EA045216B1 - 2-ISOINDOL-1,3,4-OXADIAZOLE DERIVATIVES USED AS HDAC6 INHIBITORS - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to a heterocyclic compound having histone deacetylase (hereinafter sometimes referred to as HDAC) inhibitory activity, preferably class II HDAC inhibitory activity, more preferably HDAC6 inhibitory activity, which may be useful for treating diseases of the central nervous system, including neurodegenerative diseases (Alzheimer's disease, progressive supranuclear palsy, etc.) and the like, a medicinal product containing the compound and the like.

State of the art

It is known that the nerve axon plays an important role in the transport of nutritional factor, neurotransmitter, organelle, etc. in a nerve cell and axon dysfunction, axon degeneration and intracellular accumulation of axon binding protein tau are observed in various neurodegenerative diseases (Non-Patent Document 1 and Non-Patent Document 2). Diseases characterized by intracellular accumulation of tau are collectively referred to as pathological diseases as tauopathy and include Alzheimer's disease, progressive supranuclear palsy, and the like. (Non-Patent Document 3). HDAC6 is an enzyme that plays a role in deacetylation of the axon component tubulin (Non-Patent Document 4), and microtubules containing acetylated tubulin are known to contribute to stability (Non-Patent Document 5). In addition, tubastatin A, which has HDAC6 inhibitory activity, is reported to increase tubulin acetylation in a mouse model of tauopathy and to have therapeutic efficacy (Non-Patent Document 6). Therefore, the above reports noted that HDAC6 inhibitor may be a therapeutic drug for Alzheimer's disease and progressive supranuclear palsy by stabilizing the axon.

As heterocyclic compounds, for example, the following compounds are known.

(1) Patent Document 1 discloses a compound represented by the following formula:

CF ₃ o^ ¹ / A \ R2 _R 3 χ^^Ύ^ \ ( ^Β where each symbol is one as defined herein, which is an HDAC inhibitor and is effective for the treatment of the following: autoimmune diseases, inflammatory diseases, metabolic/bone -articular degenerative diseases, neurodegenerative diseases/central nervous system diseases (for example, schizophrenia, Alzheimer's disease (dementia type Alzheimer's), Parkinson's disease, Huntington's disease, Rubinstein-Taybi syndrome, muscular dystrophy, Rett syndrome, Charcot-Marie-Tooth disease, depression ), neoplastic diseases, etc.

(2) Patent Document 2 discloses a compound represented by the following formula:

wherein each symbol is as defined herein, which is an HDAC inhibitor and is effective for the treatment of the following: autoimmune diseases, inflammatory diseases, metabolic/musculoskeletal degenerative diseases, neurodegenerative/central nervous system diseases (eg, schizophrenia, Alzheimer's disease (dementia of the Alzheimer's type), Parkinson's disease, Huntington's disease, Rubinstein-Taybi syndrome, muscular dystrophy, Rett syndrome, Charcot-Marie-Tooth disease, depression), neoplastic diseases, etc.

(3) Patent Document 3 discloses a compound represented by the following formula:

wherein each symbol is as defined herein, which is an HDAC inhibitor and is effective for the treatment of the following: autoimmune diseases, inflammatory diseases, metabolic/musculoskeletal degenerative diseases, neurodegenerative/central nervous system diseases (e.g. schizophrenia, Alzheimer's disease (dementia of the Alzheimer's type), Parkinson's disease, Huntington's disease, Rubinstein-Taybi syndrome, muscular dystrophy, Rett syndrome, Charcot-Marie-Tooth disease, depression), neoplastic diseases, etc.

(4) Patent Document 4 discloses a compound represented by the following formula:

wherein each symbol is as defined herein, which is an HDAC inhibitor and is effective for the treatment of the following: autoimmune diseases, inflammatory diseases, metabolic/musculoskeletal degenerative diseases, neurodegenerative/central nervous system diseases (eg, schizophrenia, Alzheimer's disease (dementia of the Alzheimer's type), Parkinson's disease, Huntington's disease, Rubinstein-Taybi syndrome, muscular dystrophy, Rett syndrome, Charcot-Marie-Tooth disease, depression), neoplastic diseases, etc.

(5) Patent Document 5 discloses a compound represented by the following formula:

wherein each symbol is as defined herein, which is an HDAC inhibitor and is effective for the treatment of the following: autoimmune diseases, inflammatory diseases, metabolic/musculoskeletal degenerative diseases, neurodegenerative/central nervous system diseases (eg, schizophrenia, Alzheimer's disease (dementia of the Alzheimer's type), Parkinson's disease, Huntington's disease, Rubinstein-Taybi syndrome, muscular dystrophy, Rett syndrome, Charcot-Marie-Tooth disease, depression), neoplastic diseases, etc.

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

wherein each symbol is one as defined herein, which is an HDAC6 inhibitor and is effective for the treatment of the following: HDAC6-mediated diseases (eg, infections, tumor, endocrine/nutritional/metabolic diseases, psychiatric and behavioral disorders, neurological diseases, diseases of the eye and adjacent organs, cardiovascular diseases, respiratory diseases, diseases of the digestive system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue or congenital malformations, deformities and chromosomal abnormalities).

(7) Patent Document 7 discloses a compound represented by the following formula:

wherein each symbol is one as defined herein, which is an HDAC6 inhibitor and is effective for the treatment of the following: HDAC6-mediated diseases (eg, infections, tumor, endocrine/nutritional/metabolic diseases, psychiatric and behavioral disorders, neurological diseases, diseases of the eye and adjacent organs, cardiovascular diseases, respiratory diseases, diseases of the digestive system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue or congenital malformations, deformities and chromosomal abnormalities).

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

wherein each symbol is one as defined herein, which is an HDAC6 inhibitor and is effective for the treatment of the following: HDAC6-mediated diseases (for example, infections, tumor, endocrine/nutritional/metabolic diseases, psychiatric disorders and behavioral disorders, neurological diseases, diseases of the eye and adjacent organs, cardiovascular diseases, respiratory diseases, diseases of the digestive system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue or congenital malformations, deformities and chromosomal abnormalities).

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

wherein each symbol is one as defined herein, which is an HDAC6 inhibitor and is effective for the treatment of the following: HDAC6-mediated diseases (eg, infections, tumor, endocrine/nutritional/metabolic diseases, psychiatric and behavioral disorders, neurological diseases, diseases of the eye and adjacent organs, cardiovascular diseases, respiratory diseases, diseases of the digestive system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue or congenital malformations, deformities and chromosomal abnormalities).

(10) Patent Document 10 discloses a compound represented by the following formula:

wherein each symbol is as defined herein, which is an HDAC inhibitor and is effective for treating the following: epilepsy, attention deficit disorder, depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's disease and the like.

(11) Patent Document 11 discloses a compound represented by the following formula:

wherein each symbol is one as defined herein, which is an HDAC inhibitor and is effective for treating the following: infectious diseases, tumors, endocrine diseases, nutritional and metabolic diseases, and the like.

(12) Patent Document 12 discloses a compound represented by the following formula:

wherein each symbol is as defined herein, which is an HDAC inhibitor and is effective for the treatment of the following: autoimmune diseases, inflammatory diseases, metabolic/musculoskeletal degenerative diseases, neurodegenerative/central nervous system diseases (eg, schizophrenia, Alzheimer's disease (dementia of the Alzheimer's type), Parkinson's disease, Huntington's disease, Rubinstein-Taybi syndrome, muscular dystrophy, Rett syndrome, Charcot-Marie-Tooth disease, depression), neoplastic diseases, etc.

List of documents

Patent documents.

Patent document 1: WO 2016/031815.

Patent document 2: WO 2017/014321.

Patent document 3: WO 2017/014170.

Patent document 4: WO 2017/033946.

Patent Document 5: WO 2019/027054.

Patent Document 6: WO 2017/018803.

Patent Document 7: WO 2017/018804.

Patent Document 8: WO 2017/018805.

Patent Document 9: WO 2017/023133.

Patent document 10: WO 2018/165520.

Patent Document 11: WO 2020/022794.

Patent Document 12: WO 2020/158762.

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Non-patent documents.

Non-Patent Document 1: Front Cell Neurosci., 9,343 (2015).

Non-Patent Document 2: Neuromolecular Med., 2:89-99 (2002).

Non-Patent Document 3: Cold Spring Harb Perspect Med., 2:a006254 (2012).

Non-patent document 4: Nature, 417:455-458 (2002).

Non-Patent Document 5: Proc. Natl. Acad. Sci., USA, 107:21238–21239 (2010).

Non-Patent Document 6: Alzheimer's Res. Ther., 6:12 (2014).

The essence of the invention

Problems solved by the invention.

The present invention relates to the preparation of a heterocyclic compound having an inhibitory effect on HDAC, which is effective for the treatment of the following: diseases of the central nervous system, including neurodegenerative diseases (Alzheimer's disease, progressive supranuclear palsy, etc.), etc., and a drug containing the connection.

Ways to solve problems.

The inventors of the present invention have conducted extensive research to solve the above problems and have found that the compound represented by the following formula (I) has an excellent HDAC inhibitory effect, and based on these findings, they have completed the present invention.

Accordingly, the present invention relates to the following.

1. The compound described by formula (I)

where R is an optionally substituted cyclic group and R is an optionally substituted cyclic group, or a salt thereof (hereinafter sometimes referred to as compound (I) in the present invention).

2. A compound or salt according to paragraph 1 above, which is described by formula (I’)

where each character is as defined in paragraph 1 above.

3. A compound or salt according to paragraph 1 above, where

R ¹ means (1) a C _3-10 cycloalkyl group, optionally substituted with 1 to 3 halogen atoms, (2) a C _6-14 aryl group, optionally substituted with 1 to 3 substituents selected from the group consisting of the following: (i) a halogen atom, (ii) a cyano group, and (iii) a C _1-6 alkyl group, optionally substituted with 1 to 3 halogen atoms, (3) a 5- or 6-membered monocyclic aromatic heterocyclic group, optionally substituted with 1 to 3 substituents selected from the group consisting of: (i) a halogen atom, (ii) a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (iii) a C _{1- a 6} alkoxy group, or (4) a 3-8 membered monocyclic non-aromatic heterocyclic group; And

R ² means (1) a C _3-10 cycloalkyl group, optionally substituted with 1 to 3 halogen atoms, (2) a C ₆ - ₁₄ aryl group, optionally substituted with 1 to 3 substituents selected from the group consisting of the following: (i) a halogen atom and (ii) a C _1-6 alkyl group, optionally substituted with 1 to 3 halogen atoms, (3) a 5- or 6-membered monocyclic aromatic heterocyclic group, optionally substituted with 1 to 3 substituents selected from the group consisting of the following: (i) a halogen atom, (ii) a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (iii) a C _1-6 alkoxy group, or ( 4) 3-8-membered monocyclic non-aromatic heterocyclic group.

4. A compound or salt according to paragraph 1 above, where

R ¹ means (1) a C _3-10 cycloalkyl group, optionally substituted with 1 to 3 halogen atoms, or (2) a 5- or 6-membered monocyclic aromatic heterocyclic group, optionally

- 4 045216 substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom, (ii) a C _1-6 alkyl group, optionally substituted with 1 to 3 halogen atoms, and (iii) a C _1-6 alkoxy group; And

R ² means (1) a C _6-14 aryl group, optionally substituted with 1 to 3 substituents selected from the group consisting of the following: (i) a halogen atom and (ii) a C _1-6 alkyl group, optionally substituted with with 1 to 3 halogen atoms, or (2) a 5- or 6-membered monocyclic aromatic heterocyclic group, optionally substituted with 1 to 3 substituents selected from the group consisting of: (i) a halogen atom, (ii) a C _1-6 alkyl group, optionally substituted with 1 to 3 halogen atoms, and (iii) a C _1-6 alkoxy group.

5. A compound or salt according to paragraph 1 above, where

R ¹ means (1) a C ₃ - ₁₀ cycloalkyl group, or (2) a 6-membered monocyclic aromatic heterocyclic group, optionally substituted with 1 to 3 halogen atoms; And

R ² means (1) a C _6-14 aryl group, optionally substituted with 1 to 3 halogen atoms, or (2) a 6-membered monocyclic aromatic heterocyclic group, optionally substituted with 1 to 3 halogen atoms.

6. 6-[5-(Difluoromethyl)-1,3,4-oxαdiαzol-2-yl]-2-[(1R,2R)-2-hydroxy-1,2-di(niridin-2-yl)ethyl ]-2,3dihydro-III-isoindol-1-one or its salt.

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-III-isoindol-1-one or its salt.

8. 2-[(1R,2R)-1,2-Bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2yl] -2,3-dihydro-1H-isoindol-1-one or its salt.

9. A medicinal product containing a compound or salt according to paragraph 1 above.

10. The drug according to paragraph 9 above, which is an inhibitor of histone deacetylase 6.

11. A medicinal product according to paragraph 9 above, which is a means for the prevention or treatment of Alzheimer's disease or progressive supranuclear palsy.

12. A compound or salt according to paragraph 1 above for use in the prevention or treatment of Alzheimer's disease or progressive supranuclear palsy.

13. A method of inhibiting histone deacetylase 6 in a mammal, which comprises administering an effective amount of the compound or salt of paragraph 1 above to the mammal.

14. A method of preventing or treating Alzheimer's disease or progressive supranuclear palsy in a mammal, which includes administering an effective amount of the compound or salt of paragraph 1 above to the mammal.

