixture was diluted with 20% Pd(OH) ２To this was added 50 mg of 5-(4-ethoxy-4-oxobutoxy)pyridine-2-carboxylic acid. The mixture was degassed and purged with argon, and then stirred overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. The insoluble matter was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure to obtain the title compound (205 mg). Reference Example 24: 5-(4-ethoxy-4-oxobutoxy)pyridine-2-carboxylic acid [Step 1] Preparation of benzyl 5-(4-ethoxy-4-oxobutoxy)picolinate Ethyl 4-bromobutanoate (0.059 mL) was added to a mixture of benzyl 5-hydroxypicolinate (86 mg), potassium carbonate (103 mg), and DMF (1.9 mL), and the mixture was stirred overnight at 80°C. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (131 mg). [Step 2] Preparation of 5-(4-ethoxy-4-oxobutoxy)pyridine-2-carboxylic acid Benzyl 5-(4-ethoxy-4-oxobutoxy)picolinate (131 mg) obtained in Step 1 was dissolved in isopropanol (4 mL) and THF (1 mL), and the mixture was diluted with 20% Pd(OH) ２Benzyl 4-hydroxypicolinate (4-hydroxypicolinic acid, 500 mg) was added to the reaction mixture. After degassing and purging with argon, the mixture was stirred overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. The insoluble matter was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was suspended in hexane-chloroform (10:1) (15 mL). The precipitate was collected by filtration. The precipitate was washed with hexane and dried to obtain the title compound (75 mg). Reference Example 25: 4-(2-Ethoxy-2-oxoethoxy)pyridine-2-carboxylic acid [Step 1] Preparation of benzyl 4-hydroxypicolinate 4-Hydroxypicolinic acid (500 mg) was dissolved in NMP (5 mL), and 60% sodium hydride (158 mg) was added in portions under ice-cooling and stirring. The mixture was stirred at room temperature for 1 hour, and then benzyl bromide (0.43 mL) was added, followed by stirring at 40°C overnight. After cooling to room temperature, a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (346 mg). [Step 2] Preparation of benzyl 4-(2-ethoxy-2-oxoethoxy)picolinate Benzyl 4-hydroxypicolinate (346 mg) obtained in Step 1 was mixed with potassium carbonate (625 mg) and acetone (3 mL). To this mixture, ethyl 2-bromoacetate (0.17 mL) was added with stirring at room temperature, and the mixture was stirred at 60°C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (58 mg). [Step 3] Preparation of 4-(2-ethoxy-2-oxoethoxy)pyridine-2-carboxylic acid Benzyl 4-(2-ethoxy-2-oxoethoxy)picolinate (58 mg) obtained in Step 2 was dissolved in isopropanol (1 mL) and added with 20% Pd(OH) ２ To the mixture was added 1,4-dichloro-2,4-dichloro-1 ...

[0157] Reference Example 26 6-(2-ethoxy-2-oxoethoxy)pyrimidine-4-carboxylic acid hydrochloride [Step 1] Preparation of tert-butyl 6-(2-ethoxy-2-oxoethoxy)pyrimidine-4-carboxylate A mixture of tert-butyl 6-chloropyrimidine-4-carboxylate (274 mg), ethyl 2-hydroxyacetate (0.15 mL), potassium carbonate (529 mg), and DMF (2.6 mL) was stirred at 50°C overnight. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (253 mg). [Step 2] Preparation of 6-(2-ethoxy-2-oxoethoxy)pyrimidine-4-carboxylic acid hydrochloride To tert-butyl 6-(2-ethoxy-2-oxoethoxy)pyrimidine-4-carboxylate (300 mg) obtained in Step 1, hydrogen chloride (4 M solution in 1,4-dioxane, 3.2 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in hexane-diethyl ether (3:1) (12 mL), and the precipitate was collected by filtration. This was washed with hexane and then dried to obtain the title compound (244 mg). Reference Example 27 1-(4-ethoxy-4-oxobutan-2-yl)-1H-imidazole-4-carboxylic acid [Step 1] Preparation of benzyl 1-(4-ethoxy-4-oxobutan-2-yl)-1H-imidazole-4-carboxylate Ethyl 3-bromobutanoate (0.20 mL) was added to a mixture of benzyl 1H-imidazole-4-carboxylate (205 mg), potassium carbonate (741 mg), and DMF (2 mL) under ice-cooling and stirring, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (348 mg).[Step 2] Preparation of 1-(4-ethoxy-4-oxobutan-2-yl)-1H-imidazole-4-carboxylic acid Benzyl 1-(4-ethoxy-4-oxobutan-2-yl)-1H-imidazole-4-carboxylate (348 mg) obtained in Step 1 was dissolved in isopropanol (3.5 mL) and THF (1 mL), and the mixture was diluted with 20% Pd(OH). ２ To the mixture was added 35 mg of HCl. The mixture was degassed and purged with argon, and then stirred overnight at room temperature under a hydrogen atmosphere at normal pressure. The insoluble matter was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was suspended in hexane-ethyl acetate (10:1) (15 mL), and the precipitate was collected by filtration. This was washed with hexane and then dried to obtain the title compound (184 mg). Reference Example 28 6-(3-ethoxy-3-oxopropyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid [Step 1] Preparation of benzyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate Benzyl bromide (0.28 mL) was added to a mixture of 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid (468 mg), potassium carbonate (536 mg), and DMF (6.5 mL), and the mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (389 mg). [Step 2] Preparation of benzyl (E)-6-(3-ethoxy-3-oxoprop-1-en-1-yl)imidazo[1,2-a]pyridine-2-carboxylate Benzyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate (300 mg) obtained in Step 1 was reacted with Pd(OAc) ２(20 mg), tri-o-tolylphosphine (55 mg), DIPEA (0.31 mL), ethyl acrylate (0.30 mL), and DMF (1.8 mL) were mixed. This mixture was degassed and replaced with argon, and then stirred at 110°C overnight. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and insoluble matter was filtered off through Celite, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (226 mg). [Step 3] Preparation of 6-(3-ethoxy-3-oxopropyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid. Benzyl (E)-6-(3-ethoxy-3-oxoprop-1-en-1-yl)imidazo[1,2-a]pyridine-2-carboxylate (226 mg) obtained in Step 2 was dissolved in isopropanol (2 mL), THF (2.5 mL), and methanol (5 mL), and 10% Pd—C (100 mg) was added. The mixture was degassed and purged with argon, and then stirred at 50°C under a 0.4 MPa hydrogen atmosphere for 5 hours. Insoluble matter was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was suspended in hexane-ethyl acetate (10:1) (20 mL), and the precipitate was collected by filtration. This was washed with hexane and then dried to obtain the title compound (149 mg). Reference Example 29 5-[1-(3-ethoxy-3-oxopropyl)piperidin-4-yl]pyridine-2-carboxylic acid dihydrochloride [Step 1] Preparation of tert-butyl 5-[1-(3-ethoxy-3-oxopropyl)piperidin-4-yl]picolinate Ethyl 3-bromopropanoate (0.11 mL) was added to a mixture of tert-butyl 5-(piperidin-4-yl)picolinate (180 mg), DIPEA (0.24 mL), and acetonitrile (2 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (203 mg).[Step 2] Preparation of 5-[1-(3-ethoxy-3-oxopropyl)piperidin-4-yl]pyridine-2-carboxylic acid dihydrochloride To tert-butyl 5-[1-(3-ethoxy-3-oxopropyl)piperidin-4-yl]picolinate (203 mg) obtained in Step 1, hydrogen chloride (4 M 1,4-dioxane solution, 5.6 mL) was added, and the mixture was stirred at 50°C overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was suspended in hexane-chloroform (10:1) (20 mL), and the precipitate was collected by filtration. This was washed with hexane and then dried to obtain the title compound (158 mg). Reference Example 30 7-(3-ethoxy-3-oxopropyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid dihydrochloride [Step 1] Preparation of methyl 7-(2,2,2-trifluoroacetyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate A solution of 4-bromo-1-(2,2,2-trifluoroacetyl)-1,2,5,6-tetrahydropyridine-3-carbaldehyde (2.9 g) in 1,4-dioxane (50 mL) was degassed and then stirred at room temperature under an argon atmosphere with Pd(OAc). ２(0.23 g), Dave-Phos (0.81 g), sodium acetate (1.7 g), and methyl 2-acetamidoacrylate (1.9 g) were added, and the mixture was stirred at 80°C for 2 hours, and then at 100°C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.7 g). [Step 2] Preparation of 7-((benzyloxy)carbonyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid. To a solution of methyl 7-(2,2,2-trifluoroacetyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate (1.7 g) obtained in Step 1 in THF (20 mL) and water (20 mL) was added 4 M aqueous sodium hydroxide solution (5.8 mL) while stirring at room temperature. After stirring at room temperature for 1 hour, benzyl chloroformate (0.92 mL) was added and stirred for 2 hours. To the reaction mixture was added 1 M hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was diluted with diethyl ether-hexane (1:1), and the insoluble matter was collected by filtration and dried to obtain the title compound (1.2 g). [Step 3] Preparation of 2-benzyl 6-(tert-butyl) 3,4-dihydro-2,7-naphthyridine-2,6(1H)-dicarboxylate. To 7-((benzyloxy)carbonyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid (1.2 g) obtained in Step 2 and DMAP (47 mg) were added tert-butanol (15 mL) and THF (15 mL). While stirring at room temperature, di-tert-butyl dicarbonate (2.5 g) was added and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.1 g).[Step 4] Preparation of tert-butyl 5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate hydrochloride. To a solution of 2-benzyl 6-(tert-butyl) 3,4-dihydro-2,7-naphthyridine-2,6(1H)-dicarboxylate (1.1 g) obtained in Step 3 in 2-propanol (10 mL) and THF (10 mL) was added 5% Pd—C (0.62 g) while stirring at room temperature under an argon atmosphere. The mixture was then stirred at room temperature under a 0.4 MPa hydrogen atmosphere for 4 hours. The reaction mixture was diluted with ethyl acetate, and insoluble matter was removed by filtration. Hydrogen chloride (4 M in 1,4-dioxane, 1.5 mL) was added. The mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The precipitate was collected by filtration and dried to give the title compound (0.75 g). [Step 5] Preparation of tert-butyl 7-(3-ethoxy-3-oxopropyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate. To a solution of tert-butyl 5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate hydrochloride (0.35 g) obtained in Step 4 in acetonitrile (5 mL) was added DIPEA (0.89 mL) and ethyl 3-bromopropionate (0.25 mL) while stirring at room temperature, and the mixture was stirred at 80 °C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (0.29 g). [Step 6] Preparation of 7-(3-ethoxy-3-oxopropyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid dihydrochloride To tert-butyl 7-(3-ethoxy-3-oxopropyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate (0.29 g) obtained in Step 5, hydrogen chloride (4 M solution in 1,4-dioxane, 8.7 mL) was added, and the mixture was stirred for 2 hours at 50° C. After concentration under reduced pressure, the residue was diluted with ethyl acetate, and the precipitate was collected by filtration and dried to obtain the title compound (0.24 g).

