Aminomethylcyclohexane derivative

Abstract

The present invention relates to an (aminomethyl)cyclohexane derivative useful as a medicine, a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same as an active ingredient, or a therapeutic and / or prophylactic agent for a disease mediated by antagonism of the muscarinic M4 receptor.

Description

Aminomethylcyclohexane derivatives

[0001] The present invention relates to aminomethylcyclohexane derivatives and pharmaceutically acceptable salts thereof that are useful as pharmaceuticals, as well as pharmaceutical compositions containing them as active ingredients or therapeutic and / or preventive agents for diseases associated with antagonism to muscarinic M4 receptors.

[0002] Muscarinic acetylcholine receptors (hereinafter sometimes referred to as "muscarinic receptors") are receptors that form a G protein-receptor complex in the cell membrane of certain neurons and the like. Muscarinic receptors function to increase or decrease cellular activity. Five subtypes of muscarinic receptors, M1 to M5, are known. Drugs with low subtype selectivity affect multiple muscarinic receptor subtypes, which may result in the desired efficacy not being achieved or in side effects that differ from the desired efficacy. Therefore, therapeutic drugs that are selective for only specific subtypes are desired.

[0003] Furthermore, muscarinic M4 receptor antagonists, which selectively bind to the M4 subtype of muscarinic receptors (hereinafter sometimes referred to as "muscarinic M4 receptors") and inhibit their function, are known to be effective against neurodegenerative diseases, movement disorders, or brain disorders (Patent Document 1 and Patent Document 2).

[0004] Patent Documents 1 and 2 describe compounds that bind to muscarinic M4 receptors.

[0005] International Publication No. 2019 / 079783 International Publication No. 2019 / 014427

[0006] An object of the present invention is to provide a compound useful as a muscarinic M4 receptor antagonist.

[0007] As a result of intensive research, the present inventors have found that a compound represented by the following formula (1) exhibits antagonistic activity at the muscarinic M4 receptor, and have completed the present invention. According to the present invention, there is provided an aminomethylcyclohexane derivative represented by the following formula (1) (hereinafter, also referred to as the "compound of the present invention").

[0008] That is, the present invention is as follows.

[0009] [Term 1-1] Formula (1): [In the formula, R １ is an optionally substituted C １－６ Alkyl or optionally substituted C １－６ represents alkoxy, R ５ represents a hydrogen atom, an optionally substituted C １－６ Alkyl or optionally substituted C １－６ represents alkoxy, R ２ and R ３ are each independently a hydrogen atom, an optionally substituted C １－６ Alkyl, optionally substituted C ３－１０ cycloalkyl, an optionally substituted 4-12 membered saturated heterocyclic group, or R ２ and R ３ together represent an optionally substituted 4-12 membered saturated monocyclic, bicyclic, tricyclic or spirocyclic heterocyclic group; R ４ is halogen, optionally substituted C ６－１０ aryl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted 4-12 membered saturated heterocyclic group, or an optionally substituted C ３－１０ X, Y, Z, and W each independently represent a nitrogen atom or CR ６ represents R ６ represents a hydrogen atom, an optionally substituted C １－６ alkyl, or at least one of X and Z is CR ６ When R ６ and the above R ４ are taken together to form an optionally substituted C ３－１０ and Q represents an oxygen atom, a sulfur atom, or N-H.] or a pharmaceutically acceptable salt thereof, provided that: i) N-[4-(aminomethyl)-4-methylcyclohexyl]-4-tert-butylaniline, ii) 3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-N６ -[4-(aminomethyl)-4-methylcyclohexyl]pyrazine-2,6-diamine, and pharmaceutically acceptable salts thereof.

[0010] [Term 1-2] Formula (1): [In the formula, R １ and R ５ are each independently a hydrogen atom, an optionally substituted C １－６ Alkyl or optionally substituted C １－６ represents alkoxy, R ２ and R ３ are each independently a hydrogen atom, an optionally substituted C １－６ Alkyl, optionally substituted C ３－１０ cycloalkyl, an optionally substituted 4-12 membered saturated heterocyclic group, or R ２ and R ３ together represent an optionally substituted 4-12 membered saturated monocyclic, bicyclic or spirocyclic heterocyclic group; R ４ is halogen, optionally substituted C ６－１０ aryl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered saturated heterocyclic group; X, Y, Z, and W each independently represent a nitrogen atom or CR ６ represents R ６ represents a hydrogen atom, an optionally substituted C １－６ alkyl, or at least one of X and Z is CR ６ When R ６ and the above R ４ together to form an optionally substituted C ３－１０ and R represents an alkyl, aryl, aryl or aryl group, or an optionally substituted 4- to 12-membered saturated heterocyclic group, and Q represents an oxygen atom, a sulfur atom, or N—H, or a pharmaceutically acceptable salt thereof.

[0011] [Section 2-1] R １ and R ５ "Optionally substituted C" selected from １－６ alkyl," or "optionally substituted C １－６The substitutable substituents in "alkoxy" are each independently 1 to 3 of the same or different halogen or deuterium, ２ and R ３ "Optionally substituted C" selected from １－６ The substitutable substituents in "alkyl" are each independently 1 to 3 of the same or different, halogen, C １－６ Alkoxy, C ３－１０ cycloalkyl, or a 4- to 12-membered saturated heterocyclic group, ３－１０ The cycloalkyl or 4-12 membered saturated heterocyclic group may further include oxo, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ Haloalkoxy, and C １－６ alkylcarbonylamino; R ２ and R ３ "Optionally substituted C" selected from ３－１０ The substitutable substituents in the "optionally substituted 4- to 12-membered saturated heterocyclic group" or "optionally substituted 4- to 12-membered saturated heterocyclic group" are each independently 1 to 3 of the same or different, such as halogen, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ alkoxy, or a 4- to 12-membered saturated heterocyclic group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, oxo, C １－６ Alkyl, C １－６ Alkoxy and C １－６ alkylcarbonyl, R ２ and R ３ and R are taken together to form an "optionally substituted 4-12 membered monocyclic, bicyclic, tricyclic or spirocyclic saturated heterocyclic group", and each of the substitutable substituents is independently 1 to 3 of the same or different halogen, oxo, hydroxyl group, cyano group, C １－６ Alkyl, C １－６ Alkoxy, C ６－１０Aryl, 5-10 membered heteroaryl, deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ is an alkylthio group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ One or more hydrogen atoms in the alkoxy may be deuterium, and R ４ "Optionally substituted C" selected from ６－１０ The substitutable substituents in the "aryl" or "optionally substituted 5-10 membered heteroaryl" are each independently 1 to 3 of the same or different halogen, cyano group, amino group, carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, diC １－６ alkylaminocarbonyl, or C １－６ is cycloalkoxy, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４ "Optionally substituted 4-12 membered saturated heterocyclic group" or "optionally substituted C ３－１０ The substitutable substituents in "cycloalkyl" are each independently 1 to 3 of the same or different halogen, cyano group, amino group, carbonyl group, C １－６Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C ２－６ alkenyl, or oxo, １－６ The alkyl may further include halogen, C ６－１０ Aryl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ The cycloalkyl may be further substituted with one or more halogens, and R ６ "Optionally substituted C" selected from １－６ The substitutable substituents in "alkyl" are each independently 1 to 3 of the same or different halogens, ４ and R ６ When these are taken together, "optionally substituted C ３－１０ The substitutable substituents in the "optionally substituted 4- to 12-membered saturated heterocyclic group" or "optionally substituted 4- to 12-membered saturated heterocyclic group" are each independently 1 to 3 of the same or different, such as oxo, C １－６ Alkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, 5-10 membered heteroaryl, or 4-12 membered saturated heterocyclic group, among which C ３－１０ Cycloalkyl, C ６－１０ Substituents for cyclic structures such as aryl, 5-10 membered heteroaryl, or 4-12 membered saturated heterocyclic groups are R ４ and R ６ Together they form C ３－１０ Item 1-1, wherein the compound forms a fused ring structure or a spiro structure with a cycloalkyl or a 4- to 12-membered saturated heterocyclic group, or a pharmaceutically acceptable salt thereof.

[0012] [Section 2-2] R １ and R ５ "Optionally substituted C" selected from １－６ alkyl," or "optionally substituted C １－６The substitutable substituents in "alkoxy" are each independently 1 to 3 of the same or different halogens, ２ and R ３ "Optionally substituted C" selected from １－６ The substitutable substituents in "alkyl" are each independently 1 to 3 of the same or different, halogen, C ３－１０ cycloalkyl, or a 4-12 membered saturated heterocyclic group, R ２ and R ３ "Optionally substituted C" selected from ３－１０ The substitutable substituents in the "optionally substituted 4- to 12-membered saturated heterocyclic group" or "optionally substituted 4- to 12-membered saturated heterocyclic group" are each independently 1 to 3 of the same or different, such as halogen, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ alkoxy, or a 4- to 12-membered saturated heterocyclic group, １－６ Alkyl or the C １－６ The alkoxy may be further substituted with one or more halogens, and R ２ and R ３ and R are taken together to form an "optionally substituted 4-12 membered monocyclic, bicyclic or spirocyclic saturated heterocyclic group", and each of the substitutable substituents is independently 1 to 3 of the same or different halogen, oxo, hydroxyl group, cyano group, C １－６ Alkyl, C １－６ Alkoxy, C ６－１０ aryl, or 5-10 membered heteroaryl, １－６ Alkyl or the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４ "Optionally substituted C" selected from ６－１０ The substitutable substituents in the "optionally substituted aryl," "optionally substituted 5-10 membered heteroaryl," or "optionally substituted 4-12 membered saturated heterocyclic group" are each independently 1 to 3 of the same or different halogen, cyano group, amino group, carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C６－１０ Aryl, 5-10 membered heteroaryl, C １－６ alkoxy, or a 4- to 12-membered saturated heterocyclic group, １－６ Alkyl and the C ３－１０ The cycloalkyl may be further substituted with one or more halogens, and R ６ "Optionally substituted C" selected from １－６ The substitutable substituents in "alkyl" are each independently 1 to 3 of the same or different halogens, ４ and R ６ When these are taken together to form "optionally substituted C ３－１０ The substitutable substituents in the "optionally substituted 4- to 12-membered saturated heterocyclic group" or "optionally substituted 4- to 12-membered saturated heterocyclic group" are each independently 1 to 3 of the same or different, such as oxo, C １－６ Alkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, 5-10 membered heteroaryl, or 4-12 membered saturated heterocyclic group, among which C ３－１０ Cycloalkyl, C ６－１０ Substituents for cyclic structures such as aryl, 5-10 membered heteroaryl, or 4-12 membered saturated heterocyclic groups are R ４ and R ６ Together they form C ３－１０ Item 3. The compound according to Item 1 or 2, which forms a fused ring structure or a spiro structure with a cycloalkyl or a 4- to 12-membered saturated heterocyclic group, or a pharmaceutically acceptable salt thereof.

[0013] [Section 3] R １ is C １－３ alkyl, and the C １－３ The alkyl may be substituted with one or more fluorines, or １－３ Item 10. The compound or pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein one or more hydrogen atoms in the alkyl are deuterium.

[0014] [Section 4] R ５

[0023] The compound or pharmaceutically acceptable salt thereof according to any one of the above items, wherein is a hydrogen atom.

[0015] [Section 5-1] R ２ is a hydrogen atom, and R３ is C １－６ Alkyl, C ３－１０ cycloalkyl, or a 4- to 12-membered saturated heterocyclic group, wherein the C １－６ The alkyl group may be selected from the group consisting of 1 to 3 of the same or different halogens, C ３－１０ Optionally substituted with cycloalkyl or 4-12 membered saturated heterocyclic group, ３－１０ The cycloalkyl or 4-12 membered saturated heterocyclic group may further include 1 to 3 oxo, C １－６ Alkyl, C １－６ Alkoxy, C １－６ may be substituted with alkylcarbonyl, or R ２ and R ３ and R are taken together to form a monocyclic, bicyclic, tricyclic or spirocyclic 4-12 membered saturated heterocyclic group, wherein each of the 4-12 membered saturated heterocyclic groups independently has 1 to 3 of the same or different halogen, oxo, hydroxyl group, cyano group, C １－６ Alkyl, C １－６ Alkoxy, Deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ is an alkylthio group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ Item 10. The compound or pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein one or more hydrogen atoms in the alkoxy may be deuterium.

[0016] [Section 5-2] R ２ is a hydrogen atom, and R ３ is C １－６ Alkyl, C ３－１０ cycloalkyl, or a 4- to 12-membered saturated heterocyclic group, wherein the C １－６ The alkyl may further comprise 1 to 3 of the same or different halogens, C ３－１０Optionally substituted with cycloalkyl or 4-12 membered saturated heterocyclic group, ３－１０ Cycloalkyl and the 4-12 membered saturated heterocyclic group are substituted with halogen, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ alkoxy, or a 4-12 membered saturated heterocyclic group, or R ２ and R ３ taken together to form a monocyclic, bicyclic or spirocyclic 4-12 membered saturated heterocyclic group, wherein the 4-12 membered saturated heterocyclic groups each independently contain 1 to 3 of the same or different deuterium atoms, halogen, oxo, hydroxyl group, cyano group, C １－６ Alkyl, C １－６ Alkoxy, C ６－１０ aryl, or 5-10 membered heteroaryl, １－６ Alkyl or the C １－６ The compound or a pharmaceutically acceptable salt thereof according to any one of the above items, wherein the alkoxy may be further substituted with one or more halogen atoms.

[0017] [Item 6] The compound or pharmaceutically acceptable salt thereof according to any one of the above items, wherein at least one of X, Y, Z, and W is a nitrogen atom.

[0018] [Item 7] The compound according to any one of the above items, wherein Q is N--H, or a pharmaceutically acceptable salt thereof.

[0019] [Item 8] The compound according to any one of the above items, which is represented by formula (2), or a pharmaceutically acceptable salt thereof:

[0020] [Section 9-1] R ２ and R ３ are taken together to form a monocyclic, bicyclic, tricyclic or spirocyclic 4-12 membered saturated heterocyclic group, and the optionally substituted 4-12 membered saturated heterocyclic group has 1 to 3 identical or different substituents selected from the group consisting of halogen, oxo, hydroxyl group, cyano group, C １－６ Alkyl, C １－６ Alkoxy, Deuterium, C １－６ Alkylcarbonyl, C １－６Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ is an alkylthio group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ Item 10. The compound or pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein one or more hydrogen atoms in the alkoxy may be deuterium.

[0021] [Section 9-2] R ２ and R ３ together form a monocyclic, bicyclic, or spirocyclic 4-12 membered saturated heterocyclic group, each of which independently contains one or more hydroxyl groups, C １－６ Alkyl or C １－４ The compound according to any one of the preceding items, which is substituted with alkoxy, or a pharmaceutically acceptable salt thereof.

[0022] [Section 10-1] R ４ is C ６－１０ aryl, 5-10 membered heteroaryl, or 4-12 membered saturated heterocyclic group; R ４ "Optionally substituted C" selected from ６－１０ The substitutable substituents in the "aryl" or "optionally substituted 5-10 membered heteroaryl" are each independently a halogen, a cyano group, an amino group, a carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, diC １－６ alkylaminocarbonyl, or C １－６ cycloalkyloxy, １－６ The alkyl may further include halogen, C ３－１０Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４ The substitutable substituents in the "optionally substituted 4-12 membered saturated heterocyclic group" selected from the group consisting of: １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C ２－６ alkenyl, or oxo, １－６ The alkyl may further include halogen and C ６－１０ aryl, and the C ３－１０ The compound according to any one of the above items, wherein cycloalkyl is optionally further substituted with one or more halogens, or a pharmaceutically acceptable salt thereof.

[0023] [Section 10-2] R ４ "Optionally substituted C" selected from ６－１０ The substitutable substituents in the "optionally substituted aryl," "optionally substituted 5-10 membered heteroaryl," or "optionally substituted 4-12 membered saturated heterocyclic group" are each independently 1 to 3 of the same or different, such as halogen, C １－６ Alkyl, or C ３－１０ Item 10. The compound according to any one of the preceding items, wherein the compound is cycloalkyl, or a pharmaceutically acceptable salt thereof.

[0024] [Section 11-1] R ４ is an optionally substituted 5-10 membered heteroaryl, R ４ The substitutable substituents in the "optionally substituted 5-10 membered heteroaryl" selected from the group consisting of:１－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, diC １－６ Alkylaminocarbonyl, C １－６ cycloalkyloxy, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The compound according to any one of the above items, wherein the alkoxy may be further substituted with one or more halogen atoms, or a pharmaceutically acceptable salt thereof.

[0025] [Section 11-2] R ４ are 5-10 membered heteroaryl, each independently containing one or two of the same or different halogen, C １－３ Alkyl, or C ３－６ The compound according to item 10-2, which is substituted by cycloalkyl, or a pharmaceutically acceptable salt thereof.

[0026] [Section 12-1] R ４ Item 11-1, wherein R is an optionally substituted 5- or 6-membered nitrogen-containing heteroaryl, or a pharmaceutically acceptable salt thereof.

[0027] [Section 12-2] R ４ The compound according to Item 11-2, wherein is a 5- or 6-membered nitrogen-containing heteroaryl, or a pharmaceutically acceptable salt thereof.

[0028] [Section 13-1] R ４ Item 11-1, wherein R is an optionally substituted 5-membered nitrogen-containing heteroaryl or an optionally substituted pyridine, or a pharmaceutically acceptable salt thereof.

[0029] [Term 14] Equation (3) or Equation (4): wherein U and V each independently represent a nitrogen atom or CR ４Ｃ wherein at least one of U and V is a nitrogen atom; ４Ａ is a hydrogen atom, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｂ is a hydrogen atom, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｃ represents a hydrogen atom, a halogen atom, a cyano group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｄ represents a hydrogen atom, a halogen atom, a cyano group, an amino group, a carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｅ , R ４Ｆ , R ４Ｇ are each independently a hydrogen atom, a halogen atom, a cyano group, an amino group, a carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６and alkoxy may be further substituted with one or more halogen atoms.] or a pharmaceutically acceptable salt thereof.

[0030] [Section 15-1] R ２ and R ３ and (1a-1) to (1a-2) form a monocyclic, bicyclic, tricyclic or spirocyclic, optionally substituted 4-12 membered saturated heterocyclic group, which is any one of the following (1a-1) to (1a-8), (1a-10) to (1a-18), and the optionally substituted 4-12 membered saturated heterocyclic group has 1 to 3 identical or different substituents, which are halogen, oxo, hydroxyl group, cyano group, C １－６ Alkyl, C １－６ Alkoxy, Deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ is an alkylthio group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ Item 10. The compound or pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein one or more hydrogen atoms in the alkoxy may be deuterium.

[0031] [Section 15-2] R ２ and R ３ and (iii) are independently substituted or unsubstituted alkyl groups, and the substituted or unsubstituted alkyl groups are independently substituted or unsubstituted alkyl groups.

[0032] [Section 16-1] R ２ and R ３and (1a-1) to (1a-2) form a monocyclic, bicyclic, tricyclic or spirocyclic 4- to 12-membered saturated heterocyclic group, or a pharmaceutically acceptable salt thereof, which is any one of the following (1a-1) to (1a-5) or (1a-7):

[0033] [Section 16-2] R ２ and R ３ and (iii) are independently substituted or unsubstituted alkyl groups, and the monocyclic, bicyclic, or spirocyclic 4- to 12-membered saturated heterocyclic group formed by combining these groups is any one of the following (1a-1) to (1a-4):

[0034] [Section 17-1] R ２ and R ３ and (1a-2) are independently substituted or unsubstituted aryl groups. The compound according to Item 16-1, wherein the monocyclic, bicyclic, tricyclic or spirocyclic 4- to 12-membered saturated heterocyclic group formed by combining these is any one of the following (1a-1), (1a-2) or (1a-4), or a pharmaceutically acceptable salt thereof.

[0035] [Item 18-1] A compound according to Item 1-1 or a pharmaceutically acceptable salt thereof, selected from the following compounds: 6-(2-cyclopropylpyridin-3-yl)-N-[(1S,4r)-4-{[(3S,4S)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-24), 6-(2-cyclopropylpyridin-3-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-25), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(2-methoxy-7-azaspiro[3.5]nonan-7-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-37), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(4-methoxy-4-methylpiperidin-1-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-39), 6-(2-cyclopropylpyridin-3-yl)-N-[(1r,4r)-4-methyl-4-{[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl]methyl}cyclohexyl]pyridazin-3-amine (Example B-40), 6-(2-cyclopropylpyridin-3-yl)-N-[(1r,4r)-4-{[(4aR,7aS)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-46), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-50), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-[(4-methoxy-4-methylpiperidin-1-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-51), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-[(1r,4r)-4-{[(4aR,7aS)-Hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-52), 6-(2-cyclopropylpyridin-3-yl)-N-[(1S,4r)-4-{[(5S)-6,9-dioxa-2-azaspiro[4.5]decan-2-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-58), 6-(2-cyclopropylpyridin-3-yl)-N-[(1R,4r)-4-{[(5R)-6,9-dioxa-2-azaspiro[4.5]decan-2-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-59), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(5,8-dioxa-2-azaspiro[3.5]nonan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-60), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-[(5,8-dioxa-2-azaspiro[3.5]nonan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-62), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-68), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(3-methoxy-3-methylpyrrolidin-1-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-73), 6-(2-cyclopropyl-4-methyl-1H-imidazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-87), 6-(2-cyclopropyl-4-methyl-1H-imidazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-88), 6-(5-cyclopropyl-3-propyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-91), 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-92), N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-[3-methyl-5-(propan-2-yl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine (Example B-102), N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-[3-methyl-5-(1-methylcyclopropyl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine (Example B-103), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-107), 6-(4-cyclopropyl-2-methoxypyrimidin-5-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-108), 6-(5-cyclopropyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-111), 6-(5-cyclopropyl-1H-pyrazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-112), N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]-6-[3-methyl-5-(1-methylcyclopropyl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine (Example B-114), 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-115), 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-116), 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-{(1r,4r)-4-methyl-4-[(2-oxa-6-azatricyclo[3.3.1.1-3,7-]decan-6-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-121), 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-123), 6-(5-cyclopropyl-3,4-dimethyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-125), N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)methyl]-4-methylcyclohexyl}-6-[3-methyl-5-(propan-2-yl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine (Example B-129), N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]-6-[3-methyl-5-(propan-2-yl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine (Example B-130), 6-(5-cyclobutyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-132), 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-133), 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-134), N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-[3-methyl-5-(1-methylcyclobutyl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine (Example B-143), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1S,4r)-4-{[(3S,4S)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-144), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-145), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-146), N-[(1R,4r)-4-({(3R,4R)-3,4-bis[(d3)methyloxy]pyrrolidin-1-yl}methyl)-4-methylcyclohexyl]-6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)pyridazin-3-amine (Example B-149), 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(3-methyl-8-azabicyclo[3.2.1]octan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-150), 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-155), N-[(1R,4r)-4-{[(3R,4R)-3,4-bis[(d3)methyloxy](2,2,5,5-d4)pyrrolidin-1-yl]methyl}-4-methylcyclohexyl]-6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)pyridazin-3-amine (Example B-156), 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(5R,9S)-9-methoxy-1-oxa-7-azaspiro[4.4]nonan-7-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-160), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-163), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-164), 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-166), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(5R,9S)-9-methoxy-1-oxa-7-azaspiro[4.4]nonan-7-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-167), 6-(3,5-dicyclopropyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-168), 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-169), N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-[3-ethyl-5-(1-methylcyclopropyl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine (Example B-170), (5R,9S)-7-{[(1r,4R)-4-{[6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)pyridazin-3-yl]amino}-1-methylcyclohexyl]methyl}-1-oxa-7-azaspiro[4.4]nonan-9-ol (Example B-172), 6-[3-methyl-5-(1-methylcyclopropyl)-1H-pyrazol-1-yl]-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-175), N-[(1S,4r)-4-{[(3S,4S)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]-6-[3-methyl-5-(1-methylcyclopropyl)-1H-pyrazol-1-yl]pyridazin-3-amine (Example B-176), 6-(5-cyclobutyl-3-methyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-177), 6-(5-cyclobutyl-3-methyl-1H-pyrazol-1-yl)-N-[(1S,4r)-4-{[(3S,4S)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-178), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-179), 6-(5-cyclopropyl-3-ethyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-181), 6-(5-cyclopropyl-3-ethyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-182), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxy-3-methylpyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-183), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(4R)-3,4-dimethoxy-3-methylpyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-184), 6-(5-cyclopropyl-3-ethyl-1H-pyrazol-1-yl)-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-190), 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-[(1r,4r)-4-methyl-4-{[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl]methyl}cyclohexyl]pyridazin-3-amine (Example B-198), 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-199), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-215), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-216), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[4.4]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-217), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-219), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(3-oxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-220), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(1-oxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-222), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-223), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(1-oxa-7-azaspiro[4.4]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-227), 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-230), 6-(4-cyclopropyl-2-methoxypyrimidin-5-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-239), 6-(4-cyclopropyl-2-methoxypyrimidin-5-yl)-N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-240), 6-(4-cyclopropyl-2-methoxypyrimidin-5-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-241), N-[(1R,4r)-4-({(3R,4R)-3,4-bis[(d3)methyloxy]pyrrolidin-1-yl}methyl)-4-methylcyclohexyl]-6-(2-cyclopropylpyridin-3-yl)pyridazin-3-amine (Example B-243), 6-(2-cyclopropyl-4-ethyl-1H-imidazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-251), 6-(2-cyclopropyl-4-ethyl-1H-imidazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-252), 6-(5-cyclopropyl-3-ethyl-1H-pyrazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-253), 6-(5-cyclopropyl-3-ethyl-1H-pyrazol-1-yl)-N-[(1r,4r)-4-methyl-4-{[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl]methyl}cyclohexyl]pyridazin-3-amine (Example B-254), N-{(1r,4S)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-{3-ethyl-5-[(1S,2S)-2-fluorocyclopropyl]-1H-1,2,4-triazol-1-yl}pyridazin-3-amine (Example B-255), 6-(2-cyclopropyl-6-methylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-15), 6-(4-cyclopropylpyrimidin-5-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example D-22), 6-(4-cyclopropylpyrimidin-5-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example D-24), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-83), 6-(3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-85), 6-(2-cyclopropyl-6-methylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-90), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-91), N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]-6-[2-methoxy-4-(propan-2-yl)pyrimidin-5-yl]pyridazin-3-amine (Example D-96), 6-(4-cyclobutyl-2-methoxypyrimidin-5-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example D-97), 6-(3-cyclopropyl-1-ethyl-1H-pyrazol-4-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-100), 6-(3-cyclopropyl-1-ethyl-1H-pyrazol-4-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example D-102), 6-(2-cyclopropyl-6-methylpyridin-3-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example D-104), 6-(4-cyclopropyl-2-methoxypyrimidin-5-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-109), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}pyridazin-3-amine (Example K-1), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1s,4s)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-(fluoromethyl)cyclohexyl]pyridazin-3-amine (Example K-4), 1-{5-cyclopropyl-1-[6-({(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}amino)pyridazin-3-yl]-1H-1,2,4-triazol-3-yl}cyclopropan-1-ol (Example B-261), 6-[5-cyclopropyl-3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-269), 6-{5-cyclopropyl-3-[(3S)-oxolan-3-yl]-1H-1,2,4-triazol-1-yl}-N-{(1r,4S)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-273), 6-{5-cyclopropyl-3-[(3R)-oxolan-3-yl]-1H-1,2,4-triazol-1-yl}-N-{(1r,4R)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-274), 6-[5-cyclopropyl-3-(ethoxymethyl)-1H-1,2,4-triazol-1-yl]-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-276), N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-[3-(methoxymethyl)-5-(propan-2-yl)-1H-pyrazol-1-yl]pyridazin-3-amine (Example B-279), 6-{5-cyclopropyl-3-[(1R)-1-methoxyethyl]-1H-1,2,4-triazol-1-yl}-N-{(1r,4R)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-280), 6-{5-cyclopropyl-3-[(1S)-1-methoxyethyl]-1H-1,2,4-triazol-1-yl}-N-{(1r,4S)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-281), 6-(2-cyclopropylpyridin-3-yl)-N-{(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}pyridazin-3-amine (Example K-10), 2-{5-cyclopropyl-1-[6-({(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}amino)pyridazin-3-yl]-1H-1,2,4-triazol-3-yl}propan-2-ol (Example K-13), 1-{5-cyclopropyl-1-[6-({(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}amino)pyridazin-3-yl]-1H-1,2,4-triazol-3-yl}cyclopropan-1-ol (Example K-14).

