2-Isoindole-1,3,4-oxadiazole derivatives useful as HDAC6 inhibitors

Abstract

The present invention provides a heterocyclic compound that has an HDAC6 inhibitory effect and is useful for treating central nervous system disorders including neurodegenerative disorders, and a pharmaceutical containing the same. The present invention provides a compound of formula (I): JPEG2022552444000049.jpg44116 [In the formula, each symbol is as defined in the specification.] or a salt thereof.

Description

[Technical field]

[0001] The present invention relates to heterocyclic compounds that have a histone deacetylase (sometimes abbreviated as "HDAC" in the present specification) inhibitory effect, preferably a class II HDAC inhibitory effect, and more preferably an HDAC6 inhibitory effect, and that may be useful in the treatment of central nervous system diseases including neurodegenerative diseases (Alzheimer's disease, progressive supranuclear palsy, etc.), and a medicine containing the same, etc.

[0002] BACKGROUND OF THEINVENTION It is known that nerve axons play an important role in the transport of trophic factors, neurotransmitters, organelles, etc. in nerve cells, and axonal dysfunction, axonal degeneration, and intracellular accumulation of the axon-binding protein tau have been observed in various neurodegenerative diseases (Non-Patent Documents 1 and 2). Diseases characterized by intracellular tau accumulation are pathologically collectively referred to as tauopathies, including Alzheimer's disease and progressive supranuclear palsy (Non-Patent Document 3). HDAC6 is an enzyme responsible for deacetylating tubulin, a component of axons (Non-Patent Document 4), and it is known that microtubules containing acetylated tubulin contribute to stability (Non-Patent Document 5). It has also been reported that Tubastatin A, which has HDAC6 inhibitory activity, enhances tubulin acetylation and shows therapeutic efficacy in a tauopathy mouse model (Non-Patent Document 6). From the above, it is suggested that HDAC6 inhibitors may be a therapeutic drug for Alzheimer's disease and progressive supranuclear palsy through axon stabilization.

[0003] Examples of the heterocyclic compound include the following.

[0004] (1) Patent Document 1 describes a compound represented by the following formula: which is an HDAC inhibitor and is effective in treating autoimmune diseases, inflammatory diseases, metabolic / bone / joint degenerative diseases, neurodegenerative diseases / central diseases (e.g., schizophrenia, Alzheimer's disease (Alzheimer's dementia), Parkinson's disease, Huntington's disease, Rubinstein-Taybi syndrome, muscular dystrophy, Rett syndrome, Charcot-Marie-Tooth disease, depression), tumor diseases, and the like.

[0005] [ka]

[0006] [In the formula, each symbol is as defined in the document.] A compound represented by the formula:

[0007] (2) Patent Document 2 describes a compound represented by the following formula: which is an HDAC inhibitor and is effective in treating autoimmune diseases, inflammatory diseases, metabolic / bone / joint degenerative diseases, neurodegenerative diseases / central diseases (e.g., schizophrenia, Alzheimer's disease (Alzheimer's dementia), Parkinson's disease, Huntington's disease, Rubinstein-Taybi syndrome, muscular dystrophy, Rett syndrome, Charcot-Marie-Tooth disease, depression), tumor diseases, and the like.

[0008] [ka]

[0009] [In the formula, each symbol is as defined in the document.] A compound represented by the formula:

[0010] (3) Patent Document 3 describes a compound represented by the following formula: which is an HDAC inhibitor and is effective in treating autoimmune diseases, inflammatory diseases, metabolic / bone / joint degenerative diseases, neurodegenerative diseases / central diseases (e.g., schizophrenia, Alzheimer's disease (Alzheimer's dementia), Parkinson's disease, Huntington's disease, Rubinstein-Taybi syndrome, muscular dystrophy, Rett syndrome, Charcot-Marie-Tooth disease, depression), tumor diseases, and the like.

[0011] [ka]

[0012] [In the formula, each symbol is as defined in the document.] A compound represented by the formula:

[0013] (4) Patent Document 4 describes a compound represented by the following formula: which is an HDAC inhibitor and is effective in treating autoimmune diseases, inflammatory diseases, metabolic / bone / joint degenerative diseases, neurodegenerative diseases / central diseases (e.g., schizophrenia, Alzheimer's disease (Alzheimer's dementia), Parkinson's disease, Huntington's disease, Rubinstein-Taybi syndrome, muscular dystrophy, Rett syndrome, Charcot-Marie-Tooth disease, depression), tumor diseases, and the like.

[0014] [ka]

[0015] [In the formula, each symbol is as defined in the document.] A compound represented by the formula:

[0016] (5) Patent Document 5 describes a compound represented by the following formula: which is an HDAC inhibitor and is effective in treating autoimmune diseases, inflammatory diseases, metabolic / bone / joint degenerative diseases, neurodegenerative diseases / central diseases (e.g., schizophrenia, Alzheimer's disease (Alzheimer's dementia), Parkinson's disease, Huntington's disease, Rubinstein-Taybi syndrome, muscular dystrophy, Rett syndrome, Charcot-Marie-Tooth disease, depression), tumor diseases, and the like.

[0017] [ka]

[0018] [In the formula, each symbol is as defined in the document.] A compound represented by the formula:

[0019] (6) Patent Document 6 discloses a compound represented by the following formula:

[0020] [ka]

[0021] [In the formula, each symbol is as defined in the document.] A compound represented by the formula:

[0022] (7) Patent Document 7 discloses a compound of the following formula:

[0023] [ka]

[0024] [In the formula, each symbol is as defined in the document.] A compound represented by the formula:

[0025] (8) Patent Document 8 discloses a compound represented by the following formula:

[0026] [ka]

[0027] [In the formula, each symbol is as defined in the document.] A compound represented by the formula:

[0028] (9) Patent Document 9 discloses a compound represented by the following formula:

[0029] [ka]

[0030] [In the formula, each symbol is as defined in the document.] A compound represented by the formula:

[0031] (10) Patent Document 10 describes a compound represented by the following formula, which is an HDAC inhibitor and is effective in treating epilepsy, attention deficit disorder, depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's disease, and the like:

[0032] [ka]

[0033] [In the formula, each symbol is as defined in the document.] A compound represented by the formula:

[0034] (11) Patent Document 11 describes a compound represented by the following formula, which is an HDAC inhibitor and is effective in treating infectious diseases, tumors, endocrine diseases, nutritional metabolic diseases, and the like:

[0035] [ka]

[0036] [In the formula, each symbol is as defined in the document.] A compound represented by the formula:

[0037] (12) Patent Document 12 describes a compound represented by the following formula: which is an HDAC inhibitor and is effective in treating autoimmune diseases, inflammatory diseases, metabolic / bone / joint degenerative diseases, neurodegenerative diseases / central diseases (e.g., schizophrenia, Alzheimer's disease (Alzheimer's dementia), Parkinson's disease, Huntington's disease, Rubinstein-Taybi syndrome, muscular dystrophy, Rett syndrome, Charcot-Marie-Tooth disease, depression), tumor diseases, and the like.

[0038] [ka]

[0039] [In the formula, each symbol is as defined in the document.] A compound represented by the formula: [Prior art documents] [Patent documents]

[0040] [Patent Document 1] WO2016 / 031815 [Patent Document 2] WO2017 / 014321

Patent document 3

Patent document 4

Patent document 5

Patent document 6

Patent document 7

Patent document 8

Patent Document 9

Patent document 10

Patent document 11

Patent document 12

Non-licensed literature

[0041]

Non-licensed literature 1

Non-licensed Document 2

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

[0042] An object of the present invention is to provide a heterocyclic compound which has an HDAC inhibitory effect and is useful for treating central nervous system diseases including neurodegenerative diseases (e.g., Alzheimer's disease and progressive supranuclear palsy), and a medicine containing the same. [Means for solving the problem]

[0043] Means of Solving the Problems The present inventors have conducted intensive studies to solve the above problems and have found that a compound represented by the following formula (I) has excellent HDAC inhibitory activity, thereby completing the present invention. That is, the present invention is as follows.

[0044] [1] Formula (I):

[0045] [ka]

[0046] [In the formula, R 1 is an optionally substituted cyclic group, R 2 represents an optionally substituted cyclic group; or a salt thereof (hereinafter, may be abbreviated as "compound (I)").

[0047] [2] Formula (I'):

[0048] [ka]

[0049] [Each symbol in the formula has the same meaning as defined in [1] above.] The compound according to the above-mentioned [1], or a salt thereof.

[0050] [3] R 1 but, (1) C optionally substituted with 1 to 3 halogen atoms 3-10 Cycloalkyl groups, (2) (i) a halogen atom, (ii) a cyano group, and (iii) a C optionally substituted by 1 to 3 halogen atoms. 1-6 C optionally substituted with 1 to 3 substituents selected from alkyl groups 6-14 Aryl groups, (3) (i) a halogen atom, (ii) C optionally substituted by 1 to 3 halogen atoms 1-6 an alkyl group, and (iii) C 1-6 a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from an alkoxy group, or (4) A 3- to 8-membered monocyclic non-aromatic heterocyclic group, and R 2 but, (1) C optionally substituted with 1 to 3 halogen atoms 3-10 Cycloalkyl groups, (2) (i) a halogen atom, and (ii) C optionally substituted by 1 to 3 halogen atoms 1-6 C optionally substituted with 1 to 3 substituents selected from alkyl groups 6-14 Aryl groups, (3) (i) a halogen atom, (ii) C optionally substituted by 1 to 3 halogen atoms 1-6 an alkyl group, and (iii) C 1-6 a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from an alkoxy group, or (4) 3- to 8-membered monocyclic non-aromatic heterocyclic group The compound according to the above-mentioned [1], or a salt thereof.

[0051] [4] R 1 but, (1) C optionally substituted with 1 to 3 halogen atoms 3-10 a cycloalkyl group, or (2) (i) a halogen atom, (ii) a C optionally substituted by 1 to 3 halogen atoms1-6 an alkyl group, and (iii) C 1-6 a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from an alkoxy group, R 2 but, (1) (i) a halogen atom, and (ii) C optionally substituted by 1 to 3 halogen atoms 1-6 C optionally substituted with 1 to 3 substituents selected from alkyl groups 6-14 an aryl group, or (2) (i) a halogen atom, (ii) a C optionally substituted by 1 to 3 halogen atoms 1-6 an alkyl group, and (iii) C 1-6 A 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from an alkoxy group. The compound according to the above-mentioned [1], or a salt thereof.

[0052] [5] R 1 but, (1) C 3-10 a cycloalkyl group, or (2) A 6-membered monocyclic aromatic heterocyclic group optionally substituted with 1 to 3 halogen atoms, and R 2 but, (1) C optionally substituted with 1 to 3 halogen atoms 6-14 an aryl group, or (2) A 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 halogen atoms. The compound according to the above-mentioned [1], or a salt thereof.

[0053] [6] 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one or a salt thereof. [7] 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one or a salt thereof. [8] 2-[(1R,2R)-1,2-bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1H-isoindol-1-one or a salt thereof.

[0054] [9] A medicine comprising the compound described in [1] above or a salt thereof.

[10] The pharmaceutical described in [9] above, which is a histone deacetylase 6 inhibitor.

[11] The pharmaceutical agent according to [9] above, which is an agent for preventing or treating Alzheimer's disease or progressive supranuclear palsy.

[0055]

[12] The compound or salt thereof according to the above-mentioned [1] for use in the prevention or treatment of Alzheimer's disease or progressive supranuclear palsy.

[13] A method for inhibiting histone deacetylase 6 in a mammal, comprising administering to the mammal an effective amount of the compound according to [1] above or a salt thereof.

[14] A method for preventing or treating Alzheimer's disease or progressive supranuclear palsy in a mammal, which comprises administering to the mammal an effective amount of the compound according to [1] above or a salt thereof.

[15] Use of the compound or salt thereof described in [1] above for the manufacture of an agent for the prophylaxis or treatment of Alzheimer's disease or progressive supranuclear palsy. Effect of the Invention

[0056] Compound (I) has an HDAC6 inhibitory effect and may be useful in the treatment of central nervous system diseases including neurodegenerative diseases (Alzheimer's disease, progressive supranuclear palsy, etc.). [Brief description of the drawings]

[0057] [Figure 1] 1 shows the enhancing effect of acetylated tubulin in mouse brain on the compound of Example 1. The vertical axis shows the relative tubulin acetylation level, and the horizontal axis shows the dose (mg / kg). [Diagram 2] 1 shows the enhancing effect of acetylated tubulin in mouse brain on the compound of Example 3. The vertical axis shows the relative tubulin acetylation level, and the horizontal axis shows the dose (mg / kg). [Diagram 3] 1 shows the enhancing effect of acetylated tubulin in mouse brain on the compound of Example 5. The vertical axis shows the relative tubulin acetylation level, and the horizontal axis shows the dose (mg / kg). [Figure 4] 1 shows the effect of improving mouse cognitive function of the compound of Example 1. The vertical axis indicates the relative value (%) of the exploration time for a novel object, and the horizontal axis indicates the dose (mg / kg). [Diagram 5] 1 shows the effect of improving mouse cognitive function of the compound of Example 3. The vertical axis indicates the relative value (%) of the exploration time for a novel object, and the horizontal axis indicates the dose (mg / kg).

[0058] Detailed Description of the Invention The present invention will be described in detail below. First, each symbol in formula (I) will be explained.

[0059] R 1 and R 2 are the same or different and each represents an optionally substituted cyclic group. The "cyclic group" in the "optionally substituted cyclic group" includes a hydrocarbon ring group and a heterocyclic group.

[0060] The "hydrocarbon ring group" is, for example, 3-10 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, adamantyl, etc.), C 3-10Cycloalkenyl groups (e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), C 6-14 Examples of the aryl group include aryl groups (e.g., phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl).

[0061] Examples of the "heterocyclic group" include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a 7- to 10-membered bridged heterocyclic group, each of which contains, in addition to carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom as ring-constituting atoms. The "aromatic heterocyclic group" includes, for example, a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thia and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as pyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0062] The "non-aromatic heterocyclic group" includes, for example, a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrrolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrrolinyl, oxazolidinyl, pyrazolinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl ... 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as isoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl; Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexyl Examples of such 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups include tetrahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0063] Preferable examples of the "7- to 10-membered heterobridged ring group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl.