[0158] Reference Example 31 6-(3-ethoxy-3-oxopropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid hydrochloride [Step 1] Preparation of tert-butyl 1,6-naphthyridine-2-carboxylate THF (10 mL) was added to 1,6-naphthyridine-2-carboxylic acid (0.15 g) and DMAP (11 mg), and while stirring at room temperature, di-tert-butyl dicarbonate (0.38 g) was added and stirred at room temperature overnight. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (0.19 g). [Step 2] Preparation of 2-(tert-butoxycarbonyl)-6-(3-ethoxy-3-oxopropyl)-1,6-naphthyridin-6-ium bromide To a solution of tert-butyl 1,6-naphthyridine-2-carboxylate (100 mg) obtained in Step 1 in 1,4-dioxane (5 mL) was added ethyl 3-bromopropionate (0.79 mL) with stirring at room temperature, and the mixture was stirred at 110° C. for 2 days. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (92 mg). [Step 3] Preparation of 6-(3-ethoxy-3-oxopropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid hydrochloride To a solution of 2-(tert-butoxycarbonyl)-6-(3-ethoxy-3-oxopropyl)-1,6-naphthyridin-6-ium bromide (90 mg) obtained in Step 2 in THF (3 mL) was added acetic acid (0.062 mL) and sodium cyanoborohydride (41 mg) while stirring at room temperature, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the resulting crude product was dissolved in hydrogen chloride (4 M 1,4-dioxane solution, 2 mL) and stirred for 1 hour at 70° C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the precipitate was collected by filtration and dried to obtain the title compound (42 mg).Reference Example 32 7-(2-ethoxy-2-oxoethyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid dihydrochloride [Step 1] Preparation of tert-butyl 7-(2-ethoxy-2-oxoethyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate To a solution of tert-butyl 5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate hydrochloride (60 mg) obtained in Step 4 of Reference Example 30 in acetonitrile (2 mL) were added DIPEA (0.13 mL) and ethyl bromoacetate (0.029 mL) with stirring at room temperature, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (57 mg). [Step 2] Preparation of 7-(2-ethoxy-2-oxoethyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid dihydrochloride. Dichloromethane (2 mL) and trifluoroacetic acid (2 mL) were added to tert-butyl 7-(2-ethoxy-2-oxoethyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate (55 mg) obtained in Step 1, and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, the residue was diluted with ethyl acetate, and hydrogen chloride (4 M in 1,4-dioxane, 0.095 mL) was added and the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration and dried to obtain the title compound (47 mg). Reference Example 33 7-(Ethoxycarbonyl)-5,6,7,8-tetrahydroisoquinoline-3-carboxylic acid [Step 1] Preparation of ethyl 4-bromo-3-formylcyclohex-3-ene-1-carboxylate To a solution of DMF (1.4 mL) in chloroform (15 mL) was added phosphorus tribromide (1.4 mL) with stirring at room temperature, and the mixture was stirred at 70°C for 1 hour. After cooling to room temperature, a solution of ethyl 4-oxocyclohexane-1-carboxylate (1 g) in chloroform (5 mL) was added, and the mixture was stirred at 70°C for 5 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (0.82 g).[Step 2] Preparation of 7-ethyl 3-methyl 5,6,7,8-tetrahydroisoquinoline-3,7-dicarboxylate After degassing a solution of ethyl 4-bromo-3-formylcyclohex-3-ene-1-carboxylate (0.2 g) obtained in Step 1 in 1,4-dioxane (5 mL), Pd(OAc) was added under stirring at room temperature under an argon atmosphere. ２(17 mg), tri(o-tolyl)phosphine (47 mg), DIPEA (0.27 mL), and methyl 2-acetamidoacrylate (0.14 g) were added, and the mixture was stirred at 100°C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (70 mg). [Step 3] Preparation of 7-(ethoxycarbonyl)-5,6,7,8-tetrahydroisoquinoline-3-carboxylic acid To a solution of 7-ethyl 3-methyl 5,6,7,8-tetrahydroisoquinoline-3,7-dicarboxylate (20 mg) obtained in Step 2 in acetonitrile (1 mL) was added lithium iodide (30 mg) with stirring at room temperature, and the mixture was stirred at 90°C overnight. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (17 mg). Reference Example 34 6-(methoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid [Step 1] Preparation of 2-benzyl 6-methyl imidazo[1,2-a]pyridine-2,6-dicarboxylate To a solution of methyl 6-aminonicotinate (0.60 g) in 1,4-dioxane (10 mL) was added 3-bromopyruvic acid (0.724 g) with stirring at room temperature, and the mixture was stirred at 110°C for 5 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. DMF (10 mL) was added to the residue, and potassium carbonate (1.6 g) and benzyl bromide (0.94 mL) were added while stirring at room temperature, followed by stirring at 60 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (0.58 g).[Step 2] Preparation of 6-(methoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid To a solution of 2-benzyl 6-methyl imidazo[1,2-a]pyridine-2,6-dicarboxylate (0.20 g) obtained in Step 1 in methanol (10 mL) was added 10% Pd—C (68 mg) while stirring at room temperature under an argon atmosphere, and the mixture was stirred at 50° C. under a 0.4 MPa hydrogen atmosphere for 4 hours. The reaction mixture was diluted with methanol, and insoluble matter was removed by filtration. The mixture was then concentrated under reduced pressure to obtain the title compound (0.14 g). Reference Example 35 5-(Methoxycarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid [Step 1] Preparation of benzyl 5-bromopyrazolo[1,5-a]pyridine-2-carboxylate To a solution of ethyl 5-bromopyrazolo[1,5-a]pyridine-2-carboxylate (60 mg) in THF (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (28 mg) with stirring at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and ethyl acetate, 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. DMF (2 mL) was added to the residue, and potassium carbonate (93 mg) and benzyl bromide (0.053 mL) were added with stirring at room temperature, and the mixture was stirred at 50°C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (54 mg). [Step 2] Preparation of 2-benzyl 5-ethyl pyrazolo[1,5-a]pyridine-2,5-dicarboxylate To a solution of benzyl 5-bromopyrazolo[1,5-a]pyridine-2-carboxylate (50 mg) obtained in Step 1 in ethanol (1 mL) and DMF (1 mL) was added Pd(dppf)Cl with stirring at room temperature. ２ ・CH ２ Cl ２(12 mg) and DIPEA (0.052 mL) were added, and after degassing, the mixture was stirred under a carbon monoxide atmosphere at 80°C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (32 mg). [Step 3] Preparation of 5-(methoxycarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid. To a solution of 2-benzyl 5-ethyl pyrazolo[1,5-a]pyridine-2,5-dicarboxylate (30 mg) obtained in Step 2 in ethanol (5 mL) was added 10% Pd—C (20 mg) while stirring at room temperature under an argon atmosphere, and the mixture was stirred at 50°C under a hydrogen atmosphere of 0.4 MPa for 5 hours. The reaction mixture was diluted with methanol, the insoluble matter was filtered off, and then the filtrate was concentrated under reduced pressure to obtain the title compound (18 mg).