[0036] [Item 18-2] A compound according to Item 1-2 or a pharmaceutically acceptable salt thereof, selected from the following compounds: 6-(2-cyclopropylpyridin-3-yl)-N-[(1S,4r)-4-{[(3S,4S)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-24), 6-(2-cyclopropylpyridin-3-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-25), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(2-methoxy-7-azaspiro[3.5]nonan-7-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-37), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(4-methoxy-4-methylpiperidin-1-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-39), 6-(2-cyclopropylpyridin-3-yl)-N-[(1r,4r)-4-methyl-4-{[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl]methyl}cyclohexyl]pyridazin-3-amine (Example B-40), 6-(2-cyclopropylpyridin-3-yl)-N-[(1r,4r)-4-{[(4aR,7aS)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-46), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-50), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-[(4-methoxy-4-methylpiperidin-1-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-51), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-[(1r,4r)-4-{[(4aR,7aS)-Hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-52), 6-(2-cyclopropylpyridin-3-yl)-N-[(1S,4r)-4-{[(5S)-6,9-dioxa-2-azaspiro[4.5]decan-2-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-58), 6-(2-cyclopropylpyridin-3-yl)-N-[(1R,4r)-4-{[(5R)-6,9-dioxa-2-azaspiro[4.5]decan-2-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-59), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(5,8-dioxa-2-azaspiro[3.5]nonan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-60), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-[(5,8-dioxa-2-azaspiro[3.5]nonan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-62), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-68), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(3-methoxy-3-methylpyrrolidin-1-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-73), 6-(2-cyclopropyl-4-methyl-1H-imidazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-87), 6-(2-cyclopropyl-4-methyl-1H-imidazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-88), 6-(5-cyclopropyl-3-propyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-91), 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-92), N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-[3-methyl-5-(propan-2-yl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine (Example B-102), N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-[3-methyl-5-(1-methylcyclopropyl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine (Example B-103), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-106), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-107), 6-(4-cyclopropyl-2-methoxypyrimidin-5-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-108), 6-(5-cyclopropyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-111), 6-(5-cyclopropyl-1H-pyrazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-112), N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]-6-[3-methyl-5-(1-methylcyclopropyl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine (Example B-114), 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-115), 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-116), 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-{(1r,4r)-4-methyl-4-[(2-oxa-6-azatricyclo[3.3.1.1-3,7-]decan-6-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-121), 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-123), 6-(5-cyclopropyl-3,4-dimethyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-125), N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)methyl]-4-methylcyclohexyl}-6-[3-methyl-5-(propan-2-yl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine (Example B-129), N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]-6-[3-methyl-5-(propan-2-yl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine (Example B-130), 6-(5-cyclobutyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-132), 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-133), 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-134), N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-[3-methyl-5-(1-methylcyclobutyl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine (Example B-143), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1S,4r)-4-{[(3S,4S)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-144), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]undecan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-145), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-146), N-[(1R,4r)-4-({(3R,4R)-3,4-bis[(d3)methyloxy]pyrrolidin-1-yl}methyl)-4-methylcyclohexyl]-6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)pyridazin-3-amine (Example B-149), 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(3-methyl-8-azabicyclo[3.2.1]octan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-150), 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-155), N-[(1R,4r)-4-{[(3R,4R)-3,4-bis[(d3)methyloxy](2,2,5,5-d4)pyrrolidin-1-yl]methyl}-4-methylcyclohexyl]-6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)pyridazin-3-amine (Example B-156), 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(5R,9S)-9-methoxy-1-oxa-7-azaspiro[4.4]nonan-7-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-160), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-163), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-164), 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-166), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(5R,9S)-9-methoxy-1-oxa-7-azaspiro[4.4]nonan-7-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-167), 6-(3,5-dicyclopropyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-168), 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-169), N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-[3-ethyl-5-(1-methylcyclopropyl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine (Example B-170), (5R,9S)-7-{[(1r,4R)-4-{[6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)pyridazin-3-yl]amino}-1-methylcyclohexyl]methyl}-1-oxa-7-azaspiro[4.4]nonan-9-ol (Example B-172), 6-[3-methyl-5-(1-methylcyclopropyl)-1H-pyrazol-1-yl]-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-175), N-[(1S,4r)-4-{[(3S,4S)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]-6-[3-methyl-5-(1-methylcyclopropyl)-1H-pyrazol-1-yl]pyridazin-3-amine (Example B-176), 6-(5-cyclobutyl-3-methyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-177), 6-(5-cyclobutyl-3-methyl-1H-pyrazol-1-yl)-N-[(1S,4r)-4-{[(3S,4S)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-178), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-179), 6-(5-cyclopropyl-3-ethyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-181), 6-(5-cyclopropyl-3-ethyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-182), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxy-3-methylpyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-183), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(4R)-3,4-dimethoxy-3-methylpyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-184), 6-(5-cyclopropyl-3-ethyl-1H-pyrazol-1-yl)-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-190), 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-[(1r,4r)-4-methyl-4-{[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl]methyl}cyclohexyl]pyridazin-3-amine (Example B-198), 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-199), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-215), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-216), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[4.4]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-217), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-219), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(3-oxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-220), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(1-oxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-222), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-223), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(1-oxa-7-azaspiro[4.4]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-227), 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-230), 6-(4-cyclopropyl-2-methoxypyrimidin-5-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-239), 6-(4-cyclopropyl-2-methoxypyrimidin-5-yl)-N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-240), 6-(4-cyclopropyl-2-methoxypyrimidin-5-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-241), N-[(1R,4r)-4-({(3R,4R)-3,4-bis[(d3)methyloxy]pyrrolidin-1-yl}methyl)-4-methylcyclohexyl]-6-(2-cyclopropylpyridin-3-yl)pyridazin-3-amine (Example B-243), 6-(2-cyclopropyl-4-ethyl-1H-imidazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-251), 6-(2-cyclopropyl-4-ethyl-1H-imidazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-252), 6-(5-cyclopropyl-3-ethyl-1H-pyrazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-253), 6-(5-cyclopropyl-3-ethyl-1H-pyrazol-1-yl)-N-[(1r,4r)-4-methyl-4-{[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl]methyl}cyclohexyl]pyridazin-3-amine (Example B-254), N-{(1r,4S)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-{3-ethyl-5-[(1S,2S)-2-fluorocyclopropyl]-1H-1,2,4-triazol-1-yl}pyridazin-3-amine (Example B-255), 6-(2-cyclopropyl-6-methylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-15), 6-(4-cyclopropylpyrimidin-5-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example D-22), 6-(4-cyclopropylpyrimidin-5-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example D-24), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-83), 6-(3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-85), 6-(2-cyclopropyl-6-methylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-90), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-91), N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]-6-[2-methoxy-4-(propan-2-yl)pyrimidin-5-yl]pyridazin-3-amine (Example D-96), 6-(4-cyclobutyl-2-methoxypyrimidin-5-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example D-97), 6-(3-cyclopropyl-1-ethyl-1H-pyrazol-4-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-100), 6-(3-cyclopropyl-1-ethyl-1H-pyrazol-4-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example D-102), 6-(2-cyclopropyl-6-methylpyridin-3-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example D-104), 6-(4-cyclopropyl-2-methoxypyrimidin-5-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-109), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}pyridazin-3-amine (Example K-1), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1s,4s)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-(fluoromethyl)cyclohexyl]pyridazin-3-amine (Example K-4).

[0037] [Item 19-1] A compound according to Item 1-1 or a pharmaceutically acceptable salt thereof, selected from the following compounds: 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-50), 6-(2-cyclopropyl-4-methyl-1H-imidazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-87), 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-116), 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-134), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1S,4r)-4-{[(3S,4S)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-144), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-146), 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-169), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-179), 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-199), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-216), 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-230), 6-(2-cyclopropyl-4-ethyl-1H-imidazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-251), N-{(1r,4S)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-{3-ethyl-5-[(1S,2S)-2-fluorocyclopropyl]-1H-1,2,4-triazol-1-yl}pyridazin-3-amine (Example B-255), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-83), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-91), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}pyridazin-3-amine (Example K-1), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1s,4s)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-(fluoromethyl)cyclohexyl]pyridazin-3-amine (Example K-4), 1-{5-cyclopropyl-1-[6-({(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}amino)pyridazin-3-yl]-1H-1,2,4-triazol-3-yl}cyclopropan-1-ol (Example B-261), 6-[5-cyclopropyl-3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-269), 6-{5-cyclopropyl-3-[(3S)-oxolan-3-yl]-1H-1,2,4-triazol-1-yl}-N-{(1r,4S)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-273), 6-{5-cyclopropyl-3-[(3R)-oxolan-3-yl]-1H-1,2,4-triazol-1-yl}-N-{(1r,4R)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-274), 6-[5-cyclopropyl-3-(ethoxymethyl)-1H-1,2,4-triazol-1-yl]-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-276), N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-[3-(methoxymethyl)-5-(propan-2-yl)-1H-pyrazol-1-yl]pyridazin-3-amine (Example B-279), 6-{5-cyclopropyl-3-[(1R)-1-methoxyethyl]-1H-1,2,4-triazol-1-yl}-N-{(1r,4R)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-280), 6-{5-cyclopropyl-3-[(1S)-1-methoxyethyl]-1H-1,2,4-triazol-1-yl}-N-{(1r,4S)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-281), 6-(2-cyclopropylpyridin-3-yl)-N-{(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}pyridazin-3-amine (Example K-10), 2-{5-cyclopropyl-1-[6-({(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}amino)pyridazin-3-yl]-1H-1,2,4-triazol-3-yl}propan-2-ol (Example K-13), 1-{5-cyclopropyl-1-[6-({(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}amino)pyridazin-3-yl]-1H-1,2,4-triazol-3-yl}cyclopropan-1-ol (Example K-14).

[0038] [Item 19-2] A compound according to Item 1-2 or a pharmaceutically acceptable salt thereof, selected from the following compounds: 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-50), 6-(2-cyclopropyl-4-methyl-1H-imidazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-87), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-106), 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-116), 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example B-134), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1S,4r)-4-{[(3S,4S)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-144), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-146), 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-169), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-179), 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-199), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-216), 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-230), 6-(2-cyclopropyl-4-ethyl-1H-imidazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (Example B-251), N-{(1r,4S)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-{3-ethyl-5-[(1S,2S)-2-fluorocyclopropyl]-1H-1,2,4-triazol-1-yl}pyridazin-3-amine (Example B-255), 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-83), 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine (Example D-91), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}pyridazin-3-amine (Example K-1), 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1s,4s)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-(fluoromethyl)cyclohexyl]pyridazin-3-amine (Example K-4).

[0039] [Item 20] The compound according to Item 1-1 or a pharmaceutically acceptable salt thereof, selected from the following compounds: N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-7,7,9-trimethyl-6,7-dihydropyridazino[4,3-b][1,2,4]triazolo[1,5-d][1,4]oxazepin-3-amine (Example H-1), N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]-7,7,9-trimethyl-6,7-dihydropyridazino[4,3-b][1,2,4]triazolo[1,5-d][1,4]oxazepin-3-amine (Example H-3), N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-9'-methyl-6'H-spiro[cyclopropane-1,7'-pyridazino[4,3-b][1,2,4]triazolo[1,5-d][1,4]oxazepin]-3'-amine (Example H-4), N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]-9'-methyl-6'H-spiro[cyclopropane-1,7'-pyridazino[4,3-b][1,2,4]triazolo[1,5-d][1,4]oxazepine]-3'-amine (Example H-6), 7,7,9-trimethyl-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}-6,7-dihydropyridazino[4,3-b][1,2,4]triazolo[1,5-d][1,4]oxazepine-3-amine (Example H-7), N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-9'-ethyl-6'H-spiro[cyclopropane-1,7'-pyridazino[4,3-b][1,2,4]triazolo[1,5-d][1,4]oxazepine]-3'-amine (Example H-8), N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-9-ethyl-7,7-dimethyl-6,7-dihydropyridazino[4,3-b][1,2,4]triazolo[1,5-d][1,4]oxazepin-3-amine (Example H-9), N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-9'-ethyl-6'H-spiro[cyclobutane-1,7'-pyridazino[4,3-b][1,2,4]triazolo[1,5-d][1,4]oxazepin-3'-amine (Example H-10), N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-9'-methyl-6'H-spiro[cyclobutane-1,7'-pyridazino[4,3-b][1,2,4]triazolo[1,5-d][1,4]oxazepine]-3'-amine (Example H-11), (13aS)-7-({(1r,4S)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}amino)-2-methyl-11,12,13,13a-tetrahydro-9H-pyridazino[3,4-e]pyrrolo[1,2-a][1,2,4]triazolo[5,1-c][1,4]diazepin-9-one (Example H-12), (3bS)-10-({(1r,4S)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}amino)-2-methyl-3b,4,5,6-tetrahydro-8H-pyrazolo[5,1-c]pyridazino[3,4-e]pyrrolo[1,2-a][1,4]diazepin-8-one (Example H-15), (13aS)-7-({(1r,4S)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}amino)-2-ethyl-11,12,13,13a-tetrahydro-9H-pyridazino[3,4-e]pyrrolo[1,2-a][1,2,4]triazolo[5,1-c][1,4]diazepin-9-one (Example H-16), (13aS)-2-ethyl-7-{[(1r,4S)-4-{[(1R,3R,5S)-3-Methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]amino}-11,12,13,13a-tetrahydro-9H-pyridazino[3,4-e]pyrrolo[1,2-a][1,2,4]triazolo[5,1-c][1,4]diazepin-9-one (Example H-17), (13aS)-7-{[(1R,4S)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]amino}-2-ethyl-11,12,13,13a-tetrahydro-9H-pyridazino[3,4-e]pyrrolo[1,2-a][1,2,4]triazolo[5,1-c][1,4]diazepin-9-one (Example H-23), (13aS)-7-({(1s,4R)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}amino)-2-ethyl-11,12,13,13a-tetrahydro-9H-pyridazino[3,4-e]pyrrolo[1,2-a][1,2,4]triazolo[5,1-c][1,4]diazepin-9-one (Example K-3), (3bS)-10-({(1s,4R)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}amino)-2-ethyl-3b,4,5,6-tetrahydro-8H-pyrazolo[5,1-c]pyridazino[3,4-e]pyrrolo[1,2-a][1,4]diazepin-8-one (Example K-6).

[0040] [Item 21] A pharmaceutical composition comprising the compound according to any one of the above items or a pharmaceutically acceptable salt thereof.

[0041] [Item 22] A therapeutic and / or preventive agent for a disease associated with antagonism to muscarinic M4 receptors, comprising the compound according to any one of the above items or a pharmaceutically acceptable salt thereof as an active ingredient.

[0042] [Item 23-1] The therapeutic and / or preventive agent according to Item 22, wherein the disease associated with antagonism to muscarinic M4 receptors is a neurodegenerative disease, a brain injury disease, a cerebrovascular disease, a disorder of psychological development, a psychiatric disease, a mental and behavioral disorder due to the use of psychoactive substances, a malignant neoplasm, a cognitive dysfunction associated with a movement disorder, or a peripheral symptom thereof, a movement disorder, or a systemic symptom or sign thereof.

[0043] [Item 23-2] The therapeutic and / or prophylactic agent according to Item 22, wherein the disease associated with antagonism to muscarinic M4 receptors is a neurodegenerative disease, a brain injury disease, a disorder of psychological development, a psychiatric disease, a cognitive dysfunction associated with movement disorder, or a peripheral psychiatric symptom thereof, or a movement disorder.

[0044] [Item 24-1] Diseases in which antagonism to muscarinic M4 receptors is involved include dementia, Alzheimer's disease, dementia with Lewy bodies, prefrontal temporal dementia, narcolepsy, cerebrovascular disease, stroke, cerebrovascular dementia, cerebral small vessel disease, traumatic brain injury, attention deficit hyperactivity disorder, autism, Down's syndrome, schizophrenia, bipolar disorder, depression, Parkinson's disease, drug-induced parkinsonism, dystonia, Tourette's syndrome, dyskinesia, chorea, chorea associated with Huntington's disease, amyotrophic lateral sclerosis, and the like. Item 23. The therapeutic and / or prophylactic agent according to Item 22, wherein the symptom is cognitive dysfunction, behavioral symptoms, psychotic symptoms, agitation, depression, anxiety, anhedonia, apathy, lethargy, loss of motivation, impaired motivation, emotional blunting, autism, excessive daytime sleepiness, sleep disorder, fatigue, motor dysfunction, hypokinesia, tremor, rigidity, gait disorder, or postural instability associated with schizophrenia, cerebral palsy, progressive supranuclear palsy, multiple system atrophy, substance use disorder, substance dependence, addictive behavior disorder, malignant neoplasm, tumor, cachexia, and the cognitive dysfunction, behavioral symptoms, psychotic symptoms, agitation, depression, anxiety, anhedonia, apathy, lethargy, loss of motivation, impaired motivation, emotional blunting, autism, excessive daytime sleepiness, sleep disorder, fatigue, motor dysfunction, hypokinesia, tremor, rigidity, gait disorder, or postural instability associated with these diseases.

[0045] [Item 24-2] The therapeutic and / or prophylactic agent according to Item 22, wherein the disease associated with antagonism to muscarinic M4 receptors is depression, anhedonia, apathy, lethargy, loss of motivation, impaired motivation, emotional blunting, autism, excessive daytime sleepiness, sleep disorders, or fatigue, and the symptoms are caused by dementia, Alzheimer's disease, dementia with Lewy bodies, prefrontal temporal dementia, narcolepsy, cerebrovascular disease, stroke, vascular dementia, cerebral small vessel disease, traumatic brain injury, Parkinson's disease, amyotrophic lateral sclerosis, cerebral palsy, progressive supranuclear palsy, or multiple system atrophy.

[0046] [Item 24-3] The therapeutic and / or preventive agent according to Item 22, wherein the disease associated with antagonism to muscarinic M4 receptors is depression, anhedonia, apathy, lethargy, loss of motivation, impaired motivation, blunted affect, autism, excessive daytime sleepiness, sleep disorder, or fatigue, and the symptoms are caused by a malignant neoplasm, tumor, or cachexia.

[0047] [Item 24-4] The therapeutic and / or prophylactic agent according to Item 22, wherein the disease associated with antagonism to muscarinic M4 receptors is Parkinson's disease, drug-induced parkinsonism, dystonia, Tourette's syndrome, dyskinesia, chorea, chorea associated with Huntington's disease, and motor dysfunction, bradykinesia, tremor, rigidity, gait disturbance, or postural instability associated with these diseases.

[0048] [Item 24-5] The therapeutic and / or prophylactic agent according to Item 22, wherein the disease associated with antagonism to muscarinic M4 receptors is dementia, Alzheimer's disease, dementia with Lewy bodies, prefrontal temporal dementia, excessive daytime sleepiness, narcolepsy, cerebrovascular disorder, stroke, cerebrovascular dementia, cerebral small vessel disease, traumatic brain injury, attention deficit hyperactivity disorder, autism, Down's syndrome, schizophrenia, bipolar disorder, depression, Parkinson's disease, drug-induced parkinsonism, dystonia, Tourette's syndrome, dyskinesia, chorea, chorea associated with Huntington's disease, amyotrophic lateral sclerosis, cerebral palsy, progressive supranuclear palsy, cognitive dysfunction associated with multiple system atrophy, peripheral symptoms thereof, psychotic symptoms, agitation, depression, anxiety, anhedonia, apathy, sleep disorders, fatigue and motor dysfunction, bradykinesia, tremor, rigidity, gait disturbance and postural instability.

[0049] [Item 25] A method for treating and / or preventing a disease associated with antagonism to the muscarinic M4 receptor, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound according to any one of the above items, or a pharmaceutically acceptable salt thereof.

[0050] [Item 26] Use of the compound according to any one of the above items, or a pharmaceutically acceptable salt thereof, for the manufacture of a therapeutic and / or preventive agent for a disease associated with antagonism to muscarinic M4 receptors.

[0051] [Item 27] ​​The compound according to any one of the above items, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease associated with antagonism to muscarinic M4 receptors.

[0052] [Item 28] A medicine comprising a compound according to any one of the above items or a pharmaceutically acceptable salt thereof in combination with at least one drug selected from drugs classified as atypical antipsychotics.

[0053] [Item 29] A pharmaceutical agent comprising the compound according to any one of the above items or a pharmaceutically acceptable salt thereof, for use in combination with at least one or more drugs selected from drugs classified as atypical antipsychotics to treat neurodegenerative diseases, brain damage diseases, disorders of psychological development, psychiatric diseases, cognitive dysfunction associated with movement disorders, and peripheral symptoms and movement dysfunction associated with these diseases.

[0054] Muscarinic M4 receptors are widely distributed in the cerebral cortex and striatum, and functional abnormalities in these brain regions are known to be involved in various diseases. The compounds of the present invention are highly expressed in these brain regions, selectively bind to muscarinic M4 receptors, and have antagonistic effects, and are therefore useful as prophylactic and / or therapeutic agents for neurodegenerative diseases, brain injury diseases, psychological development disorders, psychiatric diseases, cognitive dysfunction associated with movement disorders, and their peripheral symptoms and movement disorders.

[0055] Figure 1 shows the results of Example B-146 in Test Example 3. Figure 2 shows the results of Example B-230-TA in Test Example 3. Figure 3 shows the results of scopolamine hydrobromide in Test Example 3.

[0056] The terms used in this specification are explained below.

[0057] The number of substituents in a group defined as "optionally substituted" or "substituted" is not particularly limited as long as substitution is possible. In addition, unless otherwise specified, the description of each group also applies when that group is a part or substituent of another group.

[0058] Examples of "halogen" include fluorine, chlorine, bromine, and iodine. Preferred are fluorine and chlorine. More preferred is fluorine.

[0059] The term "heteroatom" refers to an oxygen atom, a nitrogen atom, a sulfur atom, or the like. A nitrogen atom or an oxygen atom is preferred. A nitrogen atom is more preferred.

[0060] "C １－６ "Alkyl" means a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms. １－６ As the alkyl, preferably "C １－４ alkyl", and more preferably "C １－３ "C alkyl" is an example. １－３ Specific examples of "alkyl" include methyl, ethyl, propyl, 1-methylethyl, etc. １－４ Specific examples of "alkyl" include the above-mentioned "C １－３ In addition to the specific examples of "alkyl", butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, etc. are also included. １－６ Specific examples of "alkyl" include the above-mentioned "C １－４ In addition to the specific examples of "alkyl", pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl, etc. are included.

[0061] "C ２－６ "Alkenyl" means a straight or branched chain unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 double bonds. ２－６Alkenyl is preferably "C ２－４ "C alkenyl" is an example. ２－４ Specific examples of "alkenyl" include vinyl, propenyl, 1-methylvinyl, 1-methylpropenyl, 2-methylpropenyl, butenyl, etc. ２－６ Specific examples of "alkenyl" include the above-mentioned "C ２－４ In addition to the specific examples of "alkenyl", pentenyl, hexenyl, etc. are also included.

[0062] "The C １－６ The term "alkylaminocarbonyl" refers to the same as the above "C １－６ "DiC" means a group in which an aminocarbonyl is bonded to an "alkyl". １－６ As the "alkylaminocarbonyl", preferably "diC １－３ alkylaminocarbonyl." １－３ Specific examples of "alkylcarbonyl" include dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, ethylmethylaminocarbonyl, methylpropylaminocarbonyl, methylisopropylaminocarbonyl, etc. １－６ Specific examples of "alkylaminocarbonyl" include the above-mentioned "C １－３ In addition to the specific examples of "alkylaminocarbonyl", dibutylaminocarbonyl, dipentylaminocarbonyl, dihexylaminocarbonyl, etc. are included.

[0063] "C ３－１０ "Cycloalkyl" refers to a cyclic non-aromatic hydrocarbon group having 3 to 10 carbon atoms, and includes saturated and partially unsaturated hydrocarbon groups. It also includes partially bridged structures. ３－１０ As the "cycloalkyl", preferably "C ３－８ Cycloalkyl" is preferred, and "C ３－６ "Cycloalkyl" is an example. ３－６ Specific examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, etc. ３－８Specific examples of "cycloalkyl" include the above-mentioned "C ３－６ In addition to the specific examples of "cycloalkyl", cycloheptyl, cyclooctyl, etc. are also included. ３－１０ Specific examples of "cycloalkyl" include the above-mentioned "C ３－８ In addition to the specific examples of "cycloalkyl", cyclononyl, cyclodecyladamantyl and the like can be mentioned.

[0064] "C １－６ The term "alkylcarbonyl" refers to the above-mentioned "C １－６ "C" means a group in which a carbonyl is bonded to an "alkyl." １－６ As the "alkylcarbonyl", preferably "C １－４ "C alkylcarbonyl" is an example. １－４ Specific examples of "alkylcarbonyl" include methylcarbonyl, ethylcarbonyl, propylcarbonyl, 1-methylethylcarbonyl, butylcarbonyl, 1,1-dimethylethylcarbonyl, 1-methylpropylcarbonyl, and 2-methylpropylcarbonyl. １－６ Specific examples of "alkylcarbonyl" include the above-mentioned "C １－４ In addition to the specific examples of "alkylcarbonyl", 4-methylpentylcarbonyl, 3-methylpentylcarbonyl, 2-methylpentylcarbonyl, 1-methylpentylcarbonyl, hexylcarbonyl, etc. are included.

[0065] "C １－６ The term "alkylcarbonylamino" refers to the same as the above "C １－６ "C" means a group in which an amino group is bonded to "alkylcarbonyl." １－６ As "alkylcarbonylamino", preferably "C １－４ alkylcarbonylamino." １－４ Specific examples of "alkylcarbonylamino" include methylcarbonylamino, ethylcarbonylamino, propylcarbonyl, 1-methylethylcarbonyl, butylcarbonyl, 1,1-dimethylethylcarbonyl, 1-methylpropylcarbonyl, 2-methylpropylcarbonyl, etc. １－６Specific examples of "alkylcarbonyl" include the above-mentioned "C １－４ In addition to the specific examples of "alkylcarbonyl", 4-methylpentylcarbonyl, 3-methylpentylcarbonyl, 2-methylpentylcarbonyl, 1-methylpentylcarbonyl, hexylcarbonyl, etc. are included.

[0066] In the present invention, the term "4-12-membered saturated heterocyclic group" refers to a monocyclic, bicyclic, or tricyclic saturated heterocyclic group composed of 4 to 12 atoms, including, in addition to carbon atoms, 1 to 3 atoms independently selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, and includes a partially unsaturated heterocyclic group, a partially bridged heterocyclic group, a partially spiro-formed spiro-formed heterocyclic group, or a C ６－１０ Also included are those which form a fused ring with an aryl or a 5- to 10-membered heteroaryl. Specific examples of the "4- to 12-membered monocyclic saturated heterocyclic group" include azetidine, pyrrolidine, piperidine, piperazine, morpholine, oxazepane, oxetane, tetrahydrofuran, tetrahydropyran, azepane, oxepane, diazepine, azocane, 1,5-oxazocane, etc. In addition to the above specific examples, specific examples of the 4- to 12-membered saturated heterocyclic group of the present invention include the following. The bonding position is a bondable position on a carbon atom or nitrogen atom.

[0067] R ４ The "4-12 membered saturated heterocyclic group" in the formula (I) includes the above-mentioned "4-12 membered saturated heterocyclic group". The bonding position is a bondable position on a carbon atom or nitrogen atom. ４ Preferred examples of the ring include pyrrolidine, piperidine, morpholine, piperazine, azepane, diazepane, and the following rings:

[0068] R ２ and R ３The "4-12-membered saturated heterocyclic group" in the above means a ring bonded from a carbon atom within the definition of the "4-12-membered saturated heterocyclic group". Preferred examples include piperidine, tetrahydropyran, etc. The bonding position is a bondable position on the carbon atom.

[0069] "R ２ and R ３ "A monocyclic, bicyclic, tricyclic or spirocyclic 4-12 membered saturated heterocyclic group formed by taking together these" means a ring bonding from a nitrogen atom within the definition of the above "4-12 membered saturated heterocyclic group". Preferred examples include azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, oxazepane, piperazine, as well as the following rings. The bonding position is a nitrogen atom in the ring that can be bonded to.

[0070] "R ６ and the above R ４ Preferred examples of "a 4-12 membered saturated heterocyclic group formed by combining R ６ and the above R ４ C is formed when ３－１０ Preferred examples of "cycloalkyl" include cycloheptane and the like.

[0071] "C ６－１０ "Aryl" means a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms. ６－１０ "Aryl" is "C ３－１０ It may be fused with "cycloalkyl" or "4-12 membered saturated heterocyclic group" at any possible position. ６－１０ Specific examples of "aryl" include phenyl, 1-naphthyl, 2-naphthyl, etc. ６－１０ A preferred example of the "aryl" is phenyl. Specific examples of the fused ring structure include the groups shown below.

[0072] "C ６－１０ The term "aryloxy" refers to the same as the above "C６－１０ "C" means an oxy group substituted by "aryl." ６－１０ Specific examples of "aryl" include phenyloxy, 1-naphthyloxy, 2-naphthyloxy, etc. ６－１０ The "aryloxy" preferably includes phenyloxy.

[0073] "C １－６ The term "alkoxy" refers to the same as the above "C １～６ "C" means an oxy group substituted by "alkyl." １－６ As the "alkoxy", preferably "C １－４ "Alkoxy" is an example. １－４ Specific examples of "alkoxy" include methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, and 2-methylpropoxy. １－６ Specific examples of "alkoxy" include the above-mentioned "C １－４ In addition to the specific examples of "alkoxy", pentyloxy, 3-methylbutoxy, 2-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy, hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy and the like.

[0074] "C １－６ The term "alkylthio" refers to the same as the above "C １ー６ "C" means a thio group substituted by "alkyl." １－６ As "alkylthio", preferably "C １－３ "C alkylthio" is an example. １－３ Specific examples of "alkylthio" include methylthio, ethylthio, propylthio, and 1-methylethylthio.

[0075] "C １－６ Haloalkoxy means the same as defined above in "C １－６ C in which the hydrogen atoms of the alkyl moiety in "alkoxy" are substituted with 1 to 5 halogens１－６ It means an alkoxy group. １－６ As the "haloalkoxy", preferably "C １－２ Preferred examples include "fluoroalkoxy", and more preferred examples include trifluoromethoxy.

[0076] "C １－６ The term "alkoxycarbonyl" refers to the above-mentioned "C １－６ "C" means a group in which a carbonyl is bonded to "alkoxy." １－６ As the "alkoxycarbonyl", preferably "C １－４ "Alkoxycarbonyl" is an example. １－４ Specific examples of "alkoxycarbonyl" include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-methylethyloxycarbonyl, butoxycarbonyl, 1,1-dimethylethyloxycarbonyl, 1-methylpropyloxycarbonyl, 2-methylpropyloxycarbonyl, etc. １－６ Specific examples of "alkoxycarbonyl" include the above-mentioned "C １－４ In addition to the specific examples of "alkoxycarbonyl", 4-methylpentyloxycarbonyl, 3-methylpentyloxycarbonyl, 2-methylpentyloxycarbonyl, 1-methylpentyloxycarbonyl, hexyloxycarbonyl, etc. are included.

[0077] The term "5-10-membered heteroaryl" refers to a monocyclic or bicyclic aromatic heterocyclic group consisting of 5 to 10 atoms, including 1 to 4 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. The "5-10-membered heteroaryl" is preferably a "5-7-membered heteroaryl," more preferably a "5-7-membered nitrogen-containing heteroaryl" having 1 to 3 nitrogen atoms in the ring. Specific examples of the "5-7-membered nitrogen-containing heteroaryl" include pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl, triazolyl, and tetrazolyl. Of these, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, and triazolyl are preferred. Specific examples of the "5-10-membered nitrogen-containing heteroaryl" include, in addition to the specific examples of the "5-7-membered nitrogen-containing heteroaryl", furyl, thienyl, etc. Specific examples of the "5-10-membered heteroaryl" include, in addition to the specific examples of the "5-7-membered heteroaryl", indolyl, indazolyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl, 6,11-dihydrodibenzo[b,e]thiepinyl group, etc.

[0078] "5-10-membered heteroaryloxy" refers to an oxy group substituted by the "5-10-membered heteroaryl". Preferred examples of the "5-10-membered heteroaryloxy" include "5-7-membered heteroaryloxy", and more preferred examples include "5-7-membered nitrogen-containing heteroaryloxy" having 1 to 3 nitrogen atoms in the ring. Specific examples of the "5-7-membered nitrogen-containing heteroaryl" include pyridyloxy, pyridazinyloxy, isothiazolyloxy, pyrrolyloxy, thiazolyloxy, imidazolyloxy, pyrimidinyloxy, thiadiazolyloxy, pyrazolyloxy, oxazolyloxy, isoxazolyloxy, pyrazinyloxy, triazinyloxy, triazolyloxy, imidazolidinyloxy, oxadiazolyloxy, triazolyloxy, tetrazolyloxy, etc. Among these, pyridyloxy, pyridazinyloxy, imidazolyloxy, pyrimidinyloxy, pyrazolyloxy, or triazolyloxy is preferred. Specific examples of "5-10-membered nitrogen-containing heteroaryloxy" include, for example, those specific examples of the above "5-7-membered nitrogen-containing heteroaryloxy", as well as furyloxy, thienyloxy, etc. Specific examples of "5-10-membered heteroaryloxy" include, for example, those specific examples of the above "5-7-membered heteroaryloxy", as well as indolyloxy, indazolyloxy, quinolyloxy, isoquinolyloxy, benzofuranyloxy, benzothienyloxy, benzoxazolyloxy, benzothiazolyloxy, benzisoxazolyloxy, benzisothiazolyloxy, benzotriazolyloxy, benzimidazolyloxy, 6,11-dihydrodibenzo[b,e]thiepinyloxy group, etc.