15. Use of a compound or salt according to paragraph 1 above for the preparation of an agent for the prevention or treatment of Alzheimer's disease or progressive supranuclear palsy.

The invention effect.

Compound (I) has HDAC6 inhibitory activity and may be useful for the treatment of diseases of the central nervous system, including neurodegenerative diseases (Alzheimer's disease, progressive supranuclear palsy, etc.) and the like.

Brief description of drawings

In fig. Figure 1 shows a dependence showing the increase in the content of acetylated tubulin in the mouse brain using the compound of example 1. The relative degree of acetylation of tubulin is plotted along the vertical axis and the dose (mg/kg) is plotted along the horizontal axis.

In fig. Figure 2 shows a dependence showing the increase in the content of acetylated tubulin in the mouse brain using the compound of example 3. The relative degree of acetylation of tubulin is plotted along the vertical axis and the dose (mg/kg) is plotted along the horizontal axis.

In fig. Figure 3 shows a dependence showing the increase in the content of acetylated tubulin in the mouse brain using the compound of example 5. The relative degree of acetylation of tubulin is plotted on the vertical axis and the dose (mg/kg) is plotted on the horizontal axis.

In fig. Figure 4 shows the relationship showing the effect on improving the cognitive ability of mice using the compound of Example 1. The vertical axis shows the relative length of time to distinguish novelty (%) and the horizontal axis shows the dose (mg/kg).

In fig. Figure 5 shows the relationship showing the effect on improving the cognitive ability of mice using the compound of Example 3. The vertical axis shows the relative duration of time to distinguish novelty (%) and the horizontal axis shows the dose (mg/kg).

Detailed Description of the Invention

The present invention is described in detail.

- 5 045216

Below is a definition of each symbol used in formula (I).

R ¹ and R ² are the same or different and each represents an optionally substituted cyclic group. Examples of the cyclic group of the optionally substituted cyclic group include a hydrocarbon cyclic group and a heterocyclic group.

Examples of the hydrocarbon cyclic group include a C _3-10 cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, adamantyl, etc.), C _3-10 cycloalkenyl group (for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), Cb-14 aryl group (for example, phenyl, 1-naphthyl, 2-naphthyl, 1- anthryl, 2-anthryl, 9-anthryl), etc.

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 containing as a ring-forming atom other than a carbon atom, 1 to 4 heteroatoms selected from group consisting of the following: a nitrogen atom, a sulfur atom and an oxygen atom.

Examples of the aromatic heterocyclic group include a 5 to 14 membered (preferably 5 to 10 membered) aromatic heterocyclic group containing, as a ring-forming atom, other than a carbon atom, 1 to 4 heteroatoms selected from the group consisting of: a nitrogen atom, a sulfur atom and an oxygen atom.

Preferred 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, triazinyl, etc.; and 8-14 membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienolopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyr idinyl, oxazolopyridinyl, thiazolopyridinyl, imdazopyrazinyl , imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinil, naphthyridinyl, quinoxalinyl, quinazolinil , cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

Examples of the non-aromatic heterocyclic group include a 3 to 14 membered (preferably 4 to 10 membered) non-aromatic heterocyclic group containing, as a ring-forming atom, other than a carbon atom, 1 to 4 heteroatoms selected from the group consisting of: a nitrogen atom, a sulfur atom and an oxygen atom.

Preferred examples of the non-aromatic heterocyclic group include 3-8 membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinil, pyrazolidinil, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyran yl, morpholinil, thiomorpholinil, azepanil, diazepanil, azepinil, oxepanil, azocanil, diazocanil, etc. ; and 9-14 membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzoisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydrisoquinolyl, tetrahydroquinolyl, 4H -quinolizinyl, indolinyl , isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazole yl, tetrahydro-b-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydrisoquinolyl, etc. .

Preferred examples of the 7-10 membered bridged heterocyclic group include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl.

Examples of an optionally substituted cyclic group designated by R ¹ or R ² include a cyclic group optionally containing substituent(s) selected from the following group of substituents A.

The number of substituents on the optionally substituted cyclic group is, for example, from 1 to 3. If the number of substituents is two or more, the corresponding substituents may be the same or different.

Group of deputies A.

(1) Halogen atom (eg fluorine, chlorine, bromine, iodine);

(2) nitro group;

- 6 045216 (3) cyano group;

(4) oxo group;

(5) hydroxy group;

(6) an optionally halogenated C _1-6 alkoxy group (for example, methoxy group, difluoromethoxy group, trifluoromethoxy group, ethoxy group, 2,2,2-trifluoroethoxy group, propoxy group, isopropoxy group, butoxy group, 4,4,4-trifluorobutoxy group, isobutoxy group, sec-butoxy group, pentyloxy group , hexyloxy group);

(7) C _6-14 aryloxy group (eg, phenoxy group, naphthoxy group);

(8) C _7-16 arylalkyloxy group (eg benzyloxy group);

(9) a 5-14 membered aromatic heterocyclyloxy group (eg pyridyloxy);

(10) a 3-14 membered non-aromatic heterocyclyloxy group (eg, morpholineoxy group, piperidinyloxy group);

(11) C1-6 alkylcarbonyloxy group (eg, acetoxy group, propanoyloxy group);

(12) C ₆ .1 ₄ arylcarbonyloxy group (for example, benzoyloxy group, 1-naphthoyloxy group, 2-naphthoyloxy group);

(13) C1-6 alkoxycarbonyloxy group (eg, methoxycarbonyloxy group, ethoxycarbonyloxy group, propoxycarbonyloxy group, butoxycarbonyloxy group);

(14) mono- or di-C ₁ - ₆ alkylcarbamoyloxy group (eg, methylcarbamoyloxy group, ethylcarbamoyloxy group, dimethylcarbamoyloxy group, diethylcarbamoyloxy group);

(15) C ₆ - ₁₄ arylcarbamoyloxy group (eg, phenylcarbamoyloxy group, naphthylcarbamoyloxy group);

(16) a 5-14 membered aromatic heterocyclylcarbonyloxy group (eg, nicotinoyloxy group);

(17) a 3-14 membered non-aromatic heterocyclylcarbonyloxy group (eg, morpholinylcarbonyloxy group, piperidinylcarbonyloxy group);

(18) an optionally halogenated C1-6 alkylsulfonyloxy group (eg, methylsulfonyloxy group, trifluoromethylsulfonyloxy group);

(19) C ₆ - ₁₄ arylsulfonyloxy group, optionally substituted with C1-6 alkyl group(s) (eg, phenylsulfonyloxy group, toluenesulfonyloxy group);

(20) an optionally halogenated C1-6 alkylthio group (eg, methylthio group, difluoromethylthio group, trifluoromethylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, 4,4,4-trifluorobutylthio group, pentylthio group, hexylthio group);

(21) 5-14 membered aromatic heterocyclic group (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, thienolopyridine silt, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imdazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenox athiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl);

(22) 3-14 membered non-aromatic heterocyclic group (for example, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinil, thiazolidinil, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl , azepanil, diazepanil, azepinil, oxepanil, azocanil, diazocanil, dihydrobenzofuranil, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzoisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydrisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothia zinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-b-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydrisoquinolyl);

(23) formyl group;

(24) carboxy group;

(25) an optionally halogenated C1-6 alkylcarbonyl group (eg, acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, hexanoyl);

- 7 045216 (26) C ₆ -14 arylcarbonyl group (for example, benzoyl, 1-naphthoyl, 2-naphthoyl);

(27) a 5-14 membered aromatic heterocyclylcarbonyl group (eg, nicotinoyl, isonicotinoyl, thenoyl, furoyl);

(28) a 3-14 membered non-aromatic heterocyclylcarbonyl group (eg, morpholinylcarbonyl, piperidinylcarbonyl, pyrrolidinylcarbonyl);

(29) C _1-6 alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl);

(30) C _6-14 aryloxycarbonyl group (eg, phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl);

(31) C _7-16 arylalkyloxycarbonyl group (eg, benzyloxycarbonyl, phenethyloxycarbonyl);

(32) carbamoyl group;

(33) thiocarbamoyl group;

(34) mono- or du-Cl. ₆ alkylcarbamoyl group (for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, K-ethyl-K-methylcarbamoyl);

(35) C _6-14 arylcarbamoyl group (eg phenylcarbamoyl);

(36) 5-14 membered aromatic heterocyclylcarbamoyl group (eg, pyridylcarbamoyl, thienylcarbamoyl);

(37) a 3-14 membered non-aromatic heterocyclylcarbamoyl group (eg, morpholinylcarbamoyl, piperidinylcarbamoyl);

(38) an optionally halogenated C _1-6 alkylsulfonyl group (for example, methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl);

(39) C _6-14 arylsulfonyl group (e.g. phenylsulfonyl, 1-naphthylsulfonyl,

2-naphthylsulfonyl);

(40) 5-14 membered aromatic heterocyclylsulfonyl group (eg, pyridylsulfonyl, thienylsulfonyl);

(41) an optionally halogenated C _1-6 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl);

(42) C _6-14 arylsulfinyl group (eg, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl);

(43) a 5-14 membered aromatic heterocyclylsulfinyl group (eg, pyridylsulfinyl, thienylsulfinyl);

(44) amino group;

(45) mono- or di-C _1-6 alkylamino group (for example, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, dimethylamino group, diethylamino group, dipropylamino group, dibutylamino group, K-ethyl-K-methylamino group);

(46) mono- or di-C _6-14 arylamino group (eg phenylamino group);

(47) 5-14 membered aromatic heterocyclylamino group (eg pyridylamino group);

(48) C _7-16 arylalkyl amino group (eg benzylamino group);

(49) formylamino group;

(50) C _1-6 alkylcarbonylamino group (eg, acetylamino group, propanoylamino group, butanoylamino group);

(51) (Ci-6 alkyl)(C _1-6 alkylcarbonyl) amino group (for example, K-acetyl-K-methylamino group);

(52) C _6-14 arylcarbonylamino group (eg, phenylcarbonylamino group, naphthylcarbonylamino group);

(53) C _1-6 alkoxycarbonylamino group (for example, methoxycarbonylamino group, ethoxycarbonylamino group, propoxycarbonylamino group, butoxycarbonylamino group, tert-butoxycarbonylamino group);

(54) C7-16 arylalkyloxycarbonylamino group (for example, benzyloxycarbonylamino group);

(55) C _1-6 alkylsulfonylamino group (eg, methylsulfonylamino group, ethylsulfonylamino group);

(56) C _6-14 arylsulfonylamino group, optionally substituted with C _1-6 alkyl group(s) (eg, phenylsulfonylamino group, toluenesulfonyl amino group);

(57) an optionally halogenated C _1-6 alkyl group (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 group (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 group (for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,

- 8 045216

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 cycloalkyl group (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 cycloalkenyl group (for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl); and ( _{62) C 6_14 aryl} group (eg, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl).

R ¹ preferably means (1) a C ₃ .1o cycloalkyl group (eg cyclopropyl, cyclohexyl) optionally substituted with 1 to 3 halogen atoms (eg fluorine atom);

(2) A C ₆ - ₁₄ aryl group (for example, phenyl), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom), (ii) a cyano group, and (iii) a C1.6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom);

(3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom), (ii) a C1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), and (iii) C1-6 an alkoxy group (eg an ethoxy group); or (4) a 3-8 membered monocyclic non-aromatic heterocyclic group (eg tetrahydropyranyl).

R ¹ more preferably means (1) a C ₃ - ₁₀ cycloalkyl group (eg cyclopropyl, cyclohexyl) optionally substituted with 1 to 3 halogen atoms (eg fluorine atom); or (2) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom), (ii) a C1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), and (iii) C1-6 an alkoxy group (eg an ethoxy group).

R ¹ is particularly preferably (1) a C ₃ - ₁₀ cycloalkyl group (eg cyclopropyl, cyclohexyl); or (2) a 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl), optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom).

R ² preferably means (1) a C ₃ - ₁₀ cycloalkyl group (eg cyclopropyl, cyclohexyl) optionally substituted with 1 to 3 halogen atoms (eg fluorine atom);

(2) A C ₆ .14 aryl group (e.g., phenyl), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom, chlorine atom), and (ii) a C1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom);

(3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl), optionally substituted with 1 to 3 substituents selected from the group consisting of the following: (i) a halogen atom (e.g., fluorine atom, a chlorine atom), (ii) a C1.6 alkyl group (eg methyl) optionally substituted with 1 to 3 halogen atoms (eg a fluorine atom) and (iii) a C1.6 alkoxy group (eg ethoxy group); or (4) a 3-8 membered monocyclic non-aromatic heterocyclic group (eg tetrahydropyranyl).

R ² more preferably means (1) a C ₆ - ₁₄ aryl group (for example, phenyl), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom, chlorine atom), and (ii) a C1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom); or (2) a 5- or 6-membered monocyclic aromatic heterocyclic group (for example, pi-

- 9 045216 ridyl, pyrimidinyl), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom, chlorine atom), (ii) a C _1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), and (iii) ) C _1-6 alkoxy group (for example, ethoxy group).

R ² is particularly preferably (1) a C ₆ .1 ₄ aryl group (eg phenyl) optionally substituted with 1 to 3 halogen atoms (eg fluorine atom, chlorine atom); or (2) a 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl, pyrimidinyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom).