[0159] Reference Example 36 5-(3-ethoxy-2-fluoro-3-oxopropyl)pyridine-2-carboxylic acid hydrochloride [Step 1] Preparation of tert-butyl 5-(3-ethoxy-2-fluoro-3-oxoprop-1-en-1-yl)pyridine-2-carboxylate To a solution of tert-butyl 5-formylpyridine-2-carboxylate (83 mg), lithium chloride (34 mg), and triethyl 2-fluoro-2-phosphonoacetate (0.17 mL) in THF (4 mL), DBU (0.12 mL) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour and then stirred at room temperature overnight. Under ice cooling, the mixture was diluted with water and saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (110 mg). [Step 2] Preparation of tert-butyl 5-(3-ethoxy-2-fluoro-3-oxopropyl)pyridine-2-carboxylate A mixture of tert-butyl 5-(3-ethoxy-2-fluoro-3-oxoprop-1-en-1-yl)pyridine-2-carboxylate (60 mg) obtained in Step 1, 10% Pd—C (43 mg), THF (2 mL), and isopropanol (2 mL) was stirred overnight at room temperature under a hydrogen atmosphere of 0.38 MPa. Insoluble matter was filtered off and washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (43 mg). [Step 3] Preparation of 5-(3-ethoxy-2-fluoro-3-oxopropyl)pyridine-2-carboxylic acid hydrochloride To a solution of tert-butyl 5-(3-ethoxy-2-fluoro-3-oxopropyl)pyridine-2-carboxylate (43 mg) obtained in Step 2 in 1,4-dioxane (0.40 mL) was added hydrogen chloride (4 M 1,4-dioxane solution, 0.80 mL) while stirring at room temperature, and the mixture was stirred overnight at 50° C. After cooling to room temperature, the solvent was evaporated under reduced pressure to obtain the title compound (50 mg).Reference Example 37 5-(4-ethoxy-4-oxobutyl)pyridine-2-carboxylic acid [Step 1] Preparation of benzyl 5-(4-ethoxy-4-oxobutyl)pyridine-2-carboxylate A solution of benzyl 5-bromopyridine-2-carboxylate (0.70 g) in THF (4 mL) was degassed and treated with SPhos (39 mg) and Pd(OAc) at room temperature under an argon atmosphere. ２(11 mg) was added, the mixture was degassed, and stirred at the same temperature for 15 minutes under an argon atmosphere. 4-Ethoxy-4-oxobutylzinc bromide (0.5 M THF solution, 5.8 mL) was added dropwise thereto under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, the mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.41 g). [Step 2] Preparation of 5-(4-ethoxy-4-oxobutyl)pyridine-2-carboxylic acid A mixture of benzyl 5-(4-ethoxy-4-oxobutyl)pyridine-2-carboxylate (0.41 g) obtained in Step 1, 10% Pd—C (0.40 g), and isopropanol (11 mL) was stirred overnight at room temperature under a hydrogen atmosphere of 0.27 MPa. Insoluble matter was filtered off and washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was precipitated by adding hexane-diethyl ether-ethyl acetate (3:3:1) (3 mL). The solvent was removed and the residue was dried to obtain the title compound (0.27 g). Reference Example 38 5-{[(1-methoxy-2-methyl-1-oxopropan-2-yl)amino]methyl}pyridine-2-carboxylic acid dihydrochloride [Step 1] Preparation of tert-butyl 5-{[(1-methoxy-2-methyl-1-oxopropan-2-yl)amino]methyl}pyridine-2-carboxylate A mixture of tert-butyl 5-formylpyridine-2-carboxylate (0.10 g), methyl 2-amino-2-methylpropanoate hydrochloride (0.15 g), anhydrous magnesium sulfate (0.17 g), TEA (0.14 mL), and dichloromethane (4 mL) was stirred at room temperature for 3 hours. To this mixture, sodium triacetoxyborohydride (0.26 g) was added with stirring under ice cooling, and the mixture was stirred at room temperature for 3 days. Under ice cooling, the mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (92 mg).[Step 2] Preparation of 5-{[(1-methoxy-2-methyl-1-oxopropan-2-yl)amino]methyl}pyridine-2-carboxylic acid dihydrochloride To a solution of tert-butyl 5-{[(1-methoxy-2-methyl-1-oxopropan-2-yl)amino]methyl}pyridine-2-carboxylate (92 mg) obtained in Step 1 in 1,4-dioxane (0.5 mL) was added hydrogen chloride (4 M 1,4-dioxane solution, 1.5 mL) while stirring at room temperature, and the mixture was stirred at 50° C. for 8 hours. After cooling to room temperature and adding hexane (3 mL), the precipitate was collected by filtration, washed with hexane, and dried to obtain the title compound (88 mg). Reference Example 39 Ethyl 3-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoate 5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-N. ７ -{[1-(methoxymethyl)cyclopentyl]methyl}-N ７ To a mixture of 1H-methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine (30 mg), 5-(3-ethoxy-3-oxopropyl)pyridine-2-carboxylic acid (17 mg), and DMA (0.3 mL) was added DIPEA (0.022 mL) and HATU (31 mg) while stirring at room temperature, and the mixture was stirred at 50°C for 7 hours. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (42 mg). Reference Example 40 Ethyl 3-[6-({5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoate 5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-N ７ -{[1-(methoxymethyl)cyclopentyl]methyl}-N７ To a mixture of 1H-methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine (30 mg), 5-(3-ethoxy-3-oxopropyl)pyridine-2-carboxylic acid trifluoroacetate (25 mg), and DMA (0.5 mL) was added DIPEA (0.033 mL) and HATU (31 mg) while stirring at room temperature, and the mixture was stirred at 50°C for 7 hours. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (34 mg).