[0079] R １ Preferably, optionally substituted C １－６ Alkyl or optionally substituted C １－６ alkoxy, and the "optionally substituted C １－６ alkyl," or the "optionally substituted C １－６Preferred substituents in "alkoxy" are each independently 1 to 3 of the same or different halogens or deuterium. １ More preferably, C optionally substituted by 1 to 3 fluorine or deuterium atoms. １－３ alkyl. １ More preferably, unsubstituted C １－３ Examples include alkyl, and most preferably methyl.

[0080] R ２ and R ３ are preferably each independently a hydrogen atom, an optionally substituted C １－６ Alkyl, optionally substituted C ３－１０ cycloalkyl, an optionally substituted 4-12 membered saturated heterocyclic group, or R ２ and R ３ together represent an optionally substituted 4-12 membered saturated heterocyclic group, ２ and R ３ "Optionally substituted C" selected from １－６ The substituents in "alkyl" are each independently 1 to 3 of the same or different, such as halogen, C １－６ Alkoxy, C ３－１０ cycloalkyl or 4-12 membered saturated heterocyclic group, ３－１０ Further substituents of the cycloalkyl or 4-12 membered saturated heterocyclic group include oxo, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ Haloalkoxy, and C １－６ alkylcarbonylamino; R ２ and R ３ "Optionally substituted C" selected from ３－１０ The substituents in the "cycloalkyl" or "optionally substituted 4-12 membered saturated heterocyclic group" are preferably each independently 1 to 3 of the same or different, such as halogen, C１－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ alkoxy, or a 4- to 12-membered saturated heterocyclic group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, oxo, C １－６ Alkyl, C １－６ Alkoxy and C １－６ alkylcarbonyl, optionally substituted with one or more substituents selected from the group consisting of ２ and R ３ The substituents in the "monocyclic, bicyclic, tricyclic or spirocyclic optionally substituted 4-12 membered saturated heterocyclic group" when taken together with each other are preferably each independently 1 to 3 of the same or different halogen, oxo, hydroxyl group, cyano group, C １－６ Alkyl, C １－６ Alkoxy, C ６－１０ aryl or 5-10 membered heteroaryl, deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ is an alkylthio group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ One or more hydrogen atoms in the alkoxy may be deuterium.

[0081] R ２ and R ３ More preferably, R ２ is a hydrogen atom, and R ３ is optionally substituted C １－６ Alkyl, optionally substituted C ３－１０ cycloalkyl or an optionally substituted 4-12 membered saturated heterocyclic group, or R ２ and R ３and R are taken together to form a monocyclic, bicyclic, tricyclic or spirocyclic 4-12 membered saturated heterocyclic group; ３ "Optionally substituted C" selected from １－６ More preferred substituents in "alkyl" are 1 to 3 of the same or different halogens, C ３－１０ cycloalkyl, or a 4- to 12-membered saturated heterocyclic group; R ３ "Optionally substituted C" selected from ３－１０ More preferred examples of the substituents of "cycloalkyl" or "optionally substituted 4-12 membered saturated heterocyclic group" include oxo, C １－６ Alkyl, C １－６ Alkoxy or C １－６ alkylcarbonyl, R ２ and R ３ More preferred substituents in the "monocyclic, bicyclic, tricyclic or spirocyclic optionally substituted 4-12 membered saturated heterocyclic group" when taken together are 1 to 3 of the same or different halogen, oxo, hydroxyl group, cyano group, C １－６ Alkyl, C １－６ Alkoxy, Deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ alkylthio groups, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ One or more hydrogen atoms in the alkoxy may be deuterium.

[0082] R ２ and R ３The monocyclic, bicyclic, tricyclic or spirocyclic optionally substituted 4-12 membered saturated heterocyclic group formed by combining these groups preferably includes any of the following (1a-1) to (1a-8), (1a-10) to (1a-18), more preferably any of the following (1a-1) to (1a-5) or (1a-7), and even more preferably any of the following (1a-1), (1a-2) or (1a-4). The "optionally substituted 4-12 membered saturated heterocyclic group" preferably includes 1 to 3 of the same or different halogen, oxo, hydroxyl group, cyano group, C １－６ Alkyl, C １－６ Alkoxy, Deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ alkylthio groups, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ One or more hydrogen atoms in the alkoxy may be deuterium.

[0083] R ４ Preferably, optionally substituted C ６－１０ aryl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered saturated heterocyclic group; R ４ "Optionally substituted C" selected from ６－１０ The substituents in the "aryl" or "optionally substituted 5-10 membered heteroaryl" are preferably each independently a halogen, a cyano group, an amino group, a carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, diC １－６ alkylaminocarbonyl, or C １－６ cycloalkyloxy, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogen atoms; ４ The substituents in the "optionally substituted 4-12 membered saturated heterocyclic group" selected from the above are preferably each independently 1 to 3 of the same or different halogen, cyano group, amino group, carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C ２－６ alkenyl, or oxo, １－６ The alkyl may further include halogen and C ６－１０ aryl, and the C ３－１０ Cycloalkyl may be further substituted with one or more halogens.

[0084] R ４ More preferred examples of R include an optionally substituted 5- to 10-membered heteroaryl, even more preferred examples include an optionally substituted 5- or 6-membered nitrogen-containing heteroaryl, and even more preferred examples include an optionally substituted 5-membered nitrogen-containing heteroaryl or an optionally substituted pyridine. ４The substituents in the "optionally substituted 5-10 membered heteroaryl", "5 or 6 membered nitrogen-containing heteroaryl", "optionally substituted 5 membered nitrogen-containing heteroaryl" and "optionally substituted pyridine" selected from the above are preferably each independently a halogen, a cyano group, an amino group, a carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, diC １－６ alkylaminocarbonyl, or C １－６ cycloalkyloxy, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogen atoms.

[0085] R ４ The most preferred examples include the following (3A) or (4A). Preferably, U and V are each independently a nitrogen atom or CR ４Ｃ At least one of U and V is a nitrogen atom; ４Ａ is preferably a hydrogen atom, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogen atoms; ４Ｂ is preferably a hydrogen atom, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogen atoms; ４Ｃ is preferably a hydrogen atom, a halogen atom, a cyano group, １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogen atoms; ４Ｄ is preferably a hydrogen atom, a halogen atom, a cyano group, an amino group, a carbonyl group, １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C１－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogen atoms; ４Ｅ , R ４Ｆ , R ４Ｇ are preferably each independently a hydrogen atom, a halogen atom, a cyano group, an amino group, a carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogen atoms.

[0086] R ５ is preferably a hydrogen atom, optionally substituted C １－６ Alkyl or optionally substituted C １－６ alkoxy, and the "optionally substituted C １－６ alkyl," or the "optionally substituted C １－６ The substituents in "alkoxy" are each independently 1 to 3 of the same or different halogens or deuterium. ５ A more preferred example of the group is a hydrogen atom.

[0087] R ６ is preferably a hydrogen atom or an optionally substituted C １－６ alkyl, and the "optionally substituted C １－６ The substituents in "alkyl" include 1 to 3 identical or different halogens. ６ A more preferred example of the group is a hydrogen atom.

[0088] R ６ is preferably a hydrogen atom or an optionally substituted C １－６ alkyl, and the "optionally substituted C １－６ The substituents in "alkyl" include 1 to 3 identical or different halogens. ６ A hydrogen atom is more preferred as R. ６ and R ４ and together form an optionally substituted C ３－１０ Preferred examples of the ring structure in the cycloalkyl or optionally substituted 4-12 membered saturated heterocyclic group include the following (1b-1) to (1b-7). ３－１０ Preferred substituents of the "optionally substituted 4- to 12-membered saturated heterocyclic group" are each independently 1 to 3 of the same or different oxo, C １－６ Alkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, 5-10 membered heteroaryl, or 4-12 membered saturated heterocyclic group, among which C ３－１０ Cycloalkyl, C ６－１０ Substituents for cyclic structures such as aryl, 5-10 membered heteroaryl, or 4-12 membered saturated heterocyclic groups are R ４ and R ６ Together they form C ３－１０ It is to be noted that in the following (1b-1) to (1b-7), R ６ and R ４is a ring structure containing a pyridazine ring to which is attached, a fused ring as a substituent, and a spiro ring moiety.

[0089] X, Y, Z and W each independently represent a nitrogen atom or CR ６ Preferably, any one or more of X, Y, Z, and W is a nitrogen atom, more preferably, any one or more of X, Y, Z, and W is a nitrogen atom, and even more preferably, X and Y are nitrogen atoms and W and Z are CR ６ or X and Y are CR ６ and W and Z are nitrogen atoms.

[0090] Q is an oxygen atom, a sulfur atom, or N—H, and preferably N—H.

[0091] In the present specification, the stereochemistry of the substituents in the compounds represented by formula (1) and formula (2) and the compounds described in the examples is illustrated, for example, as follows. Here, bonds represented by thick solid lines and solid wedges represent substituents on the front side of the page, while bonds represented by thick dashed lines and dashed wedges represent substituents on the back side of the page. Wavy bonds indicate that substituents on the front and back sides of the page may be present in any proportion, and straight bonds extending outward from a ring indicate that the substituent is either on the front side or the back side of the page. Solid and dashed wedges with "abs" are used to indicate absolute configuration; solid and dashed wedges with "&" and a number indicate relative configuration but are a mixture with the corresponding enantiomer; solid and dashed wedges with "or" and a number indicate relative configuration but are enantiomerically pure compounds with an uncertain absolute configuration.

[0092] One embodiment of the compound represented by formula (1) is the following (A): (A) R １ is C １－３ alkyl, and the C １－３ The alkyl may be substituted with one or more fluorine or deuterium atoms, and R ５ is a hydrogen atom, and R ２is a hydrogen atom, and R ３ is C １－６ Alkyl, C ３－１０ cycloalkyl, or a 4- to 12-membered saturated heterocyclic group, wherein the C １－６ The alkyl group may be selected from the group consisting of 1 to 3 of the same or different halogens, C ３－１０ Optionally substituted with cycloalkyl or 4-12 membered saturated heterocyclic group, ３－１０ The cycloalkyl or 4-12 membered saturated heterocyclic group may further include 1 to 3 oxo, C １－６ Alkyl, C １－６ Alkoxy or C １－６ may be substituted with alkylcarbonyl, or R ２ and R ３ together form a monocyclic, bicyclic, tricyclic or spirocyclic 4-12 membered saturated heterocyclic group, wherein the 4-12 membered saturated heterocyclic group each independently has 1 to 3 of the same or different halogen, oxo, hydroxyl, cyano, C １－６ Alkyl, C １－６ Alkoxy, Deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ may be substituted with an alkylthio group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ One or more hydrogen atoms in the alkoxy may be deuterium, one or more of X, Y, Z and W is a nitrogen atom, R ４ is C ６－１０ aryl, 5-10 membered heteroaryl, or 4-12 membered saturated heterocyclic group; R ４ "Optionally substituted C" selected from ６－１０ The substitutable substituents in the "aryl" or "optionally substituted 5-10 membered heteroaryl" are each independently a halogen, a cyano group, an amino group, a carbonyl group, C１－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, diC １－６ alkylaminocarbonyl, or C １－６ cycloalkyloxy, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４ The substitutable substituents in the "optionally substituted 4-12 membered saturated heterocyclic group" selected from the group consisting of: １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C ２－６ alkenyl, or oxo, １－６ The alkyl may further include halogen and C ６－１０ aryl, and the C ３－１０ The cycloalkyl may be further substituted with one or more halogens, and R ６ is a hydrogen atom, C optionally substituted with 1 to 3 fluorines １－６ alkyl, or at least one of X and Z is CR ６ When R ６ and the above R ４ Together, C ３－１０ cycloalkyl, or a 4- to 12-membered saturated heterocyclic group, wherein the C ３－１０Cycloalkyl and the 4-12 membered saturated heterocyclic group include oxo, C １－６ Alkyl, C ３－１０ Cycloalkyl, C ６－１０ It may be substituted with an aryl, a 5-10 membered heteroaryl, or a 4-12 membered saturated heterocyclic group, among which C ３－１０ Cycloalkyl, C ６－１０ Substituents for cyclic structures such as aryl, 5-10 membered heteroaryl, or 4-12 membered saturated heterocyclic groups are R ４ and R ６ Together they form C ３－１０ A compound which forms a fused ring structure or a spiro structure with a cycloalkyl or a 4-12 membered saturated heterocyclic group, and Q is N--H, or a pharmaceutically acceptable salt thereof.

[0093] One embodiment of the compound represented by formula (1) is the following (B), which has a structure represented by formula (2): (B) In formula (2), R １ is C １－３ alkyl, and the C １－３ The alkyl may be substituted with one or more fluorines, and R ５ is a hydrogen atom, and R ２ is a hydrogen atom, and R ３ is C １－６ Alkyl, C ３－１０ cycloalkyl, or a 4- to 12-membered saturated heterocyclic group, wherein the C １－６ The alkyl group may be selected from the group consisting of 1 to 3 of the same or different halogens, C ３－１０ Optionally substituted with cycloalkyl or 4-12 membered saturated heterocyclic group, ３－１０ The cycloalkyl or 4-12 membered saturated heterocyclic group may further include 1 to 3 oxo, C １－６ Alkyl, C １－６ Alkoxy, C １－６ may be substituted with alkylcarbonyl, or R ２ and R ３ are taken together to form a monocyclic, bicyclic, tricyclic or spirocyclic 4-12 membered saturated heterocyclic group, wherein the 4-12 membered saturated heterocyclic group each independently has 1 to 3 of the same or different halogen, oxo, hydroxyl, cyano, C１－６ Alkyl, C １－６ Alkoxy, Deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ may be substituted with an alkylthio group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ One or more hydrogen atoms in the alkoxy may be deuterium, and R ４ is an optionally substituted 5-10 membered heteroaryl, R ４ The substituents in the "optionally substituted 5-10 membered heteroaryl" selected from the group consisting of: １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, diC １－６ Alkylaminocarbonyl, C １－６ cycloalkyloxy, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and the compound wherein Q is N--H, or a pharmaceutically acceptable salt thereof.

[0094] One embodiment of the compound represented by formula (1) is the following (C), which has a structure of formula (2): (C) In formula (2), R１ is C １－３ alkyl, and the C １－３ The alkyl may be substituted with one or more fluorines, and R ５ is a hydrogen atom, and R ２ and R ３ are taken together to form a monocyclic, bicyclic, tricyclic or spirocyclic 4-12 membered saturated heterocyclic group, and the optionally substituted 4-12 membered saturated heterocyclic group has 1 to 3 identical or different substituents selected from the group consisting of halogen, oxo, hydroxyl group, cyano group, C １－６ Alkyl, C １－６ Alkoxy, Deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ is an alkylthio group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ One or more hydrogen atoms in the alkoxy may be deuterium, and R ４ is an optionally substituted 5-6 membered heteroaryl, R ４ The substituents in the "optionally substituted 5-6 membered heteroaryl" selected from the group consisting of: １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, diC １－６ alkylaminocarbonyl, or C １－６ cycloalkyloxy, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and the compound wherein Q is N--H, or a pharmaceutically acceptable salt thereof.

[0095] One embodiment of the compound represented by formula (1) is the following (D), which is a structure of formula (2): (D) In formula (2), R １ is C １－３ alkyl, and the C １－３ The alkyl may be substituted with one or more fluorines, and R ５ is a hydrogen atom, and R ２ and R ３ are taken together to form a monocyclic, bicyclic, tricyclic or spirocyclic 4-12 membered saturated heterocyclic group, and the optionally substituted 4-12 membered saturated heterocyclic group has 1 to 3 identical or different substituents selected from the group consisting of halogen, oxo, hydroxyl group, cyano group, C １－６ Alkyl, C １－６ Alkoxy, Deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ is an alkylthio group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ One or more hydrogen atoms in the alkoxy may be deuterium, and R ４ is an optionally substituted 5-membered nitrogen-containing heteroaryl or an optionally substituted pyridine, R ４ The substituents in the "optionally substituted 5-membered heteroaryl" or "optionally substituted pyridine" selected from the above are each independently a halogen, a cyano group, an amino group, a carbonyl group, C１－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, diC １－６ alkylaminocarbonyl, or C １－６ cycloalkyloxy, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and the compound wherein Q is N--H, or a pharmaceutically acceptable salt thereof.

[0096] One embodiment of the compound represented by formula (1) is the following (E), which has a structure of formula (3) or formula (4): (E) In formula (3) or formula (4), R １ is C １－３ alkyl, and the C １－３ The alkyl may be substituted with one or more fluorines, and R ５ is a hydrogen atom, and R ２ and R ３ together form an optionally substituted 4-12 membered saturated monocyclic, bicyclic, tricyclic or spirocyclic heterocyclic group, and the 4-12 membered saturated heterocyclic group is any one of the following (1a-1) to (1a-8) or (1a-10) to (1a-18): The 4- to 12-membered saturated heterocyclic group has 1 to 3 identical or different substituents, which may be halogen, oxo, hydroxyl, cyano, C １－６ Alkyl, C １－６ Alkoxy, C ６－１０ Aryl, 5-10 membered heteroaryl, deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ is an alkylthio group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ One or more hydrogen atoms in the alkoxy may be deuterium; U and V are each independently a nitrogen atom or CR ４Ｃ wherein at least one of U and V is a nitrogen atom; ４Ａ is a hydrogen atom, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｂ is a hydrogen atom, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６The alkoxy may be further substituted with one or more halogens, and R ４Ｃ represents a hydrogen atom, a halogen atom, a cyano group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｄ represents a hydrogen atom, a halogen atom, a cyano group, an amino group, a carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｅ , R ４Ｆ , R ４Ｇ are each independently a hydrogen atom, a halogen atom, a cyano group, an amino group, a carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC１－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogen atoms, and the compound wherein Q is N--H, or a pharmaceutically acceptable salt thereof.

[0097] One embodiment of the compound represented by formula (1) is the following (F), which has a structure of formula (3) or formula (4): (F) In formula (3) or formula (4), R １ is C １－３ alkyl, and the C １－３ The alkyl may be substituted with one or more fluorines, and R ５ is a hydrogen atom, and R ２ and R ３ together form a monocyclic, bicyclic, tricyclic or spirocyclic optionally substituted 4-12 membered saturated heterocyclic group, and the 4-12 membered saturated heterocyclic group is any one of the following (1a-1) to (1a-5) or (1a-7): The 4- to 12-membered saturated heterocyclic group has 1 to 3 identical or different substituents, which may be halogen, oxo, hydroxyl, cyano, C １－６ Alkyl, C １－６ Alkoxy, C ６－１０ Aryl, 5-10 membered heteroaryl, deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ is an alkylthio group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６One or more hydrogen atoms in the alkoxy may be deuterium; U and V are each independently a nitrogen atom or CR ４Ｃ wherein at least one of U and V is a nitrogen atom; ４Ａ is a hydrogen atom, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｂ is a hydrogen atom, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｃ represents a hydrogen atom, a halogen atom, a cyano group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｄ represents a hydrogen atom, a halogen atom, a cyano group, an amino group, a carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｅ , R ４Ｆ , R ４Ｇ are each independently a hydrogen atom, a halogen atom, a cyano group, an amino group, a carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６The alkoxy may be further substituted with one or more halogen atoms, and the compound wherein Q is N--H, or a pharmaceutically acceptable salt thereof.

[0098] One embodiment of the compound represented by formula (1) is the following (G), which has a structure of formula (3) or formula (4): (G) In formula (3) or formula (4), R １ is C １－３ alkyl, and the C １－３ The alkyl may be substituted with one or more fluorines, and R ５ is a hydrogen atom, and R ２ and R ３ together form a monocyclic, bicyclic, tricyclic or spirocyclic optionally substituted 4-12 membered saturated heterocyclic group, and the 4-12 membered saturated heterocyclic group is any one of the following (1a-1) to (1a-2) or (1a-4): The 4- to 12-membered saturated heterocyclic group has 1 to 3 identical or different substituents, which may be halogen, oxo, hydroxyl, cyano, C １－６ Alkyl, C １－６ Alkoxy, C ６－１０ Aryl, 5-10 membered heteroaryl, deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ is an alkylthio group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ One or more hydrogen atoms in the alkoxy may be deuterium; U and V are each independently a nitrogen atom or CR ４Ｃ wherein at least one of U and V is a nitrogen atom; ４Ａ is a hydrogen atom, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｂ is a hydrogen atom, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｃ represents a hydrogen atom, a halogen atom, a cyano group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６The alkoxy may be further substituted with one or more halogens, and R ４Ｄ represents a hydrogen atom, a halogen atom, a cyano group, an amino group, a carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｅ , R ４Ｆ , R ４Ｇ are each independently a hydrogen atom, a halogen atom, a cyano group, an amino group, a carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogen atoms, and the compound wherein Q is N--H, or a pharmaceutically acceptable salt thereof.

[0099] One embodiment of the compound represented by formula (1) is (H) below. (H) R １ is C １－３ alkyl, and the C １－３The alkyl may be substituted with one or more fluorines, and R ５ is a hydrogen atom, and R ２ and R ３ together form an optionally substituted 4-12 membered saturated monocyclic, bicyclic, tricyclic or spirocyclic heterocyclic group, and the 4-12 membered saturated heterocyclic group is any one of the following (1a-1) to (1a-4): The 4- to 12-membered saturated heterocyclic group has 1 to 3 identical or different substituents, which may be halogen, oxo, hydroxyl, cyano, C １－６ Alkyl, C １－６ Alkoxy, C ６－１０ Aryl, 5-10 membered heteroaryl, deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ is an alkylthio group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ One or more hydrogen atoms in the alkoxy may be deuterium, W and Z are nitrogen atoms, Y is CH, and X is CR ６ and the R ６ and R ４ Together, C ３－１０ cycloalkyl, or a 4- to 12-membered saturated heterocyclic group, wherein the C ３－１０ Cycloalkyl and the 4-12 membered saturated heterocyclic group include oxo, C １－６ Alkyl, C ３－１０ Cycloalkyl, C ６－１０ It may be substituted with an aryl, a 5-10 membered heteroaryl, or a 4-12 membered saturated heterocyclic group, among which C ３－１０ Cycloalkyl, C ６－１０ Substituents for cyclic structures such as aryl, 5-10 membered heteroaryl, or 4-12 membered saturated heterocyclic groups are R ４ and R６ Together they form C ３－１０ A compound which forms a fused ring structure or a spiro structure with a cycloalkyl or a 4-12 membered saturated heterocyclic group, and Q is N--H, or a pharmaceutically acceptable salt thereof.

[0100] "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. For example, acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, and organic acid salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, para-toluenesulfonate, and camphorsulfonate. Examples of base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, and aluminum salt, as well as organic base salts such as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, and N,N-dibenzylethylamine. Furthermore, examples of "pharmaceutically acceptable salts" include amino acid salts with basic or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, and glutamic acid.

[0101] Suitable salts of starting compounds and intermediates, and salts acceptable as pharmaceutical raw materials, are conventional non-toxic salts, including acid addition salts such as organic acid salts (e.g., acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate, para-toluenesulfonate, etc.) and inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.); salts with amino acids (e.g., arginine, aspartic acid, glutamic acid, etc.); metal salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) and alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.); ammonium salts; and organic base salts (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), which can be appropriately selected by those skilled in the art.

[0102] When it is desired to obtain a salt of the compound of the present invention, if the compound of the present invention is obtained in the form of a salt, it may be purified as is, or if it is obtained in the free form, it may be dissolved or suspended in an appropriate organic solvent, and an acid or a base may be added to form a salt by a conventional method.

[0103] In the present invention, one or more hydrogen atoms constituting the compound may be substituted with deuterium (D), and deuterium converters converted to these deuterium (D) atoms are also included in the compounds of the present invention.

[0104] The compounds of the present invention may exist in the form of hydrates and / or solvates with various solvents (such as ethanol solvates), and these hydrates and / or solvates are also included in the compounds of the present invention. Furthermore, the present invention also includes all tautomers, all existing stereoisomers, and all crystalline forms of the compounds of the present invention, as well as mixtures thereof.

[0105] The compounds of the present invention may exist in the form of optical isomers based on optically active centers, atropisomers based on axial or planar chirality resulting from restricted intramolecular rotation, other stereoisomers, tautomers, geometric isomers, and the like, and all possible isomers and mixtures thereof, including these, are included in the scope of the present invention.

[0106] In particular, optical isomers and atropisomers can be obtained as racemates, or as optically active isomers when optically active starting materials or intermediates are used. If necessary, at an appropriate stage in the production process described below, the racemates of the corresponding starting materials, intermediates, or final products can be physically or chemically resolved into their optical antipodes by known separation methods such as a method using an optically active column or fractional crystallization. Specifically, for example, in the diastereomeric method, two diastereomers are formed from a racemate by reaction with an optically active resolving agent. These different diastereomers generally have different physical properties and can be resolved by known methods such as fractional crystallization.

[0107] The methods for producing the compound of the present invention are described below, but the methods for producing the compound of the present invention are not limited to these. The compound of the present invention represented by formula (1) can be produced, for example, by the following Production Methods 1 to 3.

[0108] Production Method 1 Among the compounds represented by formula (1), compound a-13 can be produced, for example, by the following production method. (In the formula, R １ ~R ４ is the same as item 1)

[0109] The above aryl halide a-9 and amine compound a-12 can be prepared by the method described separately in the Examples or can be purchased as commercially available products.

[0110] [Step 1-1] Compound a-2 is produced by reacting compound a-1 with tert-butyldimethylchlorosilane in the presence of a suitable base in a suitable solvent, thereby producing a compound in which the alcohol is protected with a silyl group. The base used for alcohol protection is preferably triethylamine, sodium hydride, or imidazole, more preferably imidazole. The solvent used in the alcohol protection step is appropriately selected from the solvents exemplified below, and preferably dimethylformamide or tetrahydrofuran. The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually −78°C to 100°C, preferably −10°C to 40°C.

[0111] [Step 1-2] Compound a-3 is produced by reacting compound a-2 with an alkyl halide in the presence of an alkyl halide and a suitable base in a suitable solvent. The base used in the alkylation reaction is preferably lithium diisopropylamide or lithium hexamethyldisilazane, more preferably lithium diisopropylamide. The solvent used in the alkylation step is appropriately selected from the solvents exemplified below, and preferably diethyl ether or tetrahydrofuran. The reaction time is usually 5 minutes to 48 hours, preferably 5 minutes to 2 hours. The reaction temperature is usually −78°C to 100°C, preferably −78°C to 10°C.

[0112] [Step 1-3] Compound a-4 is produced by reducing the ester by reacting compound a-3 in the presence of a reducing agent in a suitable solvent. The reducing agent used in the reduction reaction is preferably lithium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride, more preferably sodium bis(2-methoxyethoxy)aluminum hydride. The solvent used in the ester reduction step is appropriately selected from the solvents exemplified below, and preferably includes diethyl ether or tetrahydrofuran. The reaction time is usually 5 minutes to 48 hours, preferably 5 minutes to 2 hours. The reaction temperature is usually −78°C to 100°C, preferably −10°C to 100°C.

[0113] [Step 1-4] Compound a-5 is produced by oxidizing the alcohol by reacting compound a-4 with an oxidizing agent and a base in a suitable solvent. The oxidizing agent used in the oxidation reaction is preferably pyridinium chlorochromate, sulfur trioxide pyridine complex, or oxalyl chloride, more preferably sulfur trioxide pyridine complex. The solvent used in the alcohol oxidation step is appropriately selected from the solvents exemplified below, and a mixed solvent of dimethyl sulfoxide and chloroform is preferred. The reaction time is usually 5 minutes to 48 hours, preferably 5 minutes to 2 hours. The reaction temperature is usually −78°C to 100°C, preferably −78°C to 30°C.

[0114] [Step 1-5] Compound a-6 is produced by reacting compound a-5 with 2,2-dimethyl-1,3-propanediol and an organic compound in a suitable solvent. The organic compound to be added is preferably trimethylchlorosilane or triisopropylchlorosilane, more preferably trimethylchlorosilane. The solvent used in this step is appropriately selected from the solvents exemplified below, and preferably diethyl ether or tetrahydrofuran. The reaction time is usually 5 minutes to 48 hours, preferably 30 minutes to 4 hours. The reaction temperature is usually −78°C to 100°C, preferably −10°C to 50°C.

[0115] [Step 1-6] Compound a-7 is produced by reacting compound a-6 with phthalimide, an organophosphorus reagent, and a Mitsunobu reagent in a suitable solvent. The organophosphorus reagent is preferably triphenylphosphine or tributylphosphine, more preferably tributylphosphine. Furthermore, the Mitsunobu reagent is preferably diethyl azodicarboxylate or diisopropyl azodicarboxylate, more preferably diisopropyl azodicarboxylate. The solvent used in this step is appropriately selected from the solvents exemplified below, and preferably diethyl ether or tetrahydrofuran. The reaction time is usually 5 minutes to 48 hours, preferably 30 minutes to 4 hours. The reaction temperature is usually −78°C to 100°C, preferably −10°C to 50°C.

[0116] [Step 1-8] Compound a-8 is produced by reacting compound a-7 with a base in a suitable solvent. A preferred example of the base is hydrazine hydrate. The solvent used in this step is appropriately selected from the solvents exemplified below, and a preferred example is a mixed solvent of ethanol and water. The reaction time is usually 5 minutes to 48 hours, preferably 30 minutes to 6 hours. The reaction temperature is usually −78° C. to 100° C., preferably 24° C. to 100° C.

[0117] [Step 1-9] Compound a-10 is produced by reacting compound a-8 with compound a-9 in the presence of a base in a suitable solvent. The base is preferably cesium carbonate, potassium carbonate, or N,N-diisopropylethylamine, more preferably potassium carbonate. The solvent used in this step is appropriately selected from the solvents exemplified below, and preferably dimethylformamide or N-methylpyrrolidone. The reaction time is usually 5 minutes to 48 hours, preferably 30 minutes to 6 hours. The reaction temperature is usually 50°C to 200°C, preferably 50°C to 160°C.

[0118] [Step 1-10] Compound a-11 is produced by reacting compound a-10 in the presence of an acid in a suitable solvent. The acid is preferably hydrochloric acid or formic acid, more preferably formic acid. The solvent used in this step is appropriately selected from the solvents exemplified below, and preferably acetone or water. The reaction time is usually 5 minutes to 48 hours, preferably 30 minutes to 6 hours. The reaction temperature is usually -78°C to 100°C, preferably 50°C to 100°C.

[0119] [Step 1-11] Compound a-13 is produced by reacting compound a-11 with compound a-12 in the presence of a reducing agent in a suitable solvent. The reducing agent is preferably sodium triacetoxyborohydride, formic acid, picoline borane, or sodium cyanoborohydride, more preferably picololine borane or formic acid. The solvent used in this step is appropriately selected from the solvents exemplified below, and preferably acetonitrile or tetrahydrofuran. The reaction time is usually 5 minutes to 48 hours, preferably 30 minutes to 6 hours. The reaction temperature is usually −78°C to 100°C, preferably −10°C to 100°C.