A preferred compound is compound (I), where

R ¹ means (1) a C _3-10 cycloalkyl group (eg cyclopropyl, cyclohexyl) optionally substituted with 1 to 3 halogen atoms (eg fluorine atom), (2) a C _6-14 aryl group (eg phenyl ), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom), (ii) a cyano group, and (iii) a C1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), ( 3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom), (ii) a C _1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), and (iii) C _{1 -6} alkoxy group (eg ethoxy group), or (4) 3-8 membered monocyclic non-aromatic heterocyclic group (eg tetrahydropyranyl); And

R ² means (1) a C _3-10 cycloalkyl group (eg cyclopropyl, cyclohexyl) optionally substituted with 1 to 3 halogen atoms (eg fluorine atom), (2) a C _6-14 aryl group (eg phenyl ), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom, chlorine atom), and (ii) a C _1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), (3 ) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom, chlorine atom), (ii) a C _1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), and (iii) ) a C _1-6 alkoxy group (eg an ethoxy group), or (4) a 3-8 membered monocyclic non-aromatic heterocyclic group (eg tetrahydropyranyl).

A more preferred compound is compound (I), where

R ¹ means (1) a C _3-10 cycloalkyl group (eg cyclopropyl, cyclohexyl) optionally substituted with 1 to 3 halogen atoms (eg fluorine atom), or (2) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom), (ii) a C _1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), and (iii) C _{1 -6} alkoxy group (for example, ethoxy group); And

R ² means (1) a C _6-14 aryl group (eg phenyl), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

- 10 045216 (i) a halogen atom (eg fluorine atom, chlorine atom), and (ii) a C _1-6 alkyl group (eg methyl) optionally substituted with 1 to 3 halogen atoms (eg fluorine atom) , or (2) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom, chlorine atom), (ii) a C _1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), and (iii) ) C _1-6 alkoxy group (for example, ethoxy group).

A particularly preferred compound is compound (I), where

R ¹ is (1) a C _3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl), or (2) a 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl), optionally substituted with 1 to 3 halogen atoms (for example, fluorine atom); And

R ² means (1) a C _6-14 aryl group (eg, phenyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom), or (2) a 6-membered monocyclic aromatic heterocyclic group ( eg pyridyl, pyrimidinyl) optionally substituted with 1 to 3 halogen atoms (eg fluorine atom, chlorine atom).

The configuration of compound (I) is preferably described by the formula (I') wherein each symbol is as defined above (hereinafter sometimes referred to as compound (I') in the present invention).

Examples of embodiments of compound (I) are the following compounds: compound (I'-1) and compound (I'-2).

Compound (I'-1).

Compound (I'), where

R ¹ means an optionally substituted hydrocarbon cyclic group; And

R ² means an optionally substituted hydrocarbon cyclic group.

Compound (I'-1a).

Compound (I'), where

R ¹ means (1) C ₃ . _{a 10} cycloalkyl group (eg, cyclopropyl, cyclohexyl), optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), or (2) a C _{6-1 4} aryl group (eg, phenyl), optionally substituted with from 1 to 3 alternates selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom), (ii) a cyano group, and (iii) a C _1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom); And

R ² is (1) a C ₃ - ₁₀ cycloalkyl group (eg cyclopropyl, cyclohexyl) optionally substituted with 1 to 3 halogen atoms (eg fluorine atom), or (2) a C _{6 -} 1 ₄ aryl group (eg , phenyl), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom, chlorine atom), and (ii) a C _1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom).

Compound (I'-1b).

Compound (I'), where

R ¹ means C ₃ . ₁₀ a cycloalkyl group (eg cyclopropyl, cyclohexyl) optionally substituted with 1 to 3 halogen atoms (eg fluorine atom); And

R ² is a C _6- 1 ₄ aryl group (eg phenyl), optionally substituted with

- 11 045216 up to 3 alternates selected from a group consisting of the following:

(i) a halogen atom (eg, fluorine atom, chlorine atom), and (ii) a C _1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom).

Compound (I'-1c).

Compound (I'), where

R1 is a C _3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl), and

R ² is a C _6-14 aryl group (eg phenyl) optionally substituted with 1 to 3 halogen atoms (eg fluorine atom, chlorine atom).

Connection (1'-2).

Compound (I'), where

R ¹ is an optionally substituted heterocyclic group, and

R ² means an optionally substituted heterocyclic group.

Compound (1'-2a).

Compound (I'), where

R ¹ means (1) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom), (ii) _{a C} i- ₆ alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), and (iii) C _{1 -6} alkoxy group (eg ethoxy group), or (2) 3-8 membered monocyclic non-aromatic heterocyclic group (eg tetrahydropyranyl); And

R ² means (1) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom, chlorine atom), (ii) a C _1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), and (iii ) a C _1-6 alkoxy group (eg an ethoxy group), or (2) a 3-8 membered monocyclic non-aromatic heterocyclic group (eg tetrahydropyranyl).

Compound (I'-2b).

Compound (I'), where

R ¹ means

A 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom), (ii) a C _1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), and (iii) C _{1 -6} alkoxy group (for example, ethoxy group); And

R ² is a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl), optionally substituted with 1 to 3 substituents selected from the group consisting of the following:

(i) a halogen atom (eg, fluorine atom, chlorine atom), (ii) a C _1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), and (iii ) C _1-6 alkoxy group (for example, ethoxy group).

Connection (1'-2c).

Compound (I'), where

R ¹ is a 6-membered monocyclic aromatic heterocyclic group (eg pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl) optionally substituted with 1 to 3 halogen atoms (eg fluorine atom); And

R ² means a 6-membered monocyclic aromatic heterocyclic group (eg pyridyl, pyrimidinyl) optionally substituted with 1 to 3 halogen atoms (eg fluorine atom, chlorine atom).

Specific examples of compound (I) include compounds of examples 1-150. Of these, compound (I) 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-hydroxy-1,2-di(pyridine) is preferable -2yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (example 1) or its salt, 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2yl]-2-[ (1 R,2R)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1 -(pyridin-2-yl)ethyl]-2,3-dihydro-1 H-isoindol-1-one

- 12 045216 (example 3) or its salt, 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 its salt, 6-[5-(difluoromethyl)-1,3,4oxadiazol-2-yl ] -2-[(1 R,2R)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1 -(pyridin-2-yl)ethyl]-2,3-dihydro-1Hisoindol-1- it (example 7) or its salt or 2-[(1R,2S)-1-cyclopropyl-2-(4-fluorophenyl)-2-hydroxyethyl]6-[5-(difluoromethyl)-1,3,4-oxadiazole -2-yl]-2,3-dihydro-1H-isoindol-1-one (Example 9) or a salt thereof, more preferably 6-[5-(difluoromethyl)-1,3,4-oxαdiαzol-2-yl] -2-[(1R,2R)-2-hydroxy-1,2-di(niridin-2yl)ethyl]-2,3-dihydro-III-isoindol-1-one (example 1) or its salt, 6- [5-(difluoromethyl)-1,3,4-oxadiazol-2yl]-2-[(1 R,2R)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1 -(pyridin-2 -yl)ethyl]-2,3-dihydro-1 H-isoindol-1-one (example 3) or its salt or 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 its salt.

When compound (I) is in the form of a salt, examples thereof include metal salts, ammonium salt, salts with an organic base, salts with an inorganic acid, salts with an organic acid, salts with a basic or acidic amino acid, and the like. Preferable examples of the metal salt include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt, etc. Preferable examples of the organic base salt include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dichlorohexylamine, K,K'-dibenzylethylenediamine and the like. Preferable examples of the inorganic acid salt include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the organic acid salt include those 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. Preferable examples of the basic amino acid salt include salts with arginine, lysine, ornithine and the like. Preferable examples of the acidic amino acid salt include salts with aspartic acid, glutamic acid and the like.

Of these, a pharmaceutically acceptable salt is preferred. For example, if the compound contains an acidic functional group, examples thereof include inorganic salts such as alkali metal salts (for example, sodium salt, potassium salt and the like), alkaline earth metal salts (for example, calcium salt, magnesium salt and the like). ) etc., ammonium salt and the like, and if the compound contains an alkaline functional group, examples thereof include salts with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. the like, and salts 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, p-toluenesulfonic acid, etc. .

Method of obtaining.

The procedure for preparing compound (I) is described below.

The starting compound and the reagent used and the compound obtained in each step by the following production procedure may all be in the form of a salt, and examples of such a salt include salt-like compounds (I) and the like.

If the compound obtained in each step is in free form, it can be converted into the real salt by a well-known procedure. If the compound obtained in each step is a salt, it can be converted to the actual free form or another salt by a generally known procedure.

The compound obtained in each step can be used directly as a reaction mixture or as a crude product for the next reaction. Alternatively, the compound obtained in each step can be isolated from the reaction mixture and purified by conventional techniques, for example, by separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, and the like.

If the starting compound and reagent used in each step are commercially available, a directly commercially available product may also be used.

In the reaction at each stage, if the reaction time varies depending on the type of reagent and solvent used, it is usually 1 min-48 h, preferably 10 min-8 h, unless otherwise specified.

In the reaction at each stage, if the reaction temperature varies depending on the type of reagent and solvent used, it is usually -78-300°C, preferably -78-150°C, unless otherwise specified.

In the reaction at each stage, if the pressure varies depending on the type of reagent and solvent used, it is usually 1-20 atm, preferably 1-3 atm, unless otherwise specified.

A microwave synthesizer such as an Initiator from Biotage and the like can be used in each reaction step. If the reaction temperature varies depending on the type of reagent and solvent used, it is usually in the range of room temperature -300°C, preferably 50-250°C, unless otherwise specified. If the reaction time varies depending on the type of reagent and solvent used, it is usually 1 minute-48 hours, preferably 1 minute-8 hours, unless otherwise specified.

In the reaction at each stage, the reagent is used in an amount equal to 0.5-20 equivalents, preferably 0.8-5 equivalents. in terms of substrate, unless otherwise stated. If the reagent is used as a catalyst, the reagent is used in an amount of 0.001-1 eq., preferably 0.01-0.2 eq. in terms of substrate. If a reagent is used as a solvent for a reaction, the reagent is used in the amount required for dissolution.

Unless otherwise stated, the reaction in each step is carried out without a solvent or by dissolving or suspending the starting compound in a suitable solvent. Examples of the solvent include those described in the examples and the following solvents.

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: %K-dimethylformamide, N-methylpyrrolidone, etc.;

halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.;

nitriles: acetonitrile, etc.;

sulfoxides: dimethyl sulfoxide, etc.;

aromatic organic bases: pyridine, etc.;

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 solvent can be used as a mixture of two or more types thereof in a suitable ratio.

If a base is used in the reaction in each step, examples thereof include those described in the examples and the following bases.

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] -7undecene, 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.

If an acid or acid catalyst is used in the reaction at each stage, examples thereof include those described in the examples and the following acids and acid catalysts.

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 acid: boron trifluoride-diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ferric chloride, etc.

Unless otherwise indicated, the reaction at each stage is carried out according to a well-known procedure, for example, according to the method described in Jikken Kagaku Kouza, 5th edition, vol. 13-19 (the Chemical Society of Japan ed.); Shin Jikken Kagaku Kouza, vol. 14-15 (the Chemical Society of Japan ed.); Fine Organic Chemistry, Revised 2nd edition (L.F. Tietze, Th. Eicher, Nankodo); Organic Name Reactions, the Reaction Mechanism and Essence, Revised Edition (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, vol. l-14 (Elsevier Japan); Strategic Applications of Named Reactions in Organic Synthesis (translated by Kiyoshi Tomioka, Kagakudojin); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, etc., or according to the method described in the examples.

At each step, the deprotection or deprotection reaction is carried out according to a well-known procedure, for example the method described in Protective Groups in Organic Synthesis, 4th ed, Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G. M. Wuts); Protecting Groups 3rd ed.

- 14 045216

Thieme, 2004 (P.J. Kocienski), etc., or according to the method described in the examples.

Examples of the protecting group of the hydroxy group of an alcohol and the like. and phenolic hydroxy groups include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, tetrahydropyranyl ether and the like; ester-type carboxylate protecting groups such as acetate and the like; ester-type sulfonate protecting groups such as methanesulfonate and the like; carbonate ester type protecting groups such as tert-butyl carbonate, etc., etc.

Examples of the aldehyde carbonyl group protecting group include acetal type protecting groups such as dimethylacetal and the like; cyclic protecting groups of the acetal type, such as 1,3-dioxane, etc., etc.

Examples of the ketone carbonyl group protecting group include ketal type protecting groups such as dimethyl ketal and the like; ketal type cyclic protecting groups such as 1,3-dioxane and the like; oxime type protecting groups such as O-methyloxime and the like; hydrazone type protecting groups such as N, N-dimethylhydrazone, etc., etc.

Examples of the carboxy protecting group include ester type protecting groups such as methyl ester and the like; amide type protecting groups such as N,N-dimethylamide, etc., etc.

Examples of the thiol protecting group include ether type protecting groups such as benzyl thioether and the like; ester type protecting groups such as thioacetate, thiocarbonate, thiocarbamate, etc., etc.

Examples of the amino group and aromatic heterocycle protecting group such as imidazole, pyrrole, indole and the like include carbamate type protecting groups such as benzylcarbamate and the like; amide type protecting groups such as acetamide and the like; alkylamine type protecting groups such as N-triphenylmethylamine and the like; sulfonamide type protecting groups such as methanesulfonamide and the like, etc.

The protecting groups can be removed by conventional methods, for example, by acid, base, ultraviolet radiation, hydrazine, phenylhydrazine, sodium N-methyldithiocarmabate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide) and the like, according to restoration technique, etc.

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

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

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

If the Wittig reaction is carried out in each step, examples of the Wittig reagent used include alkylidene phosphoranes and the like. Alkylidenephosphoranes can be prepared by a well-known procedure, for example, by the reaction of a phosphonium salt with a strong base.