[0160] Reference Example 41 Ethyl 3-[6-({5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoate 5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-N ７ -{[1-(methoxymethyl)cyclopentyl]methyl}-N ７To a mixture of 1H-methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine (30 mg), 5-(3-ethoxy-3-oxopropyl)pyridine-2-carboxylic acid trifluoroacetate (26 mg), and DMA (0.5 mL) was added DIPEA (0.033 mL) and HATU (31 mg) while stirring at room temperature, and the mixture was stirred at 50°C for 7 hours. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (34 mg). Reference Example 42 Ethyl 3-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]-2-methylpropanoate By a method similar to Reference Example 39, using 5-(3-ethoxy-2-methyl-3-oxopropyl)pyridine-2-carboxylic acid (18 mg) instead of 5-(3-ethoxy-3-oxopropyl)pyridine-2-carboxylic acid, the title compound (35 mg) was obtained. Reference Example 43 Methyl 2-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carboxylate 5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-N ７ -{[1-(methoxymethyl)cyclopentyl]methyl}-N ７To a mixture of 5,6-methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine (30 mg), 6-(methoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid (17 mg), and NMP (0.5 mL) was added COMU (41 mg) and DIPEA (0.022 mL) while stirring at room temperature, and the mixture was stirred overnight at 70° C. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography to obtain the title compound (23 mg). Reference Example 44 Ethyl 2-({[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]methyl}(methyl)amino)acetate 5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-N ７ -{[1-(methoxymethyl)cyclopentyl]methyl}-N ７ To a mixture of 1H-methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine (30 mg), 5-{[(2-ethoxy-2-oxoethyl)(methyl)amino]methyl}pyridine-2-carboxylic acid dihydrochloride (25 mg), and DMA (0.3 mL) was added DIPEA (0.049 mL) and HATU (31 mg) while stirring at room temperature, and the mixture was stirred at 50°C for 7 hours. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (33 mg). Reference Example 45 Ethyl 4-[4-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1H-imidazol-1-yl]butanoate 5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-N ７ -{[1-(methoxymethyl)cyclopentyl]methyl}-N ７To a mixture of 1-methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine (30 mg), 1-(4-ethoxy-4-oxobutyl)-1H-imidazole-4-carboxylic acid (17 mg), and DMA (0.3 mL) was added DIPEA (0.022 mL) and COMU (35 mg) while stirring at room temperature, and the mixture was stirred at 50°C overnight. 1-(4-ethoxy-4-oxobutyl)-1H-imidazole-4-carboxylic acid (17 mg), DIPEA (0.022 mL), and COMU (35 mg) were added, and the mixture was stirred at 50°C for 7 hours. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (23 mg).

[0161] Reference Example 46 Ethyl 4-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoate 5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-N ７ -{[1-(methoxymethyl)cyclopentyl]methyl}-N ７To a mixture of 1H-methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine (80 mg), 5-(4-ethoxy-4-oxobutyl)pyridine-2-carboxylic acid (56 mg), and DMA (2.1 mL) was added DIPEA (0.12 mL) and HATU (90 mg) while stirring at room temperature, and the mixture was stirred at 55°C overnight. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate, water, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (65 mg). Reference Example 47 Ethyl 3-[6-({5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]propanoate 5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-N ７ -{[1-(methoxymethyl)cyclopentyl]methyl}-N ７ To a mixture of 5,6-methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine (30 mg), 7-(3-ethoxy-3-oxopropyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid dihydrochloride (26 mg), and DMA (0.4 mL) was added HATU (29 mg) and DIPEA (0.049 mL) while stirring at room temperature, and the mixture was stirred overnight at 55° C. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography to obtain the title compound (23 mg). Reference Example 48 Ethyl 3-[6-({5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]propanoate

[0113] According to the method similar to Reference Example 47, 5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-N ７-{[1-(methoxymethyl)cyclopentyl]methyl}-N ７ 5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-N-methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine ７ -{[1-(methoxymethyl)cyclopentyl]methyl}-N ７ Using 5-methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine (30 mg), the title compound (22 mg) was obtained. Reference Example 49 Ethyl 4-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoate 5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-N ７ -{[1-(methoxymethyl)cyclohexyl]methyl}-N ７ To a mixture of 1H-methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine (30 mg), 5-(4-ethoxy-4-oxobutyl)pyridine-2-carboxylic acid (22 mg), and DMA (0.3 mL) was added DIPEA (0.027 mL) and HATU (37 mg) while stirring at room temperature, and the mixture was stirred at 55°C for 6 hours. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (36 mg). Reference Example 50 Ethyl 4-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoate 5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-N ７ -{[1-(methoxymethyl)cyclopentyl]methyl}-N ７To a mixture of 1H-methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine (30 mg), 5-(4-ethoxy-4-oxobutyl)pyridine-2-carboxylic acid (22 mg), and DMA (0.3 mL) was added DIPEA (0.027 mL) and HATU (38 mg) while stirring at room temperature, and the mixture was stirred at 55°C for 6 hours. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (33 mg).

[0162] Reference Example 51 Ethyl 3-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoate 5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-N ７ -{[1-(methoxymethyl)cyclohexyl]methyl}-N ７ To a mixture of 1,3-methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine (30 mg), 5-(3-ethoxy-3-oxopropyl)pyridine-2-carboxylic acid (16 mg), and DMA (0.3 mL) was added DIPEA (0.021 mL) and HATU (30 mg) while stirring at room temperature, and the mixture was stirred at 50°C for 7 hours. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (38 mg). Reference Example 52 Ethyl 4-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoate 5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-N ７ -{[1-(methoxymethyl)cyclohexyl]methyl}-N ７To a mixture of 1H-methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine (30 mg), 5-(4-ethoxy-4-oxobutyl)pyridine-2-carboxylic acid (22 mg), and DMA (0.3 mL) was added DIPEA (0.026 mL) and HATU (37 mg) while stirring at room temperature, and the mixture was stirred at 55°C for 6 hours. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (35 mg). Reference Example 53 Ethyl N-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{(1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridine-3-carbonyl]-N-methylglycinate HATU (15 mg) was added to a mixture of 6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridine-3-carboxylic acid (20 mg), DIPEA (0.019 mL), and DMF (0.3 mL), and the mixture was stirred at room temperature for 10 minutes. Hydrochloride (5.9 mg) was added and stirred at the same temperature for 2 hours. DIPEA (0.011 mL) and HATU (15 mg) were added thereto and stirred at room temperature overnight. Saturated aqueous sodium bicarbonate, water and ethyl acetate were added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (9.4 mg). Reference Example 129 Ethyl 2-[4-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1H-imidazol-1-yl]acetate 5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-N ７-{[1-(methoxymethyl)cyclopentyl]methyl}-N ７ To a mixture of 1-methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine (30 mg), 1-(2-ethoxy-2-oxoethyl)-1H-imidazole-4-carboxylic acid (15 mg), and DMA (0.5 mL) was added DIPEA (0.022 mL), HATU (31 mg), and DMAP (0.77 mg) while stirring at room temperature. The mixture was stirred at the same temperature overnight and then at 50°C overnight. To this mixture, 1-(2-ethoxy-2-oxoethyl)-1H-imidazole-4-carboxylic acid (6.3 mg), DIPEA (0.011 mL), and HATU (14 mg) were added, and the mixture was stirred at 50°C for 7 hours. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (14 mg).