[0120] Production Method 2 Among the compounds represented by formula (1), compound b-5 can be produced, for example, by the following production method. (In the formula, R １ ~R ４ is the same as item 1)

[0121] The above b-4 is R ４ The boronic acid is a boronic acid consisting of the formula: and a boronic acid ester may also be used. The compounds described in the examples are commercially available.

[0122] The above steps 2-1, 2-2, and 2-3 are the same reactions as steps 1-8, 1-9, and 1-10 in Production Method 1, respectively. [Step 2-4] Compound b-5 is produced by reacting compound b-3 with compound b-4, a catalyst, and a base in a suitable solvent. Examples of the catalyst include transition metals such as palladium, nickel, rhodium, cobalt, and platinum, as well as salts thereof, complexes thereof, and carriers such as polymers. The base is preferably sodium carbonate, potassium carbonate, cesium carbonate, or cesium fluoride, more preferably potassium carbonate or sodium carbonate. The solvent used in this step is appropriately selected from the solvents exemplified below, and preferably includes dioxane, water, or dimethoxyethane. The reaction time is usually 5 minutes to 48 hours, preferably 5 minutes to 2 hours. The reaction temperature is usually −78° C. to 120° C., preferably 24° C. to 120° C.

[0123] Production Method 3 Among the compounds represented by formula (1), compound c-2 can be produced, for example, by the following production method. (In the formula, R １ ~R ４ is the same as item 1)

[0124] The above c-1 is a cyclic amine compound and can be purchased by the method described separately in the Examples or as a commercially available product. [Step 3-1] Compound c-2 is produced by reacting compound b-3 with compound c-1 in a suitable solvent in the presence of a base. The base is preferably triethylamine or diisopropylethylamine, more preferably diisopropylethylamine. The solvent used in this step is appropriately selected from the solvents exemplified below, and preferably N-methylpyrrolidone or dimethylacetamide. The reaction time is usually 5 minutes to 48 hours, preferably 30 minutes to 2 hours. The reaction temperature is usually 24°C to 250°C, preferably 100°C to 220°C.

[0125] The base used in each step of each of the above-mentioned production methods should be selected appropriately depending on the reaction, the types of raw material compounds, and the like. Examples of the base include alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali carbonates such as sodium carbonate and potassium carbonate, metal hydrides such as sodium hydride and potassium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as sodium methoxide and sodium t-butoxide, organometallic bases such as butyllithium and lithium diisopropylamide, and organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU).

[0126] The solvent used in each step of the above-mentioned production methods should be selected appropriately depending on the type of reaction and raw material compounds, etc., and examples thereof include alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ketone; halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as tetrahydrofuran (THF) and dioxane; aromatic hydrocarbons such as toluene and benzene; aliphatic hydrocarbons such as hexane and heptane; esters such as ethyl acetate and propyl acetate; amides such as N,N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide (DMSO); and nitriles such as acetonitrile. These solvents can be used alone or in combination. Depending on the type of reaction, organic bases can also be used as solvents.

[0127] The compound of the present invention represented by formula (1) or an intermediate thereof can be separated and purified by methods known to those skilled in the art. Examples of such methods include extraction, distribution, reprecipitation, column chromatography (e.g., silica gel column chromatography, ion exchange column chromatography, or preparative liquid chromatography), and recrystallization. Examples of recrystallization solvents that can be used include alcoholic solvents such as methanol, ethanol, or 2-propanol; etheric solvents such as diethyl ether; ester solvents such as ethyl acetate; aromatic hydrocarbon solvents such as benzene or toluene; ketone solvents such as acetone; halogenated solvents such as dichloromethane or chloroform; hydrocarbon solvents such as hexane; aprotic solvents such as dimethylformamide or acetonitrile; water; or a mixture of these solvents. Other purification methods include those described in Volume 1 of "Experimental Chemistry Lectures" (edited by the Chemical Society of Japan, Maruzen). The molecular structure of the compound of the present invention can be easily determined by spectroscopic techniques such as nuclear magnetic resonance, infrared absorption, and circular dichroism spectroscopy, as well as mass spectrometry, with reference to the structures derived from the respective starting compounds.

[0128] Furthermore, the intermediates or final products in the above production methods can be converted into other compounds included in the present invention by appropriately converting their functional groups, particularly by extending various side chains from amino, hydroxyl, carbonyl, halogen, etc., and by carrying out the above-mentioned protection and deprotection as necessary. The conversion of functional groups and extension of side chains can be carried out by common methods (see, for example, Comprehensive Organic Transformations, R.C. Larock, John Wiley & Sons Inc. (1999)).

[0129] The compound of the present invention represented by formula (1) or a pharmaceutically acceptable salt thereof may have asymmetry or a substituent having an asymmetric carbon, and such compounds may have optical isomers. The compounds of the present invention include mixtures or isolated isomers of these isomers, and can be produced by conventional methods. Examples of production methods include a method using a raw material having an asymmetric center or a method introducing asymmetry at an intermediate stage. For example, in the case of optical isomers, optical isomers can be obtained by using optically active raw materials or by performing optical resolution or the like at an appropriate stage in the production process. Examples of optical resolution methods include a diastereomeric method in which, when the compound represented by formula (1) or an intermediate thereof has a basic functional group, a salt is formed using an optically active acid (e.g., monocarboxylic acid such as mandelic acid, N-benzyloxyalanine, lactic acid, etc.; dicarboxylic acid such as tartaric acid, o-diisopropylidenetartaric acid, malic acid, etc.; sulfonic acid such as camphorsulfonic acid, bromocamphorsulfonic acid, etc.) in an inert solvent (e.g., alcoholic solvents such as methanol, ethanol, 2-propanol, etc.; ether solvents such as diethyl ether; ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, aprotic solvents such as acetonitrile, etc.). When the compound of the present invention represented by formula (1) or an intermediate thereof has an acidic functional group such as a carboxyl group, optical resolution can also be performed by forming a salt using an optically active amine (e.g., organic amines such as 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine, etc.).

[0130] The temperature for salt formation is selected from the range of −50°C to the boiling point of the solvent, preferably from the range of 0°C to the boiling point, and more preferably from room temperature to the boiling point of the solvent. To improve optical purity, it is desirable to first raise the temperature to near the boiling point of the solvent. When filtering out the precipitated salt, cooling can be performed as needed to improve the yield. The amount of optically active acid or amine used is preferably in the range of about 0.5 to about 2.0 equivalents relative to the substrate, preferably around 1 equivalent. If necessary, the crystals can be recrystallized in an inert solvent (e.g., alcoholic solvents such as methanol, ethanol, and 2-propanol; etheric solvents such as diethyl ether; ester solvents such as ethyl acetate; hydrocarbon solvents such as toluene; aprotic solvents such as acetonitrile; or a mixed solvent of two or more of the above solvents) to obtain a highly pure optically active salt. Furthermore, if necessary, the optically resolved salt can be treated with an acid or base by a conventional method to obtain a free form.

[0131] Of the raw materials and intermediates in each of the production methods explained above, those for which the production method is not particularly described are commercially available compounds or can be synthesized from commercially available compounds by methods known to those skilled in the art or methods similar thereto.

[0132] The compound of the present invention selectively binds to the muscarinic M4 receptor and exhibits antagonistic activity, and can therefore serve as a therapeutic and / or preventive agent for neurodegenerative diseases, brain injury diseases, psychological developmental disorders, psychiatric disorders, cognitive dysfunction associated with movement disorders, and peripheral symptoms and movement dysfunction associated with these diseases. Specifically, the compound may serve as a novel therapeutic and / or preventive agent for cognitive dysfunction associated with dementia (e.g., Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia), excessive daytime sleepiness (e.g., narcolepsy), cerebrovascular disorders (e.g., stroke, vascular dementia, cerebral small vessel disease), traumatic brain injury, attention deficit hyperactivity disorder, autism, Down's syndrome, schizophrenia, bipolar disorder, depression, Parkinson's disease, drug-induced parkinsonism, dystonia, Tourette's syndrome, dyskinesia, chorea (e.g., chorea associated with Huntington's disease), amyotrophic lateral sclerosis, cerebral palsy, progressive supranuclear palsy, multiple system atrophy, peripheral symptoms thereof (e.g., psychotic symptoms, agitation, depression, anxiety, anhedonia, apathy, sleep disorders, fatigue), and motor dysfunction (e.g., bradykinesia, tremor, rigidity, gait disturbance, and postural instability). The compounds of the present invention are also useful in treating diseases involving antagonism of muscarinic M4 receptors, such as dementia, Alzheimer's disease, dementia with Lewy bodies, prefrontal temporal dementia, narcolepsy, cerebrovascular disease, stroke, vascular dementia, cerebral small vessel disease, traumatic brain injury, attention deficit hyperactivity disorder, autism, Down's syndrome, schizophrenia, bipolar disorder, depression, Parkinson's disease, drug-induced parkinsonism, dystonia, Tourette's syndrome, dyskinesia, chorea, chorea associated with Huntington's disease, muscle spasms, and the like. The compound may serve as a novel therapeutic and / or preventive agent for amyotrophic lateral sclerosis, cerebral palsy, progressive supranuclear palsy, multiple system atrophy, substance use disorder, substance dependence, addictive behavior disorder, malignant neoplasm, tumor, cachexia, and cognitive dysfunction, behavioral symptoms, psychotic symptoms, agitation, depression, anxiety, anhedonia, apathy, lethargy, loss of motivation, impaired motivation, emotional blunting, autism, excessive daytime sleepiness, sleep disorders, fatigue, motor dysfunction, hypokinesia, tremor, rigidity, gait disturbance, postural instability, etc. In the present invention, "prevention" refers to the act of administering the active ingredient of the present invention to healthy individuals who have not developed a disease, for the purpose of preventing the onset of a disease, for example."Treatment" refers to the act of administering the active ingredient of the present invention to a person (patient) who has been diagnosed by a doctor as having developed a disease.

[0133] The compound of the present invention may be administered orally, parenterally, or rectally, and the daily dosage varies depending on the type of compound, the administration method, the symptoms and age of the patient, etc. For example, in the case of oral administration, typically about 0.01 to 1000 mg, preferably about 0.1 to 500 mg, per kg body weight of a human or mammal can be administered once or in divided doses. In the case of parenteral administration such as intravenous injection, typically about 0.01 mg to 300 mg, preferably about 1 mg to 100 mg, per kg body weight of a human or mammal can be administered.

[0134] The compounds of the present invention can be administered orally or parenterally, either directly or after formulation using an appropriate dosage form. Examples of dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices. The formulations are prepared by known methods using pharmaceutically acceptable additives. Depending on the purpose, additives that can be used include excipients, disintegrants, binders, flow agents, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners, and flavors. Specific examples of additives include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.

[0135] The compound of the present invention is useful as a therapeutic agent for Alzheimer's disease, a drug for preventing the progression of mild cognitive impairment and mild cognitive impairment due to Alzheimer's disease, a therapeutic agent for multiple sclerosis, a therapeutic agent for amyotrophic lateral sclerosis, a therapeutic agent for spinal muscular atrophy, a therapeutic agent for spinocerebellar degeneration, a therapeutic agent for myoclonus, a therapeutic agent for restless legs, a therapeutic agent for chorea associated with Huntington's disease, a typical antipsychotic, an antipsychotic, an atypical antipsychotic, an antidepressant, a mood stabilizer, a psychostimulant, a therapeutic agent for Parkinson's disease, a It can be used in combination with vodopa preparations, dopamine receptor agonists, monoamine oxidase B inhibitors, dopamine release promoters, noradrenergic agonists, levodopa potentiators, adenosine A2A receptor inhibitors, cerebral circulation improvers, anti-anxiety drugs, hypnotics / sedatives, benzodiazepine receptor agonists, melatonin receptor agonists, orexin receptor antagonists, autonomic nervous system agonists, lifestyle improvement drugs, anticancer drugs, antihypertensive drugs, calcium channel blockers, beta-blockers, antiarrhythmic drugs, and antithrombotic drugs.

[0136] The present invention will be explained in more detail below with reference to the following examples and experimental examples, but the present invention is not limited thereto. The compound names shown in the following examples and experimental examples do not necessarily conform to the IUPAC nomenclature.

[0137] To simplify the description in the specification, the following abbreviations may be used in the Reference Examples, Examples, and Tables in the Examples. Abbreviations used as substituents include Me for methyl and Ph for phenyl. TFA for trifluoroacetic acid. Symbols used in NMR include J for coupling constant, s for singlet, d for doublet, t for triplet, q for quartet, quint for quintet, sep for septet, m for multiplet, and br for broad singlet or multiplet. Combinations of these, for example, dd for a double doublet, td for a triple doublet, br s for a broad singlet, and br m for a broad multiplet.

[0138] In addition, the following abbreviations may be used in this specification: CbzCl: benzyl chloroformate CDCl ３: deuterated chloroform CPME: cyclopentyl methyl ether DBU: 1,8-diazabicyclo[5.4.0]-7-undecene DIBAL: diisobutylaluminum hydride DIPEA: diisopropylethylamine DMAP: 4-dimethylaminopyridine DME: 1,2-dimethoxyethane DMEAD: bis(2-methoxyethyl) azodicarboxylate DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HPLC: high performance liquid chromatography LTBA: lithium tri-tert-butoxyaluminum hydride MTBE: methyl tert-butyl ether NMP: N-methylpyrrolidone PyBOP: 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate TCFH: chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate TEA: triethylamine TFA: trifluoroacetic acid THF: tetrahydrofuran TMSCl: trimethylsilyl chloride TPTU: O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate

[0139] The measurement conditions for the high-performance liquid chromatograph mass spectrometer (LCMS) are as follows. The observed mass spectrometry value [MS (m / z)] is indicated as MH+, and the retention time is indicated as Rt (min). For each measured value, the measurement conditions used for the measurement are indicated by A, B, C, or D.

[0140] Measurement condition A Detection equipment: ACQUITY TM SQ detector (Waters) HPLC: ACQUITY TM UPLC system column: Waters ACQUITY TMUPLC BEH C18 (1.7 μm, 2.1 mm × 30 mm) Solution A: 0.06% formic acid / H2O, Solution B: 0.06% formic acid / MeCN Gradient condition: 0.0–1.3 min linear gradient from 2% to 96% B Flow rate: 0.8 mL / min UV: 220 nm and 254 nm Column temperature: 40°C

[0141] Measurement condition B Detector: Shimadzu LCMS-2020 Column: Phenomenex TM Kinetex TM (1.7μm C18, 50 mm×2.10 mm) Solvent: A solution: MeCN, B solution: 0.05% TFA / H2O Gradient Condition: 0.0 min; A / B = 10:90 0.0-1.9 min; A / B = 99:1 1.9-3.0 min; A / B = 10:90 Flow rate: 0.5 mL / min ΜV: 220 nm Column temperature: 40℃

[0142] Measurement condition C Detection equipment: ACQUITY TM SQ detector (Waters) HPLC: ACQUITY TM UPLC system column: Waters ACQUITY TM UPLC BEH C18 (1.7 μm, 2.1 mm × 30 mm) Solution A: 0.06% formic acid / H2O, Solution B: 0.06% formic acid / MeCN Gradient conditions: 0.0–0.8 min linear gradient from 2% B to 96%, 0.8–1.3 min isocratic B 2% Flow rate: 0.8 mL / min UV: 220 nm and 254 nm Column temperature: 40°C

[0143] Measurement condition D Detection equipment: ACQUITY TM SQ detector (Waters) HPLC: ACQUITY TMUPLC system Column: Xbridge C18, 3.5 μm, 4.6 × 50 mm Solution A: 10 mM NH4HCO3 / H2O, Solution B: MeCN Gradient conditions: 5% increase to 95% B within 1.3 min, 95% B for 1.7 min Flow rate: 1.7 mL / min UV: 220 nm and 254 nm Column temperature: 50°C

[0144] Reference Example α-3 3-chloro-6-(2-chloro-5-fluorophenyl)pyridazine a) Preparation of 3-chloro-6-(2-chloro-5-fluorophenyl)pyridazine (Reference Example α-3) 3-Chloro-6-iodopyridazine (8.3 g), (2-chloro-5-fluorophenyl)boronic acid (5 g), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (1 g), and potassium carbonate (11.9 g) were dissolved in dimethoxyethane (70 mL) and water (23 mL) and heated at 80°C for 3 hours. After cooling, water was added, and the resulting reaction solution was subjected to separation and extraction with ethyl acetate and water. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to give Reference Example α-3 (4.8 g). 1 H-NMR (CDCl3) δ: 7.15 (1H, dq, J = 9.9, 2.9 Hz), 7.46-7.49 (2H, m), 7.58 (1H, d, J = 9.1 Hz), 7.87 (1H, d, J = 8.5 Hz).

[0145] Example A-3 6-(2-chloro-5-fluorophenyl)-N-((1r,4r)-4-(((3,3-dimethylbutyl)(methyl)amino)methyl)-4-methylcyclohexyl)pyridazin-3-amine

[0146] a) Preparation of tert-butyl ((4-amino-1-methylcyclohexyl)methyl)carbamate (Reference Example α-5) tert-butyl (1-methyl-4-oxocyclohexyl)methylcarbamate (250 mg), palladium carbide 5% (66 mg), and ammonium formate (229 mg) were added and heated at 50°C for 3 hours. After cooling, the mixture was filtered through Celite, and the solvent was evaporated under reduced pressure to obtain a crude product. The obtained tert-butyl ((4-amino-1-methylcyclohexyl)methyl)carbamate was used directly in the next step. LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 243 / 1.383 / B

[0147] b) Preparation of tert-butyl (((1r,4r)-4-((6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)amino)-1-methylcyclohexyl)methyl)carbamate (Reference Example α-7) 3-Chloro-6-(2-chloro-5-fluorophenyl)pyridazine (125 mg), tert-butyl ((4-amino-1-methylcyclohexyl)methyl)carbamate (250 mg) and N,N-diisopropylethylamine (533 mg) were dissolved in butanol (5 mL) and heated at 170°C for 2 hours under microwave irradiation. Water was added, and the resulting reaction solution was subjected to liquid separation and extraction with ethyl acetate and water. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give tert-butyl (((1r,4r)-4-((6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)amino)-1-methylcyclohexyl)methyl)carbamate (39 mg) and tert-butyl (((1s,4s)-4-((6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)amino)-1-methylcyclohexyl)methyl)carbamate (32 mg). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 449 / 1.793 / B LC-MS: [M+H]+ / Rt (min) / measurement conditions: 449 / 1.781 / B

[0148] c) Preparation of 6-(2-chloro-5-fluorophenyl)-N-((1r,4r)-4-(((3,3-dimethylbutyl)amino)methyl)-4-methylcyclohexyl)pyridazin-3-amine (Example A-2) tert-Butyl (((1r,4r)-4-((6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)amino)-1-methylcyclohexyl)methyl)carbamate (39 mg) was dissolved in TFA (0.5 mL) and chloroform (0.5 mL) and stirred for 1 hour. The solvent was evaporated under reduced pressure, and then 3,3-dimethylbutanal (11 mg) and magnesium sulfate (52 mg) were added to the resulting residue, which was then dissolved in methanol (2 mL). After stirring for 50 hours at room temperature, the mixture was cooled to 0°C and sodium borohydride (3 mg) was added. Water was added, and the resulting reaction solution was subjected to liquid separation and extraction with ethyl acetate-water. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by aminosilica gel column chromatography (elution solvent: hexane / ethyl acetate) to give 6-(2-chloro-5-fluorophenyl)-N-((1r,4r)-4-(((3,3-dimethylbutyl)amino)methyl)-4-methylcyclohexyl)pyridazin-3-amine (35 mg). 1 H-NMR (CDCl3) δ: 0.89 (9H, s), 0.97 (3H, s), 1.36-1.49 (9H, m), 1.99 (2H, dd, J = 9.1, 3.7 Hz), 2.39 (2H, s), 2.56-2.60 (2H, m), 3.70 (1H, s), 4.82 (1H, d, J = 7.9 Hz), 6.62 (1H, d, J = 9.1 Hz), 6.99-7.04 (1H, m), 7.38 (1H, dd, J = 8.8, 5.2 Hz), 7.47 (1H, dd, J = 9.1, 3.0 Hz), 7.58 (1H, d, J = 9.1 Hz).

[0149] d) Preparation of 6-(2-chloro-5-fluorophenyl)-N-((1r,4r)-4-(((3,3-dimethylbutyl)(methyl)amino)methyl)-4-methylcyclohexyl)pyridazin-3-amine (Example A-3) 6-(2-chloro-5-fluorophenyl)-N-((1r,4r)-4-(((3,3-dimethylbutyl)amino)methyl)-4-methylcyclohexyl)pyridazin-3-amine (25 mg) and formaldehyde (3 mg) were dissolved in chloroform (1 mL), and sodium triacetoxyborohydride (24 mg) was added. After stirring for 16 hours, water was added, and the resulting reaction solution was subjected to liquid separation and extraction with ethyl acetate and water. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give 6-(2-chloro-5-fluorophenyl)-N-((1r,4r)-4-(((3,3-dimethylbutyl)(methyl)amino)methyl)-4-methylcyclohexyl)pyridazin-3-amine (22 mg). 1 H-NMR (CDCl3) δ: 0.87 (9H, s), 0.91 (3H, d, J = 7.3 Hz), 1.32-1.46 (8H, m), 1.99 (2H, d, J = 4.9 Hz), 2.11 (2H, s), 2.27 (3H, s), 2.36-2.40 (2H, m), 3.64 (1H, s), 4.81 (1H, d, J = 7.9 Hz), 6.63 (1H, d, J = 9.1 Hz), 7.02 (1H, td, J = 6.5, 3.0 Hz), 7.38 (1H, dd, J = 8.5, 4.9 Hz), 7.47 (1H, dd, J = 9.1, 3.0 Hz), 7.58 (1H, d, J = 9.1 Hz).

[0150] Reference Example α-16 N-[(1r,4r)-4-(aminomethyl)-4-methylcyclohexyl]-6-(4,4-difluoropiperidin-1-yl)-5-methyl-1,2,4-triazin-3-amine

[0151] a) Preparation of 2-[(4-{[tert-butyl(dimethyl)silyl]oxy}-1-methylcyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione (Reference Example α-9) A solution of DMEAD (59.6 g) in THF (326 mL) was added dropwise at 0°C to a solution of (4-{[tert-butyl(dimethyl)silyl]oxy}-1-methylcyclohexyl)methanol (55 g), phthalimide (43.2 g), and triphenylphosphine (66.8 g) in THF (653 mL), and the mixture was stirred for 1 hour and then at room temperature overnight. After completion of the reaction, the reaction solution was washed with hexane / water and the resulting organic layer was dried over sodium sulfate. After distilling off the solvent, a hexane / toluene (3:1) mixture (220 mL) was added to the residue to form a suspension, which was stirred at room temperature for 1 hour. The precipitate was then filtered off, and the filtrate was concentrated to give the crude product of Reference Example α-9 (85 g). This was used in the next step without further purification. LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 388 / 1.091 / C

[0152] b) Preparation of 2-[(4-hydroxy-1-methylcyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione (Reference Example α-10) To a solution of the crude product (85 g) of 2-[(4-{[tert-butyl(dimethyl)silyl]oxy}-1-methylcyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione in ethanol (850 mL) was added 3N aqueous hydrochloric acid (340 mL) at 0°C, and the mixture was then returned to room temperature and stirred for 2 hours. After completion of the reaction, the solution was concentrated and diluted with chloroform (425 mL), and then neutralized by gradually adding saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to give Reference Example α-10 (41.89 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 274 / 0.825 / A

[0153] c) Preparation of 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4-methylcyclohexyl methanesulfonate (Reference Example α-11) To a solution of 2-[(4-hydroxy-1-methylcyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione (34.1 g) and DIPEA (43.6 mL) in chloroform (416 mL) was added dropwise at 0°C, and the mixture was stirred for 1 hour. After completion of the reaction, the reaction solution was separated and washed with hexane / water, and the resulting organic layer was washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate. After distilling off the solvent, a hexane / toluene (1:2) mixture (220 mL) was added to the residue to form a suspension. The suspension was stirred at room temperature for 1 hour, and the precipitate was collected by filtration to obtain the crude product of Reference Example α-11 (38.3 g). This was used in the next step without further purification. LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 352 / 0.944 / A

[0154] d) Preparation of 2-{[(1r,4r)-4-azido-1-methylcyclohexyl]methyl}-1H-isoindole-1,3(2H)-dione (Reference Example α-12) NaN ３ To a suspension of (17.71 g) of 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4-methylcyclohexyl methanesulfonate in DMF (182 mL) was added a solution of the crude product (38.3 g) of 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4-methylcyclohexyl methanesulfonate in DMF (182 mL) at room temperature, and the mixture was heated to 70°C and stirred for 5 hours. After completion of the reaction, the reaction solution was separated and washed with toluene / saturated aqueous sodium bicarbonate, and the resulting organic layer was dried over sodium sulfate. After distilling off the solvent, methanol (90 mL) was added to the residue to form a suspension. After stirring at room temperature for 1 hour, the precipitate was collected by filtration to obtain Reference Example α-12 (25.95 g). This product was used in the next step without further purification. LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 299 / 0.858 / C

[0155] e) Preparation of 2-{[(1r,4r)-4-amino-1-methylcyclohexyl]methyl}-1H-isoindole-1,3(2H)-dione (Reference Example α-13) A solution of 2-{[(1r,4r)-4-azido-1-methylcyclohexyl]methyl}-1H-isoindole-1,3(2H)-dione (25.95 g) in THF (217 mL) was added dropwise to a mixture of 20 wt % palladium hydroxide / carbon (12.21 g) in MeOH (217 mL) at 0°C, followed by slow addition of ammonium formate (27.4 g), and the mixture was allowed to warm to room temperature and stirred for 2 hours. After filtration through Celite, the solvent was evaporated, and the resulting residue was diluted with a mixture of ethyl acetate / chloroform (1:1) and washed with saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off. The residue obtained was purified by aminosilica gel column chromatography (elution solvent: chloroform) to obtain Reference Example α-13 (23.6 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 273 / 0.670 / A

[0156] f) Preparation of 2-({(1r,4r)-4-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]-1-methylcyclohexyl}methyl)-1H-isoindole-1,3(2H)-dione (Reference Example α-14) Tripotassium phosphate and 3,6-dichloro-5-methyl-1,2,4-triazine (120 mg) were added to a solution of 2-{[(1r,4r)-4-amino-1-methylcyclohexyl]methyl}-1H-isoindole-1,3(2H)-dione (100 mg) in acetonitrile (0.70 mL), and the mixture was stirred at room temperature for 2 hours. After filtration through Celite, the solvent was evaporated to give 2-({(1r,4r)-4-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]-1-methylcyclohexyl}methyl)-1H-isoindole-1,3(2H)-dione (129 mg). 1H-NMR (400 MHz, CDCl3): 1.04 (3H, s), 1.36-1.54 (6H, m), 1.96-2.02 (2H, m), 2.44 (3H, s), 3.55 (2H, s), 3.77 (1H, br s), 5.13 (1H, br s), 7.73 (2H, dd, J = 5.5, 3.0 Hz), 7.86 (2H, dd, J = 5.2, 2.7 Hz).

[0157] g) Preparation of 2-{[(1r,4r)-4-{[6-(4,4-difluoropiperidin-1-yl)-5-methyl-1,2,4-triazin-3-yl]amino}-1-methylcyclohexyl]methyl}-1H-isoindole-1,3(2H)-dione (Reference Example α-15) A reaction solution of H-isoindole-1,3(2H)-dione (172 mg), 4,4-difluoropiperidine (130 mg), tripotassium phosphate (274 mg), and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (36 mg) in dimethoxyethane (0.43 mL) was stirred at 80°C under a nitrogen atmosphere for 5 hours. After completion of the reaction, the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example α-15 (47 mg). 1 H-NMR (400 MHz, CDCl3): 1.03 (3H, s), 1.34-1.45 (2H, m), 1.49-1.53 ​​(4H, m), 1.99-2.04 (2H, m), 2.07-2.17 (4H, m), 2.37 (3H, s), 3.23-3.27 (4H, m), 3.54 (2H, s), 3.77 (1H, br s), 4.76 (1H, d, J = 7.9 Hz), 7.73 (2H, dd, J = 5.5, 3.0 Hz), 7.86 (2H, dd, J = 5.5, 3.0 Hz).

[0158] h) Preparation of N-[(1r,4r)-4-(aminomethyl)-4-methylcyclohexyl]-6-(4,4-difluoropiperidin-1-yl)-5-methyl-1,2,4-triazin-3-amine (Reference Example α-16) Hydrazine monohydrate (23 μL) was added to a solution of Reference Example α-15 (46 mg) in ethanol (1.4 mL) and water (0.48 mL), and the mixture was stirred at 80° C. for 5 hours. The reaction solution was returned to room temperature, and a 5 wt % aqueous sodium hydroxide solution was added. After extraction with chloroform, the organic layer was dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give Reference Example α-16 (26 mg). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 355 / 0.684 / A

[0159] In Examples A-1 to A-17, A-19, and A-21 to A-46, the corresponding starting compounds were treated in the same manner as in Example A-3 to obtain the compounds. The corresponding starting compounds were purchased as commercially available products or were treated in the same manner as in the separately described Reference Examples to obtain the compounds. In Example A-18, the corresponding starting compounds were treated in the same manner as in Examples A-3 and α-16 to obtain the compound shown in the table below.