[0064] R 1 or R 2 Examples of the substituent in the "optionally substituted cyclic group" represented by the following formula (1) include a cyclic group which may have a substituent selected from the following substituent group A. The number of substituents in the "optionally substituted cyclic group" is, for example, 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0065] [Substituent group A] (1) Halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) Optionally halogenated C 1-6alkoxy groups (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy); (7) C 6-14 Aryloxy groups (e.g., phenoxy, naphthoxy), (8) C 7-16 aralkyloxy groups (e.g., benzyloxy), (9) 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy), (10) 3- to 14-membered non-aromatic heterocyclic oxy groups (e.g., morpholinyloxy, piperidinyloxy), (11) C 1-6 Alkyl-carbonyloxy groups (e.g., acetoxy, propanoyloxy), (12) C 6-14 Aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), (13) C 1-6 Alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) Mono- or di-C 1-6 Alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy); (15) C 6-14 Aryl-carbamoyloxy groups (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy); (16) 5- to 14-membered aromatic heterocyclylcarbonyloxy groups (e.g., nicotinoyloxy), (17) 3- to 14-membered non-aromatic heterocyclylcarbonyloxy groups (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) Optionally halogenated C 1-6 Alkylsulfonyloxy groups (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy), (19)C 1-6 C optionally substituted with an alkyl group 6-14 Arylsulfonyloxy groups (e.g., phenylsulfonyloxy, toluenesulfonyloxy), (20) Optionally halogenated C 1-6 alkylthio groups (e.g., methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio); (21) 5- to 14-membered aromatic heterocyclic groups (e.g., thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopy ... lysinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl). (22) 3- to 14-membered non-aromatic heterocyclic groups (e.g., aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl, dihydro tetrahydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl), (23) a formyl group, (24) a carboxy group, (25) Optionally halogenated C 1-6 Alkyl-carbonyl groups (e.g., acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, hexanoyl), (26)C 6-14 Aryl-carbonyl groups (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl), (27) 5- to 14-membered aromatic heterocyclic carbonyl groups (e.g., nicotinoyl, isonicotinoyl, thenoyl, furoyl), (28) 3- to 14-membered non-aromatic heterocyclylcarbonyl groups (e.g., morpholinylcarbonyl, piperidinylcarbonyl, pyrrolidinylcarbonyl), (29)C 1-6 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl); (30)C 6-14 Aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), (31)C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl); (32) a carbamoyl group, (33) a thiocarbamoyl group, (34) Mono- or di-C 1-6 Alkyl-carbamoyl groups (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl), (35)C 6-14 Aryl-carbamoyl groups (e.g., phenylcarbamoyl), (36) 5- to 14-membered aromatic heterocyclic carbamoyl groups (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl groups (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) Optionally halogenated C 1-6 alkylsulfonyl groups (e.g., methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl); (39)C 6-14 Arylsulfonyl groups (e.g., phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl), (40) 5- to 14-membered aromatic heterocyclylsulfonyl groups (e.g., pyridylsulfonyl, thienylsulfonyl), (41) Optionally halogenated C 1-6 Alkylsulfinyl groups (e.g., methylsulfinyl, ethylsulfinyl), (42)C 6-14 Arylsulfinyl groups (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (43) 5- to 14-membered aromatic heterocyclylsulfinyl groups (e.g., pyridylsulfinyl, thienylsulfinyl), (44) an amino group, (45) Mono- or di-C 1-6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino); (46) Mono- or di-C 6-14 Arylamino groups (e.g., phenylamino), (47) 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), (48)C 7-16 aralkylamino groups (e.g., benzylamino), (49) a formylamino group, (50)C 1-6 Alkyl-carbonylamino groups (e.g., acetylamino, propanoylamino, butanoylamino), (51)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino); (52)C 6-14 Aryl-carbonylamino groups (e.g., phenylcarbonylamino, naphthylcarbonylamino); (53)C 1-6alkoxycarbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino); (54)C 7-16 aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (55)C 1-6 Alkylsulfonylamino groups (e.g., methylsulfonylamino, ethylsulfonylamino), (56)C 1-6 C optionally substituted with an alkyl group 6-14 Arylsulfonylamino groups (e.g., phenylsulfonylamino, toluenesulfonylamino), (57) Optionally halogenated C 1-6 alkyl groups (e.g., methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl); (58)C 2-6 alkenyl groups (e.g., ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl); (59)C 2-6 alkynyl groups (e.g., ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl); (60)C 3-10cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, adamantyl); (61)C 3-10 Cycloalkenyl groups (e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), and (62)C 6-14 Aryl groups (e.g., phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl).

[0066] R 1 As for the following: (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 cycloalkyl groups (e.g., cyclopropyl, cyclohexyl); (2)(i) A halogen atom (e.g., a fluorine atom), (ii) a cyano group, and (iii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl group (e.g., methyl) C which is optionally substituted by 1 to 3 substituents selected from 6-14 Aryl groups (e.g., phenyl), (3)(i) a halogen atom (e.g., a fluorine atom), (ii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methyl), and (iii) C 1-6 Alkoxy groups (e.g., ethoxy) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl) optionally substituted by 1 to 3 substituents selected from (4) 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., tetrahydropyranyl) is preferred.

[0067] Among them, R 1 As for the following: (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 a cycloalkyl group (e.g., cyclopropyl, cyclohexyl), or (2)(i) A halogen atom (e.g., a fluorine atom), (ii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methyl), and (iii) C 1-6 Alkoxy groups (e.g., ethoxy) A 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl) optionally substituted by 1 to 3 substituents selected from is preferred.

[0068] Especially R 1 As for the following: (1) C 3-10 a cycloalkyl group (e.g., cyclopropyl, cyclohexyl), or (2) A 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms). is preferred.

[0069] R 2 As for the following: (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 cycloalkyl groups (e.g., cyclopropyl, cyclohexyl); (2)(i) Halogen atoms (e.g., fluorine atoms, chlorine atoms), and (ii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl group (e.g., methyl) C which is optionally substituted by 1 to 3 substituents selected from 6-14 Aryl groups (e.g., phenyl), (3)(i) A halogen atom (e.g., a fluorine atom, a chlorine atom), (ii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methyl), and (iii) C 1-6 Alkoxy groups (e.g., ethoxy) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl) optionally substituted by 1 to 3 substituents selected from (4) 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., tetrahydropyranyl) is preferred.

[0070] Among them, R 2 As for the following: (1)(i) Halogen atoms (e.g., fluorine atoms, chlorine atoms), and (ii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl group (e.g., methyl) C which is optionally substituted by 1 to 3 substituents selected from 6-14 an aryl group (e.g., phenyl), or (2)(i) A halogen atom (e.g., a fluorine atom, a chlorine atom), (ii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methyl), and (iii) C 1-6 Alkoxy groups (e.g., ethoxy) A 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl) optionally substituted by 1 to 3 substituents selected from is preferred.

[0071] Especially R 2 As for the following: (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms, chlorine atoms) 6-14 an aryl group (e.g., phenyl), or (2) A 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl) optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atom, chlorine atom). is preferred.

[0072] Compound (I) may be R 1 but, (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 cycloalkyl groups (e.g., cyclopropyl, cyclohexyl); (2)(i) A halogen atom (e.g., a fluorine atom), (ii) a cyano group, and (iii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl group (e.g., methyl) C which is optionally substituted by 1 to 3 substituents selected from 6-14 Aryl groups (e.g., phenyl), (3)(i) a halogen atom (e.g., a fluorine atom), (ii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methyl), and (iii) C 1-6 Alkoxy groups (e.g., ethoxy) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl) optionally substituted by 1 to 3 substituents selected from (4) 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., tetrahydropyranyl) and R 2 but, (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 cycloalkyl groups (e.g., cyclopropyl, cyclohexyl); (2)(i) Halogen atoms (e.g., fluorine atoms, chlorine atoms), and (ii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl group (e.g., methyl) C which is optionally substituted by 1 to 3 substituents selected from 6-14 Aryl groups (e.g., phenyl), (3)(i) A halogen atom (e.g., a fluorine atom, a chlorine atom), (ii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methyl), and (iii) C 1-6 Alkoxy groups (e.g., ethoxy) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl) optionally substituted by 1 to 3 substituents selected from (4) 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., tetrahydropyranyl) Preferred are compounds,

[0073] Among them, compound (I) is R 1 but, (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 a cycloalkyl group (e.g., cyclopropyl, cyclohexyl), or (2)(i) A halogen atom (e.g., a fluorine atom), (ii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methyl), and (iii) C 1-6 Alkoxy groups (e.g., ethoxy) A 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl) optionally substituted by 1 to 3 substituents selected from and R 2 but, (1)(i) Halogen atoms (e.g., fluorine atoms, chlorine atoms), and (ii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl group (e.g., methyl) C which is optionally substituted by 1 to 3 substituents selected from 6-14 an aryl group (e.g., phenyl), or (2)(i) A halogen atom (e.g., a fluorine atom, a chlorine atom), (ii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methyl), and (iii) C 1-6 Alkoxy groups (e.g., ethoxy) A 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl) optionally substituted by 1 to 3 substituents selected from Preferred are compounds,

[0074] In particular, compound (I) is R 1 but, (1) C 3-10 a cycloalkyl group (e.g., cyclopropyl, cyclohexyl), or (2) A 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms). and R 2 but, (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms, chlorine atoms) 6-14 an aryl group (e.g., phenyl), or (2) A 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl) optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atom, chlorine atom). Preferred are compounds,

[0075] The configuration of compound (I) is represented by the formula (I'):

[0076] [ka]

[0077] [In the formula, each symbol has the same meaning as defined above.] (hereinafter, sometimes abbreviated as compound (I')).

[0078] As preferred embodiments of compound (I), the following compound groups (compound (I'-1) and compound (I'-2)) can be mentioned.

[0079] Compound (I'-1) R 1 is an optionally substituted hydrocarbon ring group, and R 2 is an optionally substituted hydrocarbon ring group.

[0080] Compound (I'-1a) R 1 but, (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 a cycloalkyl group (e.g., cyclopropyl, cyclohexyl), or (2)(i) A halogen atom (e.g., a fluorine atom), (ii) a cyano group, and (iii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl group (e.g., methyl) C which is optionally substituted by 1 to 3 substituents selected from 6-14 Aryl groups (e.g., phenyl) and R 2 but, (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 a cycloalkyl group (e.g., cyclopropyl, cyclohexyl), or (2)(i) Halogen atoms (e.g., fluorine atoms, chlorine atoms), and (ii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl group (e.g., methyl) C which is optionally substituted by 1 to 3 substituents selected from 6-14 Aryl groups (e.g., phenyl) Compound (I') is:

[0081] Compound (I'-1b) R 1 C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 a cycloalkyl group (e.g., cyclopropyl, cyclohexyl), and R 2 (i) a halogen atom (e.g., a fluorine atom, a chlorine atom), and (ii) C optionally substituted with 1 to 3 halogen atoms (e.g., a fluorine atom). 1-6 C optionally substituted with 1 to 3 substituents selected from alkyl groups (e.g., methyl) 6-14 Compound (I') is an aryl group (e.g., phenyl).

[0082] Compound (I'-1c) R 1 But, C 3-10 a cycloalkyl group (e.g., cyclopropyl, cyclohexyl), and R 2 may be substituted with 1 to 3 halogen atoms (e.g., fluorine atoms, chlorine atoms) 6-14 Compound (I') is an aryl group (e.g., phenyl).

[0083] Compound (I'-2) R 1 is an optionally substituted heterocyclic group, and R 2 is an optionally substituted heterocyclic group.

[0084] Compound (I'-2a) R 1 but, (1)(i) a halogen atom (e.g., a fluorine atom), (ii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methyl), and (iii) C 1-6 Alkoxy groups (e.g., ethoxy) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl) optionally substituted by 1 to 3 substituents selected from (2) 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., tetrahydropyranyl) and R 2 but, (1)(i) A halogen atom (e.g., a fluorine atom, a chlorine atom), (ii) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methyl), and (iii) C 1-6 Alkoxy groups (e.g., ethoxy) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl) optionally substituted by 1 to 3 substituents selected from (2) 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., tetrahydropyranyl) Compound (I') is:

[0085] Compound (I'-2b) R 1 (i) a halogen atom (e.g., a fluorine atom), (ii) C optionally substituted with 1 to 3 halogen atoms (e.g., a fluorine atom), 1-6 Alkyl groups (e.g., methyl), and (iii) C 1-6 a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl) optionally substituted by 1 to 3 substituents selected from alkoxy groups (e.g., ethoxy), and R 2(i) a halogen atom (e.g., a fluorine atom, a chlorine atom), (ii) C optionally substituted with 1 to 3 halogen atoms (e.g., a fluorine atom), 1-6 Alkyl groups (e.g., methyl), and (iii) C 1-6 Compound (I') which is a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl, pyrimidinyl) optionally substituted by 1 to 3 substituents selected from alkoxy groups (eg, ethoxy).

[0086] Compound (I'-2c) R 1 is a 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms), and R 2 is a 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl, pyrimidinyl) optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom).

[0087] Specific examples of compound (I) include the compounds of Examples 1 to 150. 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example 1) or a salt thereof, 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example 3) or a salt thereof, 2-[(1R,2R)-1,2-bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1H-isoindol-1-one (Example 5) or a salt thereof, 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example 7) or a salt thereof, 2-[(1R,2S)-1-cyclopropyl-2-(4-fluorophenyl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1H-isoindol-1-one (Example 9) or a salt thereof, is preferred, especially 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example 1) or a salt thereof, 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example 3) or a salt thereof, 2-[(1R,2R)-1,2-bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1H-isoindol-1-one (Example 5) or a salt thereof is preferred.

[0088] When compound (I) is a salt, such salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Suitable examples of metal salts include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts and barium salts; and aluminum salts. Suitable examples of salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc. Suitable examples of salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Suitable examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc. Suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc. Among these, pharma- ceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, it may be an inorganic salt such as an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), or an ammonium salt; when the compound has a basic functional group, it may be a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, or phosphoric acid, or a salt with an organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid.

[0089] [Manufacturing method]

[0090] The production method of compound (I) is explained below.

[0091] The raw materials and reagents used in each step of the following production methods, as well as the resulting compounds, may each form a salt. Examples of such salts include the same salts as those of the above-mentioned compound (I).

[0092] When the compound obtained in each step is a free compound, it can be converted into the desired salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted into a free form or another type of desired salt by a method known per se.

[0093] The compound obtained in each step can be used in the next reaction either as a reaction solution or as a crude product, or the compound obtained in each step can be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc. in accordance with a conventional method.

[0094] When the raw materials and reagent compounds for each step are commercially available, the commercially available products can be used as they are.

[0095] In the reaction of each step, the reaction time may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

[0096] In the reactions of each step, the reaction temperature may vary depending on the reagents and solvents used, but is usually from -78°C to 300°C, preferably from -78°C to 150°C, unless otherwise specified.

[0097] In the reaction of each step, the pressure may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.

[0098] In the reactions of each step, a microwave synthesis device such as Biotage Initiator may be used. The reaction temperature may vary depending on the reagents and solvents used, but is usually room temperature to 300° C., preferably 50° C. to 250° C., unless otherwise specified. The reaction time may vary depending on the reagents and solvents used, but is usually 1 minute to 48 hours, preferably 1 minute to 8 hours, unless otherwise specified.

[0099] In the reaction of each step, unless otherwise specified, the reagent is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalents, relative to the substrate. When the reagent also serves as a reaction solvent, the reagent is used in an amount equivalent to the solvent.

[0100] Unless otherwise specified, the reactions in each step are carried out without a solvent or by dissolving or suspending the components in a suitable solvent. Specific examples of the solvent include those described in the Examples and the following. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc.; Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, etc.; Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Sulfoxides: dimethyl sulfoxide, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: ethyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; water. The above solvents may be used as a mixture of two or more kinds in an appropriate ratio.

[0101] When a base is used in the reaction of each step, for example, the base shown below or the base described in the Examples can be used. Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, cesium carbonate, potassium acetate, etc.; Organic bases: triethylamine, diethylamine, N,N-diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; Organolithium compounds: n-butyllithium, etc.

[0102] When an acid or an acid catalyst is used in the reaction of each step, for example, the acids and acid catalysts shown below or the acids and acid catalysts described in the Examples can be used. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ferric chloride, etc.

[0103] Unless otherwise specified, the reactions in each step are carried out by a method known per se, for example, in Experimental Chemistry Lectures, 5th Edition, Vol. 13-19 (edited by the Chemical Society of Japan); New Experimental Chemistry Lectures, Vol. 14-15 (edited by the Chemical Society of Japan); Precision Organic Chemistry, Revised 2nd Edition (LF Tietze, Th. Eicher, Nankodo); Revised Organic Named Reactions: Their Mechanisms and Key Points (by Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volumes I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (by Jie Jack Li, published by OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol. 1-14 (Elsevier Japan Co., Ltd.); Organic Synthesis Strategies Learned from Named Reactions (translated and supervised by Kiyoshi Tomioka, published by Kagaku Dojin); Comprehensive Organic Transformations (VCH Publishers The method may be carried out in accordance with the method described in, for example, the 1989 issue of "The Method for Producing a Fluorescent Protein," published by the Japanese Patent Laid-Open Publication No. 2002-2003444, or the method described in the Examples.

[0104] In each step, the protection or deprotection reaction of a functional group is carried out according to a method known per se, for example, a method described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004, or a method described in the Examples. Examples of the protecting group for the hydroxyl group of an alcohol or the like or a phenolic hydroxyl group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylate-type protecting groups such as acetate; sulfonate-type protecting groups such as methanesulfonate; and carbonate-type protecting groups such as tert-butyl carbonate. Examples of the protecting group for the carbonyl group of an aldehyde include acetal-type protecting groups such as dimethylacetal; and cyclic acetal-type protecting groups such as 1,3-dioxane. Examples of protecting groups for the carbonyl group of a ketone include ketal-type protecting groups such as dimethyl ketal; cyclic ketal-type protecting groups such as 1,3-dioxane; oxime-type protecting groups such as O-methyloxime; and hydrazone-type protecting groups such as N,N-dimethylhydrazone. Examples of the carboxyl-protecting group include ester-type protecting groups such as methyl ester; and amide-type protecting groups such as N,N-dimethylamide. Examples of the thiol-protecting group include ether-type protecting groups such as benzylthioether; and ester-type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate. Examples of the protecting group for an amino group or an aromatic heterocycle such as imidazole, pyrrole, or indole include carbamate-type protecting groups such as benzylcarbamate; amide-type protecting groups such as acetamide; alkylamine-type protecting groups such as N-triphenylmethylamine; and sulfonamide-type protecting groups such as methanesulfonamide. The protecting group can be removed by a method known per se, for example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or a reduction method.