[0163] Example 1 3-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoic acid To a solution of ethyl 3-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoate (21 mg) in ethanol (0.5 mL) was added dropwise with stirring at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and neutralized with 6 M hydrochloric acid, water was added, and the resulting precipitate was collected by filtration and dried to obtain the title compound (17 mg). Example 2 3-[6-({5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoic acid To a solution of ethyl 3-[6-({5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoate (34 mg) in ethanol (0.5 mL) was added dropwise with stirring at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was neutralized with 6 M hydrochloric acid and concentrated under reduced pressure. Water was added to the residue, and the resulting precipitate was collected by filtration and dried to give the title compound (29 mg).Example 3 3-[6-({5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoic acid To a solution of ethyl 3-[6-({5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoate (34 mg) in ethanol (0.5 mL) was added dropwise with stirring at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and neutralized with 6 M hydrochloric acid, water was added, and the resulting precipitate was collected by filtration and dried to obtain the title compound (27 mg). Example 4 Ethyl 3-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]-2-methylpropanoate To a solution of ethyl 3-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]-2-methylpropanoate (35 mg) in ethanol (0.5 mL) was added 1 M aqueous sodium hydroxide solution (0.25 mL) with stirring at room temperature. A 1 M aqueous solution of sodium hydroxide (0.25 mL) was added dropwise to the mixture, and the mixture was stirred at the same temperature for 2.5 hours. 1 M aqueous sodium hydroxide solution (0.25 mL) was added thereto, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with 6 M hydrochloric acid and concentrated under reduced pressure. Water was added to the residue, and the precipitate was collected by filtration and dried to obtain the title compound (27 mg).Example 5 2-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carboxylate Methyl 2-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carboxylate (23 mg), THF (0.5 mL), and water (0.5 mL) were added. To a mixture of 10 mL of 4 M sodium hydroxide solution (0.042 mL) was added with stirring at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with water and neutralized with 6 M hydrochloric acid. The resulting precipitate was collected by filtration and dried to obtain the title compound (18 mg).

[0164] Example 6 Ethyl 2-({[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]methyl}(methyl)amino)acetate To a mixture of ethyl 2-({[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]methyl}(methyl)amino)acetate (33 mg), THF (0.1 mL), and ethanol (0.5 mL) was added 1 M Aqueous sodium hydroxide solution (0.23 mL) was added, and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was neutralized with 6 M hydrochloric acid, and the solvent was evaporated under reduced pressure. Water was added, and the resulting precipitate was collected by filtration and dried to obtain the title compound (21 mg). Example 7 Ethyl 4-[4-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1H-imidazol-1-yl]butanoate To a mixture of 4-[4-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1H-imidazol-1-yl]butanoate (23 mg), THF (0.2 mL), and ethanol (0.5 mL) was added 1 M aqueous sodium hydroxide solution (0.17 mL) with stirring at room temperature. The reaction mixture was neutralized with 6 M hydrochloric acid and concentrated under reduced pressure. Water and 1 M hydrochloric acid were added, and the resulting precipitate was collected by filtration and dried to obtain the title compound (17 mg).Example 8 4-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoic acid Ethyl 4-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoate (30 mg), THF (0.1 mL), and ethanol (0.5 mL) were stirred at room temperature, and 1 M aqueous sodium hydroxide solution (0.22 mL) was added, followed by stirring at the same temperature for 1.5 hours. The reaction mixture was neutralized with 6 M hydrochloric acid and concentrated under reduced pressure, water and 1 M hydrochloric acid were added, and the resulting precipitate was collected by filtration and dried to obtain the title compound (24 mg). Example 9 Ethyl 3-[6-({5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]propanoate Ethyl 3-[6-({5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]propanoate (22 mg), THF (0.5 To a mixture of 4 M sodium hydroxide solution (0.037 mL) and water (0.5 mL) was added 4 M aqueous sodium hydroxide solution (0.037 mL) while stirring at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with water and neutralized with 6 M hydrochloric acid. The precipitate was collected by filtration and dried to obtain the title compound (18 mg).Example 10 3-[6-({5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]propanoate Ethyl 3-[6-({5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]propanoate (22 mg), THF (0.5 mL), and water (0.5 mL) were added to a solution of ethyl 3-[6-({5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]propanoate (22 mg), THF (0.5 mL), and water (0.5 mL) To a mixture of 10 mL of 4 M sodium hydroxide solution (0.037 mL) was added with stirring at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with water and neutralized with 6 M hydrochloric acid. The precipitate was collected by filtration and dried to obtain the title compound (18 mg).

[0165] Example 11 Ethyl 4-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoate To a mixture of ethyl 4-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoate (36 mg), THF (0.1 mL), and ethanol (0.5 mL) was added 1 M aqueous sodium hydroxide solution (0.26 mL) with stirring at room temperature. To the reaction mixture was added dropwise 6 M hydrochloric acid and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was neutralized with 6 M hydrochloric acid and concentrated under reduced pressure. Water and 1 M hydrochloric acid were added, and the resulting precipitate was collected by filtration and dried to obtain the title compound (30 mg). Example 12 Ethyl 4-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoate To a mixture of ethyl 4-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoate (33 mg), THF (0.1 mL), and ethanol (0.5 mL) was added 1 M aqueous sodium hydroxide solution (0.23 mL) with stirring at room temperature. To the reaction mixture was added dropwise 6 M hydrochloric acid and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was neutralized with 6 M hydrochloric acid and concentrated under reduced pressure. Water and 1 M hydrochloric acid were added, and the resulting precipitate was collected by filtration and dried to obtain the title compound (26 mg).Example 13 3-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoate Ethyl 3-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoate (38 mg), THF (0.2 mL), and ethanol (0.5 mL) were added with 1 M aqueous sodium hydroxide solution (0.27 mL) at room temperature with stirring. To the reaction mixture was added dropwise 6 M hydrochloric acid and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was neutralized with 6 M hydrochloric acid and concentrated under reduced pressure. Water and 1 M hydrochloric acid were added, and the resulting precipitate was collected by filtration and dried to obtain the title compound (34 mg). Example 14 Ethyl 4-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoate To a mixture of ethyl 4-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoate (35 mg), THF (0.1 mL), and ethanol (0.5 mL) was added 1 M aqueous sodium hydroxide solution (0.25 mL) with stirring at room temperature. To the reaction mixture was added dropwise 6 M hydrochloric acid and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was neutralized with 6 M hydrochloric acid and concentrated under reduced pressure. Water and 1 M hydrochloric acid were added, and the resulting precipitate was collected by filtration and dried to obtain the title compound (30 mg).Example 27 3-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoic acid Ethyl 3-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoate (36 mg), THF (0.52 mL), methanol (0.52 mL), and water (0.52 mL) were dissolved in 10 ml of ethyl acetate. To a mixture of 1 mL of ethanol (2 mL) and 1 mL of ethanol (2 mL) was added lithium hydroxide monohydrate (12 mg) while stirring at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and neutralized with 2 M hydrochloric acid. The resulting precipitate was collected by filtration and dried to obtain the title compound (27 mg).