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

If the Friedel-Crafts reaction is carried out in each step, 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 (eg, an alkyl halide, alcohol, olefin, etc.). Alternatively, it is also possible to use an organic acid or an inorganic acid instead of a Lewis acid and an anhydride such as acetic anhydride and the like. can also be used instead of acid chloride.

When an aromatic nucleophilic substitution reaction is carried out in each step, a nucleophile (eg, amine, imidazole, etc.) and a base (eg, organic base, etc.) are used as reagents.

If a nucleophilic addition reaction of a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) of a carbanion, or a nucleophilic substitution reaction with a carbanion is carried out in each step, examples of the base used to generate the carbanion include organolithium compounds, metal alkoxides, inorganic bases, organic bases and etc.

If the Grignard reaction is carried out in each step, examples of the Grignard reagent used include arylmagnesium halides such as phenylmagnesium bromide and the like; and alkylmagnesium halides such as methylmagnesium bromide and the like. The Grignard reagent can be prepared by a generally known procedure, for example, by reacting an alkyl halide or aryl halide with magnesium metal or from an isopropylmagnesium chloride-lithium chloride complex in ether, tetrahydrofuran, or the like. as a solvent.

If the Knoevenagel condensation reaction is carried out at each stage, a compound having an activated methylene group with two electron-withdrawing groups (for example, malonic acid, diethyl malonate, malononitrile, etc.) and a base (for example, an organic base, a metal alkoxide, etc.) is used as a reagent. inorganic base).

If the Vilsmeier-Hack reaction is carried out at each stage, phosphoryl chloride and an amide derivative (for example, N,N-dimethylformamide, etc.) are used as the reagent.

If the azidation reaction of an alcohol, alkyl halide or sulfonate is carried out in each step, examples of the azidation reagent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide and the like. For example, for the azidation reaction of an alcohol, a method using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), a method using trimethylsilyl azide and Lewis acid, a method using diphenylphosphoryl azide, triphenylphosphine and azodicarboxylate, etc. P.

If the reductive amination reaction is carried out in each step, examples of the reducing reagent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like. When the substrate is an amine, examples of the carbonyl used include paraformaldehyde, aldehydes such as acetaldehyde and the like, and ketones such as cyclohexanone and the like. When the substrate is carbonyl, examples of the amine used include ammonia, primary amines such as methylamine and the like; secondary amines such as dimethylamine, etc., etc.

When the Mitsunobu reaction is carried out in each step, azodicarboxylate (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as the reagent.

If an esterification reaction, an amidation reaction or a urea derivatization reaction is carried out in each step, examples of the reagent used include acyl halides such as acid chlorides, acid bromohydrides and the like; activated carboxylic acids such as anhydrides, activated esters, sulfates and the like. Examples of the carboxylic acid activating reagent include carbodiimide condensing reagents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl) and the like; triazine coupling reagents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM) and the like; carbonate condensing reagents such as 1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxytrisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methylpyridinium iodide (Mikayama reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate and the like; O-(7-α3benzotriαzol-1-yl)-N,N,N',N'-tetraαmethyluronium hexαfluorophosphate (HATU); sulfuric acid; their combinations, etc. If a carbodiimide condensing reagent is used, an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the like can be added to the reaction system.

If the coupling reaction is carried out in each step, examples of the metal catalyst used include palladium compounds such as palladium(P) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium( P), tris(dibenzylideneacetone)dipalladium(0), 1,1'-bis(diphenylphosphino)ferrocene palladium(P) chloride, etc.; nickel compounds such as tetrakis(triphenylphosphine)nickel(0) and the like; rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride and the like; cobalt compounds; copper compounds such as copper oxide, copper(I) iodide and the like; platinum compounds, etc. In addition, a base can be added to the reaction system, and examples thereof include inorganic bases and the like.

If the thiocarbonylation reaction is carried out at each stage, phosphorus pentasulfide is usually used as the thiocarbonylation reagent. Alternatively, a reagent containing the structure of 1,3,2,4-dithiadiphosphetane-2,4-disulfide (for example, 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lavesson's reagent ) etc.) can also be used instead of phosphorus pentasulfide.

If the halogenation reaction is carried out in each step, examples of the halogenation reagent used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, trichloroisocyanuric acid and the like. In addition, the reaction can be accelerated by using a radical initiator such as heat, light, benzoyl peroxide, azobisisobutyronitrile and the like in the reaction system.

When the hydroxy group halogenation reaction is carried out in each step, examples of the halogenating reagent used include hydrohalic acids and inorganic acid halides, particularly hydrochloric acid, thionyl chloride, phosphorus oxychloride and the like. for chlorination, 48% hydrobromic acid, etc. for bromination. In addition, a method for preparing an alkyl halide by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide and the like can be used. Alternatively, a two-step technique for preparing the alkyl halide may also be used, involving converting the alcohol to the corresponding sulfonate and then reacting the sulfonate with lithium bromide, lithium chloride or sodium iodide.

If the 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 triethylphosphite, tri(isopropyl)phosphite and the like.

When the sulfonate esterification reaction is carried out in each step, examples of the sulfonating reagent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride and the like.

If the hydrolysis reaction is carried out at each stage, an acid or a base is used as a reagent. For the acid hydrolysis reaction of tert-butyl ether, formic acid, triethylsilane, etc. can be added. for the reductive capture of the tert-butyl cation that is formed simultaneously.

If the dehydration reaction is carried out in each step, examples of the dehydration reagent used include sulfuric acid, phosphorus dipentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.

When the alkylation reaction is carried out in each step, an electrophile (eg, an alkyl halide, etc.) and a base (eg, an organic base, an inorganic base, a metal alkoxide, a metal amide, etc.) are used as reagents.

If the cyanidation reaction is carried out in each step, examples of the reagent used include metal cyanides such as copper cyanide, potassium cyanide and the like.

Compound (I) can be prepared by the production methods shown in the following Scheme 1 or Scheme 2. Each symbol in the formulas in the schemes is as defined above unless otherwise indicated.

In addition, compound (I) can be obtained by carrying out a protecting group reaction, a deprotecting reaction, an amidation reaction, a sulfonamidation reaction, a urea derivatization reaction, a carbamoylation reaction, an alkylation reaction, a Mitsunobu reaction, a hydrogenation reaction, an oxidation reaction, a reduction reaction, halogenation reactions, coupling reactions, nucleophilic carbanion addition reactions, Grignard reactions, deoxofluorination reactions, dehydration reactions, and the like. individually or two or more of them in combination.

The following compound (Ia) (compound ( _I ) wherein R ¹ is R ^1a ) can be prepared by the procedure shown in the following Scheme 1. R ^1a is an optionally substituted cyclopropyl group, an optionally substituted C _{6_14} aryl group, or an optionally substituted A 5- or 6-membered monocyclic aromatic heterocyclic group. Other designations are as defined above.

- 17 045216

Scheme 1

Compound (4) can be prepared by coupling compound (2) with compound (3) 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)-9,9dimethylxanthene (alias: Xantphos) and bis(dibenzylideneacetone)palladium(0) and the like. Examples of the base include N,N-dicyclohexylmethylamine.

Compound (7) can be obtained by introducing compound (6) into a dihydration cyclization reaction. A combination of Burges' reagent or p-toluenesulfonyl chloride and a base is used as a reagent. Examples of the base include the above-mentioned organic bases (eg, N,N-diisopropylethylamine, triethylamine, etc.).

Compound (12) can be obtained by introducing compound (9), compound (10) and compound (11) into a three-component condensation reaction. Examples of the reagent used include formic acid.

Compound (14) can be prepared by introducing compound (12) into a Stetter reaction with compound (13). A combination of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide and a base is used as a reagent. Examples of the base include triethylamine.

Compound (15) can be obtained by introducing compound (14) into a reduction reaction. Examples of the reagent used include sodium borohydride and potassium tri(sec-butyl)borohydride. As stereoisomers of the product, only anti-form (15a) below or a mixture of anti-form (15a) and syn-form (15b) below is obtained (the stereochemical configuration of the formula is relative).

(15a) (15b)

Compound (Ia) can be prepared by introducing compound (16) into an alkylation reaction with compound (8), then into a cyclization reaction. After the cyclization reaction, an alkylation reaction is carried out, but it can be carried out in stages. In this case, the cyclization reaction can be carried out in an alkaline or acidic environment. Examples of the base include triethylamine, DIPEA, potassium acetate and the like. Examples of the acid used include acetic acid and the like.

The following compound (Ib) (compound (I) wherein R ¹ is R ^1b ) can be prepared from

- 18 045216 compound (17) according to the procedure shown in the following scheme 2. R ^1b means an optionally substituted cycloalkyl group, an optionally substituted C _6-14 aryl group, an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group, or an optionally substituted 3- An 8-membered monocyclic non-aromatic heterocyclic group.

X stands for halogen atom. Other designations are as defined above.

pMe

Me-N _{Ηα λ}

N_

O ov) )—\ R ^1b amidation reaction

HN—( ---------BUT (17)

0-7 R ^1b “%

Me-N LMe (19)

R ² -MdX (20) Grignard reaction

R ² —Li (21) nucleophilic substitution reaction with carbanion

HN—(

R ² (22)

M Dib removal reaction , , __/ protecting group * he R ²

R ^,b

N ₂ Y—( Voh

R ²

Br (c) alkylation reaction E N-N and cyclization reaction )—\

------------------c O

R ^1b

OH R ² (1b) (23) (24)

Scheme 2

Compound (23) can be obtained by introducing compound (22) into a reduction reaction. Examples of the reagent used include sodium borohydride and potassium tri(sec-butyl)borohydride. Alternatively, a combination of aluminum triisopropoxide and 2-propanol can also be used. As stereoisomers of the product, only the anti form (23a) below or a mixture of the anti form (23a) and the syn form (23b) below is obtained (the stereochemical configuration of the formula is relative).

Compound (Ib) can be prepared by introducing compound (24) into an alkylation reaction with compound (8), then into a cyclization reaction. After the cyclization reaction, an alkylation reaction is carried out, but it can be carried out in stages. In this case, the cyclization reaction can be carried out in an alkaline or acidic environment. Examples of the base include triethylamine, DIPEA, potassium acetate and the like. Examples of the acid used include acetic acid and the like.

Compounds (2), (3), (9), (10), (11), (13), (17), (18), (20) and (21), which are used as raw materials in each production method , can be easily purchased or can be obtained using a well-known method.

If isomerization occurs, the configurational isomers (E, Z forms) of compound (I) can be isolated and purified, for example, by conventional separation means such as extraction, recrystallization, distillation, chromatography and the like. and get a clean connection. In addition, the corresponding pure isomer can also be obtained by isomerization of the double bond using heat, an acid catalyst, a transition metal complex, a metal-based catalyst, a radical catalyst, illumination, a strongly basic catalyst, and the like, according to the procedure described in Shin Jikken Kagaku Kouza, 14 (The Chemical Society of Japan ed.), p. 251 to 253; or 4th edition Jikken Kagaku Kouza, 19 (The Chemical Society of Japan ed.), p. 273 to 274; or similar technique.

Compound (I) contains a stereoisomer depending on the type of substituent, and each stereoisomer and mixture thereof are included in the present invention.

Compound (I) may be a hydrate or a non-hydrate.

If a particular product is obtained in the free form by the above reaction, it can be converted into a salt by the usual procedure, or if a particular product is obtained as a salt, it can be converted into the free form or another salt by the usual method. The compound (I) thus obtained can also be isolated from the reaction mixture and purified by known techniques such as phase transfer, concentration, solvent extraction, distillation, crystallization, recrystallization, chromatography and the like.

If compound (I) contains a configuration isomer, diastereoisomer, conformer, etc., each can be isolated by the above separation and purification procedures if desired. Besides,

- 19 045216 if compound (I) is racemic, the d-form and 1-form can be isolated by conventional optical separation such as preparative high performance liquid chromatography (preparative HPLC), supercritical fluid chromatography (preparative SFC) and the like.

The thus obtained compound (I), the other reaction intermediate and the starting compounds can be isolated from the reaction mixture and purified by conventional techniques such as, for example, extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin layer chromatography, preparative high performance liquid chromatography (preparative HPLC), preparative mild pressure liquid chromatography (preparative mild pressure LC), etc.

The salt of compound (I) can be prepared according to a generally known procedure. For example, if compound (I) is a basic compound, it can be prepared by adding an inorganic acid or an organic acid, or if compound (I) is an acidic compound, by adding an organic base or an inorganic base.

If compound (I) contains an optical isomer, each optical isomer and a mixture thereof are included in the scope of the present invention, and these isomers can optionally be subjected to optical separation or can be prepared accordingly by a generally known procedure.

Compound (I) may be a crystal.

A crystal of compound (I) can be obtained by a well-known crystallization procedure.

Examples of the crystallization technique include a solution crystallization technique, a vapor crystallization technique, a melt crystallization technique, and the like.