[0105] In each step, when a reduction reaction is carried out, examples of the reducing agent used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and tetramethylammonium triacetoxyborohydride; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane; etc. When a carbon-carbon double bond or triple bond is reduced, a catalyst such as palladium-carbon or Lindlar catalyst may be used.

[0106] In each step, when an oxidation reaction is carried out, examples of the oxidizing agent used include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, and tert-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodates such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese-containing reagents such as manganese dioxide and potassium permanganate; lead compounds such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0107] In each step, when a radical cyclization reaction is carried out, examples of the radical initiator used include azo compounds such as azobisisobutyronitrile (AIBN), water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA), triethylboron in the presence of air or oxygen, benzoyl peroxide, etc. Examples of the radical reaction reagent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, etc.

[0108] When a Wittig reaction is carried out in each step, examples of the Wittig reagent used include alkylidene phosphoranes, etc. The alkylidene phosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

[0109] When the Horner-Emmons reaction is carried out in each step, examples of the reagent used include phosphonoacetates such as methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like; and bases such as alkali metal hydrides, organolithium compounds and the like.

[0110] In each step, when the Friedel-Crafts reaction is carried out, examples of the reagent used include a combination of a Lewis acid and an acid chloride, or a combination of a Lewis acid and an alkylating agent (e.g., alkyl halides, alcohols, olefins, etc.). Alternatively, an organic acid or an inorganic acid can be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride can be used instead of the acid chloride.

[0111] In each step, when an aromatic nucleophilic substitution reaction is carried out, a nucleophile (eg, amines, imidazole, etc.) and a base (eg, organic bases, etc.) are used as reagents.

[0112] In each step, when a nucleophilic addition reaction by a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbanion, or a nucleophilic substitution reaction by a carbanion is performed, examples of the base used to generate the carbanion include organolithiums, metal alkoxides, inorganic bases, and organic bases.

[0113] In each step, when a Grignard reaction is carried out, examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide, and alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or an aryl halide with metallic magnesium or an isopropylmagnesium chloride-lithium chloride complex in a solvent such as ether or tetrahydrofuran.

[0114] In each step, when a Knoevenagel condensation reaction is carried out, an active methylene compound sandwiched between two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile, etc.) and a base (e.g., organic bases, metal alkoxides, inorganic bases) are used as reagents.

[0115] In each step, when the Vilsmeier-Haack reaction is carried out, phosphoryl chloride and an amide derivative (eg, N,N-dimethylformamide, etc.) are used as reagents.

[0116] In each step, when an azidation reaction of alcohols, alkyl halides, or sulfonic acid esters is carried out, examples of the azidation agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide, etc. For example, when azidating alcohols, there are a method using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), a method using trimethylsilyl azide and a Lewis acid, and a method using diphenylphosphoryl azide, triphenylphosphine, and an azodicarboxylate.

[0117] In each step, when a reductive amination reaction is carried out, examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, etc. When the substrate is an amine compound, examples of the carbonyl compound used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, examples of the amines used include ammonia, primary amines such as methylamine, and secondary amines such as dimethylamine.

[0118] In each step, when Mitsunobu reaction is carried out, an azodicarboxylate (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

[0119] In the case where an esterification reaction, an amidation reaction, or a urea reaction is carried out in each step, examples of the reagent to be used include acyl halides such as acid chlorides and acid bromides; and activated carboxylic acids such as acid anhydrides, active esters, and sulfates. Examples of activating agents for carboxylic acids include carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl); triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; or combinations thereof. When a carbodiimide-based condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), or dimethylaminopyridine (DMAP) may be further added to the reaction.

[0120] In each step, when a coupling reaction is carried out, examples of the metal catalyst used include palladium compounds such as palladium acetate (II), tetrakis(triphenylphosphine)palladium (0), dichlorobis(triphenylphosphine)palladium (II), dichlorobis(triethylphosphine)palladium (II), tris(dibenzylideneacetone)dipalladium (0), and 1,1'-bis(diphenylphosphino)ferrocenepalladium (II) chloride; nickel compounds such as tetrakis(triphenylphosphine)nickel (0); rhodium compounds such as tris(triphenylphosphine)rhodium (III) chloride; cobalt compounds; copper compounds such as copper oxide and copper iodide (I); and platinum compounds. A base may be added to the reaction, and examples of such bases include inorganic bases.

[0121] When a thiocarbonylation reaction is carried out in each step, diphosphorus pentasulfide is typically used as the thiocarbonylating agent. In addition to diphosphorus pentasulfide, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure, such as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent), may also be used.

[0122] In each step, when a halogenation reaction is carried out, examples of the halogenating agent used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, trichloroisocyanuric acid, etc. Furthermore, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.

[0123] In each step, when a halogenation reaction of a hydroxy group is carried out, examples of the halogenating agent used include hydrohalic acid and an acid halide of an inorganic acid, specifically, for chlorination, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc., and for bromination, 48% hydrobromic acid, etc. may be mentioned. In addition, a method of obtaining an alkyl halide from an alcohol by the reaction of triphenylphosphine with carbon tetrachloride or carbon tetrabromide, etc. may be used. Alternatively, a method of synthesizing an alkyl halide through a two-step reaction in which an alcohol is converted into a sulfonic acid ester and then reacted with lithium bromide, lithium chloride, or sodium iodide may be used.

[0124] When Arbuzov reaction is carried out in each step, examples of the reagent used include alkyl halides such as ethyl bromoacetate and the like; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite and the like.

[0125] When a sulfonyl esterification reaction is carried out in each step, examples of the sulfonylating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

[0126] In each step, when a hydrolysis reaction is carried out, an acid or a base is used as a reagent. When an acid hydrolysis reaction of a tert-butyl ester is carried out, formic acid or triethylsilane may be added to reductively trap the by-product tert-butyl cation.

[0127] When a dehydration reaction is carried out in each step, examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.

[0128] In each step, when an alkylation reaction is carried out, an electrophile (eg, alkyl halide, etc.) and a base (eg, organic bases, inorganic bases, metal alkoxides, metal amides, etc.) are used as reagents.

[0129] In each step, when a cyanation reaction is carried out, examples of the reagent used include metal cyanides such as copper cyanide and potassium cyanide.

[0130] Compound (I) can be synthesized according to the production method shown in the following Scheme 1 or Scheme 2. The abbreviations in each general formula in the reaction scheme are the same as defined above unless otherwise specified. Furthermore, if desired, compound (I) can be produced by carrying out a protection reaction, a deprotection reaction, an amidation reaction, a sulfonamidation reaction, a urea reaction, a carbamoylation reaction, an alkylation reaction, a Mitsunobu reaction, a hydrogenation reaction, an oxidation reaction, a reduction reaction, a halogenation reaction, a coupling reaction, a nucleophilic addition reaction by a carbanion, a Grignard reaction, a deoxygenative fluorination reaction, a dehydration reaction, or the like, either alone or in combination of two or more thereof.

[0131] Among the compounds (I), the compound (Ia) (R 1 R 1a The compound represented by Scheme 1 below can be prepared by the method represented by Scheme 1 below. 1a is an optionally substituted cyclopropyl group, 6-14 It represents an aryl group, or an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group. The other symbols are as defined above.

[0132] [ka]

[0133] Compound (4) can be produced by subjecting compound (2) and compound (3) to a coupling reaction using a palladium catalyst and a base under a carbon monoxide atmosphere. Examples of the palladium catalyst include a combination of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (also known as Xantphos) and bis(dibenzylideneacetone)palladium(0). Examples of the base include N,N-dicyclohexylmethylamine.

[0134] Compound (7) can be produced by the dehydration cyclization reaction of compound (6). The reagent used can be a Burgess reagent or a combination of p-toluenesulfonyl chloride and a base. The base can be the above-mentioned organic base (e.g., N,N-diisopropylethylamine, triethylamine, etc.).

[0135] Compound (12) can be produced by subjecting compound (9), compound (10) and compound (11) to a three-component condensation reaction. The reagent used can be formic acid.

[0136] Compound (14) can be produced by subjecting compound (12) and compound (13) to the Stetter reaction. The reagent used can be a combination of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide and a base. The base can be triethylamine.

[0137] Compound (15) can be produced by subjecting compound (14) to a reduction reaction. Examples of reagents used include sodium borohydride and potassium tri(sec-butyl)borohydride. Regarding the ratio of stereoisomers in the product, only the anti isomer (15a) shown below is obtained, or a mixture of anti isomer (15a) and syn isomer (15b) is obtained (stereochemistry in the formula indicates the relative configuration).

[0138] [ka]

[0139] Compound (Ia) can be produced by alkylation of compound (16) and compound (8) followed by cyclization. The cyclization occurs after the alkylation, but may proceed stepwise. In this case, the cyclization can be carried out under basic or acidic conditions. Examples of bases include triethylamine, DIPEA, potassium acetate, etc. Examples of acids used include acetic acid, etc.

[0140] Among the compounds (I), the compound (Ib) (R 1 R 1b The compound (17) can be produced by the method of Scheme 2 below. 1b is an optionally substituted cycloalkyl group, 6-14 It represents an aryl group, an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group, or an optionally substituted 3- to 8-membered monocyclic non-aromatic heterocyclic group. X represents a halogen atom. The other symbols are as defined above.

[0141] [ka]

[0142] Compound (23) can be produced by subjecting compound (22) to a reduction reaction. Examples of reagents used include sodium borohydride and potassium tri(sec-butyl)borohydride. Alternatively, a combination of aluminum triisopropoxide and 2-propanol can be used. Regarding the ratio of stereoisomers in the product, only the anti isomer (23a) shown below is obtained, or a mixture of the anti isomer (23a) and syn isomer (23b) is obtained (the stereochemistry in the formula indicates the relative configuration).

[0143] [ka]

[0144] Compound (Ib) can be produced by alkylation of compound (24) and compound (8) followed by cyclization. The cyclization occurs after the alkylation, but may proceed stepwise. In this case, the cyclization can be carried out under basic or acidic conditions. Examples of bases include triethylamine, DIPEA, potassium acetate, etc. Examples of acids used include acetic acid, etc.

[0145] Compounds (2), (3), (9), (10), (11), (13), (17), (18), (20), and (21) used as starting materials in each of the above-mentioned production methods are either readily available commercially or can be produced by methods known per se.

[0146] As for the configurational isomer (E,Z isomer) of compound (I), when isomerization occurs, it can be isolated and purified by ordinary separation means such as extraction, recrystallization, distillation, chromatography, etc., to produce a pure compound. In addition, according to the method described in New Experimental Chemistry Lectures 14 (edited by the Chemical Society of Japan), pages 251-253, and 4th Edition Experimental Chemistry Lectures 19 (edited by the Chemical Society of Japan), pages 273-274, or methods equivalent thereto, the isomerization of the double bond can be advanced by heating, an acid catalyst, a transition metal complex, a metal catalyst, a radical species catalyst, light irradiation, or a strong base catalyst, to obtain the corresponding pure isomer.

[0147] Compound (I) may have stereoisomers depending on the type of substituents, and both the isomers alone and mixtures thereof are included in the present invention. Compound (I) may be in the form of a hydrate or a non-hydrate. When the target compound is obtained in a free state by the above reaction, it may be converted into a salt according to a conventional method, and when it is obtained as a salt, it may be converted into a free form or another salt according to a conventional method. Compound (I) thus obtained can be isolated and purified from the reaction solution by known means, such as transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography, etc. When compound (I) exists as configurational isomers (configurational isomers), diastereomers, conformers, etc., they can be isolated by the above-mentioned separation and purification means, if desired. When compound (I) is a racemate, it can be separated into d- and l-isomers by conventional optical resolution means, for example, preparative high performance liquid chromatography (preparative HPLC) and supercritical fluid chromatography (preparative SFC).

[0148] Compound (I) thus obtained, other reaction intermediates and starting compounds thereof can be isolated and purified from the reaction mixture by a method known per se, for example, extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin layer chromatography, preparative high performance liquid chromatography (preparative HPLC), medium pressure preparative liquid chromatography (medium pressure preparative LC), or the like.

[0149] The salt of compound (I) can be produced by a method known per se, for example, by adding an inorganic acid or an organic acid when compound (I) is a basic compound, or by adding an organic base or an inorganic base when compound (I) is an acidic compound. When compound (I) may have optical isomers, all of these individual optical isomers and mixtures thereof are naturally included in the scope of the present invention, and if desired, these isomers can be optically resolved or individually produced according to known means.

[0150] Compound (I) may be in a crystalline form. The crystals of compound (I) can be produced by crystallizing compound (I) using a crystallization method known per se. Examples of the crystallization method include crystallization from a solution, crystallization from vapor, and crystallization from a melt.

[0151] The "crystallization method from solution" generally involves changing a factor related to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of solvent to transition from a non-saturated state to a supersaturated state. Specific examples of the method include a concentration method, a slow cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, and a flux method. Examples of the solvent to be used include aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, etc.), saturated hydrocarbons (e.g., hexane, heptane, cyclohexane, etc.), ethers (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitriles (e.g., acetonitrile, etc.), ketones (e.g., acetone, etc.), sulfoxides (e.g., dimethyl sulfoxide, etc.), acid amides (e.g., N,N-dimethylformamide, etc.), esters (e.g., ethyl acetate, isopropyl acetate, etc.), alcohols (e.g., methanol, ethanol, 2-propanol, etc.), and water. These solvents are used alone or in a mixture of two or more at an appropriate ratio (e.g., 1:1 to 1:100 (volume ratio)). If necessary, seed crystals can also be used.

[0152] The "crystallization method from vapor" includes, for example, a vaporization method (sealed tube method, gas flow method), a gas phase reaction method, a chemical transport method, and the like.

[0153] Examples of the "crystallization method from a melt" include the normal freezing method (pulling method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method), and special growth method (VLS method, liquid phase epitaxy method).

[0154] A suitable example of the crystallization method includes a method in which compound (I) is dissolved in an appropriate solvent (e.g., alcohols such as methanol and ethanol) at a temperature of 20 to 120°C, and the resulting solution is cooled to a temperature equal to or lower than the temperature at which the compound was dissolved (e.g., 0 to 50°C, preferably 0 to 20°C). The thus obtained crystals of the present invention can be isolated, for example, by filtration. The crystals thus obtained are generally analyzed by powder X-ray diffraction. Methods for determining the crystal orientation include mechanical and optical methods.

[0155] The crystals of compound (I) obtained by the above-mentioned production method are expected to be highly pure, high quality, low hygroscopic, and stable even when stored for a long period of time under normal conditions. In addition, they are also excellent in biological properties (e.g., pharmacokinetics (absorption, distribution, metabolism, excretion), efficacy expression), and can be useful as a medicine.

[0156] Compound (I) may be a prodrug. A prodrug of compound (I) refers to a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, i.e., a compound that is enzymatically oxidized, reduced, hydrolyzed, or the like to be converted to compound (I), or a compound that is hydrolyzed by gastric acid or the like to be converted to compound (I). Examples of prodrugs of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated, or phosphorylated [e.g., the amino group of compound (I) is eicosanoylated, alanylated, pentylamino, or the like]. carbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, or tert-butylated compounds; compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (e.g., compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonylated); compounds Compounds in which the carboxy group of (I) is esterified or amidated [e.g., compounds in which the carboxy group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, or methylamidated], etc. These compounds can be produced from compound (I) by a method known per se. In addition, the prodrug of compound (I) may be one that is converted into compound (I) under physiological conditions, as described in "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198, published by Hirokawa Shoten in 1990.

[0157] In this specification, compound (I) and a prodrug of compound (I) may be collectively referred to as "the compound of the present invention".