[0166] Example 40 1-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridazin-3-yl]azetidine-3-carboxylic acid [Step 1] Preparation of 6-chloro-N-{5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}pyridazine-3-carboxamide 5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-N ７ -{[1-(ethoxymethyl)cyclopentyl]methyl}-N ７To a solution of 1,3-methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine (51 mg) and 6-chloropyridazine-3-carboxylic acid (16 mg) in DMF (1 mL) was added EEDQ (26 mg) while stirring at room temperature, and the mixture was stirred at the same temperature for 26 hours. To this mixture, 6-chloropyridazine-3-carboxylic acid (4.9 mg) and EEDQ (7.6 mg) were added under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium bicarbonate, water, dilute hydrochloric acid, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (34 mg). [Step 2] Preparation of ethyl 1-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridazin-3-yl]azetidine-3-carboxylate

[0111] The 6-chloro-N-{5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}pyridazine-3-carboxamide (15 mg) obtained in Step 1, ethyl azetidine-3-carboxylate hydrochloride (7.9 mg), DIPEA (0.021 mg), and 1H-imidazo[4,5-b]pyridin-2-yl]pyridazine-3-carboxamide (15 mg) were added to a 100 ml flask. A mixture of 100 mL of toluene (0.5 mL) and NMP (0.5 mL) was stirred for 2 hours at 70° C. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography to obtain the title compound (11 mg).[Step 3] Preparation of 1-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridazin-3-yl]azetidine-3-carboxylic acid Ethyl 1-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridazin-3-yl]azetidine-3-carboxylate (11 mg) obtained in Step 2, THF (0.5 mL), and ethanol (0.5 mL) were added. To a mixture of 10 mL of 2M sodium hydroxide (0.047 mL) was added dropwise with stirring at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and neutralized with 2 M hydrochloric acid. The resulting precipitate was collected by filtration and dried to obtain the title compound (7.5 mg). Example 93 N-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}-5-[2-(methanesulfonylcarbamoyl)ethyl]pyridine-2-carboxamide To a solution of 3-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoic acid (40 mg) in dichloromethane (0.5 mL) was added DMAP (20 mg), EDCI (15 mL) and HCl under ice-cooling. To the mixture was added 1.5 mg of HCl, followed by methanesulfonamide (7.0 mg), and the mixture was stirred at room temperature overnight. To this mixture, DMAP (7.5 mg) and EDCI (5.9 mg) were added under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with 1 M hydrochloric acid, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography.The solvent was evaporated under reduced pressure, and a mixed solvent of hexane and diethyl ether was added to the residue. The precipitate was collected by filtration and dried to obtain the title compound (30 mg). Example 111 N-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}-5-[2-(methoxycarbamoyl)ethyl]pyridine-2-carboxamide To a solution of 3-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoic acid (20 mg) in DMF (0.5 mL) were added DIPEA (0.016 mL) and HATU (15 mg) at room temperature, and the mixture was stirred at the same temperature for 10 minutes. O-Methylhydroxylamine hydrochloride (3.3 mg) was added to this mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and after the solvent was evaporated under reduced pressure, the residue was diluted with a hexane-chloroform mixed solvent. The slurry was stirred, and the precipitate was collected by filtration and dried to obtain the title compound (15 mg). Example 116 5-{2-[(Cyclopropanesulfonyl)carbamoyl]ethyl}-N-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}pyridine-2-carboxamide CDI (10 mg) was added to a solution of 3-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoic acid (20 mg) in THF (0.61 mL) at room temperature, and the mixture was stirred at the same temperature overnight. To this was added cyclopropanesulfonamide (5.6 mg) and DBU (0.014 mL), and the mixture was stirred at room temperature for 6 hours.The reaction mixture was diluted with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, and the solvent was evaporated under reduced pressure. The residue was diluted with a hexane-chloroform mixed solvent, and the slurry was stirred. The precipitate was collected by filtration and dried to obtain the title compound (19 mg). Example 122 1-({[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]methyl}amino)cyclobutane-1-carboxylic acid 5-[6-Ethoxy-5-(trifluoromethyl)pyridin-3-yl]-N. ７ -{[1-(methoxymethyl)cyclohexyl]methyl}-N ７ To a mixture of 1,3-methyl-1H-imidazo[4,5-b]pyridine-2,7-diamine (30 mg), 5-({[1-(methoxycarbonyl)cyclobutyl]amino}methyl)pyridine-2-carboxylic acid dihydrochloride (27 mg), and DMA (0.61 mL), DIPEA (0.047 mL) and HATU (32 mg) were added at room temperature, and the mixture was stirred at 55° C. for 11 hours. After cooling to room temperature, the reaction mixture was diluted with water and saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography to give methyl 1-({[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]methyl}amino)cyclobutane-1-carboxylate (41 mg). This was diluted with ethanol (1.1 mL) and THF (0.18 mL), and 2 M aqueous sodium hydroxide solution (0.14 mL) was added under ice-cooling, followed by stirring at room temperature for 3 hours. The reaction mixture was neutralized with 2 M hydrochloric acid and then diluted with water. The precipitate was collected by filtration and dried to give the title compound (29 mg).

[0167] Tables 1 to 65 below show Reference Examples and Example compounds. In the tables, "Reference Reference Example" means that the compound was produced using the corresponding raw materials by a method similar to the production method of the compound of the Reference Example number corresponding to that number. For example, a Reference Example compound with a Reference Reference Example number of 1 means that it was produced by a method similar to Reference Example 1. In the tables, "Reference Example" means that the compound was produced using the corresponding raw materials by a method similar to the production method of the compound of the Example number corresponding to that number. For example, an Example compound with a Reference Example number of 1 means that it was produced by a method similar to Example 1. In the tables, "Chemical Name" means the name of the compound corresponding to the Reference Example and Example number. In the tables, "Data" means instrumental analysis data of the compound. For example, mass spectrometry data (m / z value), １ This includes H NMR data (peak δ (ppm)), elemental analysis data (composition (%) of C, H, and N), etc.

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[0233] The following are examples of biological tests of the compounds used in the present invention.

[0234] The pharmacological activity of each compound of the Examples was examined by the following tests. In the following explanation, each compound of the Examples may be referred to as each "test compound."

[0235] Test Example 1: Evaluation of M3 PAM activity CHO-K1 cells (hereinafter sometimes referred to as "M3R-expressing cells") stably expressing the M3 receptor by introducing the human muscarinic M3 receptor gene (GenBank accession number: NM_000740.2) were incubated at 37°C, 5% CO ２ The cells were subcultured under the conditions described above using a growth medium. The growth medium used was alpha Modified Eagle Minimum Essential Medium (α-MEM, D8042, Sigma) containing heat-inactivated fetal bovine serum (Cat. No. 172012, Sigma) at a final concentration of 10%, GlutaMAX® (Cat. No. 35050, GIBCO) at a final concentration of 2 mM, penicillin and streptomycin (penicillin-streptomycin mixed solution, Cat. No. 26253-84, Nacalai Tesque) at a final concentration of 20 U / mL and 20 μg / mL of streptomycin, and G418 (Cat. No. 16513-26, Nacalai Tesque) at a final concentration of 0.2 mg / mL.

[0236] Intracellular Ca ２＋ On the day before the measurement of the concentration, M3R-expressing cells were suspended in growth medium and seeded into a black, clear-bottom 96-well plate (Cat. No. 215006, Porvair Sciences) at 40,000 cells / well. The M3R-expressing cells seeded into the 96-well plate were incubated at 37°C, 5% CO ２ The cells were cultured overnight under the conditions.