[0160] Example B-216 N-((1r,4r)-4-((1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl)-4-methylcyclohexyl)-6-(2-cyclopropylpyridin-3-yl)pyridazin-3-amine

[0161] a) Preparation of ethyl (1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carboxylate (Reference Example β-2) Ethyl trans-4-hydroxycyclohexanecarboxylate (55 g) was dissolved in DMF (79 mL), and tert-butyldimethylchlorosilane (100 g) and imidazole (47 g) were added while maintaining the temperature at 20°C or below. The mixture was stirred at 0°C for 30 minutes and then at room temperature for 16 hours. Water was added, and the resulting reaction solution was subjected to liquid separation and extraction with hexane-water. The organic layer was washed with saturated saline and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give ethyl (1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carboxylate (127 g, 71 wt% pure). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 287 / 0.208 / A

[0162] b) Preparation of ethyl (1s,4s)-4-((tert-butyldimethylsilyl)oxy)-1-methylcyclohexane-1-carboxylate (Reference Example β-3) A hexane solution of lithium diisopropylamide (95 mL, 1.1 M) was added to THF (53 mL) at −78° C. Ethyl (1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carboxylate (55 g) dissolved in THF (53 mL) was added dropwise while maintaining the temperature below −60° C. After stirring for 1 hour, methyl iodide (16 m) in THF (16 mL) was added dropwise and the mixture was stirred for 2 hours. Water was added, and the resulting reaction solution was subjected to liquid separation and extraction with toluene and water. The organic layer was washed with saturated brine and then dried over sodium sulfate. After the solvent was distilled off under reduced pressure, ethyl (1s,4s)-4-((tert-butyldimethylsilyl)oxy)-1-methylcyclohexane-1-carboxylate (18 g, 86 wt % pure) was obtained. LC-MS: [M+H]+ / Rt (min) / measurement conditions: 340 / 1.089 / A

[0163] c) Preparation of ((1s,4s)-4-((tert-butyldimethylsilyl)oxy)-1-methylcyclohexyl)methanol (Reference Example β-4) THF (50 mL) was added to sodium bis(2-methoxyethoxy)aluminum hydride (24 g), and ethyl (1s,4s)-4-((tert-butyldimethylsilyl)oxy)-1-methylcyclohexane-1-carboxylate (18 g) dissolved in THF (50 mL) was added dropwise at 0°C. The mixture was stirred for 1 hour at 0°C and then for 1 hour at room temperature. A 30 wt % aqueous solution of Rochelle salt was added, and the resulting reaction solution was subjected to liquid separation and extraction with toluene and water. The organic layer was washed with saturated saline and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give ((1s,4s)-4-((tert-butyldimethylsilyl)oxy)-1-methylcyclohexyl)methanol (14 g, 97 wt % pure). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 259 / 0.983 / A

[0164] d) Preparation of (1s,4s)-4-((tert-butyldimethylsilyl)oxy)-1-methylcyclohexane-1-carbaldehyde (Reference Example β-5) ((1s,4s)-4-((tert-butyldimethylsilyl)oxy)-1-methylcyclohexyl)methanol (80 g) and triethylamine (216 mL) were dissolved in chloroform (413 mL) and DMSO (207 mL). Sulfur trioxide-pyridine complex (200 g) was added in five portions while maintaining the temperature at 15°C or below. After stirring for 2 hours at 0°C, water was added and the resulting reaction solution was subjected to liquid separation and extraction with toluene-water. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give (1s,4s)-4-((tert-butyldimethylsilyl)oxy)-1-methylcyclohexane-1-carbaldehyde (77 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 257 / 1.421 / A

[0165] e) Preparation of (1s,4s)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexane-1-ol (Reference Example β-6) (1s,4s)-4-((tert-butyldimethylsilyl)oxy)-1-methylcyclohexane-1-carbaldehyde (1.1 g) and 2,2-dimethyl-1,3-propanediol (1.34 g) were dissolved in THF (8.6 mL), and trimethylchlorosilane (0.16 mL) was added at 0°C. After stirring for 2 hours, a water:methanol=1:1 solution (9 mL) was added and the mixture was stirred for 2.5 hours. Water was added, and the resulting reaction solution was subjected to liquid separation and extraction with toluene-water. The organic layer was washed with saturated brine and then dried over sodium sulfate. After the solvent was distilled off under reduced pressure, (1s,4s)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexan-1-ol (0.95 g) was obtained. 1 H-NMR (CDCl3) δ: 0.60 (3H, s), 0.82 (2H, d, J = 2.4 Hz), 0.84 (3H, d, J = 6.1 Hz), 1.07 (5H, td, J = 7.1, 4.9 Hz), 1.29-1.40 (3H, m), 1.41-1.48 (2H, m), 1.61 (2H, dq, J = 17.4, 4.3 Hz), 1.69-1.76 (2H, m), 3.29 (2H, t, J = 5.2 Hz), 3.51 (2H, dd, J = 6.4, 4.6 Hz), 3.70 (1H, dd, J = 7.0, 3.4 Hz), 4.18 (1H, s).

[0166] f) Preparation of 2-((1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl)isoindoline-1,3-dione (Reference Example β-7) Tributylphosphine (1.5 mL), phthalimide (0.9 g), and (1s,4s)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexan-1-ol (0.8 g) were dissolved in THF (6 mL). A solution of diisopropyl azodicarboxylate (1.24 g) in THF (6 mL) was added dropwise at 0°C, and the mixture was stirred at 0°C for 1 hour. After stirring at room temperature for 16 hours, water was added, and the resulting reaction solution was subjected to liquid separation and extraction with toluene and water. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure. The resulting solid was dissolved in methanol (22 mL) and stirred at room temperature for 3 hours. The resulting solid was collected by filtration using a Kiriyama funnel to give 2-((1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl)isoindoline-1,3-dione (0.57 g). 1 H-NMR (CDCl3) δ: 0.72 (3H, t, J = 7.9 Hz), 1.15 (6H, d, J = 15.2 Hz), 1.55 (9H, ddd), 2.42 (2H, ddd), 3.40 (2H, d, J = 11.0 Hz), 3.61 (2H, d, J = 11.0 Hz), 3.99 (1H, s), 4.09 (1H, tt, J = 12.5, 4.0 Hz), 7.69 (2H, td, J = 5.6, 3.5 Hz), 7.80 (2H, td, J = 5.3, 3.3 Hz).

[0167] g) Preparation of (1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexan-1-amine (Reference Example β-8) Ethanol (13 mL) and water (4.3 mL) were added to 2-((1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl)isoindoline-1,3-dione (1.24 g) and hydrazine hydrate (0.84 mL), and the mixture was heated at 80°C for 3 hours. A 10% wt aqueous solution of sodium hydroxide was added, and the resulting reaction solution was subjected to liquid separation and extraction with chloroform and water. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give (1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexan-1-amine (0.89 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 228 / 0.592 / A

[0168] h) Preparation of 6-chloro-N-((1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl)pyridazin-3-amine (Reference Example β-9) (1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl-1-amine (350 mg), 3,6-dichloropyridazine (413 mg), and potassium carbonate (532 mg) were dissolved in DMF (1.5 mL) and heated at 130°C for 2.5 hours. Aqueous sodium hydroxide solution was added, and the resulting reaction solution was subjected to liquid separation and extraction with chloroform and water. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to give 6-chloro-N-((1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl)pyridazin-3-amine (522 mg). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 340 / 1.022 / A

[0169] i) Preparation of 6-(2-cyclopropylpyridin-3-yl)-N-((1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl)pyridazin-3-amine (Reference Example β-10) Water (4 mL) and THF (13 mL) were added to 2-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.7 g), 6-chloro-N-((1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl)pyridazin-3-amine (1.2 g), (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.193 g), and cesium carbonate (3.45 g), and the mixture was heated at 75°C for 3 hours. After filtration through Celite and distilling off the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol) to give 6-(2-cyclopropylpyridin-3-yl)-N-((1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl)pyridazin-3-amine (1.1 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 212 / 0.614 / A

[0170] j) Preparation of (1r,4r)-4-((6-(2-cyclopropylpyridin-3-yl)pyridazin-3-yl)amino)-1-methylcyclohexane-1-carbaldehyde (Reference Example β-11) 6-(2-Cyclopropylpyridin-3-yl)-N-((1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl)pyridazin-3-amine (1.1 g) was dissolved in acetone (6 mL), formic acid (6 mL), and water (1.2 mL), and the mixture was heated at 75° C. for 15 hours. 1 M aqueous sodium hydroxide solution was added to the resulting reaction solution, which was then subjected to liquid separation and extraction with chloroform and water. The organic layer was washed with saturated saline, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol) to give (1r,4r)-4-((6-(2-cyclopropylpyridin-3-yl)pyridazin-3-yl)amino)-1-methylcyclohexane-1-carbaldehyde (820 mg). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 337 / 1.242 / B

[0171] k) Preparation of N-((1r,4r)-4-((1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl)-4-methylcyclohexyl)-6-(2-cyclopropylpyridin-3-yl)pyridazin-3-amine (Example B-216) Acetonitrile (0.5 mL) was added to (1r,4r)-4-((6-(2-cyclopropylpyridin-3-yl)pyridazin-3-yl)amino)-1-methylcyclohexane-1-carbaldehyde (30 mg), 1,4-dioxa-9-azaspiro[5.5]undecane hydrochloride (35 mg), sodium formate (22 mg), trimethyl orthoformate (24 mg), and formic acid (25 mg), and the mixture was heated at 85° C. for 2 hours. The resulting reaction solution to which aqueous solution was added was subjected to liquid separation and extraction with ethyl acetate and water. The organic layer was washed with saturated brine, and the resulting residue was then purified by amino silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give N-((1r,4r)-4-((1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl)-4-methylcyclohexyl)-6-(2-cyclopropylpyridin-3-yl)pyridazin-3-amine (25 mg).1 H-NMR (CDCl3) δ: 0.89-0.94 (5H, m), 1.15-1.20 (2H, m), 1.33-1.61 (8H, m), 1.81-1.88 (2H, m), 1.96-2.04 (2H, m), 2.09-2.17 (3H, m), 2.44-2.50 (2H, m), 2.53-2.59 (2H, m), 3.46 (2H, s), 3.63-3.75 (5H, m), 4.77 (1H, d, J = 7.9 Hz), 6.68 (1H, d, J = 9.2 Hz), 7.13 (1H, dd, J = 7.3, 4.9 Hz), 7.45 (1H, d, J = 9.2 Hz), 7.75 (1H, dd, J = 7.3, 1.8 Hz), 8.47 (1H, dd, J = 4.9, 1.8 Hz).

[0172] Reference Example β-13 3-chloro-6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)pyridazine To a solution of cyclopropanecarboxylic acid (0.30 g), ethanimidamide hydrochloride (0.49 g), and DIPEA (2.74 mL) in DMF (11.6 mL) was added HATU (1.46 g) at room temperature and stirred overnight. 3-Chloro-6-hydrazinylpyridazine (0.76 g) was added to the reaction solution, followed by acetic acid (2.00 mL), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was separated and washed with toluene and saturated brine. The resulting organic layer was separated and washed with saturated aqueous sodium bicarbonate solution and then dried over sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to give 3-chloro-6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)pyridazine (0.21 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 236 / 0.709 / A

[0173] Reference Example β-14 3-chloro-6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)pyridazine Concentrated hydrochloric acid (11.4 mol / L, 0.42 mL) was added to a solution of 1-cyclopropylbutane-1,3-dione (1.75 g) and 3-chloro-6-hydrazinopyridazine (2.00 g) in ethanol (28 mL), and the mixture was stirred at 75°C for 5 hours. After completion of the reaction, chloroform was added to the reaction solution, which was then washed with water and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (elution solvent: hexane:ethyl acetate) to give 3-chloro-6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)pyridazine (2.46 g). 1 H-NMR (400 MHz, CDCl3): 0.64-0.68 (2H, m), 1.00-1.05 (2H, m), 2.25 (3H, s), 2.79-2.86 (1H, m), 5.84 (1H, s), 7.55 (1H, d, J = 9.1 Hz), 8.10 (1H, d, J = 9.1 Hz).

[0174] Reference Example β-16 3-chloro-6-(2-cyclopropyl-4-ethyl-1H-imidazol-1-yl)pyridazine

[0175] a) Preparation of 2-cyclopropyl-4-ethyl-1H-imidazole (Reference Example β-15) Cyclopropanecarboxamidine hydrochloride (3.00 g) and potassium carbonate (6.88 g) were suspended in a mixed solvent of tetrahydrofuran (58.2 mL) and water (8.32 mL) at room temperature, and the mixture was stirred at 70°C for 5 minutes. A solution of 1-bromo-butan-2-one (1.49 mL) in tetrahydrofuran (25.2 mL) was added dropwise to the reaction solution over 1 hour at 70°C. The reaction solution was then stirred at 70°C for 3.5 hours. After completion of the reaction, saturated aqueous sodium bicarbonate was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved at 70°C using a mixed solvent of hexane and ethyl acetate at a ratio of 1:2. The solution was cooled to 0° C. to precipitate a pale yellow solid, which was collected by filtration to obtain Reference Example β-15 (1.21 g). 1H-NMR (400 MHz, CDCl3): 0.90-0.94 (4H, m), 1.21 (3H, t, J = 7.7 Hz), 1.84-1.91 (1H, m), 2.57 (2H, dq, J = 1.2, 7.7 Hz), 6.57 (1H, s).

[0176] b) Preparation of 3-chloro-6-(2-cyclopropyl-4-ethyl-1H-imidazol-1-yl)pyridazine (Reference Example β-16) To a solution of Reference Example β-15 (1.59 g) obtained in the above experiment in N-methylpyrrolidone (2.84 mL) was added sodium hydride (0.521 g) at 0°C. The reaction solution was stirred at room temperature for 30 minutes and then added to a solution of 3,6-dichloropyridazine (2.54 g) in N-methylpyrrolidone (2.84 mL) at 0°C. The reaction solution was stirred at room temperature for 16 hours, after which sodium hydride (0.260 g) and 3,6-dichloropyridazine (1.27 g) were further added, and the mixture was stirred at room temperature for 5.5 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and then water and saturated brine were added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (elution solvent: hexane:ethyl acetate) to give a residue containing Reference Example β-16. This residue was dissolved in isopropyl acetate, washed with 50% saturated brine, and dried over sodium sulfate, and then the solvent was evaporated under reduced pressure to give Reference Example β-16 (1.03 g). 1 H-NMR (400 MHz, CDCl3): 0.97-1.02 (2H, m), 1.11-1.16 (2H, m), 1.24 (3H, t, J = 7.4 Hz), 2.09 (1H, tt, J = 8.2, 3.8 Hz), 2.60 (2H, ddd), 7.16 (1H, t, J = 1.2 Hz), 7.65 (1H, d, J = 9.2 Hz), 7.78 (1H, d, J = 9.2 Hz).

[0177] Reference Example β-21 6-(5-cyclopropyl-1H-pyrazol-1-yl)-N-[(1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl]pyridazin-3-amine

[0178] a) Preparation of ethyl 2-(cyclopropanecarbonyl)-3-(dimethylamino)acrylate (Reference Example β-17) A mixture of ethyl 3-cyclopropyl-3-oxopropanoate (0.80 g) and N,N-dimethylformamide dimethyl acetal (1.08 mL) was stirred at 110°C for 1 hour. The reaction mixture was returned to room temperature and evaporated under reduced pressure to give Reference Example β-17 (1.08 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 212 / 0.663 / A

[0179] b) Preparation of ethyl 1-(6-chloropyridazin-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylate (Reference Example β-18) A reaction solution of Reference Example β-17 (3.00 g) obtained in the above experiment and 3-chloro-6-hydrazinopyridazine (4.11 g) in dimethylformamide (28 mL) was stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate was added to the reaction solution, and the mixture was washed with water and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example β-18 (1.84 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 293 / 0.905 / A

[0180] c) Preparation of ethyl 5-cyclopropyl-1-(6-{[(1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl]amino}pyridazin-3-yl)-1H-pyrazole-4-carboxylate (Reference Example β-19) To a solution of Reference Example β-18 (1.55 g) in dimethylformamide (2.6 mL), (1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexan-1-amine (0.60 g) and potassium carbonate (1.09 g) were added, and the mixture was stirred at 130°C for 2 hours. After completion of the reaction, chloroform was added to the reaction solution, which was then washed with water and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example β-19 (0.73 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 484 / 1.119 / A

[0181] d) Preparation of 5-cyclopropyl-1-(6-{[(1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl]amino}pyridazin-3-yl)-1H-pyrazole-4-carboxylic acid (Reference Example β-20) Lithium hydroxide monohydrate (0.16 g) was added to a solution of Reference Example β-19 (0.73 g) in ethanol (2.5 mL) and water (2.5 mL), and the mixture was stirred at 80°C for 2 hours. The reaction solution was returned to room temperature, diluted hydrochloric acid was added, and the mixture was extracted with 10% methanol-chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give Reference Example β-20 (0.65 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 456 / 0.913 / A

[0182] e) Preparation of 6-(5-cyclopropyl-1H-pyrazol-1-yl)-N-[(1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl]pyridazin-3-amine (Reference Example β-21) Reference Example β-20 (0.65 g) obtained in the above experiment was heated at 195°C for 5 hours. The resulting residue was purified by aminosilica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example β-21 (0.21 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 412 / 0.982 / A

[0183] Reference Example β-23 (3R,4R)-3,4-bis(methoxy)pyrrolidine hydrochloride

[0184] a), b) Preparation of (3R,4R)-3,4-bis(methoxy)pyrrolidine hydrochloride (Reference Example β-23) (3R,4R)-tert-butyl 3,4-dihydroxypyrrolidine-1-carboxylate (1 g) was dissolved in DMF (15 mL), and sodium hydride (55% w / w, 0.47 g) was added in three portions at 0°C. After stirring for 1 hour, methyl iodide (1.7 g) was added dropwise at 0°C, and the mixture was stirred at room temperature for 4 hours. Water was added, and the resulting reaction solution was subjected to liquid separation and extraction with ethyl acetate and water. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: chloroform:methanol) to give (3R,4R)-tert-butyl 3,4-dimethoxypyrrolidine-1-carboxylate (Reference Example β-22). A 4M solution of hydrochloric acid in ethyl acetate was added to the obtained (3R,4R)-tert-butyl 3,4-bis(methoxy)pyrrolidine-1-carboxylate, and the mixture was stirred for 1 hour. The solvent was then evaporated to give (3R,4R)-3,4-bis(methoxy)pyrrolidine hydrochloride (Reference Example β-23) (0.52 g). 1 H-NMR (DMSO) δ: 3.12-3.20 (2H, m), 3.25 (2H, d, J = 12.8 Hz), 3.30-3.34 (7H, m), 4.01 (2H, d, J = 3.7 Hz), 9.35 (2H, br s).

[0185] Reference Example β-26 (R)-tert-butyl 3,3-difluoro-4-methoxypyrrolidine-1-carboxylate

[0186] a) Preparation of (3R,4R)-tert-butyl 3-hydroxy-4-methoxypyrrolidine-1-carboxylate (Reference Example β-24) (3R,4R)-tert-butyl 3,4-dihydroxypyrrolidine-1-carboxylate (1 g) was dissolved in DMF (15 mL), and sodium hydride (55% w / w, 0.23 g) was added in three portions at 0°C. After stirring for 1 hour, methyl iodide (0.8 g) was added dropwise at 0°C, and the mixture was stirred at room temperature for 4 hours. Water was added, and the resulting reaction solution was subjected to liquid separation and extraction with ethyl acetate and water. The organic layer was washed with saturated saline and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: chloroform:methanol) to give (3R,4R)-tert-butyl 3-hydroxy-4-methoxypyrrolidine-1-carboxylate.

[0187] b) Preparation of (R)-tert-butyl 3-methoxy-4-oxopyrrolidine-1-carboxylate (Reference Example β-25) (3R,4R)-tert-butyl 3-hydroxy-4-methoxypyrrolidine-1-carboxylate (4.9 g), potassium bromide (0.27 g), tetrabutylammonium bromide (0.36 g), and AZADOL (0.173 g) were dissolved in chloroform (90 mL) and saturated aqueous sodium hydrogen carbonate solution (45 mL), and aqueous sodium hypochlorite solution (11% w / w, 22.9 g) was added at 0°C. After stirring at room temperature for 3 hours, sodium thiosulfate (10 g) and water were added, and the resulting reaction solution was subjected to liquid separation and extraction with chloroform-water. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to obtain (R)-tert-butyl 3-hydroxy-4-methoxypyrrolidine-1-carboxylate (Reference Example β-25). 3-Methoxy-4-oxopyrrolidine-1-carboxylate (4.95 g) was obtained. 1H-NMR (CDCl3) δ: 1.45 (9H, dd, J = 19.0, 6.1 Hz), 3.39 (1H, dd, J = 11.6, 6.7 Hz), 3.52 (3H, t, J = 12.5 Hz), 3.74 (1H, d, J = 19.6 Hz), 3.84 (1H, br s), 3.92 (1H, t, J = 7.6 Hz), 4.12 (1H, d, J = 7.3 Hz).

[0188] c) Preparation of (R)-tert-butyl 3,3-difluoro-4-methoxypyrrolidine-1-carboxylate (Reference Example β-26) (R)-tert-butyl 3-methoxy-4-oxopyrrolidine-1-carboxylate (4.8 g) was dissolved in dichloromethane (113 mL), and diethylaminosulfur trifluoride (10.9 g) was added at 0°C, followed by stirring at room temperature for 16 hours. Aqueous sodium carbonate solution was added, and the resulting reaction solution was subjected to liquid separation and extraction with ethyl acetate and water. The organic layer was washed with saturated saline and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give (R)-tert-butyl 3,3-difluoro-4-methoxypyrrolidine-1-carboxylate (3.12 g). 1 H-NMR (CDCl3) δ: 1.44 (9H, d, J = 3.0 Hz), 1.52 (2H, s), 3.53 (3H, d, J = 24.4 Hz), 3.64 (3H, tt, J = 11.6, 4.8 Hz), 3.76-3.80 (1H, m).

[0189] Reference Example β-29 (1R,5S,7r)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl

[0190] a) Preparation of tert-butyl (1R,5S,7s)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (Reference Example β-27) Sodium borohydride (0.31 g) was added in three portions to a suspension of tert-butyl (1R,5S)-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (2.00 g) in methanol (12 mL) under ice cooling, and the mixture was stirred for 1.5 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with toluene. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain Reference Example β-27 (2.02 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 244 / 0.705 / A

[0191] b) Preparation of tert-butyl (1R,5S,7r)-7-[(4-nitrobenzoyl)oxy]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (Reference Example β-28) To a solution of Reference Example β-27 (1.07 g), 4-nitrobenzoic acid (0.74 g), and triphenylphosphine (2.88 g) in tetrahydrofuran (22 mL), diisopropyl azodicarboxylate (2.16 mL) was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, toluene was added to the reaction solution, and the mixture was washed with water. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example β-28 (1.12 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 393 / 1.119 / A

[0192] c) Preparation of tert-butyl (1R,5S,7r)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (Reference Example β-29) Sodium hydroxide (0.88 g) was added to a suspension of Reference Example β-28 (1.12 g) in ethanol (3.2 mL) and water (6.4 mL), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was subjected to liquid separation and extraction with chloroform and water. The resulting organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example β-29 (0.38 g). 1H-NMR (400 MHz, CDCl3): 1.47 (9H, s), 1.55-1.69 (3H, m), 2.06-2.13 (2H, m), 3.63-3.70 (2H, m), 3.73-3.80 (2H, m), 4.03 (1H, br s), 4.15 (1H, br s), 4.82-4.90 (1H, m).

[0193] Reference Example β-32 tert-butyl (3R,4R)-3,4-dihydroxypyrrolidine-1-carboxylate-2,2,5,5-d4

[0194] a) Preparation of (3S,4S)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione (Reference Example β-30) D-(-)-Tartaric acid (42 g) and benzylamine (30 g) were dissolved in xylene (300 mL), and refluxed for 8 hours with a Dean-Stark apparatus attached. After cooling to room temperature, the mixture was filtered, and ethanol (300 mL) was added and heated. After cooling, the resulting crystals were filtered to obtain (3S,4S)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione (47 g). 1 H-NMR (DMSO) δ: 4.34 (2H, dd, J = 21.3, 6.1 Hz), 4.54 (2H, dd, J = 22.2, 14.9 Hz), 6.28 (2H, s), 7.23-7.34 (5H, m).

[0195] b) Preparation of (3R,4R)-1-benzylpyrrolidine-2,2,5,5-d4-3,4-diol (Reference Example β-31) To a solution of lithium aluminum deuteride (4 g) in THF (70 mL) was added a solution of (3S,4S)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione (5.3 g) in THF (150 mL) was added dropwise. After stirring at room temperature for 4 hours, the mixture was cooled to 0°C, and water (7 g), 15% aqueous sodium hydroxide solution (7 mL), and water (21 mL) were added in that order, followed by stirring overnight. The reaction solution was filtered through Celite, and the solvent was evaporated to give (3R,4R)-1-benzylpyrrolidine-2,2,5,5-d4-3,4-diol (5.3 g). 1H-NMR (CDCl3) δ: 3.66-3.82 (2H, m), 4.03-4.20 (2H, m), 4.84 (2H, dd, J = 42.7, 20.7 Hz), 7.36-7.45 (5H, m).

[0196] c) Preparation of tert-butyl (3R,4R)-3,4-dihydroxypyrrolidine-1-carboxylate-2,2,5,5-d4 (Reference Example β-32) Methanol (67 mL) was added to palladium hydroxide-carbon (1.5 g) and (3R,4R)-1-benzylpyrrolidine-2,2,5,5-d4-3,4-diol (5.3 g), and the mixture was stirred under a hydrogen atmosphere for 4 hours. Di-tert-butyl dicarbonate (7 g) was added, and the mixture was stirred for 4 hours, followed by filtration through Celite. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: chloroform:methanol) to give tert-butyl (3R,4R)-3,4-dihydroxypyrrolidine-1-carboxylate-2,2,5,5-d4 (2.9 g). 1 H-NMR (CD3OD) δ: 1.42-1.49 (9H, m), 4.03 (2H, s).

[0197] Reference Example β-33 Rac-tert-butyl (1R,2R,4S)-2-hydroxy-2-methyl-7-azabicyclo[2.2.1]heptane-7-carboxylate

[0198] a) Preparation of Rac-tert-butyl (1R,2R,4S)-2-hydroxy-2-methyl-7-azabicyclo[2.2.1]heptane-7-carboxylate (Reference Example β-33) Rac-tert-butyl (1R,4S) 2-oxo-7-azabicyclo[2.2.1]heptane-7-carboxylate (1.1 g) was dissolved in THF (20 mL), and a methylmagnesium bromide-THF solution (3 M, 2.6 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 2 hours, and saturated aqueous ammonium chloride solution (30 mL) was added. The resulting reaction solution was subjected to liquid separation and extraction with ethyl acetate and water. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to obtain rac-tert-butyl (1R,2R,4S)-2-hydroxy-2-methyl-7-azabicyclo[2.2.1]heptane-7-carboxylate (920 mg).

[0199] Reference Example β-35 6,10-dioxa-2-azaspiro[4.5]decane

[0200] a) Preparation of 2-benzyl-6,10-dioxa-2-azaspiro[4.5]decane (Reference Example β-34) To a solution of 1-benzylpyrrolidin-3-one (1 g) and 1,3-propanediol (1.23 mL) in THF (19 mL), TMSCl (0.94 mL) was added at room temperature, and the mixture was stirred under reflux for 9 hours. The reaction solution was returned to room temperature and added dropwise to a saturated aqueous solution of sodium bicarbonate. After separation and extraction with toluene, the resulting organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example β-34 (0.67 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 234 / 0.594 / A

[0201] b) Preparation of 6,10-dioxa-2-azaspiro[4.5]decane (Reference Example β-35) Formic acid (0.33 mL) and TEA (0.40 mL) were added sequentially to a mixture of 2-benzyl-6,10-dioxa-2-azaspiro[4.5]decane (0.67 g) and 20 wt % palladium hydroxide / carbon (0.81 g) in THF (9.5 mL), and the mixture was stirred overnight at room temperature. After filtration through Celite, the solvent was distilled off to obtain Reference Example β-35 (0.17 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 144 / 0.261 / A

[0202] Reference Example β-42 5,8-dioxa-2-azaspiro[3.5]nonane 1-trifluoroacetate

[0203] a) Preparation of 2,2-bis[(benzyloxy)methyl]oxirane (Reference Example β-36) To a solution of potassium tert-butoxide (3.25 g) in dimethyl sulfoxide (44 mL), trimethylsulfoxonium iodide (7.54 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. The above reaction solution was added dropwise to a separately prepared solution of 1,3-bis(benzyloxy)propan-2-one (7.12 g) in dimethoxyethane (44 mL) and dimethyl sulfoxide (44 mL) under ice-cooling over 30 minutes, and the mixture was stirred at 10°C for 2 hours. After completion of the reaction, the mixture was separated and extracted with toluene and water. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain Reference Example β-36 (7.49 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 285 / 1.115 / A

[0204] b) Preparation of 1-(benzyloxy)-2-[(benzyloxy)methyl]-3-(2-hydroxyethoxy)propan-2-ol (Reference Example β-37) Compound β-36 (7.49 g) was added to a solution of sodium tert-butoxide (3.04 g) in ethylene glycol (53 mL) at 75°C, and the mixture was stirred for 3 hours. The reaction mixture was returned to room temperature, and ammonium chloride (1.41 g) and water were added, followed by extraction with chloroform. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain Reference Example β-37 (9.12 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 347 / 0.933 / A

[0205] c) Preparation of 2,2-bis[(benzyloxy)methyl]-1,4-dioxane (Reference Example β-38) To a solution of Reference Example β-37 (9.12 g) in tetrahydrofuran (80 mL), potassium tert-butoxide (3.54 g) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 4-Toluenesulfonyl chloride (6.02 g) was added under ice-cooling, and the mixture was stirred at room temperature for 14 hours. Potassium tert-butoxide (3.84 g) and tetrahydrofuran (15 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was separated and extracted with ethyl acetate and water. The resulting organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give Reference Example β-38 (8.32 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 329 / 1.121 / A

[0206] d) Preparation of (1,4-dioxane-2,2-diyl)dimethanol (Reference Example β-39) Palladium hydroxide on carbon (2.51 g) was added to a solution of Reference Example β-38 (5.88 g) in tetrahydrofuran (179 mL), and the mixture was stirred under a hydrogen atmosphere at 45° C. for 7 hours. After filtration through Celite, the solvent was evaporated under reduced pressure to give Reference Example β-39 (2.64 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 149 / 0.201 / A

[0207] e) Preparation of (1,4-dioxane-2,2-diyl)bis(methylene)bis(trifluoromethanesulfonate) (Reference Example β-40) A solution of trifluoromethanesulfonic anhydride (6.92 mL) in chloroform (14 mL) was added dropwise to a solution of Reference Example β-39 (2.45 g) and pyridine (3.48 mL) in chloroform (41 mL) under ice-cooling, and the mixture was stirred for 1 hour. After completion of the reaction, the reaction solution was washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain Reference Example β-40 (4.54 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 413 / 1.088 / A

[0208] f) Preparation of 2-benzyl-5,8-dioxa-2-azaspiro[3.5]nonane (Reference Example β-41) A reaction solution of Reference Example β-40 (3.95 g) obtained in the above experiment, benzylamine (1.15 mL), and N,N-diisopropylethylamine (4.18 mL) in acetonitrile (32 mL) was heated under reflux for 4 hours. The reaction solution was returned to room temperature, 2-methoxy-2-methylpropane was added, and the mixture was washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain Reference Example β-41 (1.86 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 220 / 0.417 / A

[0209] g) Preparation of 5,8-dioxa-2-azaspiro[3.5]nonane-1-trifluoroacetate (Reference Example β-42) Palladium hydroxide on carbon (1.19 g) was added to a solution of Reference Example β-41 (1.86 g) and glacial acetic acid (0.97 mL) in tetrahydrofuran (57 mL), and the mixture was stirred at 45° C. under a hydrogen atmosphere for 6 hours. After filtration through Celite, the solvent was evaporated under reduced pressure. Trifluoroacetic acid (1.50 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure to give Reference Example β-42 (1.98 g). 1 H-NMR (400 MHz, CD3OD): 1.98 (1H, s), 3.62-3.65 (2H, m), 3.71-3.74 (2H, m), 3.76 (2H, s), 3.99-4.06 (4H, m).