The solution crystallization technique is a typical technique for shifting an unsaturated state to a supersaturated state by changing factors affecting the solubility of compounds (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of solvent. Specific examples thereof include a concentration technique, a slow cooling technique, a reaction technique (diffusion technique, electrolysis technique), a hydrothermal growth technique, a flux technique, and the like. Examples of the solvent used include aromatic hydrocarbons (for example, benzene, toluene, xylene, etc.), halogenated hydrocarbons (for example, dichloromethane, chloroform, etc.), saturated hydrocarbons (for example, hexane, heptane, cyclohexane, etc. .), ethers (for example, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitriles (for example, acetonitrile, etc.), ketones (for example, acetone, etc.), sulfoxides ( for example, dimethyl sulfoxide, etc.), acid amides (for example, K,K-dimethylformamide, etc.), esters (for example, ethyl acetate, isopropyl acetate, etc.), alcohols (for example, methanol, ethanol, 2-propanol, etc.), water, etc. These solvents are used alone or in combination of two or more in a suitable ratio (eg, 1:1 to 1:100 (volume ratio)). If necessary, a seed crystal can be used.

The vapor crystallization technique is, for example, evaporation technique (sealed tube technique, gas flow technique), gas phase reaction technique, chemical transportation transport reaction technique, etc.

The melt crystallization technique is, for example, the conventional freezing technique (pulling technique, temperature gradient technique, Brigman technique), zone melting technique (concentration equalization technique for zone melting, floating zone technique), special growth technique (VLS technique, liquid phase eptaxy technique ) and so on.

Preferable examples of the crystallization technique include a technique comprising dissolving compound (I) in a suitable solvent (for example, alcohols such as methanol, ethanol, etc.) at a temperature of from 20 to 120° C. and cooling the resulting solution to a temperature (for example, from 0 to 50°C, preferably 0 to 20°C), not exceeding the dissolution temperature, etc.

The crystals of the present invention thus obtained can be isolated, for example, by filtration or the like.

The analysis technique for the resulting crystal is a typical crystal analysis technique using X-ray powder diffraction. As a technique for determining crystal orientation, a mechanical technique or an optical technique and the like can also be used.

The crystal of compound (I) obtained by the above production procedure may have high purity, high quality and low hygroscopicity, may not be denatured even after long-term storage under normal conditions, and can be expected to have excellent stability. In addition, it may have excellent biological characteristics (eg, pharmacokinetics (absorption, distribution, metabolism, excretion), expression efficiency, etc.) and may be extremely useful as a drug.

Compound (I) may be a prodrug. A prodrug of compound (I) means a compound that is converted to compound (I) by a reaction due to the presence of an enzyme, gastric acid, or the like. under physiological conditions in a living organism, i.e., a compound that is converted into compound (I) by oxidation, reduction, enzyme hydrolysis, etc.; compound - 20 045216 which is converted into compound (I) by hydrolysis or the like. due to the presence of stomach acid, etc. Examples of the prodrug of compound (I) include a compound obtained by introducing an amino group in compound (I) into acylation, alkylation or phosphorylation (for example, a compound obtained by introducing an amino group into compound (I) into eicosanylation, alanylation, pentylaminocarbonylation, (5-methyl-2 -oxo-1,3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofurylation, pyrrolidylmethylation, pivaloyloxymethylation or tert-butylation); a compound obtained by introducing a hydroxy group in compound (I) by acylation, alkylation, phosphorylation or boration (for example, a compound obtained by introducing a hydroxy group in compound (I) by acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation or dimethylaminomethylcarbonylation) ; a compound obtained by introducing a carboxy group in compound (I) in esterification or amidation (for example, a compound obtained by introducing a carboxy group in compound (I) ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2- oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethylesterification or methylamidation), etc. These compounds can be prepared from compound (I) by a generally known procedure.

A prodrug of compound (I) may also be one that is converted to compound (I) under physiological conditions, as described in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), vol. 7, Design of Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990).

In the present specification, compound (I) and the prodrug of compound (I) are sometimes collectively referred to as the compound of the present invention.

Compound (I) may be a hydrate, non-hydrate, solvate or non-solvate.

In addition, compound (I) may be a compound labeled or substituted with an isotope (eg, ² H, ³ H, ⁿ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²⁵ I) and the like. The labeled or isotope-substituted compound can be used, for example, as a radiotracer (PET tracer) used in positron emission tomography (PET) and useful in medicine for making a diagnosis and the like.

Compound (I) also includes a deuterium-containing form in which 1H is converted to ^2H (D).

Compound (I) also includes its tautomer.

Compound (I) may be a pharmaceutically acceptable co-crystal or a salt thereof. A joint crystal or a salt thereof means a crystalline substance formed by two or more special solids at room temperature, each having different physical characteristics (eg, structure, melting point, heat of fusion, hygroscopicity, solubility and stability). The co-crystal or its salt can be obtained by a well-known co-crystallization procedure.

Compound (I) can also be used as a radiotracer for PET.

Since the compound of the present invention has excellent HDAC inhibitory activity, preferably class II HDAC inhibitory activity, more preferably HDAC6 inhibitory activity, it can also be useful as a safe drug based on such activity .

For example, a drug of the present invention containing a compound of the present invention may be expected to have low toxicity (eg, acute toxicity, chronic toxicity, genetic toxicity, hematotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and be used for a mammal (such as mouse, rat, hamster, rabbit, cat, dog, cattle, sheep, monkey, human) as a prophylactic or therapeutic agent for HDAC-related diseases, preferably for class II HDAC-related diseases, more preferably for HDAC6-related diseases, more precisely, the diseases described below in paragraphs (1)-(7).

In fairness, the compound of the present invention can be expected to have low genetic toxicity, and therefore the drug of the present invention can be expected to have low genetic toxicity.

(1) Inflammatory diseases (eg, 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), postoperative or post-traumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, damage to the gastric mucosa, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, diabetic nephropathy , uveitis, hidradenitis suppurativa, etc.).

(2) Autoimmune diseases (eg, rheumatoid arthritis, psoriasis, inflammatory disease

- 21 045216 intestines (e.g. Crohn's disease, ulcerative colitis, etc.), Sjögren's syndrome, Behçet's disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, discoid lupus erythematosus, Castleman's disease, ankylosis-induced spondylitis, polymyositis, dermatomyositis ( DM), polyarteritis nodosa (PN), mixed connective tissue disease (MCTD), scleroderma, lupus erythematosus profundus, 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, etc.), (3) Osteoarticular degenerative disease (eg, rheumatoid arthritis, osteoporosis, osteoarthritis, etc.).

(4) Neoplastic diseases [eg, malignancy, angiogenesis, glaucoma, juvenile hemangioma, multiple myeloma, chronic sarcoma, metastatic melanoma, Kaposi's sarcoma, vascular proliferation, cachexia, metastatic breast cancer, cancer (eg, colorectal cancer (eg, familial colorectal cancer, hereditary non-polypous colorectal cancer, gastrointestinal stromal tumor, etc.), lung cancer (eg, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, etc.), mesothelioma, pancreatic cancer (eg , pancreatic ductal cancer, etc.), gastric cancer (for example, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma, etc.), breast cancer (for example, invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer glands, etc.), ovarian cancer (for example, epithelial ovarian carcinoma, extragonadal germinoma, ovarian germinoma, ovarian tumor with low malignant potential, etc.), prostate cancer (for example, hormone-dependent prostate cancer, hormone-independent prostate cancer glands, etc.), liver cancer (for example, primary liver cancer, extrahepatic bile duct cancer, etc.), thyroid cancer (for example, papillary thyroid carcinoma, etc.), kidney cancer (for example, renal cell carcinoma, transitional cell carcinoma of the kidney and urinary tract, etc.), uterine cancer, brain tumor (eg, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, etc.), melanoma, sarcoma, cancer bladder, hematological cancer, etc., including multiple myeloma, pituitary adenoma, glioma, acoustic neuroma, retinoblastoma, pharynx cancer, laryngeal cancer, tongue cancer, thymoma, esophageal cancer, duodenal cancer, colorectal cancer, rectal cancer, hepatoma, pancreatic endocrine tumor, bile duct cancer, gallbladder cancer, penile cancer, urinary duct cancer, testicular tumor, vulvar cancer, cervical cancer, endometrial cancer, uterine sarcoma, holonic 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 proliferative bone marrow disease, pancreatic endocrine tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, cancer of unknown primary site), leukemia (eg, acute leukemia (eg, acute lymphocytic leukemia, acute myelocytic leukemia, etc.), chronic leukemia (eg, chronic lymphocytic leukemia, chronic myelocytic leukemia, etc.), myelodysplastic syndrome), uterine sarcoma (eg, mixed mesodermal tumor, leiomyosarcoma uterus, endometrial stromal tumor, etc.), myelofibrosis, etc.).

(5) Neurodegenerative diseases and/or diseases of the central nervous system:

(i) psychiatric illnesses (e.g. depression, major depression, bipolar depression, dysthymic disorder, emotional disorder (seasonal affective disorder, etc.), recurrent depression, postpartum depression, stress disorder, depressive symptom, mania, anxiety, generalized anxiety disorder, state anxiety syndrome, panic disorder, phobia, social phobia, social anxiety disorder, obsessive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, Tourette's syndrome, autism, autistic-like syndrome, fragile X syndrome, Rett syndrome, adjustment disorder, bipolar disorder, neurosis, schizophrenia (eg, positive symptom, negative symptom, cognitive symptom), cognitive dysfunction associated with schizophrenia, chronic fatigue syndrome, anxiety neurosis, compulsive neurosis, epilepsy, anxiety state, anxious mental state, emotional abnormality, cyclothymia, nervous erethism, dizziness, drug addiction, low sexual excitability, attention deficit hyperactivity disorder (ADHD), psychotic major depression, refractory major depression, treatment-resistant depression, hereditary paraplegia);

(ii) neurodegenerative diseases (eg, Alzheimer's disease, dementia of the Alzheimer's type, senile dementia of the Alzheimer's type, Parkinson's disease, muscular dystrophy, Parkinson's disease associated with dementia, Huntington's disease, multi-infarct dementia, lobar frontotemporal degeneration (progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia and parkinsonism associated with the MART mutation (FTDP-17), frontotemporal dementia, Pick's disease, dementia with argyrophilic grains, etc.), dementia of the Par-

- 22 045216 Kinson, Niemann-Pick syndrome, Down's disease, multi-infarct dementia, post-encephalitic parkinsonism, dementia with Lewy bodies, Rubinstein-Taybi syndrome, HIV-associated dementia, amyotrophic lateral sclerosis (ALS), motor neurogenesis disease (MND), disease Creutzfeldt-Jakob or prion disease, cerebral palsy, multiple sclerosis, Riley-Day syndrome);

(iii) age-related cognitive impairment (eg, age-related memory impairment, senile dementia);

(iv) sleep disorders (for example, hereditary sleep disorders (for example, psychophysiological insomnia, etc.), acquired sleep disorder, circadian rhythm disorders (for example, jet lag syndrome (desynchronosis after a transmeridian flight), sleep disturbance due to shift work) work, irregular sleep-wake cycle, delayed sleep phase syndrome, shifted sleep phase syndrome, non-24-hour sleep-wake cycle, etc.), parasomnia, sleep disorders associated with an internal medical or mental disorder (for example, chronic obstructive pulmonary diseases, Alzheimer's disease, Parkinson's disease, cerebrovascular dementia, schizophrenia, depression, anxiety neurosis), stress insomnia, insomnia, insomnia with neurosis, sleep apnea syndrome);

(v) respiratory depression caused by anesthesia, traumatic disease or neurodegenerative disease, etc.;

(vi) traumatic brain injury, cerebral apoplexy, anorexia nervosa, eating disorder, anorexia nervosa, bulimia, other eating disorder, alcoholism, alcohol abuse, alcohol amnesia, alcohol paranoia, alcohol dependence, alcohol withdrawal syndrome, alcohol insanity, alcohol poisoning , alcoholic jealousy, alcoholic mania, alcohol-dependent mental disorder, alcoholic insanity, pharmacophilia, pharmacophobia, pharmacomania, drug or drug withdrawal syndrome, migraine, stress headache, catatonic headache, diabetic neuropathy, obesity, diabetes, muscle spasm, disease Meniere's, autonomic ataxia, alopecia, glaucoma, hypertension, heart disease, tachycardia, congestive heart failure, hyperventilation, bronchial asthma, apnea, sudden infant death syndrome, inflammatory disease, allergic disease, impotence, menopausal disorder, infertility, cancer, immunodeficiency syndrome, HIV infection-induced, stress-induced immunodeficiency syndrome, cerebrospinal meningitis, acromegaly, incontinence, metabolic syndrome, osteoporosis, peptic ulcer, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, stress gastrointestinal disorder, stress vomiting, peptic ulcer, diarrhea, constipation, postoperative intestinal obstruction;

(vii) pain (pain, cancer pain, acute pain caused by inflammation, pain caused by chronic inflammation, postoperative pain (incision pain, deep pain, visceral pain, chronic pain after surgery, etc.), muscle pain ( muscle pain associated with chronic pain in illness, stiff shoulder, etc.), arthralgia, toothache, pain in the temporomandibular joint, headache (migraine, catatonic headache, headache associated with fever, headache, associated with hypertension), visceral pain (heart pain, angina pain, abdominal pain, kidney pain, urinary tract pain, bladder pain), pain during childbirth and gynecological pain (pain during the intermenstrual period, dysmenorrhea, labor pains), neuropathic pain (herniated disc, nerve root pain, neuralgia after herpes zoster, trigeminal neuralgia, lumbago, etc.), peripheral neuropathy (CIPN) after taking anticancer drugs (anticancer drug taxane-based (eg, paclitaxel (Taxol), docetaxel), vinca alkaloid anticancer agent (eg, vincristine, vinblastine), platinum drug (eg, cisplatin, carboplatin, oxaliplatin), molecularly targeted drug (eg, bortezomib), and etc.) and associated neurological symptoms (chemotherapy-induced neuropathic pain (CINP))).