[0158] Compound (I) may be any of a hydrate, a non-hydrate, a solvate, and a non-solvate. Compound (I) may also contain isotopes (e.g., 2 H, 3 H, 11 C. 14 C. 18 F, 35 S, 125The compound may be a compound labeled or substituted with an isotope, for example, a compound that is used as a tracer for use in positron emission tomography (PET) (PET tracer), and may be useful in fields such as medical diagnosis. 1 H 2 Deuterium converted to H(D) is also encompassed in compound (I). Compound (I) also encompasses tautomers. Compound (I) may be a pharma- ceutically acceptable cocrystal or cocrystal salt. Here, a cocrystal or cocrystal salt refers to a crystalline substance that is composed of two or more distinct solids at room temperature, each of which has different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). A cocrystal or cocrystal salt can be prepared according to a cocrystallization method known per se. Compound (I) may be used as a PET tracer.

[0159] The compound of the present invention has excellent HDAC inhibitory activity, preferably class II HDAC inhibitory activity, and more preferably HDAC6 inhibitory activity, and therefore may be useful as a safe medicine based on this activity. For example, the pharmaceutical agent of the present invention comprising the compound of the present invention is expected to have low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, hematotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and can be used as an agent for preventing or treating HDAC, preferably class II HDAC, more preferably HDAC6-related diseases, more specifically, diseases described in the following (1) to (7), in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans). The compound of the present invention is expected to have particularly low genotoxicity, and the pharmaceutical agent of the present invention comprising the compound of the present invention is expected to have low genotoxicity.

[0160] (1) Inflammatory diseases (e.g., acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory response syndrome (SIRS), inflammation after surgery or trauma, pneumonia, nephritis, meningitis, cystitis, pharyngitis, gastric mucosal injury, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, diabetic nephropathy, uveitis, hidradenitis suppurativa, etc.), (2) Autoimmune diseases (e.g., rheumatoid arthritis, psoriasis, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, etc.), Sjogren's syndrome, Behcet's syndrome, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, discoid lupus erythematosus, Castleman's disease disease), ankylosing spondylitis, polymyositis, dermatomyositis (DM), polyarteritis nodosa (PN), mixed connective tissue disease (MCTD), scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I diabetes, autoimmune Hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, pemphigus, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, Addison's disease, abnormal immune response, arthritis, dermatitis, radiation dermatitis, primary biliary cirrhosis biliary cirrhosis), etc.) (3) Bone and joint degenerative diseases (e.g., rheumatoid arthritis, osteoporosis, osteoarthritis, etc.), (4) Neoplastic diseases (e.g., malignant tumors, neovascular glaucoma, infantile hemangioma, multiple myeloma, chronic sarcoma, metastatic melanoma, Kaposi's sarcoma, vascular proliferation, cachexia, metastasis of breast cancer, etc.), cancer (e.g., colon cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor, etc.), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, etc.), mesothelioma, pancreatic cancer (e.g., pancreatic ductal carcinoma, etc.), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma, etc.), breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer, etc.), ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low malignant potential tumor, etc.), prostate cancer cancer) (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer, etc.), liver cancer (e.g., primary liver cancer, extrahepatic bile duct cancer, etc.), thyroid cancer (e.g., medullary thyroid cancer, etc.), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter, etc.), uterine cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, etc.), melanoma, sarcoma, bladder cancer, hematopoietic tumors including multiple myeloma, pituitary adenoma, glioma, acoustic neuroma, retinal sarcoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thymoma, esophageal cancer, duodenal cancer, colon cancer, rectal cancer, hepatocellular carcinoma, pancreatic endocrine tumor, bile duct Cancer, gallbladder cancer, penile cancer, ureter cancer, testicular tumor, vulvar cancer, cervical cancer, uterine cancer, uterine sarcoma, trophoblastic disease, vaginal cancer, skin cancer, mycosis fungoides, basal cell tumor, soft tissue sarcoma, malignant lymphoma, Hodgkin's disease, myelodysplastic syndrome, adult T-cell leukemia, chronic myeloproliferative disease, pancreatic endocrine tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, cancer of unknown primary origin, etc.), leukemia (e.g., acute leukemia (e.g., acute lymphocytic leukemia, acute myeloid leukemia, etc.), chronic leukemia (e.g., chronic lymphocytic leukemia, chronic myeloid leukemia, etc.), myelodysplastic syndrome), uterine sarcoma (e.g., uterine mesodermal mixed tumor, uterine leiomyosarcoma, endometrial stromal tumor, etc.), myelofibrosis, etc.) (5) Neurodegenerative and / or central nervous system disorders (i) Mental disorders [e.g., depression, major depression, bipolar depression, dysthymic disorder, affective disorder (such as seasonal affective disorder), recurrent depression, postpartum depression, stress disorder, depressive symptoms, mania, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, phobia, social phobia, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, Tourette's syndrome, autism, autism spectrum syndrome, fragile X syndrome, Rett's syndrome, adjustment disorder, bipolar disorder, neurosis, schizophrenia (e.g., positive symptoms, negative symptoms, cognitive symptoms), cognitive dysfunction associated with schizophrenia, chronic fatigue syndrome, anxiety neurosis, obsessive-compulsive disorder, epilepsy, anxiety symptoms, dysphoric mental state, dysthymia, cyclothymia, irritability, syncope, addiction, decreased libido, attention deficit hyperactivity disorder (ADHD), psychotic major depression, refractory major depression, treatment-resistant depression, hereditary spastic paraplegia], (ii) Neurodegenerative diseases {e.g., Alzheimer's disease, Alzheimer's dementia, Alzheimer's senile dementia, Parkinson's disease, muscular dystrophy, Parkinson's disease with dementia, Huntington's disease, multi-infarct dementia, frontotemporal lobar degeneration [progressive supranuclear palsy, corticobasal degeneration] degeneration), frontotemporal lobar degeneration with MAPT gene mutation (FTDP-17), frontotemporal dementia, Pick's disease, argyrophilic granulocytic dementia, etc.], Parkinson's disease, Niemann-Pick syndrome, Down's syndrome, vascular dementia, postencephalitic Parkinson's disease, dementia with Lewy bodies, Rubinstein-Taybi syndrome, HIV-related dementia, amyotrophic lateral sclerosis (ALS), motor neurogenic disease (MND), Creutzfeldt-Jakob disease or prion disease, cerebral palsy, multiple sclerosis, familial dysautonomia}, (iii) Age-related cognitive and memory disorders (e.g., age-related memory disorder, senile dementia), (iv) Sleep disorders [e.g., intrinsic sleep disorders (e.g., psychophysiological insomnia, etc.), exogenous sleep disorders, circadian rhythm disorders (e.g., time zone shift syndrome (jet lag), shift work sleep disorder, irregular sleep-wake patterns, delayed sleep phase syndrome, advanced sleep phase syndrome, non-24-hour sleep-wake, etc.), parasomnia, sleep disorders associated with medical or psychiatric disorders (e.g., chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, vascular dementia, schizophrenia, depression, anxiety neurosis), stress insomnia, insomnia, insomnia neurosis, sleep apnea syndrome], (v) Respiratory depression caused by anesthetics, trauma, or neurodegenerative diseases, etc. (vi) traumatic brain injury, stroke, anorexia nervosa, eating disorders, anorexia nervosa, bulimia, other eating disorders, alcoholism, alcohol abuse, alcoholic amnesia, alcohol delusion, alcohol preference, alcohol withdrawal, alcoholic psychosis, alcoholism, alcoholic jealousy, alcoholic mania, alcohol-dependent mental disorder, alcoholic psychosis, drug preference, drug phobia, drug mania, drug withdrawal, migraine, stress headache, tension headache, diabetic neuropathy, obesity, diabetes, muscle spasms, Meniere's disease , autonomic nervous system imbalance, alopecia, glaucoma, high blood pressure, heart disease, tachycardia, congestive heart failure, hyperventilation, bronchial asthma, apnea, sudden infant death syndrome, inflammatory diseases, allergic diseases, impotence, menopausal disorders, infertility, cancer, immunodeficiency syndrome due to HIV infection, immunodeficiency syndrome due to stress, cerebrospinal meningitis, acromegaly, incontinence, metabolic syndrome, osteoporosis, peptic ulcer, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, stress-related gastrointestinal disorder, nervous vomiting, peptic ulcer, diarrhea, constipation, postoperative ileus, (vii) Pain (pain, cancer pain, acute pain due to inflammation, pain associated with chronic inflammation, postoperative pain (incision pain, deep pain, visceral pain, chronic postoperative pain, etc.), muscular pain (muscular pain associated with chronic pain diseases, stiff shoulders, etc.), joint pain, toothache, temporomandibular joint pain, headache (migraine, tension headache, headache associated with fever, headache associated with high blood pressure), visceral pain (cardiac pain, angina pain, abdominal pain, kidney pain, ureteral pain, bladder pain), pain in the obstetrics and gynecology field (mid-term pain, dysmenorrhea, labor pain, etc.), neuropathic pain (intervertebral disc pain) Hernia, radicular pain, postherpetic neuralgia, trigeminal neuralgia, lower back pain, etc.), peripheral neuropathy (CIPN) caused by anticancer drugs (taxane anticancer drugs (e.g., paclitaxel (Taxol), docetaxel), vinca alkaloid anticancer drugs (e.g., vincristine, vinblastine), platinum preparations (e.g., cisplatin, carboplatin, oxaliplatin), molecular targeted drugs (e.g., bortezomib), etc.) and associated neurological symptoms (anticancer drug-induced neuropathic pain (CINP)), (6) Chronic heart failure, acute heart failure, acute decompensated heart failure, ischemic heart disease, cardiomyopathy, myocarditis, valvular disease, (7) Peripheral neuropathy, etc. (e.g., demyelinating diseases and neuropathy (multiple sclerosis, Guillain-Barre syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy, familial amyloid polyneuropathy))

[0161] The medicament of the present invention is preferably used for treating an autoimmune disease, an inflammatory disease, a bone / joint degenerative disease, a neurodegenerative disease, a central nervous system disease, a neoplastic disease, or a peripheral neuropathy, and more preferably for treating an inflammatory bowel disease (preferably Crohn's disease or ulcerative colitis), systemic lupus erythematosus, rheumatoid arthritis, psoriasis, Sjogren's syndrome, Behcet's disease, multiple sclerosis, graft-versus-host disease, Alzheimer's disease (preferably Alzheimer's dementia), schizophrenia, dementia with Lewy bodies, frontotemporal lobar degeneration [progressive supranuclear palsy, corticobasal degeneration, degeneration, frontotemporal lobar degeneration with MAPT gene mutation (FTDP-17), frontotemporal dementia, Pick's disease, argyrophilic granulocytic dementia, etc.), Parkinson's disease, Huntington's disease, Rubinstein-Taybi syndrome, muscular dystrophy, Rett syndrome, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, depression, hereditary spastic paraplegia, Riley-Day syndrome, Castleman's disease, leukemia, uterine leiomyosarcoma, prostate cancer, colon cancer, multiple myeloma, cachexia, or myelofibrosis, chronic heart failure or acute heart failure or acute decompensated heart failure, ischemic heart disease, cardiomyopathy, myocarditis, valvular disease, peripheral neuropathy, etc. More preferably, the pharmaceutical agent of the present invention can be used as an agent for the prevention or treatment of Alzheimer's disease, frontotemporal lobar degeneration (progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration associated with MAPT gene mutation (FTDP-17), frontotemporal dementia, Pick's disease, argyrophilic granulocytic dementia, etc.), Charcot-Marie-Tooth disease, etc., in particular Alzheimer's disease or progressive supranuclear palsy.

[0162] Here, "prevention" of the above-mentioned disease means, for example, administering a medicine containing the compound of the present invention to a patient who has not yet developed the disease, or a patient who has developed the disease but has no subjective symptoms, who is expected to be at high risk of developing the disease due to some factor related to the disease, or administering a medicine containing the compound of the present invention to a patient who is concerned about the recurrence of the disease after treatment of the disease.

[0163] The pharmaceutical agent containing the compound of the present invention may be used alone or as a pharmaceutical composition in which the compound of the present invention is mixed with a pharmacologically acceptable carrier, according to a method known per se as a method for producing pharmaceutical preparations (e.g., a method described in the Japanese Pharmacopoeia, etc.). Pharmaceutical agents containing the compound of the present invention may be used in the form of, for example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules and microcapsules), troches, syrups, liquids, emulsions, suspensions, controlled-release preparations (e.g., immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (e.g., orally disintegrating films, oral mucosa patch films, etc.), or the like. They can be safely administered orally or parenterally (e.g., intravenously, intramuscularly, subcutaneously, intraviscerally, intranasally, intradermally, by eye drop, intracerebral, rectally, intravaginally, intraperitoneally, inside a tumor, proximal to a tumor, at a lesion) as an injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), infusion, transdermal preparation, cream, ointment, lotion, patch, suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal preparation, pulmonary preparation (inhalation preparation), eye drop, etc. The content of the compound of the present invention in the medicament of the present invention is about 0.01% by weight to about 100% by weight of the whole medicament. The dosage of the medicament of the present invention varies depending on the subject of administration, the administration route, the disease, etc., but for example, for a patient (body weight about 60 kg) with a neurodegenerative disease (e.g. Alzheimer's disease, progressive supranuclear palsy, etc.), about 0.01 mg / kg body weight to about 50 mg / kg body weight, preferably about 0.05 mg / kg body weight to about 25 mg / kg body weight, more preferably about 0.1 mg / kg body weight to about 2 mg / kg body weight of the active ingredient (compound (I)) can be administered as an oral preparation once a day or in divided doses several times a day. Examples of pharmacologically acceptable carriers include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, lubricants, binders and disintegrants in solid preparations, and solvents, solubilizing agents, suspending agents, isotonicity agents, buffers and soothing agents in liquid preparations. Furthermore, conventional additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents and wetting agents may be used appropriately and in appropriate amounts, if necessary. When the medicament of the present invention is a sustained release preparation, the dosage will vary depending on the type and content of compound (I), dosage form, duration of drug release, subject animal (e.g., mammals such as mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, cows, horses, pigs, sheep, monkeys, and humans), and purpose of administration. For example, when applied by parenteral administration, the dosage will be such that about 0.1 to about 100 mg of compound (I) is released from the administration preparation per week.

[0164] Examples of excipients include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light anhydrous silicic acid. Lubricants include, for example, magnesium stearate, calcium stearate, talc, and colloidal silica. Examples of binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, and sodium carboxymethyl cellulose. Disintegrants include, for example, starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylstarch, and L-hydroxypropylcellulose. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil. Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate. Examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.

[0165] Examples of isotonicity agents include glucose, D-sorbitol, sodium chloride, glycerin, and D-mannitol. Examples of the buffering agent include buffer solutions of phosphate, acetate, carbonate, citrate, and the like. An example of a soothing agent is benzyl alcohol. Examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, and sorbic acid. Antioxidants include, for example, sulfites, ascorbic acid, and α-tocopherol.

[0166] In the prevention and treatment of various diseases, the compound of the present invention can be used together with other drugs (hereinafter, sometimes abbreviated as concomitant drugs). Hereinafter, the medicine used when the compound of the present invention is used in combination with other drugs is referred to as the "concomitant drug of the present invention."