[0210] Reference Example β-45 Benzyl (2R)-2-methyl-3-oxopyrrolidine-1-carboxylate

[0211] a) Preparation of methyl N-[(benzyloxy)carbonyl]-D-alaninate (Reference Example β-43) A solution of sodium bicarbonate (30.1 g) in water (375 mL) was added dropwise at room temperature to a solution of methyl D-alaninate hydrochloride (25 g) and CbzCl (32.8 mL) in water (75 mL), and the mixture was stirred overnight at room temperature. The reaction solution was subjected to liquid separation and extraction with isopropyl acetate, and the resulting organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product of Reference Example β-43 (49.3 g). This was used in the next step without further purification. LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 238 / 0.805 / A

[0212] b) Preparation of 1-benzyl 3-methyl (5R)-5-methyl-4-oxopyrrolidine-1,3-dicarboxylate (Reference Example β-44) To a solution of the crude product of methyl N-[(benzyloxy)carbonyl]-D-alaninate (49.3 g) and methyl acrylate (16.8 mL) in THF (259 mL), sodium tert-butoxide (18.0 g) was added dropwise at 0°C, and the mixture was stirred for 1 hour and then overnight at room temperature. After completion of the reaction, the reaction solution was washed with toluene and water, and the resulting aqueous layer was acidified with sodium hydrogen sulfate monohydrate (29.6 g). Subsequently, the aqueous layer was extracted with toluene, and the resulting organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product of Reference Example β-44 (34.7 g). This was used in the next step without further purification. LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 292 / 0.918 / A

[0213] c) Preparation of benzyl (2R)-2-methyl-3-oxopyrrolidine-1-carboxylate (Reference Example β-45) The crude product of 1-benzyl 3-methyl (5R)-5-methyl-4-oxopyrrolidine-1,3-dicarboxylate (34.7 g) was dissolved in methanol (105 mL) and water (420 mL). 36% aqueous HCl (42 mL) was added, and the mixture was stirred at 100°C for 6 hours. The reaction solution was returned to room temperature, and the organic layer obtained by separation and extraction with toluene was washed with aqueous sodium bicarbonate and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the crude product of Reference Example β-45 (24.7 g). This was used in the next step without further purification. LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 234 / 0.839 / A

[0214] Reference Example β-46 1-(6-chloropyridazin-3-yl)-5-cyclopropyl-3-ethyl-1H-pyrazole-4-carbonitrile To a solution of 3-chloro-6-(5-cyclopropyl-3-ethyl-1H-pyrazol-1-yl)pyridazine (1.2 g) in acetonitrile (16.08 mL), chlorosulfonyl isocyanate (0.637 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. To the resulting reaction solution, DMF (0.934 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (50 mL), and the mixture was extracted with chloroform. The organic layer was then dried over sodium sulfate. After filtering off the insoluble matter, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example β-46 (0.50 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 274 / 1.003 / A

[0215] Reference Example β-48 3-{3-[1-(benzyloxy)cyclopropyl]-5-cyclopropyl-1H-1,2,4-triazol-1-yl}-6-chloropyridazine

[0216] a) Preparation of 3-[1-(benzyloxy)cyclopropyl]-5-cyclopropyl-1H-1,2,4-triazole (Reference Example β-47) To a mixed solution of cyclopropanecarboximidamide hydrochloride (1.212 g), 1-(benzyloxy)cyclopropane-1-carboxylic acid (1.68 g), and benzyltriethylammonium chloride (0.199 g) in DMF (29.1 mL) was added DIPEA (6.11 mL) under ice-cooling. The mixture was allowed to return to room temperature and stirred for 30 minutes, after which TPTU (2.86 g) was added in three portions under ice-cooling. The mixture was then allowed to return to room temperature and stirred overnight. The resulting reaction mixture was added dropwise to a solution of propanedioic acid (4.55 g) and hydrazine monohydrate (0.525 mL) in water (5 mL) under ice-cooling, and the mixture was allowed to return to room temperature and stirred overnight. The reaction solution was diluted with isopropyl acetate (85 mL), and the organic layer was washed twice with saturated brine (30 mL). Sodium sulfate was added to the organic layer to dry it, and then the solid was filtered off, and the solvent in the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example β-47 (1.41 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 256 / 0.765 / A

[0217] b) Preparation of 3-{3-[1-(benzyloxy)cyclopropyl]-5-cyclopropyl-1H-1,2,4-triazol-1-yl}-6-chloropyridazine (Reference Example β-48) 3,6-Dichloropyridazine (2.468 g) was added to a mixed solution of 3-[1-(benzyloxy)cyclopropyl]-5-cyclopropyl-1H-1,2,4-triazole (1.41 g) and potassium carbonate (3.05 g) in NMP (5.52 mL), and the mixture was heated and stirred at 110°C for 4 hours. The reaction solution was returned to room temperature and diluted with isopropyl acetate (50 mL), and the organic layer was washed three times with a mixed solution (25 mL) of saturated brine:water = 1:4. The organic layer was dried over sodium sulfate, and the solid was then filtered off, and the solvent from the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give Reference Example β-48 (1.67 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 368 / 1.187 / A

[0218] Example B-256 1-{1-[6-({(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}amino)pyridazin-3-yl]-3-(propan-2-yl)-1H-1,2,4-triazol-5-yl}cyclopropan-1-ol To a solution of 1-{1-[6-({(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}amino)pyridazin-3-yl]-3-(propan-2-yl)-1H-1,2,4-triazol-5-yl}cyclopropyl benzoate (36 mg) in tetrahydrofuran (0.57 mL) was added lithium aluminum hydride (11 mg) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, a 10 wt % aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and then dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: hexane:ethyl acetate) to obtain Example B-256 (12 mg). 1H-NMR (400 MHz, CDCl3): 0.91 (3H, s), 1.15-1.20 (2H, m), 1.22-1.27 (2H, m), 1.33 (6H, d, J = 6.7 Hz), 1.36-1.50 (6H, m), 1.53-1.60 (2H, m), 1.67 (1H, br s), 1.85 (2H, br d, J = 13.4 Hz), 1.98 (2H, br d, J = 9.8 Hz), 2.11 (2H, s), 2.44-2.50 (2H, m), 2.56 (2H, td, J = 10.4, 2.6 Hz), 3.05 (1H, td, J = 7.0, 14.0 Hz), 3.46 (2H, s), 3.65 (2H, dd, J = 6.4, 2.7 Hz), 3.71 (2H, dd, J = 6.4, 2.7 Hz), 4.76 (1H, br d, J = 7.9 Hz), 6.82 (1H, s), 6.84 (1H, d, J = 9.8 Hz), 7.88 (1H, d, J = 9.8 Hz).

[0219] Example B-261 1-{5-cyclopropyl-1-[6-({(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}amino)pyridazin-3-yl]-1H-1,2,4-triazol-3-yl}cyclopropan-1-ol Ethanol (774 μL) and THF (155 μL) were added to 6-{3-[1-(benzyloxy)cyclopropyl]-5-cyclopropyl-1H-1,2,4-triazol-1-yl}-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine (57 mg) to form a solution, followed by the addition of hydrochloric acid / methanol solution (93 μL, 2 mol / L) and 20 wt % palladium hydroxide on activated carbon (32.6 mg). The mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours, then filtered through Celite, and the solvent in the filtrate was evaporated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (elution solvent: hexane / ethyl acetate) to give Example B-261 (20.90 mg). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 524 / 1.401 / B

[0220] Example B-230-TA 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (2R,3R)-2,3-dihydroxybutanedioic acid salt To a solution of 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine (Example B-230) (3.18 g) in ethyl acetate (11.63 mL), a solution of (2R,3R)-2,3-dihydroxybutanedioic acid (1.048 g) in methanol (11.63 mL) was added and stirred at room temperature for 30 minutes. After distilling off the solvent under reduced pressure, the residue was diluted with a 1:2 mixed solution of hexane:ethyl acetate (45 mL), and the resulting suspension was stirred at room temperature for 1 hour. The solid was collected by filtration using a Kiriyama funnel to give Example B-230-TA (3.87 g). 1H-NMR (CD3OD) δ: 1.07-1.14 (4H, m), 1.18 (3H, s), 1.47-1.69 (6H, m), 1.96-2.08 (2H, m), 2.32 (3H, s), 2.64 (1H, tt, J = 8.0, 5.6 Hz), 3.02-3.20 (2H, m), 3.43 (6H, s), 3.48-3.57 (2H, m), 3.58-3.67 (2H, m), 3.77-3.87 (1H, m), 4.03-4.08 (2H, m), 4.43 (2H, s), 7.05 (1H, d, J = 9.2 Hz), 7.61 (1H, d, J = 9.2 Hz).

[0221] In Examples B-1 to B-281 and A-20, the corresponding starting compounds were reacted and treated in the same manner as in Examples B-216, B-256, and B-261 to obtain the compounds shown in the table below. The corresponding starting compounds were either purchased as commercial products or treated in the same manner as in the separately described Reference Examples.

[0222] Example C-3 6-((R)-3-ethylmorpholino)-N-((1r,4R)-4-methyl-4-(((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)methyl)cyclohexyl)pyridazin-3-amine trifluoroacetate 6-chloro-N-((1r,4r)-4-methyl-4-(((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)methyl)cyclohexyl)pyridazin-3-amine (10 mg), (R)-3-ethylmorpholine (31 mg), N,N-diisopropylethylamine (35 mg), and hydrochloric acid (20 mg) were dissolved in NMP (0.3 mL) and heated at 220°C for 2 hours under microwave irradiation. After cooling, the mixture was purified using a C18 column with reverse phase chromatography (water / acetonitrile, 0.05% TFA) to give Example C-3 (1.7 mg). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 446 / 1.341 / B

[0223] Compound γ-1 was obtained by reacting and treating the corresponding starting compound in the same manner as in Example B-216.

[0224] In Examples C-1 to C-43, the corresponding starting compounds were reacted and treated in the same manner as in Example C-3 to obtain the compounds shown in the table below. The corresponding starting compounds were purchased as commercially available products or treated in the same manner as in the separately described Reference Examples to obtain the compounds.

[0225] Example D-2 N-((1r,4r)-4-((2-oxa-8-azaspiro[4.5]decan-8-yl)methyl)-4-methylcyclohexyl)-6-(2-cyclopropylphenyl)pyridazin-3-amine 2-Cyclopropylphenylboronic acid (6 mg), N-((1r,4r)-4-((2-oxa-8-azaspiro[4.5]decan-8-yl)methyl)-4-methylcyclohexyl)-6-chloropyridazin-3-amine (10 mg), SPhos Pd G3 (2 mg), and potassium carbonate (9 mg) were dissolved in DME (0.2 mL) and water (0.07 mL), and the solution was heated at 80°C for 2 hours. After cooling, water was added, and the resulting reaction solution was subjected to liquid separation and extraction with ethyl acetate and water. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give N-((1r,4r)-4-((2-oxa-8-azaspiro[4.5]decan-8-yl)methyl)-4-methylcyclohexyl)-6-(2-cyclopropylphenyl)pyridazin-3-amine (4.3 mg). 1 H-NMR (CD3OD) δ: 0.63 (2H, td, J = 5.2, 4.1 Hz), 0.84 (2H, ddd), 0.97 (3H, s), 1.12 (1H, d, J = 6.1 Hz), 1.41-1.61 (10H, m), 1.75 (2H, t, J = 7.3 Hz), 1.94 (3H, tt, J = 8.2, 2.5 Hz), 2.12 (2H, s), 2.51 (4H, dd, J = 11.9, 6.4 Hz), 3.52 (2H, s), 3.82 (3H, dd, J = 9.2, 4.9 Hz), 6.90 (1H, d, J = 9.2 Hz), 7.06 (1H, d, J = 7.3 Hz), 7.24 (1H, td, J = 5.3, 1.4 Hz), 7.32 (2H, dd, J = 11.3, 4.6 Hz), 7.45 (1H, d, J = 9.8 Hz).

[0226] Compound δ-2 was obtained by reacting and treating the corresponding starting compound in the same manner as in Example B-216.

[0227] Reference Example δ-6 2-cyclopropyl-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0228] a) Preparation of 2-cyclopropyl-5-fluoropyridin-3-ol (Reference Example δ-4) 2-Bromo-5-fluoropyridin-3-ol (13 g), cyclopropylboronic acid (9.96 g), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (2.79 g), and potassium carbonate (18.85 g) were dissolved in toluene (102 mL) and water (34 mL) and heated at 100°C for 2 hours. Water was added, and the resulting reaction solution was subjected to separation and extraction with ethyl acetate and water. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain 2-cyclopropyl-5-fluoropyridin-3-ol. The resulting Reference Example δ-4 was used in the next step without purification. LC-MS: [M+H]+ / Rt (min) / Measuring conditions: 193 / 1.191 / A

[0229] b) Preparation of 2-cyclopropyl-5-fluoropyridin-3-yl trifluoromethanesulfonate (Reference Example δ-5) 2-Cyclopropyl-5-fluoropyridin-3-ol (10.4 g) and triethylamine (27.5 g) were dissolved in chloroform (140 mL), and trifluoromethanesulfonic anhydride (28.8 g) was added dropwise at 0°C, followed by stirring at room temperature for 16 hours. Water was added, and the resulting reaction solution was subjected to liquid separation and extraction with ethyl acetate and water. The organic layer was washed with saturated saline and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give 2-cyclopropyl-5-fluoropyridin-3-yl trifluoromethanesulfonate (8.8 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 269 / 1.086 / A

[0230] c) Preparation of 2-cyclopropyl-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Reference Example δ-6) 2-Cyclopropyl-5-fluoropyridin-3-yl trifluoromethanesulfonate (8.8 g), bis(pinacolato)diboron (8.62 g), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (1 g), and potassium acetate (4.2 g) were dissolved in dioxane (62 mL) and heated at 100°C for 3 hours. Water was added, and the resulting reaction solution was subjected to liquid separation and extraction with ethyl acetate and water. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to obtain 2-cyclopropyl-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (5.7 g). 1 H-NMR (CDCl3) δ: 0.92 (2H, tt, J = 7.6, 3.1 Hz), 1.00 (2H, tt, J = 9.1, 3.1 Hz), 1.34 (12H, dd, J = 17.7, 8.5 Hz), 2.82 (1H, tt, J = 7.9, 3.8 Hz), 7.65 (1H, dd, J = 9.1, 3.0 Hz), 8.26 (1H, d, J = 3.0 Hz).

[0231] Reference Example δ-7 1-methyl-3-(propan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole To a solution of 4-bromo-1-methyl-3-(propan-2-yl)-1H-pyrazole (1.00 g) in tetrahydrofuran (10 mL), n-butyllithium (2.6 mol / L, 2.80 mL) was added dropwise at −78°C, followed by stirring at the same temperature for 30 minutes. A solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.19 mL) in tetrahydrofuran (2.3 mL) was added dropwise at −78°C, followed by stirring at room temperature for 1 hour. After completion of the reaction, aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example δ-7 (0.79 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 251 / 1.382 / A

[0232] Reference Example δ-8 3-Bromo-2-cyclopropoxypyridine Cyclopropanol (1.24 g), 3-bromo-2-fluoropyridine (2.5 g), and cesium carbonate (6.9 g) were dissolved in DMF (28 mL) and heated at 75°C for 4 hours. After cooling, water was added, and the resulting reaction solution was separated and extracted with ethyl acetate and water. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give 3-bromo-2-cyclopropoxypyridine (1.9 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 214 / 1.953 / B

[0233] Reference Example δ-9 6-ethylcyclohex-1-en-1-yl trifluoromethanesulfonate Lithium diisopropylamide (2 M THF solution, 14 mL) was dissolved in THF (100 mL) and cooled to -78°C. A solution of 2-ethylcyclohexanone (3 g) in THF (10 mL) was then added dropwise. After stirring at -78°C for 2 hours, N-phenyltrifluoromethanesulfonamide (10.2 g) in THF (35 mL) was added dropwise. The mixture was stirred at room temperature for 16 hours, water was added, and the resulting reaction solution was subjected to liquid separation and extraction with heptane and water. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to give 6-ethylcyclohex-1-en-1-yl trifluoromethanesulfonate (2.39 g). 1 H-NMR (CDCl3) δ: 0.93 (3H, t, J = 7.6 Hz), 1.31-1.46 (1H, m), 1.50-1.58 (2H, m), 1.59-1.69 (1H, m), 1.70-1.80 (1H, m), 1.81-1.93 (1H, m), 2.07-2.25 (2H, m), 2.28-2.43 (1H, m), 5.76 (1H, td, J = 2.8, 1.2 Hz).

[0234] Reference Example δ-11 5-Bromo-4-cyclopropyl-2-methoxypyrimidine

[0235] a) Preparation of 5-bromo-2-chloro-4-cyclopropylpyrimidine (Reference Example δ-10) 5-Bromo-2-chloropyrimidine (3.00 g), cyclopropanecarboxylic acid (1.47 mL), trifluoroacetic acid (0.59 mL), and silver nitrate (0.53 g) in acetonitrile (21 mL)-water (21 mL) was added dropwise at 70°C over 30 minutes, followed by stirring for 1 hour. The reaction mixture was returned to room temperature, 10 wt% aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example δ-10 (2.37 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 235 / 1.024 / A

[0236] b) Preparation of 5-bromo-4-cyclopropyl-2-methoxypyrimidine (Reference Example δ-11) Sodium methoxide (1.39 g) was added to a solution of Reference Example δ-10 (1.50 g) in methanol (13 mL), and the mixture was heated under reflux for 2 hours. The reaction mixture was returned to room temperature, and the mixture was separated and extracted with ethyl acetate and water. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example δ-11 (1.19 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 231 / 0.971 / A

[0237] In Examples D-1 to D-121, the compounds shown in the table below were obtained by reacting and treating the corresponding starting compounds in the same manner as in Example D-2. The corresponding starting compounds were either purchased as commercial products or treated in the same manner as in the separately described Reference Examples.

[0238] Example E-1 8-(((1r,4r)-4-((6-(2-cyclopropylpyridin-3-yl)pyridazin-3-yl)oxy)-1-methylcyclohexyl)methyl)-2-oxa-8-azaspiro[4.5]decane

[0239] a) Preparation of 3-(2-cyclopropylpyridin-3-yl)-6-(((1s,4s)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl)oxy)pyridazine (Reference Example ε-1) (1s,4s)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexan-1-ol (237 mg) was dissolved in DMF (2.5 mL), and sodium hydride (88 mg) was added at 0°C, followed by stirring for 20 minutes. 3-Chloro-6-(2-cyclopropylpyridin-3-yl)pyridazine (200 mg) was added, followed by stirring at room temperature for 5 hours. Water was added to the resulting reaction solution, which was then subjected to liquid separation and extraction with chloroform-water. The organic layer was washed with saturated brine, and the resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give 3-(2-cyclopropylpyridin-3-yl)-6-(((1s,4s)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl)oxy)pyridazine (340 mg). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 424 / 1.989 / B

[0240] b) Preparation of ((1s,4s)-4-((6-(2-cyclopropylpyridin-3-yl)pyridazin-3-yl)oxy)-1-methylcyclohexane-1-carbaldehyde (Reference Example ε-2) 3-(2-Cyclopropylpyridin-3-yl)-6-(((1s,4s)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl)oxy)pyridazine (340 mg) was dissolved in acetone (2.5 mL), formic acid (2.5 mL), and water (0.5 mL), and the mixture was heated at 75°C for 15 hours. 1M aqueous sodium hydroxide solution was added to the resulting reaction solution, which was then subjected to liquid separation and extraction with chloroform-water. The organic layer was washed with saturated brine, and the resulting residue was purified by silica gel column chromatography (elution solvent: chloroform:methanol) to give Reference Example ε-2 (260 mg). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 338 / 1.603 / B

[0241] c) Preparation of 8-(((1r,4r)-4-((6-(2-cyclopropylpyridin-3-yl)pyridazin-3-yl)oxy)-1-methylcyclohexyl)methyl)-2-oxa-8-azaspiro[4.5]decane (Example E-1) Acetonitrile (0.8 mL) was added to (1s,4s)-4-((6-(2-cyclopropylpyridin-3-yl)pyridazin-3-yl)oxy)-1-methylcyclohexane-1-carbaldehyde (80 mg), 2-oxa-8-azaspiro[4.5]decane hydrochloride (63 mg), sodium formate (60 mg), trimethyl orthoformate (75 mg), and formic acid (55 mg), and the mixture was heated at 85° C. for 2 hours. The resulting reaction solution to which aqueous solution was added was subjected to liquid separation and extraction with ethyl acetate and water. The organic layer was washed with saturated saline, and the resulting residue was purified by aminosilica gel column chromatography (elution solvent: hexane:ethyl acetate) to obtain Example E-1 (5 mg). 1H-NMR (CD3OD) δ: 0.85-0.99 (2H, m), 0.99 (3H, s), 1.10-1.12 (2H, m), 1.46-1.68 (10H, m), 1.73-1.76 (2H, m), 2.02-2.10 (3H, m), 2.23 (2H, d, J = 32.3 Hz), 2.55 (4H, br s), 3.54 (2H, s), 3.84 (2H, t, J = 7.3 Hz), 5.22-5.23 (1H, m), 7.22-7.27 (2H, m), 7.76-7.83 (2H, m), 8.47 (1H, d, J = 4.9 Hz).

[0242] In Examples E-1 and E-2, the compounds shown in the table below were obtained by reacting and treating in the same manner as in Example E-1. The corresponding starting compounds were purchased as commercial products or treated in the same manner as in the separately described Reference Examples to obtain the compounds.

[0243] Reference Example ζ-3 (1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexane-1-thiol

[0244] a) Preparation of (1s,4s)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexylmethanesulfunate (Reference Example ζ-1) (1s,4s)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexan-1-ol (6.5 g) and N-ethyl-N-isopropylpropan-2-amine (7.36 g) were dissolved in chloroform (95 mL), and methanesulfonyl chloride (4.24 g) was added dropwise at 0°C, followed by stirring at room temperature for 2 hours. The resulting reaction solution was subjected to liquid separation and extraction with chloroform and water. The organic layer was washed with saturated brine, dried over sodium sulfate, and triturated in hexane-ethyl acetate to give Reference Example ζ-1 (6.8 g). 1H-NMR (CDCl3) δ: 0.69 (4H, t, J = 3.1 Hz), 0.94 (1H, s), 0.98 (3H, s), 1.12 (3H, s), 1.13 (1H, s), 1.51 (5H, dt, J = 10.8, 4.3 Hz), 1.66-1.86 (4H, m), 1.93-1.99 (2H, m), 2.97 (3H, s), 2.98 (1H, s), 3.35 (3H, dd, J = 10.7, 4.0 Hz), 3.58 (3H, td, J = 7.4, 3.5 Hz), 3.98 (1H, s), 4.55-4.62 (1H, m).

[0245] b) Preparation of S-((1r,4r)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl) ethanethioate (Reference Example ζ-2) (1s,4s)-4-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methylcyclohexyl methanesulfonate (3.3 g) and potassium thioacetate (6.15 g) were dissolved in DMF (45 mL) and heated at 90°C for 3 hours. After cooling, water was added, and the resulting reaction solution was subjected to liquid separation and extraction with ethyl acetate and water. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example ζ-2 (0.57 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 287 / 2.382 / B

[0246] c) Preparation of (1r,4r)-4-(5,5-dimethyl-1,3-diox-2-yl)-4-methylcyclohexane-1-thiol (Reference Example ζ-3) S-((1r,4r)-4-(5,5-dimethyl-1,3-diox-2-yl)-4-methylcyclohexyl)ethanethiol (1.36 g) was dissolved in THF (45 mL) and 4 M aqueous sodium hydroxide solution (4 mL) at 0°C and heated at 50°C for 3 hours. 10% aqueous hydrochloric acid was added, and the resulting reaction solution was subjected to liquid separation and extraction with chloroform and water. The organic layer was washed with saturated brine, dried over sodium sulfate, and triturated in methanol to give Reference Example ζ-3 (0.98 g).1 H-NMR (CDCl3) δ: 0.68 (3H, s), 0.96 (3H, d, J = 6.1 Hz), 1.12 (3H, s), 1.40-1.53 ​​(7H, m), 1.91 (2H, t, J = 4.6 Hz), 2.57 (1H, dt, J = 10.8, 3.2 Hz), 3.35 (2H, d, J = 10.4 Hz), 3.57 (2H, d, J = 11.0 Hz), 3.94 (1H, s).

[0247] In Examples F-1 to F-6, the compounds shown in the table below were obtained by reacting and treating the corresponding starting compounds in the same manner as in Example B-216 using Reference Example ζ-3. The corresponding starting compounds were either purchased as commercial products or treated in the same manner as in the separately described Reference Examples.

[0248] Reference Example η-4 (9aS)-3-chloro-8,9,9a,10-tetrahydro-5H,7H-pyridazino[4,3-f]pyrrolo[2,1-c][1,4]oxazepin-5-one

[0249] a) Preparation of (2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolidine (Reference Example η-1) To a solution of [(2S)-pyrrolidin-2-yl]methanol (400 mg) and 2,6-lutidine (0.92 mL) in dichloromethane (7.9 mL), tert-butyldimethylsilyl trifluoromethanesulfonate (1.2 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, an aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: chloroform:methanol) to give Reference Example η-1 (472 mg). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 216 / 0.832 / A

[0250] b) Preparation of [(2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolidin-1-yl](3,6-dichloropyridazin-4-yl)methanone (Reference Example η-2) To a solution of Reference Example η-1 (472 mg), 3,6-dichloropyridazine-4-carboxylic acid (465 mg), and 1-methylimidazole (0.61 mL) in acetonitrile (4.4 mL), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (6.92 mL) was added and stirred at room temperature for 20 hours. After completion of the reaction, ethyl acetate was added to the reaction solution, and the mixture was washed with water. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example η-2 (536 mg). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 390 / 1.252 / A

[0251] c) Preparation of (3,6-dichloropyridazin-4-yl)[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methanone (Reference Example η-3) To a solution of Reference Example η-2 (512 mg) in tetrahydrofuran (4.9 mL) and water (1.8 mL), hydrochloric acid (4.0 mol / L solution in cyclopentyl methyl ether (0.49 mL)) was added under ice-cooling, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was separated and extracted with ethyl acetate and water, the organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give Reference Example η-3 (364 mg). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 276 / 0.531 / A

[0252] d) Preparation of (9aS)-3-chloro-8,9,9a,10-tetrahydro-5H,7H-pyridazino[4,3-f]pyrrolo[2,1-c][1,4]oxazepin-5-one (Reference Example η-4) Cesium carbonate (1.10 g) was added to a solution of Reference Example η-3 (414 mg) in acetonitrile (5.6 mL), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was filtered through Celite, and the resulting filtrate was subjected to liquid separation and extraction with ethyl acetate and brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give Reference Example η-4 (268 mg). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 240 / 0.504 / A

[0253] In Examples G-1 and G-2, the starting compounds corresponding to Reference Example η-4 were reacted and treated in the same manner as in Example B-216 to give the compounds shown in the table below.