(6) Chronic heart failure or acute heart failure, acute decompensated heart failure, coronary heart disease, cardiomyopathy, myocarditis, valvular disease.

(7) Peripheral neuropathy, etc. (eg, demyelinating diseases and neuropathy (multiple sclerosis, Guillain-Barré syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot-Marie Tooth disease, hereditary sensory and autonomic neuropathy, familial amyloid polyneuropathy)) .

The drug of the present invention may preferably be used as an agent for the prevention or treatment of the following: an autoimmune disease, an inflammatory disease, an osteoarticular degenerative disease, a neurodegenerative disease, a central nervous system disease, a neoplastic disease, or a peripheral neuropathy, more preferably inflammatory bowel disease (preferably Crohn's disease or ulcerative colitis), systemic lupus erythematosus, rheumatoid arthritis, psoriasis, Sjögren's syndrome, Behçet's syndrome, multiple sclerosis, graft-versus-host disease, Alzheimer's disease (preferably dementia of the Alzheimer's type), schizophrenia, dementia with Lewy bodies, lobar frontotemporal degeneration 23 045216 (progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia and parkinsonism associated with the MART mutation (FTDP-17), frontotemporal dementia, Pick's disease, dementia with argyrophilic grains, etc.) , Parkinson's disease, Huntington's disease, Rubinstein-Taybi syndrome, muscular dystrophy, Rett syndrome, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, depression, hereditary paraplegia, Riley-Day syndrome, Castleman disease, leukemia, uterine leiomyosarcoma, prostate cancer , colon cancer, multiple myeloma, cachexia or myelofibrosis, chronic heart failure or acute heart failure, acute decompensated heart failure, ischemic heart disease, cardiomyopathy, myocarditis, valvular disease, peripheral neuropathy, etc.

The drug of the present invention is more preferably used as an agent for the prevention or treatment of the following: Alzheimer's disease, lobar frontotemporal degeneration (progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia and parkinsonism associated with the MART mutation (FTDP- 17), frontotemporal dementia, Pick's disease, dementia with argyrophilic grains, etc.), Charcot-Marie-Tooth disease, etc., in particular Alzheimer's disease or progressive supranuclear palsy.

In the present invention, the above prevention of a disease means, for example, the administration of a medicament containing a compound of the present invention to a patient who is expected to be at risk of onset due to some factor related to the disease, but who has not developed the disease, or to patients who have who have developed a disease but do not have a subjective symptom, or administering a medicament containing a compound of the present invention to patients who fear recurrence of the disease after treatment of the disease.

The drug containing the compound of the present invention can be safely administered alone or mixed with a pharmacologically acceptable carrier by a generally known method (for example, the method described in Japanese Pharmacopoeia, etc.) as in pharmaceutical preparation methods, and in such form as, for example, tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, oral disintegrating tablet, buccal tablet, etc.), pill, powder, granule, capsule (including soft capsule, lozenge, syrup, liquid, emulsion, suspension, controlled release preparation (e.g. immediate release preparation, extended release preparation, extended release microcapsule), aerosol, film (e.g. oral disintegrating film, oral mucosal adhesive film) film), injection preparation (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), intravenous drip, percutaneous preparation, cream, ointment, lotion, adhesive preparation, suppository (eg, rectal suppository, vaginal suppository) , pellet, nasal preparation, pulmonary preparation (for inhalation), eye drops, etc., for oral or parenteral administration (for example, intravenous, intramuscular, subcutaneous, intraorgan, nasal, intradermal, drop, intracerebral, rectal , intravaginal, intraperitoneal and intratumoral injection, injection near the tumor and injection into the affected area).

The content of the compound of the present invention in the drug of the present invention is from about 0.01 to 100% by weight of the total drug. The dosage of the drug of the present invention may vary depending on the subject to be administered, the route of administration, the disease, and the like. For example, for oral administration to patients (about 60 kg body weight) with a neurodegenerative disease (e.g., Alzheimer's disease, progressive supranuclear palsy, etc.), about 0.01 mg/kg body weight - about 50 mg/kg body weight, preferably about 0.05 mg/kg body weight - about 25 mg/kg body weight, more preferably about 0.1 mg/kg body weight - about 2 mg/kg body weight of the active ingredient (compound (I)) can be administered as one or more servings per day.

Examples of the pharmaceutically acceptable carrier include various organic or inorganic carrier materials that are commonly used as formulation materials, such as an excipient, a lubricant, a binding agent and a disintegrant for solid preparations; or a solvent, solubilizing agent, suspending agent, isotonic agent, buffering agent, soothing agent, or the like. for liquid preparations. In addition, if necessary, it is also possible to use suitable conventional additives such as a preservative, antioxidant, coloring agent, sweetener, adsorbent agent, wetting agent and the like in a suitable amount.

The dose of the drug of the present invention in the form of a sustained release preparation varies depending on the type and content of compound (I), the dosage form, the period of sustained release of the drug, the animal to which it is administered (for example, mammals such as mouse, rat, hamster, guinea pig, rabbit, cat, dog, cattle, horse, pig, sheep, monkey, human, etc.) and the object of administration. For example, for use via parenteral administration, between about 0.1 mg and about 100 mg of compound (I) is required to be released from the administered formulation over 1 week.

- 24 045216

Examples of the excipient include lactose, white sugar, D-mannitol, starch, corn starch, crystalline cellulose and light anhydrous silicic acid.

Examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal silicon dioxide.

Examples of the binding agent include crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose and sodium carboxymethylcellulose.

Examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, 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 and sodium carbonate, sodium citrate.

Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate and the like; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like.

Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerol and D-mannitol.

Examples of buffer reagent include buffer solutions such as phosphates, acetates, carbonates and citrates.

Examples of the demulcent agent include benzyl alcohol.

Examples of the preservative include parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid and sorbic acid.

Examples of the antioxidant include sulfites, ascorbic acid and α-tocopherol.

For the prevention or treatment of various diseases, the compound of the present invention can also be used together with another drug (hereinafter referred to as a concomitant drug in the present invention). Below, the drug used when the compound of the present invention is used together with another drug is referred to as the combination drug of the present invention.

For example, if the compound of the present invention is used as an HDAC inhibitor, preferably a class II HDAC inhibitor, more preferably an HDAC6 inhibitor, it can be used in conjunction with the following drugs:

tranquilizer (diazepam, lorazepam, clorazepate dipotassium, oxazepam, chlordiazepoxide, medazepam, oxazolam, cloxazolam, clotiazepam, bromazepam, etizolam, fludiazepam, hydroxyzine, nitrazepam, triazolam, alprazolam, etc.);

antipsychotic (chlorpromazine hydrochloride, prochlorperazine, trifluoperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride, haloperidol, clozapine, trifluoperazine dihydrochloride, fluphenazine hydrochloride , olanzapine, quetiapine infumarate, risperidone, aripiprazole, bromperidol, spiperone, reserpine, clocapramine hydrochloride, sulpiride, zotepine, thiothixene, etc.);

antiepileptic drug (phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, trimethadione, carbamazepine, phenobarbital, primidone, sultiam, sodium valproate, clonazepam, diazepam, nitrazepam, etc.);

antidepressant and therapeutic drug for manic psychosis (tricyclic or tetracyclic antidepressant (imipramine hydrochloride, clomipramine hydrochloride, desipramine hydrochloride, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, miansering hydrochloride, maprotiling hydrochloride, etc.), noxiptyline, phenelzine, sulpiride, trazodone hydrochloride, lithium carbonate, selective reverse inhibitor serotonin reuptake inhibitor (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide, sertraline hydrochloride, paroxetine hydrochloride, paroxetine hydrochloride hydrate, escitalopramoxalate, etc.), serotonin-noradrenoline reuptake inhibitor (venlafaxing hydrochloride, duloxetine hydrochloride, venlafaxing hydrochloride, etc.), norepinephrine reuptake inhibitor (reboxetine mesylate, etc.) etc.), norepinephrine-dopamine reuptake inhibitor (bupropion hydrochloride, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, seteptyline maleate, 5-HT1A agonist (buspirone hydrochloride, tandospirone citrate, osemosotan hydrochloride), etc.) benzodiazepine (clonazepam and t etc.), L-type calcium channel inhibitor (pregabalin, etc.), 5-HT1A agonist (buspirone hydrochloride, tandospirone citrate, osemosotanhydrochloride, etc.), 5-HT3 antagonist (cyamemazine, etc.), non-selective inhibitor of cardiac β-adrenergic receptors (propranolol hydrochloride, oxyprenolol hydrochloride, etc.), histamine H1 antagonist (hydroxyzine hydrochloride, etc.);

therapeutic drug for schizophrenia (chlorpromazine, haloperidol, sulpiride, clozapine, trifluoperazine hydrochloride, fluphenazine hydrochloride, olanzapine, quetiapine infumarate, risperidone, aripiprazole, etc.), CRF antagonist, other drug for anxiety (meprobamate, etc.), tachykinin antagonist (MK-869, saredutant, etc.), drug that acts on the metabotropic glutamate receptor, CCK antagonist, β3 adrenaline receptor antagonist (amibegron hydrochloride, etc.), GAT-1 inhibitor (thiagabine hydrochloride, etc.) etc.), N-type calcium channel inhibitor, carbonic anhydrase type II inhibitor, NMDA site glycine agonist, NMDA antagonist (memantine, etc.), peripheral benzodiazepine receptor agonist, vasopressin antagonist, vasopressin V1b antagonist, vasopressin V1a antagonist, phosphodiesterase inhibitor , opioid antagonist, opioid agonist, uridine, nicotinic acid receptor agonists, thyroid hormone (T3, T4), TSH, TRH, MAO inhibitor (phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), 5-HT _2A antagonist, reverse 5-HT _2A agonist, COMT inhibitor (entacapone, etc.), therapeutic drug for bipolar disorder (lithium carbonate, sodium valproate, lamotrigine, riluzole, felbamate, etc.), CB1 cannabinoid receptor antagonist (rimonabant, etc. etc.), FAAH inhibitor, sodium channel inhibitor, anti-ADHD drug (methylphenidate hydrochloride, methamphetamine hydrochloride, etc.), therapeutic drug for alcoholism, therapeutic drug for autism, therapeutic drug for chronic fatigue syndrome, therapeutic drug for seizures, therapeutic drug for fibromyalgia, therapeutic drug for headache, therapeutic drug for insomnia (etizolam, zopiclone, triazolam, zolpidem, ramelteon, indiplon, etc.), therapeutic drug for smoking cessation, therapeutic drug for myasthenia gravis, therapeutic drug for cerebral infarction, therapeutic drug for manic psychosis, therapeutic drug for hypersomnia, therapeutic drug for pain, therapeutic drug for dysthymia, therapeutic drug for autonomic dystonia, therapeutic drug for male and female female sexual dysfunction, therapeutic drug for migraine, therapeutic drug for pathological risk taking, therapeutic drug for restless leg syndrome, therapeutic drug for drug addiction, therapeutic drug for alcohol-related disease, therapeutic drug for irritable colon syndrome gut, therapeutic drug for Alzheimer's disease (donepezil, galantamine, memantine, rivastigmine, etc.), therapeutic drug for Parkinson's disease (levodopa, carbidopa, benserazide, selegiline, rasagiline, zonisamide, entacapone, amantadine, talipexole, pramipexole, ropinirole, rotigotine, apomorphine, cabergoline, pergolide, bromocriptine, istradefylline, trihexyphenidyl, biperiden, pyrogeptine, prophenamine, promethazine, droxidopa, amantadine hydrochloride, bromocriptine mesylate, trihexyphenidyl hydrochloride, selegilin hydrochloride, a combination thereof, etc.), therapeutic drug for Parkinson's disease dementia-related drug (rivastigmine), therapeutic drug for dementia with Lewy bodies (donepezil), therapeutic drug for ALS (riluzole, neurotrophic factor, etc.), therapeutic drug for hyperlipidemia such as cholesterol-lowering drug (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrate (clofibrate, etc.), squalene synthase inhibitor), therapeutic drug for abnormal behavior or dementia-related wandering (sedative drug, anti-anxiety drug, etc.), apoptosis inhibitor, anti-obesity drug, anti-diabetic drug, therapeutic drug for hypertension, therapeutic drug for hypotension, therapeutic drug for rheumatism (DMARD), anti-cancer drug, therapeutic drug for hypoparathyroidism (PTH), calcium receptor antagonist, sex hormone or its derivative (progesterone, estradiol, estradiol benzoate, etc.), neuronal differentiation accelerator, neuroregeneration promoter, non-steroidal anti-inflammatory drug (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, etc.), steroid (dexamethasone, cortisone acetate, etc.), anti-cytokine drug (TNF inhibitor, MAP kinase inhibitor, etc.), antibody - drug, nucleic acid or derivative nucleic acid, aptamer, etc.

For joint 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 or the concomitant drug can be administered to a subject at the same time, or can be administered at different times. The dose of the concomitant drug can be determined from the clinically used dose and can be suitably selected depending on the subject to be administered, the route of administration, the disease, the combination, and the like.