[0167] For example, when the compound of the present invention is used as an HDAC inhibitor, preferably a class II HDAC inhibitor, more preferably an HDAC6 inhibitor, it may be used in combination with the following drugs. Tranquilizers (diazepam, lorazepam, potassium clorazepate, oxazepam, chlordiazepoxide, medazepam, oxazolam, cloxazolam, clotiazepam, bromazepam, etizolam, fludiazepam, hydroxyzine, nitrazepam, triazolam, alprazolam, etc.), Antipsychotics (chlorpromazine hydrochloride, prochlorperazine, trifluoperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride, haloperidol, clozapine, trifluoperazine hydrochloride, fluphenazine hydrochloride, olanzapine, quetiapine fumarate, risperidone, aripiprazole, bromperidol, spiperone, reserpine, clocapramine hydrochloride, sulpiride, zotepine, thiothixene, etc.), Antiepileptic drugs (phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, trimethadione, carbamazepine, phenobarbital, primidone, sulthiame, sodium valproate, clonazepam, diazepam, nitrazepam, etc.), Antidepressants and antimanic drugs [Tricyclic or tetracyclic antidepressants (imipramine hydrochloride, clomipramine hydrochloride, desipramine hydrochloride, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, mianserin hydrochloride, maprotiline hydrochloride), noxiptiline, phenelzine, sulpiride, trazodone hydrochloride, lithium carbonate, selective serotonin reuptake inhibitors (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrochloride, sertraline hydrochloride, paroxetine hydrochloride, , paroxetine hydrochloride hydrate, escitalopram oxalate, etc.), serotonin-noradrenaline reuptake inhibitors (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride, etc.), noradrenaline reuptake inhibitors (reboxetine mesylate, etc.), noradrenaline-dopamine reuptake inhibitors (bupropion hydrochloride, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, setiptiline maleate, 5-HT 1A agonists (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.)] Benzodiazepines (e.g., clonazepam), L-type calcium channel blockers (e.g., pregabalin), 5-HT 1A Agonists (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.), 5-HT3 antagonists (cyamemazine, etc.), non-cardiac selective beta blockers (propranolol hydrochloride, oxyprenolol hydrochloride, etc.), histamine H1 antagonists (hydroxyzine hydrochloride, etc.), Antipsychotics (chlorpromazine, haloperidol, sulpiride, clozapine, trifluoperazine hydrochloride, fluphenazine hydrochloride, olanzapine, quetiapine fumarate, risperidone, aripiprazole, etc.), CRF antagonists, other antianxiety drugs (meprobamate, etc.), tachykinin antagonists (MK-869, saredutant, etc.), drugs acting on metabotropic glutamate receptors, CCK antagonists, β3-adrenergic antagonists (amibegron hydrochloride, etc.), GAT-1 inhibitors (tiagabine hydrochloride, etc.), N-type calcitonin antagonists (calcitonin, selenium, etc.), Umium channel inhibitors, type 2 carbonic anhydrase inhibitors, NMDA glycine site agonists, NMDA antagonists (memantine, etc.), peripheral benzodiazepine receptor agonists, vasopressin antagonists, vasopressin V1b antagonists, vasopressin V1a antagonists, phosphodiesterase inhibitors, opioid antagonists, opioid agonists, uridine, nicotinic acid receptor agonists, thyroid hormones (T3, T4), TSH, TRH, MAO inhibitors (phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), 5-HT 2A Antagonist, 5-HT 2AInverse agonists, COMT inhibitors (entacapone, etc.), bipolar disorder medications (lithium carbonate, sodium valproate, lamotrigine, riluzole, felbamate, etc.), cannabinoid CB1 antagonists (rimonabant, etc.), FAAH inhibitors, sodium channel blockers, anti-ADHD drugs (methylphenidate hydrochloride, methamphetamine hydrochloride, etc.), alcoholism medications, autism medications, chronic fatigue syndrome medications, convulsant medications, fibromyalgia medications, headache medications, insomnia medications (etizolam, zopiclone, triazolam, zolpidem, ramelteon, indiplon, etc.), smoking cessation medications for myasthenia gravis, for stroke, for mania, for hypersomnia, for pain, for dysthymia, for autonomic imbalance, for male and female sexual dysfunction, for migraine, for pathological gambling, for restless legs syndrome, for substance dependence, for alcohol-related disorders, for irritable bowel syndrome, for Alzheimer's disease (donepezil, galantamine, memantine, rivastigmine, etc.), for Parkinson's disease (levodopa, carbidopa, benserazide, selegiline, rasagiline, zonisamide, entacapone, amantadine, talipexole) , pramipexole, ropinirole, rotigotine, apomorphine, cabergoline, pergolide, bromocriptine, istradefylline, trihexyphenidyl, biperiten, piroheptine, prophenamine, promethazine, droxidopa, amantadine hydrochloride, bromocriptine mesylate, trihexyphenidyl hydrochloride, selegiline hydrochloride, combinations of these drugs, etc.), drugs for Parkinson's disease with dementia (rivastigmine), drugs for dementia with Lewy bodies (donepezil), drugs for ALS (riluzole, neurotrophic factors, etc.), cholesterol-lowering drugs Drugs for treating dyslipidemia (statins (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrates (clofibrate, etc.), squalene synthesis inhibitors), drugs for treating abnormal behavior or wandering disorder due to dementia (sedatives, anti-anxiety drugs, etc.), apoptosis inhibitors, anti-obesity drugs, drugs for treating diabetes, drugs for treating hypertension, drugs for treating hypotension, drugs for treating rheumatism (DMARDs), anti-cancer drugs, drugs for treating hypoparathyroidism (PTH), calcium receptor antagonists, sex hormones or their derivatives (progesterone, estradiol, estradiol benzoate, etc.),Neuronal differentiation promoters, neuronal regeneration promoters, nonsteroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, etc.), steroids (dexamethasone, cortisone acetate, etc.), anti-cytokine drugs (TNF inhibitors, MAP kinase inhibitors, etc.), antibody drugs, nucleic acids or nucleic acid derivatives, aptamer drugs, etc.

[0168] In the case of concomitant use, the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered to the subject at the same time or at a time lag. The dose of the concomitant drug may be in accordance with the dose used in clinical practice, and may be appropriately selected depending on the subject, administration route, disease, combination, etc. The administration form of the combination is not particularly limited, and it is sufficient that the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, (2) administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug, via the same administration route, (3) administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug, via the same administration route with a time lag, (4) administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug, via different administration routes, and (5) administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug, via different administration routes with a time lag (for example, administration of the concomitant drug after administration of the compound of the present invention, or administration in the reverse order). The mixing ratio of the compound of the present invention to the concomitant drug in the combination agent of the present invention can be appropriately selected depending on the subject of administration, the administration route, the disease, etc. For example, the content of the compound of the present invention in the combination agent of the present invention varies depending on the form of the formulation, but is usually about 0.01 to about 100% by weight, preferably about 0.1 to about 50% by weight, and more preferably about 0.5 to about 20% by weight based on the total formulation.

[0169] The content of the concomitant drug in the concomitant agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to about 100% by weight, preferably about 0.1 to about 50% by weight, and more preferably about 0.5 to about 20% by weight based on the total preparation. The content of additives such as carriers in the combination drug of the present invention varies depending on the form of the preparation, but is usually about 1 to about 99.99% by weight, preferably about 10 to about 90% by weight, based on the total preparation. In addition, when the compound of the present invention and the concomitant drug are separately formulated, the contents may be similar.

[0170] The amount of the concomitant drug can be set in any range as long as side effects are not a problem. The daily dose of the concomitant drug varies depending on the severity of symptoms, the age, sex, body weight, sensitivity difference, administration time, interval, properties, preparation, type, and type of active ingredient of the pharmaceutical preparation, and is not particularly limited. The amount of the drug is usually, for example, about 0.001 to about 2000 mg, preferably about 0.01 to about 500 mg, and more preferably about 0.1 to about 100 mg per 1 kg body weight of a mammal when orally administered, and is usually administered 1 to 4 times a day. When administering the combination drug of the present invention, the compound of the present invention and the combination drug may be administered at the same time or with a time lag. When administering with a time lag, the time lag varies depending on the active ingredient, dosage form, and administration method to be administered. For example, when the combination drug is administered first, the compound of the present invention is administered within 1 minute to 3 days, preferably within 10 minutes to 1 day, and more preferably within 15 minutes to 1 hour after the combination drug is administered. When the compound of the present invention is administered first, the combination drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, and more preferably within 15 minutes to 1 hour after the compound of the present invention is administered. EXAMPLES

[0171] The present invention will be further explained in detail by the following examples, test examples and formulation examples, but these are not intended to limit the present invention and may be modified without departing from the scope of the present invention. In the following examples, "room temperature" generally refers to about 10° C. to about 35° C. Ratios shown in mixed solvents are by volume unless otherwise specified. % refers to weight % unless otherwise specified.

[0172] In the examples, elution in silica gel column chromatography was performed under observation by TLC (Thin Layer Chromatography) unless otherwise specified. In the TLC observation, a 60 F TLC plate manufactured by Merck was used. 254 The developing solvent was the same as that used as the elution solvent in silica gel column chromatography. A UV detector was used for detection. In silica gel column chromatography, when NH is used, aminopropylsilane-bonded silica gel was used, and when Diol is used, 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel was used. In preparative HPLC (high performance liquid chromatography), when C18 is used, octadecyl-bonded silica gel was used. The ratios shown in the elution solvents are by volume unless otherwise specified.

[0173] 1 H NMR analysis was performed using ACD / SpecManager (trade name) software, etc. Peaks with very gentle proton peaks such as hydroxyl and amino groups may not be recorded. MS (mass spectrum) was measured by LC / MS (liquid chromatography mass spectrometer). ESI (electrospray ionization) or APCI (atomospheric pressure chemical ionization) was used as the ionization method. Data shows actual measured values ​​(found). Molecular ion peaks are usually observed, but may be observed as fragment ions. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed. Elemental analysis values ​​(Anal.) are shown as calculated values ​​(Calcd) and actual measured values ​​(Found). Powder X-ray diffraction patterns were measured using Cu-Kα characteristic X-rays on a Rigaku Ultima IV, and characteristic peaks were noted.

[0174] The following abbreviations are used in the following examples: MS: Mass spectrum M: Molar concentration CDCl3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide 1 H NMR: Proton nuclear magnetic resonance LC / MS: Liquid chromatograph mass spectrometer ESI: electrospray ionization APCI: atmospheric pressure chemical ionization AIBN: 2,2'-azobis(isobutyronitrile) Boc: tert-butoxycarbonyl CDI: 1,1'-carbonyldiimidazole CO2: Carbon dioxide DIPEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide NBS: N-bromosuccinimide TEA: Triethylamine THF: tetrahydrofuran XANTPHOS: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0175] Example 1 and Example 2 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example compound 1) 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1S,2S)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example compound 2)

[0176] A) tert-Butyl 2-[3-(methoxycarbonyl)-4-methylbenzoyl]hydrazine-1-carboxylate The following reaction was carried out in five separate reactions at the scale described. A mixture of methyl 5-bromo-2-methylbenzoate (42.0 g), tert-butyl hydrazinecarboxylate (29.1 g), bis(dibenzylideneacetone)palladium(0) (5.27 g), XANTPHOS (5.30 g), N,N-dicyclohexylmethylamine (58.3 mL) and cyclopentyl methyl ether (1000 mL) was stirred at 95 °C for 5 hours under a carbon monoxide atmosphere (0.5 MPa). The five reaction mixtures were combined and filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in a mixture of ethyl acetate and THF, and the solution was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate) and crystallized from hexane / THF to give the title compound (45.7 g). 1 H NMR (300 MHz, DMSO-d6) δ1.32-1.53 ​​(9H, m), 2.57 (3H, s), 3.86 (3H, s), 7.46 (1H, d, J = 7.9 Hz), 7.94 (1H, dd, J = 7.9, 1.5 Hz), 8.33 (1H, s), 8.93 (1H, s), 10.30 (1H, s). MS: [MH] - 307.0.

[0177] B) Methyl 5-(hydrazinecarbonyl)-2-methylbenzoate hydrochloride To tert-butyl 2-[3-(methoxycarbonyl)-4-methylbenzoyl]hydrazine-1-carboxylate (45.7 g) was added 4 M hydrogen chloride in cyclopentyl methyl ether (200 mL) at room temperature. The mixture was stirred at room temperature for 3 days. The precipitated solid was collected by filtration and dried to obtain the title compound (36.3 g). 1 H NMR (300 MHz, DMSO-d6) δ 2.59 (3H, s), 3.88 (3H, s), 7.52 (1H, d, J = 8.1 Hz), 8.03 (1H, dd, J = 7.9, 2.1 Hz), 8.36 (1H, d, J = 1.9 Hz), 9.71-10.80 (2H, m), 11.64 (1H, br s). MS: [M+H] + 209.0.

[0178] C) Methyl 5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-methylbenzoate To a mixture of methyl 5-(hydrazinecarbonyl)-2-methylbenzoate hydrochloride (36.3 g) and THF (750 mL) was added DIPEA (129 mL) at room temperature. Difluoroacetic anhydride (27.6 mL) was added dropwise to the mixture at 0 °C. The mixture was stirred at room temperature for 2 hours, and then 4-methylbenzenesulfonyl chloride (56.5 g) was added to the mixture at room temperature. The mixture was stirred at room temperature overnight, and then water was added to the mixture at room temperature, followed by extraction with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium bicarbonate, water, and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane / ethyl acetate to obtain the title compound (24.9 g). 1 H NMR (300 MHz, DMSO-d6) δ 2.63 (3H, s), 3.90 (3H, s), 7.37-7.75 (2H, m), 8.15 (1H, dd, J = 8.1, 2.1 Hz), 8.44 (1H, d, J = 2.3 Hz).

[0179] D) Methyl 2-(bromomethyl)-5-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl))benzoate To a mixture of methyl 5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-methylbenzoate (14.0 g) and benzotrifluoride (500 mL), NBS (16.7 g) and AIBN (0.857 g) were added at room temperature. The mixture was stirred at 90 °C for 1 hour under an argon atmosphere. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. DIPEA (10.0 mL) was added to a mixture of the residue and THF (500 mL) at room temperature. Diethyl phosphonate (7.40 mL) was added dropwise to the mixture at 0 °C, and the mixture was stirred overnight at room temperature. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous ammonium chloride solution, water, and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallized from hexane / ethyl acetate to obtain the title compound (12.7 g). 1 H NMR (300 MHz, CDCl3) δ 4.01 (3H, s), 5.01 (2H, s), 6.94 (1H, t, J = 51.6 Hz), 7.69 (1H, d, J = 8.3 Hz), 8.24 (1H, dd, J = 7.9, 1.9 Hz), 8.71 (1H, d, J = 1.9 Hz). MS: [M+H] + 347.0.

[0180] E) tert-Butyl [(4-methylbenzene-1-sulfonyl)(pyridin-2-yl)methyl]carbamate To a mixture of sodium p-toluenesulfinate (25.0g), tert-butyl carbamate (10.9 g) and water (140 mL) was added a mixture of pyridine-2-carbaldehyde (10.0 g) and methanol (70 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes until the suspension became a clear solution. To the mixture was added formic acid (7.16 mL) at room temperature, and the mixture was stirred at room temperature for 3 days. The precipitated solid was collected by filtration and washed with water and diisopropyl ether to obtain the title compound (23.0 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.02-1.31 (9H, m), 2.39 (3H, s), 6.06 (1H, br d, J = 10.2 Hz), 7.31-7.52 (3H, m), 7.66 (2H, d, J = 8.3 Hz), 7.77-7.84 (1H, m), 7.85-8.00 (1H, m), 8.15 (1H, br d, J = 10.5 Hz), 8.49-8.63 (1H, m).

[0181] F) tert-Butyl [2-oxo-1,2-di(pyridin-2-yl)ethyl]carbamate A mixture of tert-butyl [(4-methylbenzene-1-sulfonyl)(pyridin-2-yl)methyl]carbamate (11.0 g), pyridine-2-carbaldehyde (3.41 g), 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (1.53 g) and THF (121 mL) was degassed, and triethylamine (63.3 mL) was added dropwise to the mixture at room temperature under an argon atmosphere. The mixture was degassed again, and the mixture was stirred overnight at 60 °C under an argon atmosphere. A saturated aqueous solution of ammonium chloride was added to the mixture at room temperature, and the mixture was partitioned with water and ethyl acetate. The separated organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (9.81 g) as a crude product. The obtained compound was used in the next reaction without further purification. MS: [M+H-Boc] + 214.0.