[0254] Reference Example θ-4 (13aS)-7-chloro-2-methyl-11,12,13,13a-tetrahydro-9H-pyridazino[3,4-e]pyrrolo[1,2-a][1,2,4]triazolo[5,1-c][1,4]diazepin-9-one

[0255] a) Preparation of benzyl (2S)-2-(3-methyl-1H-1,2,4-triazol-5-yl)pyrrolidine-1-carboxylate (Reference Example θ-1) K ２ CO ３ Ethanimidamide hydrochloride (1.99 g) was added to a mixture of HATU (6.93 g) and DIPEA (5.12 mL) in DMF (20 mL) and the mixture was stirred at room temperature for 1 hour. A solution of 1-[(benzyloxy)carbonyl]-L-proline (5.0 g) in DMF (10 mL) and a suspension of HATU in DMF (20 mL) were added dropwise to the mixture at 0°C, followed by stirring at the same temperature for 1 hour and then overnight at room temperature. The reaction mixture was filtered, and the resulting filtrate was added dropwise to a mixture of monochloroacetic acid (7.58 g) and hydrazine monohydrate (1.07 mL) in DMF (20 mL) at 0°C. The mixture was stirred at the same temperature for 1 hour and then overnight at room temperature. After completion of the reaction, the mixture was separated and washed with isopropyl acetate-saturated brine. The resulting organic layer was separated and washed with saturated aqueous sodium bicarbonate solution, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol) to obtain Reference Example θ-1 (1.65 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 287 / 0.621 / A

[0256] b) Preparation of 3-methyl-5-[(2S)-pyrrolidin-2-yl]-1H-1,2,4-triazole (Reference Example θ-2) A mixture of benzyl (2S)-2-(3-methyl-1H-1,2,4-triazol-5-yl)pyrrolidine-1-carboxylate (1.65 g) and 20 wt % palladium hydroxide / carbon (0.81 g) in ethanol (29 mL) was stirred under a hydrogen atmosphere at room temperature for 3.5 hours. After filtration through Celite, the solvent was distilled off to obtain Reference Example θ-2 (0.39 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 153 / 0.145 / A

[0257] c) Preparation of (3,6-dichloropyridazin-4-yl)[(2S)-2-(3-methyl-1H-1,2,4-triazol-5-yl)pyrrolidin-1-yl]methanone (Reference Example θ-3) To a solution of 3-methyl-5-[(2S)-pyrrolidin-2-yl]-1H-1,2,4-triazole (0.68 g), 3,6-dichloropyridazine-4-carboxylic acid (0.95 g), and 1-methylimidazole (1.24 mL) in acetonitrile (17.9 mL), TCFH (1.50 g) was added and stirred overnight at room temperature. After completion of the reaction, the mixture was separated and washed with isopropyl acetate-saturated brine, and the resulting organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to give Reference Example θ-3 (0.83 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 327 / 0.462 / A

[0258] d) Preparation of (13aS)-7-chloro-2-methyl-11,12,13,13a-tetrahydro-9H-pyridazino[3,4-e]pyrrolo[1,2-a][1,2,4]triazolo[5,1-c][1,4]diazepin-9-one (Reference Example θ-4)

[0049] (3,6-dichloropyridazin-4-yl)[(2S)-2-(3-methyl-1H-1,2,4-triazol-5-yl)pyrrolidin-1-yl]methanone (0.50 g) and Cs ２ CO ３A mixture of (1.49 g) of the above-mentioned compound in acetonitrile (7.6 mL) was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to obtain Reference Example θ-4 (0.32 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 291 / 0.492 / A

[0259] Reference Example θ-8 3'-chloro-9'-methyl-6'H-spiro[cyclopropane-1,7'-pyridazino[4,3-b][1,2,4]triazolo[1,5-d][1,4]oxazepine]

[0260] a) Preparation of ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (Reference Example θ-5) A solution of diethyl cyclopropane-1,1-dicarboxylate (20 g) in THF (270 mL) was added dropwise at room temperature to a suspension of LTBA (68.3 g) in THF (270 mL), and the mixture was stirred at room temperature for 2 days. The reaction solution was added dropwise to a solution of sodium hydrogen sulfate monohydrate (89 g) in water (644 mL), followed by separation and extraction with ethyl acetate, and the resulting organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure to give Reference Example θ-5 (15 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 145 / 0.513 / A

[0261] b) Preparation of 1-{[(3,6-dichloropyridazin-4-yl)oxy]methyl}cyclopropane-1-carboxylic acid (Reference Example θ-6) A solution of ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (8.0 g) and 3,4,6-trichloropyridazine (13.2 g) in acetonitrile (111 mL) was treated with Cs ２ CO ３(27.1 g) was added and stirred overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated. The resulting residue was dissolved in acetonitrile (111 mL). A solution of sodium hydroxide (4.44 g) in water (333 mL) was then added dropwise, and the mixture was stirred overnight at room temperature. After completion of the reaction, the mixture was separated and washed with heptane / toluene (2:1), and the resulting aqueous layer was acidified with sodium hydrogen sulfate monohydrate (19.2 g). Sodium chloride (97 g) was added, and the mixture was separated and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then chloroform (111 mL) was added to the resulting residue. Insoluble matter was filtered off, and the filtrate was concentrated. The resulting residue (13 g) was stirred in MTBE (65 mL), and the solid was collected by filtration to obtain Reference Example θ-6 (11 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 165 / 0.978 / A

[0262] c) Preparation of 3,6-dichloro-4-{[1-(3-methyl-1H-1,2,4-triazol-5-yl)cyclopropyl]methoxy}pyridazine (Reference Example θ-7) To a solution of 1-{[(3,6-dichloropyridazin-4-yl)oxy]methyl}cyclopropane-1-carboxylic acid (3.6 g) and DIPEA (3.6 mL) in THF (15 mL) was added dropwise a suspension of PyBOP (7.8 g) and DIPEA (3.6 mL) in THF (7.5 mL) at 0°C, and the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, THF (15 mL) was added, followed by addition of disodium succinate (1.77 g) at 0°C, and the mixture was stirred at the same temperature for 10 minutes. Then, ethanimidamide hydrochloride (1.94 g) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added dropwise to a suspension of succinic acid (8.08 g) and hydrazine monohydrate (1 mL) in THF (15 mL) at 0°C, and the mixture was stirred overnight at room temperature. After completion of the reaction, the mixture was separated and washed with ethyl acetate-saturated brine, and the resulting organic layer was washed with saturated aqueous sodium bicarbonate and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to obtain Reference Example θ-7 (1.58 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 300 / 0.582 / A

[0263] d) Preparation of 3'-chloro-9'-methyl-6'H-spiro[cyclopropane-1,7'-pyridazino[4,3-b][1,2,4]triazolo[1,5-d][1,4]oxazepine] (Reference Example θ-8) A mixture of 3,6-dichloro-4-{[1-(3-methyl-1H-1,2,4-triazol-5-yl)cyclopropyl]methoxy}pyridazine (1.58 g) and cesium carbonate (5.15 g) in acetonitrile (26.3 mL) was stirred at 55°C for 1.5 hours. After completion of the reaction, the reaction solution was filtered, and chloroform (10 mL) was added to the residue obtained by concentrating the filtrate. Insoluble matter was filtered off, and the filtrate was concentrated. The resulting residue was stirred in MTBE (10 mL), and the solid was collected by filtration to give Reference Example θ-8 (0.73 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 264 / 0.581 / A

[0264] Reference Example θ-13 3-methyl-5-[(2S)-pyrrolidin-2-yl]-1H-pyrazole

[0265] a) Preparation of benzyl (2S)-2-(chlorocarbonyl)pyrrolidine-1-carboxylate (Reference Example θ-9) To a solution of 1-[(benzyloxy)carbonyl]-L-proline (5.00 g) and N,N-dimethylformamide (0.02 mL) in dichloromethane (35 mL), a solution of oxalyl chloride (2.58 mL) in dichloromethane (5.0 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain Reference Example θ-9 (5.36 g). LC-MS: [M-Cl+MeOH]+ / Rt (min) / Measurement conditions: 264 / 0.865 / A

[0266] b) Preparation of benzyl (2S)-2-[2-(tert-butoxycarbonyl)-3-oxobutanoyl]pyrrolidine-1-carboxylate (Reference Example θ-10) To a solution of tert-butyl acetoacetate (6.35 g) in tetrahydrofuran (25 mL), methylmagnesium chloride (2.0 mol / L solution in tetrahydrofuran (20 mL)) was added dropwise under ice cooling, and the mixture was stirred at 15°C for 1 hour. To the resulting reaction solution, a solution of Reference Example θ-9 (5.36 g) in tetrahydrofuran (10 mL) was added dropwise at 15°C, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, an aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain Reference Example θ-10. LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 390 / 1.184 / A

[0267] c) Preparation of benzyl (2S)-2-(3-oxobutanoyl)pyrrolidine-1-carboxylate (Reference Example θ-11) A solution of Reference Example θ-10 (7.80 g) in toluene (40 mL) was washed with dilute hydrochloric acid, and then paratoluenesulfonic acid monohydrate (0.76 g) was added and stirred at 80°C for 8 hours. The reaction solution was returned to room temperature, and separation and extraction were performed with toluene and water. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain Reference Example θ-11 (5.79 g). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 290 / 0.947 / A

[0268] d) Preparation of benzyl (2S)-2-(3-methyl-1H-pyrazol-5-yl)pyrrolidine-1-carboxylate (Reference Example θ-12) Hydrazine monohydrate (0.99 mL) was added to a solution of Reference Example θ-11 (5.90 g) in ethanol (41 mL), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was separated and extracted with toluene and water, the organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example θ-12 (4.15 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 286 / 0.793 / A

[0269] e) Preparation of 3-methyl-5-[(2S)-pyrrolidin-2-yl]-1H-pyrazole (Reference Example θ-13) Palladium hydroxide on carbon (4.08 g) was added to a solution of Reference Example θ-12 (4.15 g) in tetrahydrofuran (66 mL)-acetic acid (6.6 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 8 hours. After filtration through Celite, a 10 wt % aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give Reference Example θ-13 (2.20 g). 1 H-NMR (400 MHz, CDCl3): 1.76-1.88 (3H, m), 2.10-2.18 (1H, m), 2.27 (3H, s), 2.98 (1H, dt, J = 10.4, 7.2 Hz), 3.05-3.11 (1H, m), 4.21-4.25 (1H, m), 5.91 (1H, s).

[0270] In Examples H-1 to H-23, the corresponding starting compounds were reacted and treated in the same manner as in Example B-216 to obtain the compounds shown in the table below.

[0271] Example I-1 6-(2-cyclopropylpyridin-3-yl)-N-[(1S)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methoxycyclohexyl]pyridazin-3-amine Example I-2 6-(2-cyclopropylpyridin-3-yl)-N-[(1R)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methoxycyclohexyl]pyridazin-3-amine

[0272] a) Preparation of methyl 4-(benzylamino)-1-methoxycyclohexane-1-carboxylate (Reference Example λ-1) To a solution of methyl 1-methoxy-4-oxocyclohexane-1-carboxylate (400 mg) and benzylamine (274 mg) in THF (6.0 mL) was added acetic acid (0.05 mL), and then NaBH(OAc) ３(907 mg) was added and stirred at room temperature for 3 hours. After the reaction was completed, water (5 mL) was added, and the mixture was separated and extracted with ethyl acetate. The resulting organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by reversed-phase column chromatography to give Reference Example λ-1 (377 mg). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 278 / 1.626&1.690 / D

[0273] b) Preparation of methyl 4-amino-1-methoxycyclohexane-1-carboxylate (Reference Example λ-2) To a solution of methyl 4-(benzylamino)-1-methoxycyclohexane-1-carboxylate (377 mg) in methanol (5.0 mL) was added 20 wt % palladium hydroxide on carbon (50 mg), and the mixture was stirred at room temperature under a hydrogen gas atmosphere for 3 hours. After completion of the reaction, the mixture was filtered through Celite, and the solvent in the filtrate was distilled off to obtain Reference Example λ-2 (180 mg). This was used in the next step without further purification. LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 188 / 0.990&1.012 / D

[0274] c) Preparation of 4-{[6-(2-cyclopropylpyridin-3-yl)pyridazin-3-yl]amino}-1-methoxycyclohexane-1-carboxylic acid (Reference Example λ-3) tBuXPhos Pd G3 (48 mg), tBuXPhos (50.9 mg), and tBuONa were added to a solution of methyl 4-amino-1-methoxycyclohexane-1-carboxylate (169 mg) and 3-chloro-6-(2-cyclopropylpyridin-3-yl)pyridazine (140 mg) in 1,4-dioxane (5.0 mL), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, insoluble matter was removed by filtration, and then a solution of lithium hydroxide monohydrate (202 mg) in water (1.0 mL) was added to the filtrate, and the mixture was stirred at room temperature for 1 hour. A 1M aqueous solution of citric acid was added to the reaction solution so that the pH was adjusted to 5 to 6, and the solvent was evaporated to obtain a residue, which was purified by reverse phase column chromatography to obtain Reference Example λ-3 (110 mg). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 369 / 1.218 / D

[0275] d) Preparation of (4-{[6-(2-cyclopropylpyridin-3-yl)pyridazin-3-yl]amino}-1-methoxycyclohexyl)[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methanone (Reference Example λ-4) HATU (280 mg), DIPEA (189 mg), and (3R,4R)-3,4-dimethoxypyrrolidine (77.5 mg) were added to a solution of 4-{[6-(2-cyclopropylpyridin-3-yl)pyridazin-3-yl]amino}-1-methoxycyclohexane-1-carboxylic acid (182 mg) in DMF (3.0 mL), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off, and the resulting residue was purified by reverse phase column chromatography to give Reference Example λ-4 (115 mg). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 482 / 1.535 / D

[0276] e) Preparation of 6-(2-cyclopropylpyridin-3-yl)-N-[(1S)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methoxycyclohexyl]pyridazin-3-amine (Example I-1) and 6-(2-cyclopropylpyridin-3-yl)-N-[(1R)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methoxycyclohexyl]pyridazin-3-amine (Example I-2) A 1M solution of (4-{[6-(2-cyclopropylpyridin-3-yl)pyridazin-3-yl]amino}-1-methoxycyclohexyl)[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methanone (105 mg) in THF (2.0 mL) was added. A THF solution (1.7 mL) of DIBAL-H was added dropwise at 0°C, and the mixture was stirred for 4 hours. Sodium sulfate decahydrate was added to the reaction solution to terminate the reaction, and insoluble matter was removed by filtration. The filtrate was concentrated, and the resulting residue was purified by reversed-phase column chromatography, followed by preparative supercritical fluid chromatography to obtain Example I-1 (9.4 mg) and Example I-2 (21.7 mg). Reference Example I-1 LC-MS: [M+H]+ / Rt (min) / measurement conditions: 468 / 1.631 / D Reference Example I-2 LC-MS: [M+H]+ / Rt (min) / measurement conditions: 468 / 1.628 / D

[0277] The spectral data for Examples I-1 and I-2 are shown in the table below.

[0278] Reference Example μ-3 (S)-4-(6-chloropyridazin-3-yl)-5-isopropylmorpholin-3-one

[0279] a) Preparation of (S)-2-chloro-N-(1-hydroxy-3-methylbutan-2-yl)acetamide (Reference Example μ-1) To a solution of (S)-amino-3-methylbutanol (3.00 g) in tetrahydrofuran (91 mL) was added a solution of potassium carbonate (12.1 g) in water (91.0 mL) at −10° C. Chloroacetyl chloride (2.54 mL) was slowly added to the reaction solution over 4 minutes at −10° C. The reaction solution was stirred at −10° C. for 2 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain Reference Example μ-1 (4.97 g). 1 H-NMR (400 MHz, CDCl3): 0.96 (3H, d, J = 6.0 Hz), 0.99 (3H, d, J = 6.0 Hz), 1.91-2.00 (1H, m), 2.13-2.19 (1H, m), 3.71-3.80 (3H, m), 4.10 (2H, s), 6.73 (1H, br s).

[0280] b) Preparation of (S)-5-isopropylmorpholin-3-one (Reference Example μ-2) To a solution of Reference Example μ-1 (4.51 g) in dichloromethane (193 mL) was added dropwise a solution of potassium t-butoxide (11.27 g) in isopropyl alcohol (193 mL) at 0° C. over 1 hour. The reaction solution was stirred at room temperature for 2.5 hours. After completion of the reaction, 2 M aqueous hydrochloric acid and 1 M aqueous sodium hydroxide were added to the reaction solution, and the pH of the solution was adjusted to 7. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in ethyl acetate, washed with 20% saturated brine, dried over sodium sulfate, and then the solvent was evaporated under reduced pressure to give Reference Example μ-2 (3.07 g). 1H-NMR (400 MHz, CDCl3): 0.96 (3H, d, J = 6.7 Hz), 0.99 (3H, d, J = 6.7 Hz), 1.74-1.83 (1H, m), 3.27-3.32 (1H, m), 3.58 (1H, dd, J = 11.9, 7.3 Hz), 3.90 (1H, dd, J = 11.9, 4.3 Hz), 4.09 (1H, d, J = 16.5 Hz), 4.18 (1H, d, J = 16.5 Hz), 6.22-6.32 (1H, br m).

[0281] c) Preparation of (S)-4-(6-chloropyridazin-3-yl)-5-isopropylmorpholin-3-one (Reference Example μ-3) To a DMSO (15.1 mL) solution of compound μ-2 (1.08 g), tripotassium phosphate (3.20 g), and 1,10-phenanthroline (0.136 g) suspended, 3-chloro-6-iodo-pyridazine (1.81 g) and copper(I) iodide (0.144 g) were added at room temperature. The reaction solution was stirred at 60°C for 6.5 hours. After completion of the reaction, ethyl acetate was added to the reaction solution, which was washed with 50% saturated brine, washed with brine, dried over sodium sulfate, and then filtered through Celite. The solvent in the filtrate was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example μ-3 (0.850 g). 1 H-NMR (400 MHz, CDCl3): 0.89 (3H, d, J = 6.7 Hz), 0.98 (3H, d, J = 6.7 Hz), 2.03-2.12 (1H, m), 3.94 (1H, dd, J = 12.5, 3.4 Hz), 4.23-4.29 (1H, m), 4.28 (1H, d, J = 17.3 Hz), 4.44 (1H, d, J = 17.3 Hz), 4.92-4.95 (1H, m), 7.51 (1H, d, J = 9.8 Hz), 8.16 (1H, d, J = 9.8 Hz).

[0282] Reference Example μ-7 (R)-1-(6-chloropyridazin-3-yl)-5-isopropylpyrrolidin-2-one

[0283] a) Preparation of tert-butyl (R)-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-methylbutan-2-yl)carbamate (Reference Example μ-4) To a solution of (tert-butoxycarbonyl)-L-valine (3.00 g) in dichloromethane (51.1 mL) were added Meldrum's acid (1.99 g) and 4-dimethylaminopyridine (2.53 g) at −5° C. A solution of dicyclohexylcarbodiimide (3.13 g) in dichloromethane (25.6 mL) was added dropwise to this reaction solution at −5° C. over 30 minutes. The reaction solution was stirred at −5° C. for 6.5 hours. After completion of the reaction, the reaction solution was filtered. The filtrate was washed successively with a 5% aqueous potassium hydrogen sulfate solution and saturated brine. The organic layer was evaporated under reduced pressure to approximately 51.1 mL. To the obtained dichloromethane (51.1 mL) solution, acetic acid (7.67 mL) was added at -5°C. To this solution, sodium borohydride (1.31 g) was added portionwise over 3 hours at -5°C, and the reaction solution was then stirred at -5°C for 4 hours. After completion of the reaction, water was added to the reaction solution, and the organic layer was washed three times with water and twice with brine, successively. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. Diethyl ether (22 mL) was added to the obtained residue, and the mixture was allowed to stand overnight. The precipitated pale yellow needle-like solid was collected by filtration to obtain Reference Example μ-4 (2.05 g). 1 H-NMR (400 MHz, CDCl3): 0.95 (3H, d, J = 6.7 Hz), 0.97 (3H, d, J = 6.7 Hz), 1.41 (9H, s), 1.73-1.85 (7H, m), 2.07-2.16 (1H, m), 2.22-2.30 (1H, m), 3.71-3.79 (1H, m), 3.93-3.97 (1H, m), 4.47 (1H, d, J = 9.8 Hz).

[0284] b) Preparation of tert-butyl (R)-2-isopropyl-5-oxopyrrolidine-1-carboxylate (Reference Example μ-5) A solution of Reference Example μ-4 (2.05 g) in toluene (27 mL) was heated to 110° C. and stirred for 6 hours. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure to give Reference Example μ-5 (1.46 g). 1 H-NMR (400 MHz, CDCl3): 0.86 (3H, d, J = 6.7 Hz), 0.94 (3H, d, J = 6.7 Hz), 1.53 (9H, s), 1.79-1.86 (1H, m), 1.93-2.04 (1H, m), 2.19-2.27 (1H, m), 2.39-2.57 (2H, m), 4.06-4.10 (1H, m).

[0285] c) Preparation of (R)-5-isopropylpyrrolidin-2-one (Reference Example μ-6) To a solution of Reference Example μ-5 (1.20 g) in chloroform (31.0 mL) was added trifluoroacetic acid (0.813 mL) at 0° C. The reaction solution was stirred at room temperature for 6 hours. After completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added, and the aqueous layer was extracted with chloroform. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain Reference Example μ-6 (0.699 g). 1 H-NMR (400 MHz, CDCl3): 0.90 (3H, d, J = 6.7 Hz), 0.94 (3H, d, J = 6.7 Hz), 1.60-1.70 (1H, m), 1.74-1.83 (1H, m), 2.14-2.23 (1H, m), 2.33-2.39 (2H, m), 3.37-3.44 (1H, m), 6.19 (1H, br s).

[0286] d) Preparation of (R)-1-(6-chloropyridazin-3-yl)-5-isopropylpyrrolidin-2-one (Reference Example μ-7) 3-Chloro-6-iodo-pyridazine (1.32 g) and copper(I) iodide (0.105 g) were added to a DMSO (10.8 mL) solution containing Reference Example μ-6 (0.698 g), tripotassium phosphate (2.33 g), and 1,10-phenanthroline (99.0 mg) at room temperature. The reaction mixture was stirred at 60°C for 11 hours. After completion of the reaction, ethyl acetate was added to the reaction mixture, and the mixture was filtered through Celite. The filtrate was washed sequentially with 50% saturated brine and saturated brine, and then dried over sodium sulfate. The solvent in the filtrate was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example μ-7 (0.495 g). 1 H-NMR (400 MHz, CDCl3): 0.76 (3H, d, J = 7.3 Hz), 0.97 (3H, d, J = 7.3 Hz), 1.98-2.06 (1H, m), 2.12-2.23 (1H, m), 2.47-2.62 (2H, m), 2.66-2.75 (1H, m), 4.95 (1H, td, J = 3.2, 9.2 Hz), 7.48 (1H, d, J = 9.2 Hz), 8.60 (1H, d, J = 9.2 Hz).

[0287] In Examples J-1 to J-10, the corresponding starting compounds were reacted and treated in the same manner as in Example B-216 to obtain the compounds shown in the table below. The corresponding starting compounds were either purchased as commercial products or treated in the same manner as in the separately described Reference Examples to obtain the compounds.

[0288] Reference Example π-7 (1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexan-1-amine

[0289] a) Preparation of ethyl (1s,4s)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-formylcyclohexane-1-carboxylate (Reference Example π-1) To a solution of lithium diisopropylamide (1.07 mol / L, 39.3 mL) in tetrahydrofuran (50 mL) was added dropwise a solution of ethyl (1r,4r)-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexane-1-carboxylate (7.25 g) in tetrahydrofuran (18 mL) at −78° C., followed by stirring at the same temperature for 30 minutes. A solution of ethyl formate (5.13 mL) in tetrahydrofuran (2.0 mL) was added dropwise at −78° C., followed by stirring at the same temperature for 3 hours. After completion of the reaction, acetic acid (3.6 mL) was added to the reaction solution, and the mixture was allowed to cool to room temperature. Toluene was added to the reaction solution, and the mixture was washed with water and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give Reference Example π-1 (6.53 g). LC-MS: [M+H]+ / Rt (min) / Measuring conditions: 315 / 1.304 / A

[0290] b) Preparation of ethyl (1r,4r)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-(difluoromethyl)cyclohexane-1-carboxylate (Reference Example π-2) To a solution of Reference Example π-1 (9.90 g) in chloroform (63 mL), N,N-diethylaminosulfur trifluoride (5.04 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The resulting organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example π-2 (7.37 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 337 / 1.454 / A

[0291] c) Preparation of [(1r,4r)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-(difluoromethyl)cyclohexyl]methanol (Reference Example π-3) A solution of compound π-2 (2.00 g) in tetrahydrofuran (9.0 mL) was added dropwise to a solution of sodium bis(2-methoxyethoxy)aluminum hydride (2.73 g) in tetrahydrofuran (18 mL) under ice cooling, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, a 30 wt % aqueous solution of Rochelle salt was added, and the mixture was extracted with toluene. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain Reference Example π-3 (1.59 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 295 / 1.287 / A

[0292] d) Preparation of (1r,4r)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-(difluoromethyl)cyclohexane-1-carbaldehyde (Reference Example π-4) To a solution of Reference Example π-3 (1.30 g), triethylamine (4.48 mL), and dimethyl sulfoxide (3.35 mL) in chloroform (6.7 mL), sulfur trioxide-pyridine complex (3.21 g) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, toluene was added to the reaction solution, and the mixture was washed with water and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain Reference Example π-4 (1.18 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 293 / 1.371 / A

[0293] e) Preparation of (1r,4r)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexan-1-ol (Reference Example π-5) A reaction solution of Reference Example π-4 (1.40 g), 1,4-dioxa-9-azaspiro[5.5]undecane monohydrochloride (2.28 g), potassium formate (1.32 g), trimethylsilyl acetate (2.95 mL), and formic acid (1.05 mL) in acetonitrile (10 mL) was heated under reflux for 19 hours. After ice-cooling the reaction solution, hydrochloric acid (1.00 mol / L, 19.6 mL) was added and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was washed with chloroform. A 20 wt % aqueous sodium hydroxide solution was added to the obtained aqueous layer, and the mixture was extracted with chloroform. The obtained organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example π-5 (0.74 g). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 320 / 0.376 / A

[0294] f) Preparation of 2-{(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}-1H-isoindole-1,3(2H)-dione (Reference Example π-6) To a solution of Reference Example π-5 (720 mg), phthalimide (663 mg), and 1,1'-azobis(N,N-dimethylformamide) (776 mg) in cyclopentyl methyl ether (23 mL) was added tri-n-butylphosphine (1.17 mL) dropwise at −15° C., and the mixture was stirred at room temperature for 5 days. After completion of the reaction, toluene was added to the reaction solution, and the mixture was washed with DMF-water, water, and saturated brine. The resulting organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example π-6 (474 ​​mg). LC-MS: [M+H]+ / Rt (min) / Measurement conditions: 449 / 0.645 / A

[0295] g) Preparation of (1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexan-1-amine (Reference Example π-7) A 40 wt % solution of methylamine in methanol (0.95 mL) was added to a solution of Reference Example π-6 (474 ​​mg) in ethanol (5.3 mL), and the mixture was heated under reflux for 4 hours. After completion of the reaction, a 10 wt % aqueous sodium hydroxide solution was added, and the mixture was stirred for 30 minutes. The reaction solution was extracted with toluene, and the organic layer was washed with saturated brine. The obtained organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by trituration (washing solvent: hexane:ethyl acetate) to give Reference Example π-7 (227 mg). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 319 / 0.263 / A

[0296] Reference Example π-13 (1s,4s)-4-{[6-(2-cyclopropylpyridin-3-yl)pyridazin-3-yl]amino}-1-(difluoromethyl)cyclohexane-1-carbaldehyde

[0297] a) Preparation of ethyl (1r,4r)-1-(difluoromethyl)-4-hydroxycyclohexane-1-carboxylate (Reference Example π-8) To a solution of ethyl (1r,4r)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-(difluoromethyl)cyclohexane-1-carboxylate (6.25 g) in ethanol (18.57 mL) was added a solution of hydrochloric acid / CPME (18.57 mL, 4 mol / L), and the mixture was stirred at room temperature for 2 hours. After confirming the disappearance of the raw materials, the solvent was distilled off under reduced pressure, and the resulting crude product of Reference Example π-8 (4.14 g) was used directly in the next step. LC-MS: [M+H]+ / Rt (min) / measurement conditions: 223 / 0.713 / A

[0298] b) Preparation of ethyl (1s,4s)-1-(difluoromethyl)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclohexane-1-carboxylate (Reference Example π-9) To a solution of Reference Example π-8 (4.40 g), phthalimide (5.48 g), and N,N,N',N'-tetramethylazodicarboxamide (6.41 g) in CPME (62 mL), tributylphosphine (9.67 mL) was added dropwise under ice cooling, and the mixture was stirred for 1 hour. The reaction solution was then allowed to warm to room temperature and stirred overnight. The reaction solution was diluted with toluene (120 mL), and the organic layer was washed three times with a mixed solution (120 mL) of DMF:water = 1:9, followed by washing twice with water (120 mL) and once with saturated brine (60 mL). The organic layer was dried over sodium sulfate, and the solid was filtered off. The solvent in the filtrate was evaporated under reduced pressure. Ethanol (65 mL) was added to the resulting residue to form a suspension. After stirring at room temperature for 1 hour, the solid was filtered off using a Kiriyama funnel to obtain the crude product (2.87 g) of Reference Example π-9. LC-MS: [M+H]+ / Rt (min) / measurement conditions: 352 / 1.088 / A

[0299] c) Preparation of ethyl (1s,4s)-4-amino-1-(difluoromethyl)cyclohexane-1-carboxylate (Reference Example π-10) Hydrazine monohydrate (2.45 mL) was added to a 3:1 mixture (27.4 mL) of Reference Example π-9 (4.9 g) in ethanol:water, and the mixture was stirred under reflux for 2 hours. The reaction solution was returned to room temperature, diluted with water (85 mL), and extracted three times with chloroform (85 mL). The combined organic layer was washed twice with saturated brine (55 mL) and dried over sodium sulfate. The solid was then filtered off, and the solvent in the filtrate was evaporated under reduced pressure. The crude product (1.82 g) of Reference Example π-10 obtained was used directly in the next step. LC-MS: [M+H]+ / Rt (min) / measurement conditions: 352 / 1.088 / A

[0300] d) Preparation of ethyl (1s,4s)-4-{[6-(2-cyclopropylpyridin-3-yl)pyridazin-3-yl]amino}-1-(difluoromethyl)cyclohexane-1-carboxylate (Reference Example π-11) Potassium carbonate (250 mg) was added to a solution of Reference Example π-10 (100 mg) and 3-chloro-6-(2-cyclopropylpyridin-3-yl)pyridazine (157 mg) in NMP (452 ​​μL), and the reaction solution was stirred at 140° C. for 12 hours. The reaction solution was returned to room temperature, and the solid was removed by filtration through Celite. The filtrate was concentrated, and the resulting residue was purified by aminosilica gel column chromatography (elution solvent: hexane:ethyl acetate) to give Reference Example π-11 (93 mg). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 222 / 1.200 / B

[0301] e) Preparation of [(1s,4s)-4-{[6-(2-cyclopropylpyridin-3-yl)pyridazin-3-yl]amino}-1-(difluoromethyl)cyclohexyl]methanol (Reference Example π-12) A solution of Reference Example π-11 (93 mg) in THF (0.7 mL) was added dropwise to a solution of sodium bis(2-methoxyethoxy)aluminum hydride (218 μL) in THF (1.4 mL) under ice cooling, and the mixture was stirred at that temperature for 30 minutes, then returned to room temperature and stirred for 5 hours. After confirming the consumption of the raw materials, a 30 wt % Rochelle brine solution (2 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Aqueous sodium hydroxide (4 mL, 1.5 mol / L) and saturated brine (4 mL) were added to the reaction solution, which was then extracted three times with chloroform (4 mL). The combined organic layer was dried over sodium sulfate. The solid was filtered off, and the solvent in the filtrate was evaporated under reduced pressure to give a crude product (72 mg) of Reference Example π-12, which was used directly in the next step. LC-MS: [M+H]+ / Rt (min) / Measuring conditions: 375 / 0.477 / A

[0302] f) Preparation of (1s,4s)-4-{[6-(2-cyclopropylpyridin-3-yl)pyridazin-3-yl]amino}-1-(difluoromethyl)cyclohexane-1-carbaldehyde (Reference Example π-13) To a solution of Reference Example π-12 (72 mg), TEA (161 μL), and DMSO (214 μL) in chloroform (427 μL), sulfur trioxide-pyridine complex (107 mg) was added under ice-cooling, and the reaction solution was returned to room temperature and stirred for 3 hours. Aqueous sodium hydroxide solution (0.3 mL, 1.5 mol / L) was added to the reaction solution, diluted with chloroform (0.6 mL), and the organic layer was washed three times with water (1.2 mL), then with saturated brine (0.6 mL), and dried over sodium sulfate. The solid was filtered off, and the filtrate was concentrated to give the crude product of Reference Example π-13 (71.89 mg), which was used directly in the next step. LC-MS: [M+MeOH+H]+ / Rt (min) / Measurement conditions: 405 / 0.518 / A

[0303] Example K-14 1-{5-cyclopropyl-1-[6-({(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}amino)pyridazin-3-yl]-1H-1,2,4-triazol-3-yl}cyclopropan-1-ol

[0304] a) Preparation of (1s,4s)-4-[(6-{3-[1-(benzyloxy)cyclopropyl]-5-cyclopropyl-1H-1,2,4-triazol-1-yl}pyridazin-3-yl)amino]-1-(difluoromethyl)cyclohexane-1-carboxylic acid (Reference Example π-14) A solution of lithium hydroxide (47.2 mg) in water (986 μL) was added to a solution of ethyl (1s,4s)-4-[(6-{3-[1-(benzyloxy)cyclopropyl]-5-cyclopropyl-1H-1,2,4-triazol-1-yl}pyridazin-3-yl)amino]-1-(difluoromethyl)cyclohexane-1-carboxylate (218 mg) in ethanol (986 μL) at room temperature, and the reaction solution was stirred under heating and reflux for 2 hours. After the reaction solution was returned to room temperature, a solution of citric acid in water (10 mL, 1 mol / L) was added, and the mixture was extracted twice with isopropyl acetate (10 mL). The combined organic layers were washed twice with saturated brine (6 mL) and dried over sodium sulfate. The solid was filtered off, and the solvent in the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane:chloroform) to give Reference Example π-14 (179 mg). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 525 / 1.039 / A

[0305] b) Preparation of [(1s,4s)-4-[(6-{3-[1-(benzyloxy)cyclopropyl]-5-cyclopropyl-1H-1,2,4-triazol-1-yl}pyridazin-3-yl)amino]-1-(difluoromethyl)cyclohexyl](1,4-dioxa-9-azaspiro[5.5]undecane-9-yl)methanone (Reference Example π-15) To a solution of Reference Example π-14 (179 mg), 1,4-dioxa-9-azaspiro[5.5]undecane hydrochloride (86 mg), and N-ethyldiisopropylamine (174 μL) in chloroform (1.7 mL) was added HATU (182 mg) at room temperature, and the mixture was stirred overnight at room temperature. The reaction solution was washed twice with saturated aqueous ammonium chloride (2 mL), once with saturated aqueous sodium bicarbonate (2 mL), and then once with saturated brine (2 mL). The organic layer was dried over sodium sulfate, and the solid was filtered off. The solvent in the filtrate was evaporated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (elution solvent: hexane / ethyl acetate) to give Reference Example π-15 (219 mg). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 665 / 1.067 / A

[0306] c) Preparation of [(1s,4s)-4-({6-[5-cyclopropyl-3-(1-hydroxycyclopropyl)-1H-1,2,4-triazol-1-yl]pyridazin-3-yl}amino)-1-(difluoromethyl)cyclohexyl](1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methanone (Reference Example π-16) Reference Example π-15 (218 mg) was dissolved in a mixed solution (1.64 mL) of ethanol:THF=10:1, and then a solution of hydrochloric acid in methanol (328 μL, 2 mol / L) was added, followed by the addition of 20 wt % palladium hydroxide on activated carbon (69.2 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 6 hours, and then filtered through Celite. The solvent in the filtrate was evaporated under reduced pressure to give the crude product of Reference Example π-16 (188 mg). No further purification was performed and the product was used in the next step. LC-MS: [M+H]+ / Rt (min) / Measuring conditions: 574 / 0.694 / A

[0307] d) Preparation of 1-{5-cyclopropyl-1-[6-({(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}amino)pyridazin-3-yl]-1H-1,2,4-triazol-3-yl}cyclopropan-1-ol (Example K-14) A solution of Reference Example π-16 (188 mg) in THF (1 mL) was added dropwise to a solution of lithium aluminum hydride (49.8 mg) in THF (2 mL) under ice-cooling, and the mixture was stirred for 1 hour under ice-cooling. A 10 wt % aqueous sodium hydroxide solution (10 mL) was added under ice-cooling, and the mixture was further stirred for 30 minutes. The resulting reaction mixture was extracted three times with a 4:1 mixture (10 mL) of chloroform:methanol. The combined organic layer was dried over sodium sulfate, the solid was filtered off, and the solvent in the filtrate was evaporated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (elution solvent: hexane:chloroform) to give Example K-14 (51 mg). LC-MS: [M+H]+ / Rt (min) / measurement conditions: 560 / 0.472 / A

[0308] In Examples K-1 to K-16, the corresponding starting compounds were reacted and treated in the same manner as in Example B-216 or Example K-14 to obtain the compounds shown in the table below. The corresponding starting compounds were either purchased as commercial products or treated in the same manner as in the separately described Reference Examples to obtain the compounds.