There are no special restrictions imposed on the administration form when used in combination, and the compound of the present invention and the concomitant drug only need to be combined when administered. Examples of such a mode of administration include the following:

(1) administration of a single drug obtained by simultaneous treatment of a compound of the present invention and a concomitant drug;

(2) simultaneous administration of two types of preparations of the compound proposed in the present invention and the concomitant drug, which are obtained separately, by one route of administration;

(3) administering two types of preparations of the compound of the present invention and the concomitant drug, which are obtained separately, by one route of administration alternately;

(4) simultaneous administration of two types of preparations of the compound proposed in the present invention and the concomitant drug, which are obtained separately, by different routes of administration;

(5) administering two types of preparations of the compound of the present invention and the concomitant drug, which are obtained separately, by different routes of administration alternately (for example, first administering the compound of the present invention and then the concomitant drug, or in the reverse order) and etc.

The mixing ratio of the compound of the present invention and the concomitant drug in the combination agent of the present invention can be suitably selected based on the subject to be administered, the route of administration, the disease, and the like.

For example, if the content of the compound of the present invention in the combination agent of the present invention varies depending on the form of the preparation, it is generally from about 0.01 to 100% by weight, preferably from about 0.1 to 50% by weight. , more preferably about 0.5-20 wt.% based on the entire preparation.

The co-drug content of the combination agent of the present invention varies depending on the formulation form, and is typically from about 0.01 to 100% by weight, preferably from about 0.1 to 50% by weight, more preferably from about 0.1 to 50% by weight, 0.5 to 20 wt.% based on the entire preparation.

If the content of an additive such as a carrier or the like in the combination agent of the present invention varies depending on the form of the preparation, it is usually from about 1 to 99.99% by weight, preferably from about 10 to 90% by weight, based on the entire preparation.

If the compound of the present invention and the concomitant drug are prepared separately, the same content can be used.

Any amount of concomitant medication may be used as long as no side effects occur. The daily dosage of the concomitant drug varies depending on, and is not specifically limited to, the severity of the disease, age, sex, body weight, sensitivity of the subject, administration period, interval and nature, pharmacological characteristics, type of pharmaceutical drug, type of effective ingredient, etc. and the amount of drug, for example, in the case of oral administration, is usually from about 0.001 to 2000 mg, preferably from about 0.01 to 500 mg, more preferably from about 0.1 to 100 mg per 1 kg of body weight of the mammal and is usually administered with division from 1 to 4 times a day.

When the combination agent of the present invention is administered, the compound of the present invention and the concomitant drug may be administered simultaneously or may be administered alternately. If administered at intervals of time, the interval varies depending on the effective ingredient, dosage form and administration technique, and for example, if the concomitant drug is administered first, an example is a technique in which the compound of the present invention is administered over a period of time, equal to 1 minute to 3 days, preferably 10 minutes to 1 day, more preferably 15 minutes to 1 hour after administration of the concomitant drug. If the compound of the present invention is administered first, an example is a technique in which the concomitant drug is administered at a time interval of 1 minute to 1 day, preferably 10 minutes to 6 hours, more preferably 15 minutes to 1 hour after administration of the compound proposed in the present invention.

Examples

The present invention is explained in detail below with reference to examples, experimental examples and drug examples, which should not be considered limiting, and the present invention can be varied within the scope of the present invention.

In the following examples, room temperature typically means from about 10°C to about 35°C. Ratios given for mixed solvents are by volume unless otherwise noted. Percentage (%) means wt.% unless otherwise stated.

Column chromatography elution in the Examples was carried out as monitored by TLC (thin layer chromatography) unless otherwise stated. When observed by TLC, 60 F ₂₅₄ from Merck was used as the TLC plate, the solvent used as the elution solvent in column chromatography was used as the developing solvent, and a UV detector was used for detection. In silica gel column chromatography, NH means the use of aminopropylsilane-coupled silica gel and diol means the use of 3-(2,3-dihydroxypropoxy)propylsilane-coupled silica gel. In preparative HPLC (high performance liquid chromatography), the reference to C18 means the use of octadecyl-linked silica gel. The mixing ratio for the elution solvent, unless otherwise noted, is by volume.

For 1H NMR analysis, ACD/SpecManager (trade name) software etc. was used. The peaks of the hydroxy group, amino group, etc., which have a very weak proton peak, are not always described.

MS (Mass spectrum) was obtained using LC/MS (liquid chromatography-mass spectrometry). The technique used was the ESI (electrospray ionization) technique or the APCI technique (atmospheric pressure chemical ionization). Data means actual measured value (found). Although a molecular ion peak is usually observed, a fragment ion peak is sometimes observed. In the case of a salt, a molecular ion peak or a fragment ion peak in the free form is usually observed. Elemental analysis (analysis) values are described as a calculated value (calculated) and an actual measured value (found).

X-ray powder diffraction patterns were obtained using the characteristic Cu-Ka radiation of a Rigaku Ultima IV apparatus, and the characteristic peaks were described.

In the following examples, the following abbreviations are used.

MS: mass spectrum;

M: molar concentration;

CDCl ₃ : deuterochloroform;

DMSO-d ₆ : deuteromethyl sulfoxide;

1H NMR: proton nuclear magnetic resonance;

LC/MS: liquid chromatography - mass spectrometry;

ESI: electrospray ionization;

APCI: atmospheric pressure chemical ionization;

AIBN: 2,2'-azobis(isobutyronitrile);

Boc: tert-butoxycarbonyl;

CDI: 1,1'-carbonyldiimidazole;

CO ₂ : 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.

Examples 1 and example 2.

6-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1 K,2R)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl] -2,3dihydro-III-isoindol-1-one (compound of example 1).

6-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1 S,2S)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl] -2,3dihydro-III-isoindol-1-one (compound of example 2).

A) Tert-butyl 2-[3-(methoxycarbonyl)-4-methylbenzoyl]hydrazine-1-carboxylate.

The following reaction was carried out by dividing the described quantities into 5 reactions. Blend of methyl 5-bromo-2-methylbenzoate (42.0 g), tert-butylhydrazine carboxylate (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) were stirred under carbon monoxide (0.5 MPa) at 95°C for 5 hours. These five reaction mixtures were combined and filtered through celite and filtrate 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 brine, 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).

^1H NMR (300 MHz, DMSO-d6) δ 1.32-1.53 (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: [M-N] ^- 307.0.

B) Methyl 5-(hydrazinecarbonyl)-2-methylbenzoate hydrochloride.

To tert-butyl 2-[3-(methoxycarbonyl)-4-methylbenzoyl]hydrazine-1-carboxylate (45.7 g) was added a 4 M solution of cyclopentyl methyl ether hydrochloride (200 ml) at room temperature. The mixture was stirred at room temperature for 3 days. The precipitated solid was collected

- 28 045216 by filtration and dried to obtain the desired compound (36.3 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) 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.

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 4-methylbenzenesulfonyl chloride (56.5 g) was added to the mixture at room temperature. 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 sodium hydrogen carbonate, water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane/ethyl acetate to give the title compound (24.9 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) 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).

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) was added NBS (16.7 g) and AIBN (0.857 g) at room temperature. The mixture was stirred under an argon atmosphere at 90°C for 1 hour. 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 brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the mixture of residue and THF (500 ml) was added DIPEA (10.0 ml) at room temperature. Diethylphosphonate (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, water and saturated brine, 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 give the title compound (12.7 g).

1H NMR (300 MHz, CDC13) 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.

E) Tert-butyl-[(4-methylbenzene-1-sulfonyl)(pyridin-2-yl)methyl]carbamate.

To a mixture of sodium p-toluenesulfinate (25.0 g), tert-butylcarbamate (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 turned into a clear solution. Formic acid (7.16 ml) was added to the mixture 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).

1H NMR (300 MHz, DMSO-d6) δ 1.02-1.31 (9H, m), 2.39 (3H, s), 6.06 (1H, br, 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, J=10.5 Hz), 8.49-8.63 (1H, m).

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 α-hydroxyethyl)-4-methylthiazolium bromide (1.53 g) and THF (121 ml) were degassed and triethylamine (63.3 ml) was added dropwise to the mixture under argon at room temperature. The mixture was re-degassed and the mixture was stirred overnight under argon at 60°C. A saturated aqueous ammonium chloride solution was added to the mixture at room temperature, and the mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (9.81 g) as crude product. The resulting compound was used in the next step without further purification.

MS: [M+H-Boc]+ 214.0.

G) Tert-butyl-[(1RS,2RS)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl]carbamate.

Sodium borohydride (1, 72 g) at 0°C and the mixture was stirred overnight at room temperature. Water was added to the mixture at 0° C., and the mixture was stirred at room temperature for 1 hour and partitioned between water and ethyl acetate. The separated organic layer was washed with water and saturated brine. The combined aqueous layer was re-extracted with ethyl acetate and the extract was washed with water and saturated brine. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was solidified with ethyl acetate/hexane and the resulting solid was recrystallized from ethyl acetate/hexane to give the title compound (6.64 g).

¹ H 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.

H) 6-[5-(Difluoromethyl)-1,3,4-oxαdiαzol-2-yl]-2-[(1RS,2RS)-2-hydroxy-1,2-di(niridin-2-yl)ethyl ]2,3-dihydro-1H-isoindol-1-one.

Hydrogen bromide was added dropwise 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). (30% solution in acetic acid (about 5.1 M), 11.0 ml) at room temperature and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and azeotroped with toluene and toluene/ethanol to give a white solid (3.54 g). To a mixture of the resulting solid (2.83 g), methyl 2-(bromomethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzoate (2.15 g) and DMF (50 ml) was added dropwise to DIPEA (6.46 ml) at 0°C and the mixture was stirred at room temperature for 3 hours. Acetic acid (2.12 ml) was added dropwise to the mixture at room temperature and the mixture was stirred for overnight at room temperature. The mixture was poured into water at room temperature and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) and crystallized from ethyl acetate/diisopropyl ether to give 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.

I) 6-[5-(Difluoromethyl)-1,3,4-oxαdiαzol-2-yl]-2-[(1R,2R)-2-hydroxy-1,2-di(niridin-2-yl)ethyl ]-2,3dihydro-1H-isoindol-1-one (compound of Example 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 (compound of example 2).

6-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1 RS,2RS)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl] -2,3dihydro-1H-isoindol-1-one was separated into optical isomers using preparative SFC (column: CHIRALCEL OD-H, 20 mm i.d., 250 mm length, 5 µm, mobile phase: CO2/ethanol=770/230 (v/v)).

The longer retention time optical isomer fraction was concentrated under reduced pressure and the residue crystallized from hexane/ethyl acetate to give 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 minutes and then further heptane (30 ml) was added dropwise to the mixture at 50-75°C. The mixture was stirred at 50°C for 30 minutes and then at room temperature for 1 hour. 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(niridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (1.09 g, >99 % fu, retention time: 5.48 min (column analysis, column: CHIRALCEL OD-H, 4.6 mm internal diameter x 150 mm length, 5 µm, mobile phase: CO ₂ /ethanol = 770/230 (vol. ./about.))). The absolute stereochemical configuration of the compound was determined by X-ray diffraction.

^1H NMR (300 MHz, DMSO-d ₆ ) 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.

Analysis. Calculated for C ₂₃ H ₁₇ F ₂ N ₅ O ₃ : C, 61.47; N, 3.81; N, 15.58. Found: C, 61.68; N, 4.01; N, 15.80.

X-ray powder diffraction pattern of crystal (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°.

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 50-70°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 then at room temperature for 1 hour. The precipitated solid was collected by filtration and washed with diisopropyl ether to give 6-[5-(difluoromethyl)-1,3,4oxadiazol-2-yl]-2-[ (1 S,2S)-2-hydroxy-1,2-di(pyridin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (1.02 g, >99% e. e., retention time: 4.52 min (column analysis: column: CHIRALCEL OD-H, 4.6 mm internal diameter x 150 mm length, 5 µm, mobile phase: CO2/ethanol = 770/230 (v/v). ))).

- 30 045216

MS: [M+H]+ 450.1.

Example 3 and example 4.

6-[5-(Difluoromethyl)-1,3,4-oxadiαzol-2-yl]-2-[(1R,2R)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-( pyridin2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (compound of Example 3).

6-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(18.28)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-( pyridin2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (compound of Example 4).

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) were degassed and triethylamine (69.6 ml) was added dropwise to the mixture under argon at room temperature. The mixture was re-degassed and the mixture was stirred overnight under argon at 60°C. A saturated aqueous ammonium chloride solution was added to the mixture at 0°C, and the mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (7.14 g).

^1H 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).

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) was added dropwise potassium tri(sec-butyl)borohydride (1 M solution in THF, 23.9 ml) under argon at -78°C and the mixture was stirred at -78°C for 2 hours. Water (40 ml) was added to the mixture at -78°C and 2M sodium hydroxide aqueous solution (99 ml) and 30% hydrogen peroxide aqueous solution (20.3 ml) were added to the mixture while maintaining the internal temperature at 0°C or lower. The mixture was stirred at room temperature for 2 hours. Then, sodium thiosulfate pentahydrate (49.4 g) was dissolved in water (190 ml) and the resulting solution was 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 brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/heptane to give the title compound (5.62 g).

1H NMR (300 MHz, DMSO-d ₆ ) 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.

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 mret-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% solution in acetic acid, 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 resulting residue, DIPEA (13.5 ml) and DMF (29 ml) was added dropwise a solution obtained by dissolving methyl 2-(bromomethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol- 2-yl)benzoate (3.87 g) in DMF (10 ml) 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 brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane). The resulting 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 give 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.

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 (compound of Example 3) and 6-[5-(difluoromethyl)-1,3,4oxadiazol-2-yl]-2 - [(1 S,2S)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-dihydro-Schizoindol-1-one (compound example 4).