[0182] G) tert-Butyl [(1RS,2RS)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl]carbamate To a mixture of tert-butyl [2-oxo-1,2-di(pyridin-2-yl)ethyl]carbamate (9.81 g), methanol (60 mL) and THF (60 mL) was added sodium borohydride (1.72 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the mixture at 0° C., and the mixture was stirred at room temperature for 1 hour, and partitioned with water and ethyl acetate. The separated organic layer was washed with water and saturated saline. The combined aqueous layer was extracted again with ethyl acetate, and the extract was washed with water and saturated saline. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was solidified using ethyl acetate / hexane, and the obtained solid was recrystallized from ethyl acetate / hexane to obtain the title compound (6.64 g). 1H NMR (300 MHz, DMSO-d6) δ 1.11-1.35 (9H, m), 4.82-5.09 (2H, m), 5.61 (1H, d, J = 5.1 Hz), 7.02 (1H, br d, J = 8.7 Hz), 7.10 (1H, br d, J = 7.9 Hz), 7.15-7.30 (3H, m), 7.57-7.80 (2H, m), 8.42 (1H, d, J = 4.3 Hz), 8.52 (1H, br d, J = 4.1 Hz). MS: [M+H] + 316.1.

[0183] H) 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1RS,2RS)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one To a mixture of tert-butyl [(1RS,2RS)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl]carbamate (2.21 g) and acetic acid (20 mL), hydrogen bromide (30% acetic acid solution (about 5.1 M), 11.0 mL) was added dropwise at room temperature, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and azeotroped with toluene and toluene / ethanol to obtain a white solid (3.54 g). To a mixture of the obtained solid (2.83 g), methyl 2-(bromomethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzoate (2.15 g) and DMF (50 mL), DIPEA (6.46 mL) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 3 hours. To the mixture, acetic acid (2.12 mL) was added dropwise at room temperature, and the mixture was stirred at room temperature overnight. The mixture was poured into water at room temperature and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) and crystallized from ethyl acetate / diisopropyl ether to obtain the title compound (2.36 g). 1H NMR (300 MHz, DMSO-d6) δ 4.75 (1H, d, J = 18.8 Hz), 5.03 (1H, d, J = 18.8 Hz), 5.49 (1H, dd, J = 8.8, 5.8 Hz), 5.76 (1H, d, J = 9.0 Hz), 5.98 (1H, d, J = 5.6 Hz), 7.17 (1H, ddd, J = 7.3, 4.9, 1.3 Hz), 7.30-7.72 (4H, m), 7.72-7.89 (3H, m), 8.04 (1H, d, J = 0.8 Hz), 8.17-8.24 (1H, m), 8.25-8.31 (1H, m), 8.60-8.66 (1H, m). MS: [M+H] + 450.1.

[0184] I) 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example compound 1) and 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1S,2S)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example compound 2) 6-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1RS,2RS)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one was optically resolved by preparative SFC (column: CHIRALCEL OD-H, 20 mmID × 250 mmL, 5 μm, mobile phase: CO2 / ethanol = 770 / 230 (v / v)).

[0185] The fraction of the enantiomer with the longer retention time was concentrated under reduced pressure, and the residue was crystallized from hexane / ethyl acetate to obtain a white solid (1.20 g). The resulting solid (1.17 g) was dissolved in ethyl acetate (12 mL) at 70 °C, and heptane (10 mL) was added dropwise to the mixture at 70 °C. The mixture was stirred at 70 °C for 30 min, and then additional heptane (30 mL) was added dropwise to the mixture at 50 °C-75 °C. The mixture was stirred at 50 °C for 30 min and at room temperature for 1 h. The precipitated solid was collected by filtration and washed with heptane to give 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (1.09 g, >99% ee, retention time: 5.48 min (analytical column: CHIRALCEL OD-H, 4.6 mmID × 150 mmL, 5 μm, mobile phase: CO2 / ethanol = 770 / 230 (v / v)). The absolute stereochemistry of the compound was determined by X-ray crystallography. 1 H NMR (300 MHz, DMSO-d6) δ 4.75 (1H, d, J = 18.8 Hz), 5.03 (1H, d, J = 18.8 Hz), 5.49 (1H, dd, J = 8.8, 5.5 Hz), 5.76 (1H, d, J = 9.0 Hz), 5.98 (1H, d, J = 5.6 Hz), 7.17 (1H, ddd, J = 7.3, 4.9, 1.3 Hz), 7.28-7.72 (4H, m), 7.72-7.91 (3H, m), 8.04 (1H, d, J = 0.8 Hz), 8.18-8.24 (1H, m), 8.25-8.32 (1H, m), 8.60-8.67 (1H, m). MS: [M+H] + 450.1. Anal.Calcd for C 23 H 17F2N5O3: C, 61.47; H, 3.81; N, 15.58, Found: C, 61.68; H, 4.01; N, 15.80. Powder X-ray crystal diffraction pattern (diffraction angle 2θ): 5.0°, 7.1°, 9.1°, 10.8°, 16.6°, 18.3°, 19.8°, 21.6°, 22.8°, 23.7°, 26.1°

[0186] The fraction of the optical isomer with the shorter retention time was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (15 mL) at 70° C. Diisopropyl ether (30 mL) was added dropwise to the mixture at 50° C. to 70° C., and the resulting suspension was stirred at 50° C. for 1 hour. Diisopropyl ether (30 mL) was added dropwise to the mixture at 50° C., and the mixture was stirred at 50° C. for 30 minutes and at room temperature for 1 hour. The precipitated solid was collected by filtration and washed with diisopropyl ether to give 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1S,2S)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (1.02 g, >99% ee, retention time: 4.52 min (analytical column: CHIRALCEL OD-H, 4.6 mmID × 150 mmL, 5 μm, mobile phase: CO2 / ethanol=770 / 230(v / v)). MS: [M+H] + 450.1.

[0187] Examples 3 and 4 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example compound 3) 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1S,2S)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example compound 4)

[0188] A) tert-Butyl [2-(5-fluoropyridin-2-yl)-2-oxo-1-(pyridin-2-yl)ethyl]carbamate A mixture of tert-butyl [(4-methylbenzene-1-sulfonyl)(pyridin-2-yl)methyl]carbamate (12.1 g), 5-fluoropyridine-2-carbaldehyde (4.18 g), 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (1.68 g) and THF (134 mL) was degassed, and triethylamine (69.6 mL) was added dropwise to the mixture at room temperature under an argon atmosphere. The mixture was degassed again, and the mixture was stirred overnight at 60 °C under an argon atmosphere. A saturated aqueous ammonium chloride solution was added to the mixture at 0 °C, and the mixture was partitioned with water and ethyl acetate. The separated organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and crystallized from ethyl acetate / hexane to obtain the title compound (7.14 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.12-1.51 (9H, m), 6.76 (1H, d, J = 8.7 Hz), 7.25 (1H, ddd, J = 7.5, 4.9, 1.1 Hz), 7.45 (1H, br d, J = 8.3 Hz), 7.53 (1H, d, J = 7.9 Hz), 7.78 (1H, td, J = 7.7, 1.9 Hz), 7.90 (1H, td, J = 8.7, 2.6 Hz), 8.11 (1H, dd, J = 8.8, 4.7 Hz), 8.33 (1H, br d, J = 4.5 Hz), 8.64 (1H, d, J = 2.6 Hz).

[0189] B) tert-Butyl [(1RS,2RS)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]carbamate To a mixture of tert-butyl [2-(5-fluoropyridin-2-yl)-2-oxo-1-(pyridin-2-yl)ethyl]carbamate (6.59 g) and THF (100 mL), potassium tri(sec-butyl)borohydride (1 M THF solution, 23.9 mL) was added dropwise at -78 °C under an argon atmosphere, and the mixture was stirred at -78 °C for 2 hours. Water (40 mL) was added to the mixture at -78 °C, and 2 M aqueous sodium hydroxide solution (99 mL) and 30% aqueous hydrogen peroxide solution (20.3 mL) were added to the mixture while maintaining the internal temperature below 0 °C. The mixture was stirred at room temperature for 2 hours. Then, sodium thiosulfate pentahydrate (49.4 g) was dissolved in water (190 mL) and added dropwise to the mixture at 0 °C. The mixture was stirred at room temperature for 2 hours and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate / heptane to obtain the title compound (5.62 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.02-1.46 (9H, m), 4.84-5.10 (2H, m), 5.69 (1H, br d, J = 4.5 Hz), 6.98 (1H, br d, J = 8.7 Hz), 7.13-7.25 (2H, m), 7.29 (1H, dd, J = 8.7, 4.5 Hz), 7.50-7.78 (2H, m), 8.43 (1H, dd, J = 4.9, 0.8 Hz), 8.51 (1H, d, J = 2.6 Hz). MS: [M+H-Boc] + 234.0.

[0190] C) 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1RS,2RS)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one To a mixture of tert-butyl [(1RS,2RS)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]carbamate (4.09 g) and acetic acid (40 mL), hydrogen bromide (25% acetic acid solution, 10 mL) was added at room temperature. Acetic acid (20 mL) was added to the mixture at room temperature, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was azeotroped with toluene three times and dried. To a mixture of the obtained residue, DIPEA (13.5 mL), and DMF (29 mL), methyl 2-(bromomethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzoate (3.87 g) dissolved in DMF (10 mL) was added dropwise at room temperature, and the mixture was stirred at room temperature for 60 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The obtained solid was suspended in diisopropyl ether / ethyl acetate and collected by filtration. The solid was suspended in hexane / ethyl acetate = 1 / 1 (50 mL), sonicated, and stirred at 50 °C for 10 minutes. The solid was collected by filtration and washed with hexane / ethyl acetate to obtain the title compound (4.09 g). 1H NMR (300 MHz, DMSO-d6) δ 4.70 (1H, d, J = 19.6 Hz), 4.97 (1H, d, J = 20.0 Hz), 5.47-5.57 (1H, m), 5.72 (1H, d, J = 9.0 Hz), 6.05 (1H, d, J = 5.3 Hz), 7.31-7.74 (5H, m), 7.77-7.87 (2H, m), 8.05 (1H, d, J = 1.1 Hz), 8.22 (1H, dd, J = 7.9, 1.5 Hz), 8.26 (1H, t, J = 1.5 Hz), 8.57-8.69 (1H, m). MS: [M+H] + 468.1.

[0191] D) 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example compound 3) and 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1S,2S)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example compound 4) 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1RS,2RS)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (3.09 g) was optically resolved by preparative HPLC (column: CHIRALCEL OD, 50 mmID × 500 mmL, 20 μm, mobile phase: hexane / ethanol = 700 / 300 (v / v)).

[0192] The fraction of the optical isomer with the longer retention time was concentrated under reduced pressure, and the residue was crystallized from heptane / isopropyl acetate to obtain 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (1.35 g, 99% ee, retention time: 9.16 min (analysis conditions: column: CHIRALCEL OD-H, 4.6 mmID × 250 mmL, 5 μm, mobile phase: hexane / ethanol = 700 / 300 (v / v)). The absolute stereochemistry of the compound was determined by X-ray crystallography. 1 H NMR (300 MHz, DMSO-d6) δ 4.71 (1H, d, J = 18.8 Hz), 4.97 (1H, d, J = 18.8 Hz), 5.52 (1H, dd, J = 9.0, 5.3 Hz), 5.72 (1H, d, J = 9.0 Hz), 6.05 (1H, d, J = 5.3 Hz), 7.31-7.74 (5H, m), 7.77-7.89 (2H, m), 8.05 (1H, d, J = 1.1 Hz), 8.22 (1H, dd, J = 8.1, 1.7 Hz), 8.26 (1H, t, J = 1.5 Hz), 8.53-8.72 (1H, m). MS: [M+H] + 468.1. Anal.Calcd for C 23 H 16 F3N5O3·0.3H2O: C, 58.43; H, 3.54; N, 14.81, Found: C, 58.53; H, 3.53; N, 14.78. Powder X-ray crystal diffraction pattern (diffraction angle 2θ): 7.2°, 11.3°, 16.2°, 19.2°, 22.1°, 22.7°, 24.2°, 26.5°

[0193] The fraction of the optical isomer with the shorter retention time was concentrated under reduced pressure, and the residue was crystallized from heptane / isopropyl acetate to obtain 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1S,2S)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (1.37 g, 99% ee, retention time: 7.35 min (analysis conditions column: CHIRALCEL OD-H, 4.6 mmID × 250 mmL, 5 μm, mobile phase: hexane / ethanol = 700 / 300 (v / v)). MS: [M+H] + 468.1.

[0194] Example 5 and Example 6 2-[(1R,2R)-1,2-bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1H-isoindol-1-one (Example compound 5) 2-[(1S,2S)-1,2-bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1H-isoindol-1-one (Example compound 6)

[0195] A) tert-Butyl [(5-fluoropyridin-2-yl)(4-methylbenzene-1-sulfonyl)methyl]carbamate To a mixture of sodium p-toluenesulfinate (21.4 g), tert-butyl carbamate (9.36 g) and water (120 mL), 5-fluoropyridine-2-carbaldehyde (10 g) dissolved in methanol (60 mL) was added at room temperature. The mixture was stirred at room temperature for 30 minutes until the suspension became a clear solution. To the mixture, formic acid (6.13 mL) was added at room temperature, and the mixture was stirred at room temperature for 3 days. The precipitated solid was collected by filtration, washed with water and diisopropyl ether, and dried under reduced pressure to obtain the title compound (24.4 g). 1 H NMR (300 MHz, DMSO-d6) 1.10-1.28 (9H, m), 2.39 (3H, s), 6.09 (1H, d, J = 10.5 Hz), 7.44 (2H, d, J = 7.9 Hz), 7.67 (2H, d, J = 7.9 Hz), 7.81-7.97 (2H, m), 8.26 (1H, d, J = 10.2 Hz), 8.56 (1H, d, J = 2.3 Hz).

[0196] B) tert-Butyl [1,2-bis(5-fluoropyridin-2-yl)-2-oxoethyl]carbamate A mixture of tert-butyl [(5-fluoropyridin-2-yl)(4-methylbenzene-1-sulfonyl)methyl]carbamate (12.7 g), 5-fluoropyridine-2-carbaldehyde (4.18 g), 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (1.68 g) and THF (134 mL) was degassed, and triethylamine (69.6 mL) was added to the mixture at room temperature under an argon atmosphere. The mixture was degassed again, and the mixture was stirred overnight at 60 °C under an argon atmosphere. A saturated aqueous ammonium chloride solution was added to the mixture at 0 °C, and the mixture was partitioned with water and ethyl acetate. The separated organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and crystallized from hexane / ethyl acetate to obtain the title compound (7.68 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.13-1.58 (9H, m), 6.74 (1H, d, J = 8.7 Hz), 7.54 (1H, br d, J = 8.7 Hz), 7.58-7.67 (1H, m), 7.68-7.81 (1H, m), 7.91 (1H, td, J = 8.8, 2.8 Hz), 8.12 (1H, dd, J = 8.7, 4.9 Hz), 8.34 (1H, d, J = 2.6 Hz), 8.63 (1H, d, J = 3.0 Hz). MS: [M+H-Boc] + 250.0.

[0197] C) tert-Butyl [(1RS,2RS)-1,2-bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]carbamate To a mixture of tert-butyl [1,2-bis(5-fluoropyridin-2-yl)-2-oxoethyl]carbamate (7.0 g) and THF (100 mL), potassium tri(sec-butyl)borohydride (1 M THF solution, 30.1 mL) was added dropwise at -78 °C under an argon atmosphere, and the mixture was stirred at -78 °C for 2 hours. Water (20 mL) was added to the mixture at -78 °C, and 2 M aqueous sodium hydroxide solution (100 mL) and 30% aqueous hydrogen peroxide (20.5 mL) were added while maintaining the internal temperature below 0 °C. The mixture was stirred at room temperature for 4 hours. Sodium thiosulfate pentahydrate (49.7 g) was dissolved in water (200 mL) and added to the mixture at 0 °C, and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallized from hexane / ethyl acetate to obtain the title compound (5.97 g). 1H NMR (300 MHz, DMSO-d6) δ 1.01-1.48 (9H, m), 4.84-4.95 (1H, m), 4.96-5.10 (1H, m), 5.67 (1H, d, J = 5.6 Hz), 7.05 (1H, br d, J = 9.0 Hz), 7.22-7.41 (2H, m), 7.62 (2H, td, J = 8.8, 2.8 Hz), 8.40 (1H, d, J = 3.0 Hz), 8.51 (1H, d, J = 2.6 Hz). MS: [M+H-Boc] + 252.0.