[0309] Test Examples The results of pharmacological tests on representative compounds of the present invention are shown below to explain the pharmacological effects of said compounds, but the present invention is not limited to these test examples.

[0310] Test Example 1: Evaluation of binding activity to human muscarinic M4 receptor The binding affinity of the compound of the present invention to the human muscarinic M4 receptor was measured by the following method. A CHO cell membrane fraction expressing the human muscarinic M4 receptor was purchased from PerkinElmer. In the binding evaluation test, a test compound dissolved in dimethyl sulfoxide (DMSO), various receptor membrane specimens diluted with buffer, and 3The mixture was mixed with [H]N-methyl scopolamine (PerkinElmer) and incubated at room temperature for 120 minutes. Nonspecific binding to the receptor was determined by competitive binding assay in the presence of 10 μmol / L atropine sulfate hydrate (Fujifilm Wako Pure Chemical Industries, Ltd.). Radioactivity bound to the receptor was measured using a liquid scintillation counter (Aloka), and the 50% inhibitory concentration was calculated. The Ki value was evaluated from the dissociation constant calculated from the saturation binding assay and the substrate concentration, and used as the binding affinity. The resulting affinity values ​​are shown in Tables 12 to 21.

[0311] Test Example 2: Evaluation of binding activity to human muscarinic M1 receptors The binding affinity of the compounds of the present invention to human muscarinic M1 receptors was measured by the following method. CHO cell membrane fractions expressing human muscarinic M1 receptors were purchased from Levity. In the binding evaluation test, test compounds dissolved in dimethyl sulfoxide (DMSO), various receptor membrane specimens diluted with buffer, and 3 The mixture was mixed with [H]N-methyl scopolamine (Levity) and incubated at room temperature for 120 minutes. Nonspecific binding to the receptor was determined by competitive binding assay in the presence of 10 μmol / L atropine sulfate hydrate (Fujifilm Wako Pure Chemical Industries, Ltd.). Radioactivity bound to the receptor was measured using a liquid scintillation counter (Aloka), and the 50% inhibitory concentration was calculated. The Ki value was evaluated from the dissociation constant calculated from the saturation binding assay and the substrate concentration, and used as the binding affinity. The resulting affinity values ​​are shown in Table 22.

[0312] As shown in Tables 12 to 21 and 22, the compounds of the Examples obtained binding activity values ​​in this test, demonstrating selective binding to the muscarinic M4 receptor, and therefore useful as muscarinic M4 receptor antagonists. Among these, compounds with small Ki values ​​(i.e., low 50% inhibitory concentrations) in the evaluation of Test Example 1 (Tables 12 to 19) indicate particularly high binding affinity to the muscarinic M4 receptor, and therefore compounds with a binding affinity of 100 nM or less are preferred, with compounds with a binding affinity of 30 nM or less being preferred, and compounds with a binding affinity of 10 nM or less being more preferred. Furthermore, the binding affinity of the human muscarinic M1 receptor (M1 binding Ki value) determined in Test Example 2 divided by the binding affinity of the human muscarinic M4 receptor (M4 binding Ki value) determined in Test Example 1 was used as the binding selectivity to the muscarinic M4 receptor (M4 selectivity), and the compounds of the Examples were evaluated (Table 23). A higher M4 selectivity value indicates more selective binding to the muscarinic M4 receptor compared to the muscarinic M1 receptor, and the M4 selectivity of the compounds of the present invention is 10-fold or more, preferably 20-fold or more, more preferably 40-fold or more, and even more preferably 60-fold or more. Furthermore, the results of evaluating the binding selectivity to the muscarinic M4 receptor for scopolamine hydrobromide, a subtype-nonselective muscarinic receptor antagonist, are shown in Test Example 1, Test Example 2, and Table 24.

[0313] Test Example 3: Evaluation of the ameliorating effect on motivational impairment The ameliorating effect of the compound of the present invention on motivational impairment was measured using a progressive ratio task in common marmosets. In this task, common marmosets could receive rewards from a feeding device (Physiotech Co., Ltd.) by touching a figure displayed on a touch panel. The number of touches required to obtain one reward was gradually increased with each reward. The test was terminated when the animal did not make a single touch within 3 minutes or 30 minutes had elapsed since the start of the test. The compound of the present invention or a control compound was evaluated using animals that had been thoroughly trained in the above task. 120 minutes before the start of the test, the VMAT2 inhibitor tetrabenazine (Tokyo Chemical Industry Co., Ltd.) was administered subcutaneously as a motivational impairment inducer, or the vehicle was administered subcutaneously. 30 minutes before the start of the test, the compound of the present invention or the vehicle was administered subcutaneously as a test substance. For evaluation of control compounds, scopolamine hydrobromide, a subtype-nonselective muscarinic receptor antagonist, or vehicle was administered intramuscularly. Animals were repeatedly treated with these compounds with a washout period, and the evaluation was performed. The number of touches required to obtain the last reward (breakpoint) was analyzed as an index of motivation. To evaluate the induction of motivational impairment by tetrabenazine, breakpoints in the vehicle + vehicle group and the vehicle + tetrabenazine group were analyzed using a linear mixed model followed by a Dunnett test. To evaluate the ameliorative effect of the compound of the present invention or control compound on motivational impairment, breakpoints in the vehicle + tetrabenazine group and the vehicle + compound of the present invention or control compound group were analyzed using a linear mixed model followed by a Dunnett test. The results obtained are shown in FIGS.

[0314] As shown in the graphs of Figures 1 to 3, the compounds of the examples showed an improving effect on motivational disorders in common marmosets. On the other hand, as shown in Figure 3, the subtype-nonselective scopolamine hydrobromide showed an aggravating effect on motivational disorders.

[0315] The compounds of the present invention have binding affinity for human muscarinic M4 receptors, and by selectively binding to the muscarinic M4 receptor and exhibiting antagonistic activity, are expected to be useful as therapeutic and / or preventive agents for neurodegenerative diseases, brain injury diseases, psychological developmental disorders, psychiatric disorders, cognitive dysfunction associated with movement disorders, and their peripheral symptoms and movement dysfunction.

Claims

1. Formula (1): [In the formula, R １ is an optionally substituted C １－６ Alkyl or optionally substituted C １－６ represents alkoxy, R ５ represents a hydrogen atom, an optionally substituted C １－６ Alkyl or optionally substituted C １－６ represents alkoxy, R ２ and R ３ are each independently a hydrogen atom, an optionally substituted C １－６ Alkyl, optionally substituted C ３－１０ cycloalkyl, an optionally substituted 4-12 membered saturated heterocyclic group, or R ２ and R ３ together represent an optionally substituted 4-12 membered saturated monocyclic, bicyclic, tricyclic or spirocyclic heterocyclic group; R ４ is halogen, optionally substituted C ６－１０ aryl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted 4-12 membered saturated heterocyclic group, or an optionally substituted C ３－１０ X, Y, Z, and W each independently represent a nitrogen atom or CR ６ represents R ６ represents a hydrogen atom, an optionally substituted C １－６ alkyl, or at least one of X and Z is CR ６ When R ６ and the above R ４ are taken together to form an optionally substituted C ３－１０ and Q represents an oxygen atom, a sulfur atom, or N-H.] or a pharmaceutically acceptable salt thereof, provided that: i) N-[4-(aminomethyl)-4-methylcyclohexyl]-4-tert-butylaniline, ii) 3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-N ６ -[4-(aminomethyl)-4-methylcyclohexyl]pyrazine-2,6-diamine, and pharmaceutically acceptable salts thereof.

2. R １ and R ５ "Optionally substituted C" selected from １－６ alkyl," or "optionally substituted C １－６ The substitutable substituents in "alkoxy" are each independently 1 to 3 of the same or different halogen or deuterium, ２ and R ３ "Optionally substituted C" selected from １－６ The substitutable substituents in "alkyl" are each independently 1 to 3 of the same or different, such as halogen, C １－６ Alkoxy, C ３－１０ cycloalkyl, or a 4- to 12-membered saturated heterocyclic group, ３－１０ The cycloalkyl or 4-12 membered saturated heterocyclic group may further include oxo, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ Haloalkoxy, and C １－６ alkylcarbonylamino; R ２ and R ３ "Optionally substituted C" selected from ３－１０ The substitutable substituents in the "optionally substituted 4- to 12-membered saturated heterocyclic group" or "optionally substituted 4- to 12-membered saturated heterocyclic group" are each independently 1 to 3 of the same or different, such as halogen, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ alkoxy, or a 4- to 12-membered saturated heterocyclic group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, oxo, C １－６ Alkyl, C １－６ Alkoxy and C １－６ alkylcarbonyl, R ２ and R ３ and R are taken together to form an "optionally substituted 4-12 membered monocyclic, bicyclic, tricyclic or spirocyclic saturated heterocyclic group", and each of the substitutable substituents is independently 1 to 3 of the same or different halogen, oxo, hydroxyl group, cyano group, C １－６ Alkyl, C １－６ Alkoxy, C ６－１０ Aryl, 5-10 membered heteroaryl, deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ is an alkylthio group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ One or more hydrogen atoms in the alkoxy may be deuterium, and R ４ "Optionally substituted C" selected from ６－１０ The substitutable substituents in the "aryl" or "optionally substituted 5-10 membered heteroaryl" are each independently 1 to 3 of the same or different halogen, cyano group, amino group, carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, diC １－６ alkylaminocarbonyl, or C １－６ is cycloalkoxy, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４ "Optionally substituted 4-12 membered saturated heterocyclic group" or "optionally substituted C ３－１０ The substitutable substituents in "cycloalkyl" are each independently 1 to 3 of the same or different halogen, cyano group, amino group, carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C ２－６ alkenyl, or oxo, １－６ The alkyl may further include halogen, C ６－１０ Aryl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ The cycloalkyl may be further substituted with one or more halogens, and R ６ "Optionally substituted C" selected from １－６ The substitutable substituents in "alkyl" are each independently 1 to 3 of the same or different halogens, ４ and R ６ When these are taken together, "optionally substituted C ３－１０ The substitutable substituents in the "optionally substituted 4- to 12-membered saturated heterocyclic group" or "optionally substituted 4- to 12-membered saturated heterocyclic group" are each independently 1 to 3 of the same or different, such as oxo, C １－６ Alkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, 5-10 membered heteroaryl, or 4-12 membered saturated heterocyclic group, among which C ３－１０ Cycloalkyl, C ６－１０ Substituents for cyclic structures such as aryl, 5-10 membered heteroaryl, or 4-12 membered saturated heterocyclic groups are R ４ and R ６ Together they form C ３－１０ The compound according to claim 1, which forms a fused ring structure or a spiro structure with a cycloalkyl or a 4- to 12-membered saturated heterocyclic group, or a pharmaceutically acceptable salt thereof.

3. R １ is C １－３ alkyl, and １－３ The alkyl may be substituted with one or more fluorines, or １－３ 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms in the alkyl are deuterium.

4. R ５ The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein is a hydrogen atom.

5. R ２ is a hydrogen atom, and R ３ is C １－６ Alkyl, C ３－１０ cycloalkyl, or a 4- to 12-membered saturated heterocyclic group, wherein the C １－６ The alkyl group may be selected from the group consisting of 1 to 3 of the same or different halogens, C ３－１０ Optionally substituted with cycloalkyl or 4-12 membered saturated heterocyclic group, ３－１０ The cycloalkyl or 4-12 membered saturated heterocyclic group may further include 1 to 3 oxo, C １－６ Alkyl, C １－６ Alkoxy, C １－６ may be substituted with alkylcarbonyl, or R ２ and R ３ and R are taken together to form a monocyclic, bicyclic, tricyclic or spirocyclic 4-12 membered saturated heterocyclic group, wherein each of the 4-12 membered saturated heterocyclic groups independently has 1 to 3 of the same or different halogen, oxo, hydroxyl group, cyano group, C １－６ Alkyl, C １－６ Alkoxy, Deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ is an alkylthio group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms in the alkoxy may be deuterium.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein any one or more of X, Y, Z and W is a nitrogen atom.

7. The compound according to any one of claims 1 to 6, wherein Q is N--H, or a pharmaceutically acceptable salt thereof.

8. The compound according to any one of claims 1 to 7, represented by formula (2), or a pharmaceutically acceptable salt thereof.

9. R ２ and R ３ are taken together to form a monocyclic, bicyclic, tricyclic or spirocyclic 4-12 membered saturated heterocyclic group, and the optionally substituted 4-12 membered saturated heterocyclic group has 1 to 3 identical or different substituents selected from the group consisting of halogen, oxo, hydroxyl group, cyano group, C １－６ Alkyl, C １－６ Alkoxy, Deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ is an alkylthio group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms in the alkoxy may be deuterium.

10. R ４ is C ６－１０ aryl, 5-10 membered heteroaryl, or 4-12 membered saturated heterocyclic group; R ４ "Optionally substituted C" selected from ６－１０ The substitutable substituents in the "aryl" or "optionally substituted 5-10 membered heteroaryl" are each independently a halogen, a cyano group, an amino group, a carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, diC １－６ alkylaminocarbonyl, or C １－６ cycloalkyloxy, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４ The substitutable substituents in the "optionally substituted 4-12 membered saturated heterocyclic group" selected from the group consisting of: １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C ２－６ alkenyl, or oxo, １－６ The alkyl may further include halogen and C ６－１０ aryl, and the C ３－１０ The compound according to any one of claims 1 to 9, wherein the cycloalkyl is optionally further substituted with one or more halogens, or a pharmaceutically acceptable salt thereof.

11. R ４ is an optionally substituted 5-10 membered heteroaryl, R ４ The substitutable substituents in the "optionally substituted 5-10 membered heteroaryl" selected from the group consisting of: １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, diC １－６ Alkylaminocarbonyl, C １－６ cycloalkyloxy, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The compound according to any one of claims 1 to 9, wherein the alkoxy is optionally further substituted with one or more halogens, or a pharmaceutically acceptable salt thereof.

12. R ４ The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein is an optionally substituted 5- or 6-membered nitrogen-containing heteroaryl.

13. R ４ 12. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein is an optionally substituted 5-membered nitrogen-containing heteroaryl or an optionally substituted pyridine.

14. Equation (3) or (4): wherein U and V each independently represent a nitrogen atom or CR ４Ｃ wherein at least one of U or V is a nitrogen atom; ４Ａ is a hydrogen atom, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｂ is a hydrogen atom, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｃ represents a hydrogen atom, a halogen atom, a cyano group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｄ represents a hydrogen atom, a halogen atom, a cyano group, an amino group, a carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, or diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The alkoxy may be further substituted with one or more halogens, and R ４Ｅ , R ４Ｆ , R ４Ｇ are each independently a hydrogen atom, a halogen atom, a cyano group, an amino group, a carbonyl group, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－６ Alkylcarbonyl, C １－６ Alkoxy, 4-12 membered saturated heterocyclic group, C １－６ Alkylcarbonylamino, diC １－６ alkylaminocarbonyl, １－６ The alkyl may further include halogen, C ３－１０ Cycloalkyl, hydroxyl and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. ３－１０ Cycloalkyl and the C １－６ The compound according to any one of claims 1 to 13, wherein the alkoxy is optionally further substituted with one or more halogen atoms.

15. R ２ and R ３ and (1a-1) to (1a-2) form a monocyclic, bicyclic, tricyclic or spirocyclic optionally substituted 4-12 membered saturated heterocyclic group, which is any one of the following (1a-1) to (1a-8), (1a-10) to (1a-18), and the optionally substituted 4-12 membered saturated heterocyclic group has 1 to 3 identical or different substituents, which are halogen, oxo, hydroxyl group, cyano group, C １－６ Alkyl, C １－６ Alkoxy, Deuterium, C １－６ Alkylcarbonyl, C １－６ Alkoxycarbonyl, C １－６ alkylcarbonylamino, 5-10 membered heteroaryloxy, C ６－１０ Aryloxy, or C １－６ is an alkylthio group, １－６ Alkyl or the C １－６ Alkoxy may further include halogen, hydroxyl, and C １－６ and the C may be substituted with one or more substituents selected from the group consisting of alkoxy. １－６ The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms in the alkoxy may be deuterium.

16. R ２ and R ３ and (3) are independently substituted or unsubstituted alkyl groups, and the monocyclic, bicyclic, tricyclic, or spirocyclic 4- to 12-membered saturated heterocyclic group formed by these groups together is any one of the following (1a-1) to (1a-5) or (1a-7):

17. R ２ and R ３ and (3) are independently substituted or unsubstituted alkyl groups, and the monocyclic, bicyclic, tricyclic, or spirocyclic 4- to 12-membered saturated heterocyclic group formed by these groups together is any one of the following (1a-1), (1a-2), or (1a-4), or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds: 6-(2-cyclopropylpyridin-3-yl)-N-[(1S,4r)-4-{[(3S,4S)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(2-methoxy-7-azaspiro[3.5]nonan-7-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(4-methoxy-4-methylpiperidin-1-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-[(1r,4r)-4-methyl-4-{[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl]methyl}cyclohexyl]pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-[(1r,4r)-4-{[(4aR,7aS)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-[(4-methoxy-4-methylpiperidin-1-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-[(1r,4r)-4-{[(4aR,7aS)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-[(1S,4r)-4-{[(5S)-6,9-dioxa-2-azaspiro[4.5]decan-2-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-[(1R,4r)-4-{[(5R)-6,9-dioxa-2-azaspiro[4.5]decan-2-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(5,8-dioxa-2-azaspiro[3.5]nonan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-[(5,8-dioxa-2-azaspiro[3.5]nonan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(3-methoxy-3-methylpyrrolidin-1-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(2-cyclopropyl-4-methyl-1H-imidazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(2-cyclopropyl-4-methyl-1H-imidazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-propyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine, N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-[3-methyl-5-(propan-2-yl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine, N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-[3-methyl-5-(1-methylcyclopropyl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine, 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(4-cyclopropyl-2-methoxypyrimidin-5-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-1H-pyrazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]-6-[3-methyl-5-(1-methylcyclopropyl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine, 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-{(1r,4r)-4-methyl-4-[(2-oxa-6-azatricyclo[3.3.1.1-3,7-]decan-6-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(5-cyclopropyl-3,4-dimethyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)methyl]-4-methylcyclohexyl}-6-[3-methyl-5-(propan-2-yl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine, N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]-6-[3-methyl-5-(propan-2-yl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine, 6-(5-cyclobutyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine, N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-[3-methyl-5-(1-methylcyclobutyl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1S,4r)-4-{[(3S,4S)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, N-[(1R,4r)-4-({(3R,4R)-3,4-bis[(d3)methyloxy]pyrrolidin-1-yl}methyl)-4-methylcyclohexyl]-6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)pyridazin-3-amine, 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(3-methyl-8-azabicyclo[3.2.1]octan-8-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, N-[(1R,4r)-4-{[(3R,4R)-3,4-bis[(d3)methyloxy](2,2,5,5-d4)pyrrolidin-1-yl]methyl}-4-methylcyclohexyl]-6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)pyridazin-3-amine, 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(5R,9S)-9-methoxy-1-oxa-7-azaspiro[4.4]nonan-7-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(5R,9S)-9-methoxy-1-oxa-7-azaspiro[4.4]nonan-7-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(3,5-dicyclopropyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-[3-ethyl-5-(1-methylcyclopropyl)-1H-1,2,4-triazol-1-yl]pyridazin-3-amine, (5R,9S)-7-{[(1r,4R)-4-{[6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)pyridazin-3-yl]amino}-1-methylcyclohexyl]methyl}-1-oxa-7-azaspiro[4.4]nonan-9-ol, 6-[3-methyl-5-(1-methylcyclopropyl)-1H-pyrazol-1-yl]-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine, N-[(1S,4r)-4-{[(3S,4S)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]-6-[3-methyl-5-(1-methylcyclopropyl)-1H-pyrazol-1-yl]pyridazin-3-amine, 6-(5-cyclobutyl-3-methyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(5-cyclobutyl-3-methyl-1H-pyrazol-1-yl)-N-[(1S,4r)-4-{[(3S,4S)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxy-3-methylpyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(4R)-3,4-dimethoxy-3-methylpyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-pyrazol-1-yl)-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-[(1r,4r)-4-methyl-4-{[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl]methyl}cyclohexyl]pyridazin-3-amine, 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[4.4]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(3-oxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(1-oxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(1-oxa-7-azaspiro[4.4]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(4-cyclopropyl-2-methoxypyrimidin-5-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(4-cyclopropyl-2-methoxypyrimidin-5-yl)-N-{(1r,4r)-4-[(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(4-cyclopropyl-2-methoxypyrimidin-5-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, N-[(1R,4r)-4-({(3R,4R)-3,4-bis[(d3)methyloxy]pyrrolidin-1-yl}methyl)-4-methylcyclohexyl]-6-(2-cyclopropylpyridin-3-yl)pyridazin-3-amine, 6-(2-cyclopropyl-4-ethyl-1H-imidazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(2-cyclopropyl-4-ethyl-1H-imidazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-pyrazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-pyrazol-1-yl)-N-[(1r,4r)-4-methyl-4-{[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl]methyl}cyclohexyl]pyridazin-3-amine, N-{(1r,4S)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-{3-ethyl-5-[(1S,2S)-2-fluorocyclopropyl]-1H-1,2,4-triazol-1-yl}pyridazin-3-amine, 6-(2-cyclopropyl-6-methylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(4-cyclopropylpyrimidin-5-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(4-cyclopropylpyrimidin-5-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(2-cyclopropyl-6-methylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine, N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]-6-[2-methoxy-4-(propan-2-yl)pyrimidin-5-yl]pyridazin-3-amine, 6-(4-cyclobutyl-2-methoxypyrimidin-5-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(3-cyclopropyl-1-ethyl-1H-pyrazol-4-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(3-cyclopropyl-1-ethyl-1H-pyrazol-4-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(2-cyclopropyl-6-methylpyridin-3-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(4-cyclopropyl-2-methoxypyrimidin-5-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1s,4s)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-(fluoromethyl)cyclohexyl]pyridazin-3-amine, 1-{5-cyclopropyl-1-[6-({(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}amino)pyridazin-3-yl]-1H-1,2,4-triazol-3-yl}cyclopropan-1-ol, 6-[5-cyclopropyl-3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-{5-cyclopropyl-3-[(3S)-oxolan-3-yl]-1H-1,2,4-triazol-1-yl}-N-{(1r,4S)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-{5-cyclopropyl-3-[(3R)-oxolan-3-yl]-1H-1,2,4-triazol-1-yl}-N-{(1r,4R)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-[5-cyclopropyl-3-(ethoxymethyl)-1H-1,2,4-triazol-1-yl]-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-[3-(methoxymethyl)-5-(propan-2-yl)-1H-pyrazol-1-yl]pyridazin-3-amine, 6-{5-cyclopropyl-3-[(1R)-1-methoxyethyl]-1H-1,2,4-triazol-1-yl}-N-{(1r,4R)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-{5-cyclopropyl-3-[(1S)-1-methoxyethyl]-1H-1,2,4-triazol-1-yl}-N-{(1r,4S)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-{(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}pyridazin-3-amine, 2-{5-cyclopropyl-1-[6-({(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}amino)pyridazin-3-yl]-1H-1,2,4-triazol-3-yl}propan-2-ol, 1-{5-cyclopropyl-1-[6-({(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}amino)pyridazin-3-yl]-1H-1,2,4-triazol-3-yl}cyclopropan-1-ol.

19. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds: 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(2-cyclopropyl-4-methyl-1H-imidazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1S,4r)-4-{[(3S,4S)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-[5-cyclopropyl-3-(propan-2-yl)-1H-1,2,4-triazol-1-yl]-N-[(1r,4r)-4-{[(1R,3s,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)-N-[(1R,4r)-4-{[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]methyl}-4-methylcyclohexyl]pyridazin-3-amine, 6-(2-cyclopropyl-4-ethyl-1H-imidazol-1-yl)-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, N-{(1r,4S)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-{3-ethyl-5-[(1S,2S)-2-fluorocyclopropyl]-1H-1,2,4-triazol-1-yl}pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(2-cyclopropyl-5-fluoropyridin-3-yl)-N-{(1r,4r)-4-methyl-4-[(2-oxa-8-azaspiro[4.5]decan-8-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-{(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}pyridazin-3-amine, 6-(5-cyclopropyl-3-ethyl-1H-1,2,4-triazol-1-yl)-N-[(1s,4s)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-(fluoromethyl)cyclohexyl]pyridazin-3-amine, 1-{5-cyclopropyl-1-[6-({(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}amino)pyridazin-3-yl]-1H-1,2,4-triazol-3-yl}cyclopropan-1-ol, 6-[5-cyclopropyl-3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-{5-cyclopropyl-3-[(3S)-oxolan-3-yl]-1H-1,2,4-triazol-1-yl}-N-{(1r,4S)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-{5-cyclopropyl-3-[(3R)-oxolan-3-yl]-1H-1,2,4-triazol-1-yl}-N-{(1r,4R)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-[5-cyclopropyl-3-(ethoxymethyl)-1H-1,2,4-triazol-1-yl]-N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, N-{(1r,4r)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}-6-[3-(methoxymethyl)-5-(propan-2-yl)-1H-pyrazol-1-yl]pyridazin-3-amine, 6-{5-cyclopropyl-3-[(1R)-1-methoxyethyl]-1H-1,2,4-triazol-1-yl}-N-{(1r,4R)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-{5-cyclopropyl-3-[(1S)-1-methoxyethyl]-1H-1,2,4-triazol-1-yl}-N-{(1r,4S)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]-4-methylcyclohexyl}pyridazin-3-amine, 6-(2-cyclopropylpyridin-3-yl)-N-{(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}pyridazin-3-amine, 2-{5-cyclopropyl-1-[6-({(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}amino)pyridazin-3-yl]-1H-1,2,4-triazol-3-yl}propan-2-ol, 1-{5-cyclopropyl-1-[6-({(1s,4s)-4-(difluoromethyl)-4-[(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)methyl]cyclohexyl}amino)pyridazin-3-yl]-1H-1,2,4-triazol-3-yl}cyclopropan-1-ol.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

21. A therapeutic and / or preventive agent for a disease associated with antagonism to muscarinic M4 receptors, comprising as an active ingredient the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

22. The therapeutic and / or preventive agent according to claim 21, wherein the disease associated with antagonism to muscarinic M4 receptors is a neurodegenerative disease, a brain injury disease, a cerebrovascular disease, a disorder of psychological development, a psychiatric disease, a mental and behavioral disorder due to the use of psychoactive substances, a malignant neoplasm, a cognitive dysfunction associated with a movement disorder, or peripheral symptoms, movement disorder, or systemic symptoms and signs thereof.

23. Diseases in which antagonism to muscarinic M4 receptors is involved include dementia, Alzheimer's disease, dementia with Lewy bodies, prefrontal temporal dementia, narcolepsy, cerebrovascular disease, stroke, vascular dementia, cerebral small vessel disease, traumatic brain injury, attention deficit hyperactivity disorder, autism, Down syndrome, schizophrenia, bipolar disorder, depression, Parkinson's disease, drug-induced parkinsonism, dystonia, Tourette's syndrome, dyskinesia, chorea, chorea associated with Huntington's disease, and amyotrophic lateral sclerosis. , cerebral palsy, progressive supranuclear palsy, multiple system atrophy, substance use disorder, substance dependence, addictive behavior disorder, malignant neoplasm, tumor, cachexia, and cognitive dysfunction, behavioral symptoms, psychotic symptoms, agitation, depression, anxiety, anhedonia, apathy, lethargy, loss of motivation, impaired motivation, emotional blunting, autism, excessive daytime sleepiness, sleep disorder, fatigue, motor dysfunction, hypokinesia, tremor, rigidity, gait disorder, or postural instability associated with these diseases.

24. A method for treating and / or preventing a disease associated with antagonism of the muscarinic M4 receptor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

25. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and / or preventive agent for a disease associated with antagonism to muscarinic M4 receptors.

26. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease associated with antagonism to muscarinic M4 receptors.

27. A medicine comprising a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof in combination with at least one drug selected from drugs classified as atypical antipsychotics.

28. A pharmaceutical composition comprising the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, for use in combination with at least one or more drugs selected from the group consisting of atypical antipsychotics to treat neurodegenerative diseases, brain damage diseases, disorders of psychological development, psychiatric diseases, cognitive dysfunction associated with movement disorders, and peripheral symptoms and movement dysfunction associated with these diseases.

Images