[0237] Using a calcium measurement assay kit (Screen Quest Fluo-8 Medium Removal Calcium Assay Kit, Cat. No. 36309, manufactured by AAT Bioquest), the Ca in M3R-expressing cells was measured according to the attached instructions. ２＋ On the day of measurement, the growth medium was removed, 100 μL / well of loading buffer was added to a 96-well plate, and the plate was incubated at 37°C, 5% CO ２ After culturing for 30 minutes under these conditions, the cells were left to stand at room temperature for 30 minutes. As a result, a visible light-excited calcium indicator (Fluo-8 (registered trademark), manufactured by AAT Bioquest) was loaded onto the M3R-expressing cells. A buffer solution containing a calcium indicator was used as the loading buffer. As the buffer, a final concentration of 20 mM HEPES (Cat. No. 340-01371, manufactured by Dojindo Laboratories) and a final concentration of 2.5 mM probenecid (165-15472, manufactured by Wako Pure Chemical Industries, Ltd.) was used as a pH 7.4 Hanks' balanced salt solution (HBSS buffer). Hanks' balanced salt solution was prepared by diluting 10x HBSS (Cat. No. 14065-056, manufactured by GIBCO) 10 times with ultrapure water.

[0238] Thereafter, the 96-well plate was transferred into a fluorescence screening system (FLIPR TETRA (registered trademark), Molecular Devices) to measure the intracellular Ca 2+ by the test compound. ２＋ The concentration-dependent fluorescence intensity was measured using an excitation wavelength of 470 nm to 495 nm and a fluorescence wavelength of 515 nm to 575 nm.

[0239] A medium containing a test compound or the medium alone was added to a 96-well plate, and the fluorescence intensity was measured for 2 minutes. HBSS buffer was used as the medium. The test compound was dissolved in dimethyl sulfoxide and then added to the HBSS buffer. The final concentration of dimethyl sulfoxide was set to 2.5%. The final concentration of the test compound was varied in the range of 0 μM to 30 μM. The EC50 concentration that gave approximately 20% of the maximum activity was then measured. ２０Acetylcholine (20% Effective Concentration) was added, and the fluorescence intensity was measured for 1 minute. ２０ ranged from about 10 nM to 30 nM.

[0240] The fluorescence intensity Lb when only HBSS buffer was added instead of the test compound and acetylcholine was added to a final concentration of 100 μM was defined as 100%, and the EC ２０ The fluorescence intensity La when only HBSS buffer was added instead of the test compound in the presence of acetylcholine was defined as 0%. The fluorescence intensity when the test compound was added was defined as Lc, and the enhancement rate Gr (unit: %) of the fluorescence intensity by the test compound was calculated using the following formula (1). The M3 PAM activity of the test compound was evaluated based on the enhancement rate Gr.

[0241] Gr=100×(Lc-La) / (Lb-La)...(1)

[0242] Based on the enhancement rate Gr at each concentration of the test compound, the EC of the enhancement rate Gr was calculated using a statistical program (SAS system, SAS Institute Japan) from the logistic equation. ５０ The results of this test are shown in Tables 66 to 68. EC of the enhancement rate Gr ５０ The lower the value, the higher the M3 PAM activity.

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[0246] As shown in Tables 66 to 68, all of the test compounds were found to exhibit high M3 PAM activity.

[0247] In addition, the addition of the test compound alone in the absence of acetylcholine did not increase the fluorescence intensity, indicating that the test compound does not exhibit M3 receptor agonist activity.

[0248] Test Example 2: Effect on increase in intravesical pressure induced by electrical pelvic nerve stimulation in anesthetized rats As an effect on nerve stimulation-dependent bladder contraction in vivo, the effect of the test compound on increase in intravesical pressure induced by electrical pelvic nerve stimulation in rats was measured by the following method.

[0249] Female SD rats (Japan SLC, Inc.) were anesthetized by subcutaneous administration of 1200 mg / kg of urethane (Wako Pure Chemical Industries, Ltd.), and then the rat's lower abdomen was incised along the midline. After ligating and cutting both ureters, a cannula (PE-60, Becton Dickinson) for measuring intravesical pressure was inserted into the bladder through the external urethral orifice and secured with sutures. Approximately 200 μL of saline was injected through the cannula inserted into the bladder, and the other end was connected to a pressure transducer to measure intravesical pressure.

[0250] Under a stereomicroscope, the pelvic nerve near the rat's bladder was dissected and a nerve stimulating electrode (K2-14015M-PT, Brain Science Idea Co., Ltd.) was placed. The rat's abdominal cavity was filled with liquid paraffin (26114-75, Nacalai Tesque, Inc.). After a postoperative stabilization period, the pelvic nerve was electrically stimulated using an electrical stimulator (SEN-7203, Nihon Kohden Corporation) to induce an increase in intravesical pressure. The stimulation frequency was 8 Hz, the pulse width was 0.3 ms, and the stimulation duration was 10 seconds. The voltage of the electrical stimulator was adjusted so that the increase in intravesical pressure was approximately 50% to 70% of that observed with 10 V stimulation.

[0251] Electrical stimulation was then repeated at 10-minute intervals. After the increase in intravesical pressure due to electrical stimulation had stabilized three or more times, the test compound (0.3 mg / kg), distigmine bromide (0.03 or 0.1 mg / kg), or vehicle was administered intravenously at a single dose of 1.0 mL / kg via a catheter placed in the femoral vein. The effect of the test compound on the increase in intravesical pressure was measured for 1 hour. Physiological saline was used as the vehicle, and the test compound was dissolved in dimethyl sulfoxide and then added to the vehicle. The final concentration of dimethyl sulfoxide was 10%.

[0252] The response data (intravesical pressure) was imported into a personal computer via a data collection and analysis system (PowerLab (registered trademark), manufactured by ADInstruments) and analyzed using analysis software (LabChart (registered trademark), manufactured by ADInstruments). The AUC (area under the curve of the change in intravesical pressure) of the increase in intravesical pressure for each electrical stimulus was calculated, and the rate of change Rc (unit: %) relative to the value (AUC) before administration of the test compound was calculated using the following formula (2). In formula (2), Ab represents the AUC before administration of the test compound, and Aa represents the AUC after administration of the test compound. The maximum effect (maximum rate of change Rc) within 1 hour after administration of the test compound was defined as the effect of the test compound. The greater the rate of change Rc, the greater the effect of enhancing bladder contractility and the greater the effect of increasing intravesical pressure. The results of this test are shown in Table 69.

[0253] Rc=100×(Aa-Ab) / Ab...(2)

[0254]

[0255] All of the test compounds exhibited an effect of enhancing bladder contractility. Distigmine bromide also exhibited an effect of enhancing bladder contractility, but nicotine-related side effects (fascicle spasms) were observed at 0.1 mg / kg.

[0256] Furthermore, none of the test compounds evaluated in this study induced an increase in intravesical pressure in rats without electrical stimulation, confirming that the test compounds alone did not have the effect of increasing intravesical pressure.

[0257] From the above, it was confirmed that the test compounds listed in Table 69 alone do not exhibit an effect of increasing intravesical pressure in rats, but have the effect of enhancing the increase in intravesical pressure induced by electrical stimulation of the pelvic nerve.

[0258] Furthermore, the test compound alone does not exhibit agonistic activity against the M3 receptor, but instead exhibits the effect of enhancing nerve stimulation-dependent bladder contraction. This suggests that test compounds with M3 PAM activity can enhance M3 receptor signaling levels under more physiological conditions, making them promising therapeutic targets for diseases involving the M3 receptor. Furthermore, the test compound may be able to avoid the cholinergic side effects (cholinergic crisis) reported for existing drugs (e.g., distigmine bromide), potentially making it a safer therapeutic agent.