[0198] D) 2-[(1RS,2RS)-1,2-bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1H-isoindol-1-one To a mixture of tert-butyl [(1RS,2RS)-1,2-bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]carbamate (4.34 g) and acetic acid (30.9 mL), hydrogen bromide (30% acetic acid solution (about 5.1 M), 19.4 mL) was added dropwise at room temperature, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the residue was azeotroped with toluene. To a mixture of the obtained residue, methyl 2-(bromomethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzoate (4.29 g) and DMF (50 mL), DIPEA (21.5 mL) was added dropwise at 0 °C, and the mixture was stirred at room temperature overnight. The mixture was added to water and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallized from diisopropyl ether / ethyl acetate to obtain the title compound (3.68 g). 1H NMR (300 MHz, DMSO-d6) δ 4.69 (1H, d, J = 18.8 Hz), 4.95 (1H, d, J = 18.8 Hz), 5.49 (1H, dd, J = 9.0, 5.3 Hz), 5.75 (1H, d, J = 9.0 Hz), 6.05 (1H, d, J = 5.3 Hz), 7.33-7.79 (5H, m), 7.84 (1H, d, J = 8.3 Hz), 8.06 (1H, d, J = 1.1 Hz), 8.19-8.26 (1H, m), 8.26-8.31 (1H, m), 8.62 (1H, d, J = 3.0 Hz). MS: [M+H] + 486.1.

[0199] E) 2-[(1R,2R)-1,2-bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1H-isoindol-1-one (Example compound 5) and 2-[(1S,2S)-1,2-bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1H-isoindol-1-one (Example compound 6) 2-[(1RS,2RS)-1,2-bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1H-isoindol-1-one (3.52 g) was optically resolved by preparative HPLC (column: CHIRALCEL OD, 50 mmID × 500 mmL, 20 μm, mobile phase: hexane / ethanol = 700 / 300 (v / v)).

[0200] The fraction of the optical isomer with the longer retention time was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and passed through a short silica gel column. The filtrate was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether / ethyl acetate. The resulting solid was recrystallized from heptane / ethyl acetate. The resulting solid was further recrystallized from heptane / isopropyl acetate and dried under reduced pressure at 55-60 °C to obtain a white solid (1.42 g). 593 mg of the white solid was recrystallized from pentane / isopropyl acetate to give 2-[(1R,2R)-1,2-bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1H-isoindol-1-one (506 mg, 99% ee, retention time: 7.77 min (analysis conditions: column: CHIRALCEL OD-H, 4.6 mmID × 250 mmL, 5 μm, mobile phase: hexane / ethanol / diethylamine = 700 / 300 / 1 (v / v / v)). The absolute stereochemistry of the compound was determined by X-ray crystallography. 1 H NMR (300 MHz, DMSO-d6) δ4.68 (1H, d, J = 18.4 Hz), 4.95 (1H, d, J = 18.8 Hz), 5.49 (1H, dd, J = 9.0, 5.6 Hz), 5.75 (1H, d, J = 9.0 Hz), 6.04 (1H, d, J = 6.0 Hz), 7.34-7.80 (5H, m), 7.84 (1H, d, J = 7.9 Hz), 8.05 (1H, d, J = 1.1 Hz), 8.23 ​​(1H, dd, J = 7.9, 1.5 Hz), 8.27 (1H, t, J = 1.5 Hz), 8.61 (1H, d, J = 3.0 Hz). MS: [M+H] + 486.1 Anal.Calcd for C 23 H 15 F4N5O3·0.1H2O: C, 56.70; H, 3.14; N, 14.37, Found: C, 56.57; H, 3.21; N, 14.32. Powder X-ray crystal diffraction pattern (diffraction angle 2θ): 6.1°, 9.0°, 15.7°, 16.4°, 18.1°, 19.9°, 21.7°, 22.5°, 24.8°, 25.3°

[0201] The fraction of the optical isomer with the shorter retention time was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether / ethyl acetate. The solid obtained was further recrystallized from heptane / isopropyl acetate and dried under reduced pressure to obtain a white solid (1.54 g). 100 mg of the white solid was recrystallized from pentane / isopropyl acetate to obtain 2-[(1S,2S)-1,2-bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1H-isoindol-1-one (83 mg, 99% ee, retention time: 6.43 min (analysis conditions column: CHIRALCEL OD-H, 4.6 mmID×250 mmL, 5 μm, mobile phase: hexane / ethanol / diethylamine = 700 / 300 / 1 (v / v / v)). MS: [M+H] + 486.1

[0202] Examples 7 and 8 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example compound 7) 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1S,2S)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example compound 8)

[0203] A) tert-Butyl [2-(6-fluoropyridin-2-yl)-2-oxo-1-(pyridin-2-yl)ethyl]carbamate To a mixture of tert-butyl [(4-methylbenzene-1-sulfonyl)(pyridin-2-yl)methyl]carbamate (11.9 g), 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (2.48 g) and THF (230 mL) was added 6-fluoropyridine-2-carbaldehyde (4.60 g) at room temperature under an argon atmosphere. The mixture was degassed and replaced with argon gas. Triethylamine (68.5 mL) was added dropwise to the mixture at 60 °C, and the mixture was stirred overnight at 60 °C under an argon atmosphere. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (11.4 g) as a crude product. The obtained compound was used in the next reaction without further purification. MS: [M+H] + 332.1.

[0204] B) tert-Butyl [(1RS,2RS)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]carbamate To a mixture of tert-butyl [2-(6-fluoropyridin-2-yl)-2-oxo-1-(pyridin-2-yl)ethyl]carbamate (11.4 g), methanol (100 mL) and THF (100 mL) was added sodium borohydride (1.49 g) at 0 °C. The mixture was stirred at room temperature for 2.5 hours. Water was added to the mixture at 0 °C, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from toluene, filtered, and washed with diisopropyl ether. The obtained solid was recrystallized from hexane / ethyl acetate to obtain the title compound (6.92 g). 1H NMR (300 MHz, DMSO-d6) δ 1.16-1.32 (9H, m), 4.78-4.88 (1H, m), 4.90-5.01 (1H, m), 5.74 (1H, d, J = 5.3 Hz), 6.95-7.10 (2H, m), 7.16-7.30 (3H, m), 7.68 (1H, t, J = 6.8 Hz), 7.82-7.96 (1H, m), 8.42 (1H, d, J = 4.5 Hz). MS: [M+H] + 334.1.

[0205] C) 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1RS,2RS)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one To a mixture of tert-butyl [(1RS,2RS)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]carbamate (4.55 g) and acetic acid (80 mL) was added hydrogen bromide (30% acetic acid solution (about 5.1 M), 21.4 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes, concentrated under reduced pressure, and azeotroped with toluene. DIPEA (13.6 mL) was added dropwise to a mixture of the obtained residue and DMF (50 mL) at 0 °C, and then methyl 2-(bromomethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzoate (4.51 g) dissolved in DMF (10 mL) was added to the mixture at 0 °C. The mixture was stirred from 0 °C to room temperature for 3 days. The mixture was concentrated, and water was added to the residue at room temperature. The mixture was extracted with ethyl acetate. The separated organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) and crystallized from hexane / ethyl acetate to obtain the title compound (4.29 g). 1H NMR (300 MHz, DMSO-d6) δ4.68 (1H, d, J = 18.8 Hz), 4.98 (1H, d, J = 18.8 Hz), 5.39-5.48 (1H, m), 5.71 (1H, d, J = 9.0 Hz), 6.11 (1H, d, J = 4.0 Hz), 6.95 (1H, dd, J = 8.1, 2.4 Hz), 7.32-7.73 (4H, m), 7.77-7.88 (2H, m), 7.89-8.01 (1H, m), 8.06 (1H, d, J = 0.9 Hz), 8.23 ​​(1H, dd, J = 8.0, 1.6 Hz), 8.58-8.67 (1H, m). MS: [M+H] + 468.1.

[0206] D) 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example compound 7) and 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1S,2S)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example compound 8) 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1RS,2RS)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (4.27 g) was optically resolved by preparative HPLC (column: CHIRALPAK IA, 50 mmID × 500 mmL, 20 μm, mobile phase: hexane / ethanol = 200 / 800 (v / v)).

[0207] The fraction of the optical isomer with the shorter retention time was concentrated under reduced pressure, and the residue was recrystallized from heptane / isopropyl acetate to give 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (1.72 g, >99% ee, retention time: 15.49 min (analysis conditions: column: CHIRALPAK IA, 4.6 mmID × 250 mmL, 5 μm, mobile phase: hexane / ethanol = 200 / 800 (v / v)). The absolute stereochemistry of the compound was determined by X-ray crystal structure analysis. 1 H NMR (300 MHz, DMSO-d6) δ 4.68 (1H, d, J = 18.8 Hz), 4.98 (1H, d, J = 18.8 Hz), 5.43 (1H, dd, J = 8.8, 5.8 Hz), 5.71 (1H, d, J = 8.7 Hz), 6.10 (1H, d, J = 6.0 Hz), 6.95 (1H, dd, J = 7.9, 2.6 Hz), 7.32-7.73 (4H, m), 7.76-7.89 (2H, m), 7.89-8.00 (1H, m), 8.07 (1H, d, J = 1.1 Hz), 8.23 ​​(1H, dd, J = 7.9, 1.5 Hz), 8.56-8.66 (1H, m). MS: [M+H] + 468.1. Anal.Calcd for C 23 H 16 F3N5O3·0.2H2O: C, 58.65; H, 3.51; N, 14.87, Found: C, 58.78; H, 3.75; N, 15.00. Powder X-ray crystal diffraction pattern (diffraction angle 2θ): 5.7°, 12.1°, 13.0°, 16.7°, 19.0°, 20.2°, 21.8°, 24.2°

[0208] The fraction of the optical isomer with the longer retention time was concentrated under reduced pressure, and the residue was recrystallized from heptane / isopropyl acetate to obtain 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1S,2S)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (1.84 g, 99% ee, retention time: 19.48 min (analysis conditions column: CHIRALPAK IA, 4.6 mmID × 250mmL, 5 μm, mobile phase: hexane / ethanol = 200 / 800 (v / v)). MS: [M+H] + 468.1.

[0209] Example 9 2-[(1R,2S)-1-Cyclopropyl-2-(4-fluorophenyl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1H-isoindol-1-one

[0210] A) tert-Butyl {(1R)-1-cyclopropyl-2-[methoxy(methyl)amino]-2-oxoethyl}carbamate To a mixture of (2R)-((tert-butoxycarbonyl)amino)(cyclopropyl)acetic acid (10.2 g) and THF (150 mL) was added CDI (9.22 g) at 0° C., and the mixture was stirred at 0° C. for 1 hour. N-Methoxymethanamine hydrochloride (5.55 g) and DIPEA (12.4 mL) were dissolved in DMF (30 mL) and added to the mixture at 0° C. The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate / THF. The separated organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (12.1 g). 1H NMR (300 MHz, DMSO-d6) δ 0.21-0.32 (1H, m), 0.33-0.49 (3H, m), 0.93-1.09 (1H, m), 1.36 (9H, s), 3.11 (3H, s), 3.70 (3H, s), 3.90-4.09 (1H, m), 7.06 (1H, d, J = 8.3 Hz). MS: [M+H-Boc] + 159.1.

[0211] B) tert-Butyl [(1R)-1-cyclopropyl-2-(4-fluorophenyl)-2-oxoethyl]carbamate To a mixture of tert-butyl {(1R)-1-cyclopropyl-2-[methoxy(methyl)amino]-2-oxoethyl}carbamate (8.55 g) and THF (130 mL), 4-fluorophenylmagnesium bromide (2 M diethyl ether solution, 42 mL) was added at 40 ° C. The mixture was stirred at 40 ° C. for 1 hour under a nitrogen atmosphere. To the mixture, 4-fluorophenylmagnesium bromide (2 M diethyl ether solution, 3 mL) was added at 40 ° C. The mixture was stirred at 40 ° C. for 30 minutes under a nitrogen atmosphere. The mixture was added to a saturated aqueous ammonium chloride solution at 0 ° C. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (7.80 g). 1 H NMR (300 MHz, DMSO-d6) δ 0.19-0.56 (4H, m), 0.91-1.10 (1H, m), 1.13-1.50 (9H, m), 4.09-4.50 (1H, m), 7.35 (2H, t, J = 8.8 Hz), 7.46 (1H, br d, J = 7.2 Hz), 8.04 (2H, dd, J = 8.7, 5.6 Hz). MS: [M+H-Boc] + 194.1.

[0212] C) tert-Butyl [(1R,2S)-1-cyclopropyl-2-(4-fluorophenyl)-2-hydroxyethyl]carbamate To a mixture of tert-butyl [(1R)-1-cyclopropyl-2-(4-fluorophenyl)-2-oxoethyl]carbamate (7.80 g), toluene (22 mL) and 2-propanol (23 mL), aluminum triisopropoxide (1.09 g) was added at room temperature. The mixture was stirred at 70 °C for 3 hours. The reaction mixture was added to a mixture of 0.5 M hydrochloric acid and ethyl acetate at 0 °C, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (7.79 g). 1 H NMR (300 MHz, DMSO-d6) δ-0.24--0.08 (1H, m), 0.09-0.37 (3H, m), 0.95-1.13 (1H, m), 1.26 (9H, s), 3.08-3.25 (1H, m), 4.50 (1H, t, J = 5.6 Hz), 5.37 (1H, d, J = 4.5 Hz), 6.45 (1H, br d, J = 9.4 Hz), 7.09 (2H, t, J = 9.0 Hz), 7.29-7.41 (2H, m).

[0213] D) (1S,2R)-2-Amino-2-cyclopropyl-1-(4-fluorophenyl)ethan-1-ol hydrobromide To a mixture of tert-butyl [(1R,2S)-1-cyclopropyl-2-(4-fluorophenyl)-2-hydroxyethyl]carbamate (4.79 g) and acetic acid (50 mL) was added hydrogen bromide (25% solution in acetic acid, 12.5 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was azeotroped with toluene three times. The residue was suspended in ethyl acetate (10 mL) and diisopropyl ether (40 mL) and stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration, washed with diisopropyl ether / ethyl acetate (4:1), and dried to obtain the title compound (4.29 g). 1 H NMR (300 MHz, DMSO-d6) δ-0.41--0.24 (1H, m), 0.12-0.34 (2H, m), 0.34-0.50 (1H, m), 0.77-0.97 (1H, m), 2.59 (1H, dd, J = 10.5, 3.0 Hz), 4.94 (1H, br s), 6.15 (1H, d, J = 3.8 Hz), 7.09-7.29 (2H, m), 7.37-7.52 (2H, m), 7.89 (3H, br s). MS: [M+H] + 196.1.

[0214] E) 2-[(1R,2S)-1-cyclopropyl-2-(4-fluorophenyl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1H-isoindol-1-one To a mixture of (1S,2R)-2-amino-2-cyclopropyl-1-(4-fluorophenyl)ethan-1-ol hydrobromide (3.65 g), DIPEA (10.5 mL) and DMF (30 mL), methyl 2-(bromomethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzoate (4.17 g) dissolved in DMF (12 mL) was added dropwise at room temperature. The mixture was stirred at room temperature overnight. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate), and the obtained solid was dissolved in ethyl acetate and filtered to remove insoluble matter. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from heptane / ethyl acetate to obtain the title compound (3.75 g). 1 H NMR (300 MHz, DMSO-d6) δ-0.24--0.11 (1H, m), -0.11--0.01 (1H, m), 0.28-0.51 (2H, m), 1.31-1.48 (1H, m), 3.51 (1H, dd, J = 10.2, 4.1 Hz), 4.78 (1H, d, J = 19.2 Hz), 4.88 (1H, d, J = 19.2 Hz), 5.00 (1H, t, J = 4.5 Hz), 5.74 (1H, d, J = 4.9 Hz), 7.05-7.21 (2H, m), 7.35-7.78 (3H, m), 7.90 (1H, d, J = 8.3 Hz), 8.21 (1H, d, J = 0.8 Hz), 8.29 (1H, dd, J = 7.9, 1.9 Hz). MS: [M+H] + 430.1. Anal.Calcd for C 22 H 18 F3N3O3·0.1H2O: C, 61.28; H, 4.25; N, 9.75, Found: C, 61.28; H, 4.48; N, 9.77. Powder X-ray crystal diffraction pattern (diffraction angle 2θ): 6.9°, 13.9°, 16.9°, 18.6°, 20.2°, 20.9°, 22.2°, 22.7°, 25.6°, 28.1°

[0215] The example compounds are shown in the following table. MS in the table indicates the actually measured value. The compounds of Examples 10 to 150 in the following table were produced according to the methods shown in the above examples or methods similar thereto.

[0216] [Table 1-1]

[0217] [Table 1-2]

[0218] [Table 1-3]

[0219] [Table 1-4]

[0220] [Table 1-5]

[0221] [Table 1-6]

[0222] [Table 1-7]

[0223] [Table 1-8]

[0224]

Table 1-9

[0225]

Table 1-10

[0226]

Table 1-11

[0227]

Table 1-12

[0228]

Table 1-13

[0229]

Table 1-14

[0230]

Table 1-15

[0231]

Table 1-16

[0232]

Table 1-17

[0233]

Table 1-18

[0234] [Table 1-19]

[0235] [Table 1-20]

[0236] [Table 1-21]

[0237] [Table 1-22]

[0238] Test Example 1 HDAC6 Enzyme Inhibition Assay The full-length HDAC6 gene was transfected into Sf-9 insect cells, and the HDAC6 enzyme purified by a GST affinity column was purchased from SignalChem. The HDAC6 enzyme inhibitory activity of the compounds of the present invention was evaluated using this enzyme. The enzyme was stored at -70°C before use. The HDAC6 enzyme inhibitory activity of the compounds of the present invention was evaluated using HDAC-Glo TMThe I / II Assay kit (Promega) was used to measure the activity of the compound to be tested, which was diluted with an assay buffer (24 mM Tris-HCl (pH 7.5), 1 mM MgCl2, 0.35 mM KCl, 135 mM NaCl, 0.6 mM Glutathione, 0.01% Tween-20), and 2 μL of the test compound was added to a 384-well plate. Next, 4 μL of HDAC6 enzyme solution diluted with the assay buffer was added to each well and incubated at room temperature for 60 minutes. After incubation, 2 μL of HDAC substrate-Developer solution prepared according to the Promega protocol attached to the assay kit was added to each well of the 384-well plate to initiate the enzyme reaction. After reacting for 20 minutes at room temperature, the luminescence intensity was measured using a plate reader Envision (PerkinElmer). The inhibitory activity of each example compound was calculated as a relative activity value, with the luminescence intensity of the well without the enzyme being 100% inhibition. The results are shown in Tables 2-1 and 2-2.

[0239] [Table 2-1]

[0240] [Table 2-2]

[0241] As shown in Tables 2-1 and 2-2, the compounds of the present invention have excellent HDAC6 inhibitory activity.

[0242] Test Example 2: Enhancement of acetylated tubulin in the brain The drug was suspended in 0.5% methylcellulose to the concentration shown in Table 3 to prepare the administration solution. The drug was orally administered to 8-10 week old male C57BL / 6J mice, and after the time shown in Table 3 had elapsed, the brain was removed and the hippocampus was obtained. The hippocampus was homogenized in RIPA extraction solution (Fujifilm Wako Pure Chemical Industries) supplemented with protease inhibitors (Thermo Fisher Scientific) and phosphatase inhibitors (Thermo Fisher Scientific), and then centrifuged at 15,000 g for 15 minutes to prepare a protein extract. Acetylated tubulin and total tubulin in this extract were detected by the following ELISA method. Tubulin antibody (Sigma) was immobilized on a 96-well plate (Microlite2+, Thermo Fisher Scientific) and stored at 4°C. The next day, the plate was washed four times with PBS-T, and blocking buffer (1% BSA / PBS-T) was added and reacted at 37°C for 2 hours. After washing four times with PBS-T, the above protein extract was added to capture tubulin with the antibody. After 2 hours at 37°C, the plate was washed four times with PBS-T, and anti-acetylated tubulin antibody or total tubulin antibody (Cell Signaling Technology) diluted in blocking buffer was added and reacted at 37°C for 1 hour. After washing four times with PBS-T, the plate was reacted with anti-mouse HPR (Cell Signaling Technology) at 37°C for 30 minutes. After washing the plate, HRP substrate was added and luminescence was measured with a plate reader. Quantification was performed using a logistic curve based on a dilution series using mouse hippocampal tissue extract, and the amount of acetylated tubulin relative to total tubulin was calculated to express it as the relative tubulin acetylation level. Tests were performed using SAS system 8. After F test for the vehicle group and drug group, Student t-test or Welch test was selected to test the significant difference between the two groups. * p < 0.05, ** p < 0.01, ns: not significant. The graphs show the mean value±standard error, and the results are shown in Figures 1 to 3. In the mice administered with Example Compounds 1, 3 and 5, a significant increase in the tubulin acetylation level was observed.

[0243] [Table 3]

[0244] Test Example 3: Improving cognitive function in neurodegenerative disease model mice The drug was suspended in 0.5% methylcellulose to prepare the administration solution. After repeated administration of the drug once a day for three months to 6-month-old male human P301S mutant tau (4R1N) Tg mice, a novel object recognition test was performed according to the following method. The test consisted of an object memory acquisition trial on the first day and a memory retention trial by presenting a familiar object and a novel object on the second day. On both days, the drug was administered one hour before the trial. In the acquisition trial, the mouse was placed in a measurement box (30 cm x 30 cm x 25 cm) containing two identical objects, and the number of contacts and contact time with the objects were measured for 5 minutes under 50 lux. Contact was defined as the behavior of sniffing the object. On the next day, one of the objects was replaced with a novel object, and the number of contacts and contact time with each object for 5 minutes were measured. The novelty discrimination index (NDI), which is an index of cognitive function, was calculated as the novel object contact time / (novel object contact time + familiar object contact time)%. The test was performed using SAS system 8. After F test for the vehicle-administered wild-type group and the vehicle-administered Tg group, Student t-test was selected to test the significant difference between the two groups. ** p < 0.01. Furthermore, Bartlett's test of homogeneity of variance was performed for the vehicle-administered or drug-administered Tg group, and then a one-sided Williams test was used to analyze the significant difference. ## p < 0.005. Each group consisted of 14 or 15 mice. The graphs are shown as the mean ± standard error, and the results are shown in Figures 4 and 5.

[0245] Test Example 4 Toxicity test in rats A two-week toxicity study in rats is conducted using the following test system: Test system: Rat, Sprague-Dawley [Crl:CD(SD)] Method and duration of administration: The route of administration will be oral, which is the planned route for clinical application, and the administration period will be two weeks. The frequency of administration will be once a day (7 days / week), which is the common practice in repeated administration studies. The administration method will be forced oral administration, which is common for oral administration to rodents. The dose will be 5 mL / kg, and will be administered by forced oral administration using a flexible stomach tube (between 08:00 and 15:00). The vehicle control group will be administered the vehicle in the same manner. The dose for each animal will be calculated based on the most recent body weight. Media and preparation methods: 0.5 w / v% methylcellulose solution: Weigh out the required amount of methylcellulose (METOLOSE SM-100), and gradually add it to an appropriate amount of warm water for injection while stirring to disperse the methylcellulose. Cool it to dissolve the methylcellulose, and then add more water for injection to make a 0.5% solution. As an example of toxicity evaluation, a hematological test protocol is described below. material: At the time of the planned autopsy, all animals in the test group that have been fasted overnight (approximately 16 to 21 hours) from the day before will be subjected to laparotomy under isoflurane inhalation anesthesia, and blood (approximately 1 mL) will be collected from the abdominal aorta into an EDTA-2K blood collection bottle. The collected blood will be examined according to the items and methods described below. Equipment used: Automated blood cell counter (ADVIA2120i, Siemens Healthcare Diagnostics K.K.) Inspection items (measurement methods): Red blood cell count (2-angle laser flow cytometry) Hematocrit value (calculated from red blood cell count and MCV) Hemoglobin concentration (cyanmethemoglobin modified method) Mean corpuscular hemoglobin (MCH, calculated from red blood cell count and hemoglobin concentration) Mean corpuscular hemoglobin concentration (MCHC, calculated from red blood cell count, MCV and hemoglobin concentration) Mean corpuscular volume (MCV, dual angle laser flow cytometry) Red blood cell volume distribution width (RDW, dual angle laser flow cytometry) Reticulocyte count (absolute count, laser flow cytometry with RNA staining) Platelet count (2-angle laser flow cytometry) White blood cell count (2-angle laser flow cytometry) - White blood cell differentiation (absolute count, peroxidase staining flow cytometry + 2-angle laser flow cytometry) ·Red blood cell morphology flag (MICRO: microcytic red blood cells, MACRO: macrocytic red blood cells, HYPO: hypochromic red blood cells, HYPER: hyperchromic red blood cells, ANISO: red blood cell size anisotropy, HCVAR: hemoglobin concentration, RBCF: schistose red blood cells)

[0246] Test Example 5 Bacterial reversion assay material and method Test strains: Salmonella typhimurium TA100 or TA98 Metabolic activation system: S9 mix for the Ames test prepared from livers of 7-week-old male Sprague-Dawley rats treated with phenobarbital and 5,6-benzoflavone Dosage: 78.1, 156.3, 312.5, 625, 1250, 2500 or 5000μg / plate Test Method: After culturing the bacterial cells at 37 °C for 8 h, measure the optical density of the cell suspension with a spectrophotometer (660 nm) to check whether the bacteria are growing well. Confirm that the cell number calculated from the optical density is within an acceptable range (cell number: ≥ 1 × 10 9 Cells are exposed to the test substance using the pre-incubation method (37°C, 20 min) in the presence or absence of S9 mix. After mixing with top agar, the cells are plated. The plate is incubated at 37°C for 48 hours. The presence or absence of bacterial contamination on the medium surface, solvent, and test substance solution is confirmed. Mutagenicity criteria: A test substance is considered positive if it induces a dose-dependent increase in the number of revertant colonies in either test strain in the presence or absence of S9 mix to a level equal to or greater than two-fold the mean negative control value.

[0247] Test Example 6 In vitro micronucleus test material and method Test system: TK6 cell-derived human lymphoblastoid cells Culture conditions: Cells are cultured on 6-well plastic plates in RPMI 1640 supplemented with 10 vol% heat-inactivated horse serum, 2 mmol / L sodium pyruvate, 100 units / mL penicillin and 100 μg / mL streptomycin at 37° C. under 5% CO 2 . Metabolic activation system: Rat liver S9 mix prepared from the livers of 7-week-old male Sprague-Dawley rats treated with phenobarbital and 5,6-benzoflavone. Processing conditions: (1) Treatment with S9 mix for 3 hours followed by incubation for 21 hours, (2) Continuous treatment without S9 mix for 24 hours Dosage: 450.0 μg / mL to 12.6 μg / mL Replicate cultures are prepared for each concentration. Cytotoxicity: The number of cells is counted, and the relative population doubling (RPD), as an index of cytotoxicity, is calculated using the following formula:

[0248]

number

[0249] Micronucleus Observation: For each treatment condition, the highest concentration for micronucleus assay is selected based on the precipitation and cytotoxicity of the test substance, and two lower successive concentrations are tested. The number of micronucleated cells in 4,000 mononuclear cells with cytoplasm is counted using a microscope. Statistical analysis: Fisher's exact test will be performed at the 5% and 1% right one-tailed significance levels to compare the incidence of micronucleated cells in the test article or positive control group with the incidence in the negative control group for each treatment condition. If Fisher's exact test is statistically significant in the test article group, an exact Cochran-Armitage trend test will be performed. Criteria: If the incidence of micronucleated cells among any of the test substance groups meets both criteria (1) and (2) below, the test substance is considered positive. (1) A significant difference in the incidence of micronucleated cells between the negative control groups was detected by statistical analysis, and a dose-dependent increase was also detected by statistical analysis. (2) The incidence of micronucleated cells is above the historical control range (mean + 2SD), otherwise the test substance is considered negative.

[0250] Formulation Example 1 (Capsule Production) 1) 30 mg of the compound of Example 1 2) Fine powdered cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg Total 60 mg 1), 2), 3) and 4) are mixed and filled into a gelatin capsule.

[0251] Formulation Example 2 (Tablet Production) 1) 30 g of the compound of Example 1 2) Lactose 50g 3) 15 g corn starch 4) Calcium carboxymethylcellulose 44 g 5) Magnesium stearate 1 g 1000 tablets total 140 g The total amount of 1), 2), 3) and 30g of 4) are mixed with water, vacuum dried, and then granulated. 14g of 4) and 1g of 5) are mixed with the granulated powder, and the mixture is compressed into tablets using a tablet press. In this way, 1000 tablets containing 30mg of the compound of Example 1 per tablet are obtained. [Industrial Applicability]

[0252] The compound of the present invention has an HDAC inhibitory effect and may be useful in the treatment of central nervous system diseases including neurodegenerative diseases (Alzheimer's disease, progressive supranuclear palsy, etc.).

[0253] This application is based on Japanese Patent Application No. 2019-177815 filed on September 27, 2019, the contents of which are incorporated in their entirety herein.

Claims

1. Formula (I): [Formula 1] [In the formula, R 1 (1) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 halogen atoms, (2) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom, (ii) a cyano group, and (iii) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms; (3) A 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom, (ii) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and (iii) a C 1-6 alkoxy group, or (4) a 3- to 8-membered monocyclic non-aromatic heterocyclic group, R 2 (1) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 halogen atoms, (2) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom, and (ii) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms; (3) A 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom, (ii) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and (iii) a C 1-6 alkoxy group, or (4) A compound represented by the formula: wherein R represents a 3- to 8-membered monocyclic non-aromatic heterocyclic group, or a salt thereof.

2. Formula (I'): [Case 2] [Each symbol in the formula has the same meaning as in claim 1.] The compound according to claim 1, or a salt thereof,

3. R 1 but, (1) C optionally substituted by 1 to 3 halogen atoms ３－１０ a cycloalkyl group, or (2) (i) a halogen atom, (ii) a C optionally substituted by 1 to 3 halogen atoms １－６ an alkyl group, and (iii) C １－６ a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from an alkoxy group, R 2 but, (1) (i) a halogen atom, and (ii) a C optionally substituted by 1 to 3 halogen atoms １－６ C optionally substituted with 1 to 3 substituents selected from alkyl groups ６－１４ an aryl group, or (2) (i) a halogen atom, (ii) a C optionally substituted by 1 to 3 halogen atoms １－６ an alkyl group, and (iii) C １－６ a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from an alkoxy group; 2. The compound according to claim 1, wherein:

4. R 1 but, (1) C ３－１０ a cycloalkyl group, or (2) a 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 halogen atoms, and R 2 but, (1) C optionally substituted by 1 to 3 halogen atoms ６－１４ an aryl group, or (2) The compound according to claim 1, which is a 6-membered monocyclic aromatic heterocyclic group optionally substituted with 1 to 3 halogen atoms, or a salt thereof.

5. 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one or a salt thereof.

6. 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one or a salt thereof.

7. 2-[(1R,2R)-1,2-bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1H-isoindol-1-one or a salt thereof.

8. A medicine comprising the compound according to claim 1 or a salt thereof.

9. The pharmaceutical agent according to claim 8, which is a histone deacetylase 6 inhibitor.

10. The pharmaceutical agent according to claim 8, which is a preventive or therapeutic agent for Alzheimer's disease, progressive supranuclear palsy, frontotemporal lobar degeneration associated with MAPT gene mutation (FTDP-17), frontotemporal dementia, Charcot-Marie-Tooth disease, peripheral neuropathy, amyotrophic lateral sclerosis (ALS), or cancer.

11. 2. The compound or salt thereof according to claim 1 for use in the prevention or treatment of Alzheimer's disease, progressive supranuclear palsy, frontotemporal lobar degeneration with MAPT gene mutation (FTDP-17), frontotemporal dementia, Charcot-Marie-Tooth disease, peripheral neuropathy, amyotrophic lateral sclerosis (ALS), or cancer.

12. Use of the compound or salt thereof according to claim 1 for the manufacture of an agent for the prophylaxis or treatment of Alzheimer's disease, progressive supranuclear palsy, frontotemporal lobar degeneration associated with MAPT gene mutation (FTDP-17), frontotemporal dementia, Charcot-Marie-Tooth disease, peripheral neuropathy, amyotrophic lateral sclerosis (ALS), or cancer.

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