[0259] Test Example 3: Effect in a rat lumbar spinal canal stenosis model Eight-week-old SD female rats (CLEA Japan, Inc.) were anesthetized by intraperitoneal administration of a mixed anesthesia of 40 mg / kg of ketamine (Ketalar (registered trademark), manufactured by Daiichi Sankyo Co., Ltd.) and 5 mg / kg of xylazine (Selactal (registered trademark), manufactured by Bayer Yakuhin, Ltd.). Under anesthesia, the rat's back was incised to expose the fifth and sixth lumbar vertebral arches.

[0260] A hole approximately 1.5 mm in diameter was drilled in the fifth lumbar arch, and a small piece of silicone rubber (Kokugo Co., Ltd.) was inserted into the epidural space between the fifth and sixth lumbar vertebrae. This compressed the rat's cauda equina nerve. The rat with compressed cauda equina nerve will hereinafter be referred to as the "treated rat." The small piece was 3.5 mm long, 5.0 mm wide, and 0.5 mm thick. After inserting the small piece, the incision was sutured to close it. The treated rat was then systemically administered an antibiotic (injectable Viccillin, 100 mg per rat, Meiji Seika Kaisha, Ltd.).

[0261] Two weeks after cauda equina compression, the treated rats were orally administered a fixed amount of water for injection (hereinafter referred to as "water"), and then placed in a metabolic cage (Natsume Seisakusho Co., Ltd.). The urinary volume was measured within 6 hours after the start of the water challenge. One hour before the challenge, the treated rats were orally administered a single dose of the test compound, distigmine bromide dissolved in 0.5% methylcellulose aqueous solution (vehicle), or vehicle alone. The urinary volume was measured using an electronic balance (GX-200, A&D Co., Ltd.), and the data was imported into a personal computer via a data collection and analysis system (PowerLab®, AD Instruments) and analyzed using analysis software (LabChart®, AD Instruments). The metabolic cage dimensions were 230 mm wide, 220 mm long, and 150 mm high.

[0262] The total amount of urine voided is evaluated for 6 hours after the water loading. Furthermore, 6 hours after the start of the water loading, the treated rats are removed from the metabolic cage, and the lower abdomen of the treated rats is pressed with a finger to perform finger pressure urination, and the residual urine volume is measured.

[0263] As described in Test Examples 1 and 2, the compound of the present invention exhibits M3 PAM activity and is effective in in vivo models, and is therefore useful as a preventive or therapeutic agent for dysuria and urinary storage disorder in, for example, underactive bladder, hypotonic bladder, acontractile bladder, detrusor underactivity, and neurogenic bladder.

[0264] Formulation Example 1 Tablet (oral tablet) Formulation In one 80 mg tablet: Compound of the present invention of Example 1 5.0 mg Corn starch 46.6 mg Microcrystalline cellulose 24.0 mg Methylcellulose 4.0 mg Magnesium stearate 0.4 mg The mixed powder in this ratio is tableted by a conventional method to form an oral tablet.

[0265] The compound of the present invention or a pharmaceutically acceptable salt thereof exhibits M3 PAM activity and is therefore useful as a preventive or therapeutic agent for dysuria or urine storage disorder in bladder / urinary tract diseases, glaucoma, or diabetes, in which the M3 receptor is involved.

Claims

1. The following formula [1]: [In the formula, R １ is a hydrogen atom, alkyl, or two Rs １ may combine with adjacent carbon atoms to form a 3- to 7-membered cycloalkyl or a non-aromatic heterocyclic ring containing oxygen, R ２ is a hydrogen atom, alkyl, cycloalkyl, alkyl substituted with cycloalkyl, or alkoxyalkyl, R ３ is a hydrogen atom, alkyl, or alkoxyalkyl, R ４ is pyridyl optionally substituted with one or two groups selected from the group consisting of alkyl, trihaloalkyl, alkoxy, cyano, and cycloalkyl, or phenyl optionally substituted with one to three groups selected from the group consisting of trihaloalkyl, halogen, alkoxy, and cycloalkyl, Ar is an aromatic carbocyclic group or an aromatic heterocyclic group, and the aromatic carbocyclic group and aromatic carbon heterocyclic group attached to Ar may be substituted with a group selected from the following group consisting of (1) to (3): (1) halogen (2) alkyl (3) alkoxy, L １ is a bond, (C1-C6) alkylene, (C1-C6) haloalkylene, (C1-C6) alkylene-N(Ra)-, (C1-C6) alkylene-O-, or -C(O)-, where Ra is a hydrogen atom or alkyl, X is a cycloalkyl, alkyl, non-aromatic carbon heterocyclic group optionally substituted with halogen, or a bond, L ２ is a bond, (C1-C6) alkylene, -O-(C1-C6) alkylene, or -N(Rb)-(C1-C6) alkylene, where Rb is a hydrogen atom or alkyl, Y is OH, NHSO ２ (alkyl), NHSO ２ (cycloalkyl), NHSO ２ (haloalkyl), NHSO ２ (monoalkylamino), NHSO ２ (dialkylamino), NHSO ２ an azabenzimidazole compound represented by [wherein R is (alkoxy), NH(alkoxy), or NH(alkyl)], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

2. R １ is alkyl, or two Rs １ together with adjacent carbon atoms form a 3- to 7-membered cycloalkyl, and R ２ is alkyl, and R ３ is alkyl, and R ４ is pyridyl optionally substituted with one or two groups selected from the group consisting of trihaloalkyl, alkoxy, and cycloalkyl, or phenyl optionally substituted with one to three groups selected from the group consisting of trihaloalkyl and cycloalkyl, the azabenzimidazole compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

3. R １ is combined with two adjacent carbon atoms of R １ to form a 3- to 7-membered cycloalkyl, and R ２ is alkyl, and R ３ is alkyl, and R ４ is a pyridyl substituted with a trihaloalkyl and one group selected from the group consisting of the following groups: (1) alkoxy, (2) cycloalkyl, Ar is an aromatic heterocyclic group, L １ is a bond, (C1-C6) alkylene, (C1-C6) alkylene-N(Ra)-, where Ra is alkyl, X is a bond, L ２ is a bond, Y is OH, the azabenzimidazole compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

4. The azabenzimidazole compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the azabenzimidazole compound is a compound described in any one of the following (1) to (14). (1) 3-[6-({5-[6-Cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoic acid, (2) 3-[6-({5-[2-Ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoic acid, (3) 3-[6-({5-[2-Cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoic acid, (4) 3-[6-({5-[6-Cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]-2-methylpropanoic acid, (5) 2-({5-[6-Cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carboxylic acid, (6) 2-({[6-({5-[6-Cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]methyl}(methyl)amino)acetic acid, (7) 4-[4-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1H-imidazol-1-yl]butanoic acid, (8) 4-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoic acid, (9) 3-[6-({5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]propanoic acid, (10) 3-[6-({5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]propanoic acid, (11) 4-[6-({5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoic acid, (12) 4-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoic acid, (13) 3-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]propanoic acid, (14)4-[6-({5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-({[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino)-1H-imidazo[4,5-b]pyridin-2-yl}carbamoyl)pyridin-3-yl]butanoic acid., 5. A pharmaceutical composition comprising, as an active ingredient, an azabenzoimidazole compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

6. An M3 positive allosteric modulator (PAM) comprising, as an active ingredient, an azabenzoimidazole compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

7. A prophylactic or therapeutic agent for micturition disorder, storage disorder, glaucoma or diabetes in a bladder / urinary tract disease involving an M3 receptor, comprising, as an active ingredient, an azabenzoimidazole compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

8. The prophylactic or therapeutic agent according to any one of claims 1 to 4, wherein the micturition disorder or storage disorder in a bladder / urinary tract disease involving an M3 receptor is caused by a low activity bladder, a low tone bladder, an acontractile bladder, a low activity of micturition muscles, a neurogenic bladder, urethral relaxation insufficiency or discoordination between micturition muscles and external urethral sphincter.