6-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1RS,2RS)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1(pyridine -2-yl)ethyl]-2,3-dihydro-III-isoindol-1-one (3.09 g) was separated into optical isomers using preparative HPLC (column: CHTRALCEL OD, 50 mm i.d. x 500 mm length, µm, mobile phase: hexane/ethanol=700/300 (v/v)).

The longer retention time optical isomer fraction was concentrated under reduced pressure and the residue crystallized from heptane/isopropyl acetate to give 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R, 2R)-2-(5-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2yl)ethyl]-2,3-dihydro-III-isoindol-1-one (1.35 g, 99% e.u., retention time: 9.16 min (analysis conditions, column: CHTRALCEL OD-H, 4.6 mm internal diameter x 250 mm length, 5 µm, mobile phase: hexane/ethanol = 700/300 (vol./ vol.)).The absolute stereochemical configuration of the compound was determined using x-ray diffraction.

^1H 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.

Analysis. Calculated for C ₂₃ H ₁₆ F ₃ 0 ₃ -0.3H ₂ 0: C, 58.43; N, 3.54; N, 14.81. Found: C, 58.53; N, 3.53; N,14.78.

Powder X-ray diffraction pattern of the crystal (diffraction angle 2Θ): 7.2, 11.3, 16.2, 19.2, 22.1, 22.7, 24.2, 26.5°.

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 give 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-dihydro1H-isoindol-1-one (1.37 g, 99% e. e., retention time: 7.35 min (analysis conditions, column: CHIRALCEL OD-H, 4.6 mm internal diameter x 250 mm length, 5 µm, mobile phase: hexane/ethanol = 700/300 (v/v). )).

MS: [M+H]+ 468.1.

Example 5 and example 6.

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

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

A) tert-Butyl-[(5-fluoropyridin-2-yl)(4-methylbenzene-1-sulfonyl)methyl]carbamate.

To a mixture of sodium p-toluenesulfinate (21.4 g), tert-butylcarbamate (9.36 g) and water (120 ml) was added a solution obtained by dissolving 5-fluoropyridine-2-carbaldehyde (10 g) in methanol (60 ml) , at room temperature. The mixture was stirred at room temperature for 30 minutes until the suspension turned into a clear solution. Formic acid (6.13 ml) was added to the mixture 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).

^1H NMR (300 MHz, DMSO-d6) δ 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).

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-fluoropyridin-2-carbaldehyde (4.18 g), 3- ethyl 5-(2-hydroxyethyl)-4-methylthiazolium bromide (1.68 g) and THF (134 ml) were degassed and triethylamine (69.6 ml) was added to the mixture under argon at room temperature. The mixture was re-degassed and the mixture was stirred overnight under argon at 60°C. A saturated aqueous ammonium chloride solution was added to the mixture at 0°C, and the mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and crystallized from hexane/ethyl acetate to give the title compound (7.68 g).

^1H NMR (300 MHz, DMSO-d ₆ ) 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.

C) tert-Butyl-[(1RS,2RS)-1,2-bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]carbamate.

Potassium tri(sec-butyl)borohydride was added dropwise to a mixture of tert-butyl-[1,2-bis(5-fluoropyridin-2-yl)-2-oxoethyl]carbamate (7.0 g) and THF (100 ml). (1 M solution in THF, 30.1 ml) under argon at -78°C and the mixture was stirred at -78°C for 2 hours. To the mixture was added water (20 ml) at -78°C and 2 M aqueous sodium hydroxide solution (100 ml), and 30% aqueous hydrogen peroxide solution (20.5 ml) was added thereto while maintaining the internal temperature at 0°C or lower. The mixture was stirred at room temperature for 4 hours. Sodium thiosulfate pentahydrate (49.7 g) was dissolved in water (200 ml), the resulting solution was 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 brine, 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 give 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.

D) 2-[(1RS,2RS)-1,2-Bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol2-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) dropwise hydrogen bromide (30% solution in acetic acid (about 5.1 M), 19.4 ml) was added 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. DIPEA ( 21.5 ml) at 0°C and the mixture was stirred overnight at room temperature. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from diisopropyl ether/ethyl acetate to give 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.

E) 2-[(1R,2R)-1,2-Bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol2-yl] -2,3-dihydro-1H-isoindol-1-one (compound of Example 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 (compound of Example 6).

2-[(1RS,2RS)-1,2-Bis(5-fluoropyridin-2-ul)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2yl]-2 ,3-dihydro-1H-isoindol-1-one (3.52 g) was separated into optical isomers using preparative HPLC (column: CHIRALCEL OD, 50 mm i.d. x 500 mm length, 20 µm, mobile phase: hexane/ethanol = 700 /300 (v/v)).

The longer retention time optical isomer fraction was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and the solution was 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 a 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-2yl]-2,3-dihydro-1H-isoindol-1-one (506 mg, 99% e.u., retention time: 7.77 min (assay conditions, column: CHIRALCEL OD-H, 4.6 mm inner diameter x 250 mm length, 5 µm, mobile phase: hexane/ethanol/diethylamine = 700/300/1 (v/v/v). The absolute stereochemical configuration of the compound was determined using radiography.

^1H NMR (300 MHz, DMSO-d6) δ 4.68 (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.

Analysis. Calculated for C2 ₃ H ₁₅ F ₄ N ₅ O ₃ -0.1H2O: C, 56.70; N, 3.14; N, 14.37. Found: C, 56.57; N, 3.21; N, 14.32.

Powder X-ray diffraction pattern of the crystal (diffraction angle 2θ): 6.1, 9.0, 15.7, 16.4, 18.1, 19.9, 21.7, 22.5, 24.8, 25.3°.

The optical isomer fraction with the shorter retention time was concentrated under reduced pressure, the residue was crystallized from diisopropyl ether/ethyl acetate, and the resulting solid was further recrystallized from heptane/isopropyl acetate and dried under reduced pressure to give a white solid (1.54 g). 100 mg of a White solid was recrystallized from pentane/isopropyl acetate to give 2-[(1S,2S)-1,2-bis(5-fluoropyridin-2-yl)-2hydroxyethyl]-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 (assay conditions, column: CHIRALCEL OD-H, 4.6 mm internal diameter x 250 mm length, 5 µm, mobile phase: hexane/ethanol/diethylamine = 700/300/1 (v/v/v)).

MS: [M+H]+ 486.1.

Example 7 and example 8.

6-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1R,2R)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-( pyridin2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (compound of Example 7).

6-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(18.28)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-( pyridin2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (compound of Example 8).

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-ethyl5-(2-hydroxyethyl)-4-methylthiazolium bromide (2.48 d) and THF (230 ml), 6-fluoropyridine-2-carbaldehyde (4.60 g) was added under argon at room temperature. The mixture was degassed and the gas was replaced with argon. Triethylamine (68.5 ml) was added dropwise to the mixture at 60°C, and the mixture was stirred overnight under argon at 60°C. 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 brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (11.4 g) as crude product. The resulting compound was used in the next step without further purification.

MS: [M+H]+ 332.1.

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) sodium borohydride (1.49 g) was added 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 brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized from toluene, collected by filtration and washed with diisopropyl ether. The resulting solid was recrystallized from hexane/ethyl acetate to give 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.

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) hydrogen bromide (30% solution in acetic acid (about 5.1 M), 21.4 ml) was added at room temperature. The mixture was stirred at room temperature for 30 minutes, concentrated under reduced pressure and subjected to azeotropic distillation with toluene. To a mixture of the resulting residue and DMF (50 ml), DIPEA (13.6 ml) was added dropwise at 0° C., and then a solution obtained by dissolving methyl-2-(bromomethyl)-5-(5-(difluoromethyl)1) was added to the mixture. ,3,4-oxadiazol-2-yl)benzoate (4.51 g) in DMF (10 ml), at 0°C. The mixture was stirred at 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 brine, 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 give the title compound (4.29 g).

^1H NMR (300 MHz, DMSO-d6) δ 4.68 (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.

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 (compound of Example 7) and 6-[5-(difluoromethyl)-1,3,4oxadiazol-2-yl]-2 - [(1S,2S)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2-yl)ethyl]-2,3-Dihydro-1Nisoindol-1-one (example compound 8).

6-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1 RS,2RS)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1 ( pyridin-2-yl)ethyl]-2,3-Dihydro-1H-isoindol-1-one (4.27 g) was separated into optical isomers using preparative HPLC (column: CHIRALPAK IA, 50 mm i.d. x 500 mm l., 20 µm, mobile phase: hexane/ethanol=200/800 (v/v)).

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-2yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (1.72 g, >99% e.u., retention time: 15.49 min (analysis conditions, column: CHIRALPAK IA, 4.6 mm internal diameter x 250 mm length, 5 µm, movable

- 34 045216 phase: hexane/ethanol=200/800(v/v)). The absolute stereochemical configuration of the compound was determined by X-ray diffraction.

^1H 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.

Analysis. Calculated for C ₂₃ H ₁₆ FN ₅ 0 ₃ -0.2H ₂ 0: C, 58.65; N, 3.51; N, 14.87. Found: C, 58.78; N, 3.75; N, 15.00.

Powder X-ray diffraction pattern of the crystal (diffraction angle 2Θ): 5.7, 12.1, 13.0, 16.7, 19.0, 20.2, 21.8, 24.2°.

The longer retention time optical isomer fraction 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-[(1S, 2S)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-(pyridin-2yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (1.84 g, 99% e.u., retention time: 19.48 min (analysis conditions, column: CHIRALPAK IA, 4.6 mm internal diameter x 250 mm length, 5 µm, mobile phase: hexane/ethanol = 200/800 (v/v). )).

MS: [M+H]+ 468.1.

Example 9.

2-[(1R,2S)-1-Cyclopropyl-2-(4-fluorophenyl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol2-yl]-2,3- Dihydro-1H-isoindol-1-one.

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 the resulting solution was added to the mixture at 0°C. The mixture was stirred overnight at room temperature. 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 brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 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.

B) tert-Butyl-[(1R)-1-cyclopropyl-2-(4-fluorophenyl)-2-oxoethyl]carbamate.

To a mixture of tert-butyl-{(III)-1-cyclopropyl-2-[methoxy(methyl)amino]-2-oxoethyl}carbamate (8.55 g) and THF (130 ml) was added magnesium 4-fluorophenyl bromide (2 M solution in diethyl ether, 42 ml) at 40°C. The mixture was stirred under a nitrogen atmosphere at 40°C for 1 hour. Magnesium 4-fluorophenyl bromide (2 M solution in diethyl ether, 3 ml) was added to the mixture at 40°C. The mixture was stirred under nitrogen atmosphere at 40°C for 30 minutes. The mixture was poured into 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 brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (7.80 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) 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.

C) tert-Butyl-[(1R,2S)-1-cyclopropyl-2-(4-fluorophenyl)-2-hydroxyethyl]carbamate.

Triisopropoxide was added 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 (1.09 g) 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 hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (7.79 g).

^1H 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 ).

D) (1 S,2R)-2-Amino-2-cyclopropyl-1-(4-fluorophenyl)ethane-1-olhydrobromide.

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 subjected to azeotropic distillation three times with toluene. The residue was suspended in ethyl acetate (10 ml) and diisopropyl ether (40 ml) and the resulting suspension was 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 give the title compound (4.29 g).

^1H 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.

E) 2-[(1R,2S)-1-Cyclopropyl-2-(4-fluorophenyl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol2-yl]-2, 3-dihydro-III-isoindol-1-one.

To a mixture of (1S,2R)-2-amino-2-cyclopropyl-1-(4-fluorophenyl)ethan-1-olhydrobromide (3.65 g), DIPEA (10.5 ml) and DMF (30 ml) dropwise a solution prepared by dissolving methyl 2-(bromomethyl)5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzoate (4.17 g) in DMF (12 ml) was added at room temperature . 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 separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), the resulting solid was dissolved in ethyl acetate and the solution was filtered to remove insoluble matter. The filtrate was concentrated under reduced pressure and the residue was recrystallized from heptane/ethyl acetate to give the title compound (3.75 g).

^1H 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.

Analysis. Calculated for C ₂₂ H ₁₈ F ₃ N ₃ O ₃ -0.1H ₂ O: C, 61.28; N, 4.25; N, 9.75. Found: C, 61.28; N, 4.48; N, 9.77.

Powder X-ray diffraction pattern of the crystal (diffraction angle 2θ): 6.9, 13.9, 16.9, 18.6, 20.2, 20.9, 22.2, 22.7, 25.6, 28.1°.

Example connections are shown in the following tables. MS in the tables means the actual measured value. Compounds of Examples 10-150 in the following tables were prepared using the methods described in the examples above or similar methods.

Table 1-1

EXAMPLE NAME GORAS Structure MS 1 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1K,2K)-2-hydroxy-1,2-di(pyridine in-2yl)ethyl]-2,3-dihydro-1H-isoindol-1-one R 450.2 2 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1S,2S)-2-hydroxy-1,2-di(pyride in-2yl)ethyl]-2,3-dihydro-1H-isoindol-1-one 450.2 3 6-[5-(difluoromethyl)-1,3,4-ocadiazol-2-yl]2-[(lR,2R)-2-(5-φτopπpiridin-2-yl)-2hydroxy-1-(pyridin-2 -yl)ethyl]-2,3- d ihydro-1 H-isoindol-1-one 468.1 4 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1S,28)-2-(5-fluoropyridin-2-yl)-2hydroxy-1-(pyridin-2-yl)ethyl]-2,3- d ihydro-1 H-isoindol-1-one 468.2 5 2-[(1K,2K)-1,2-bis(5-fluoropyridin-2-yl)-2hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4oxadiazol-2-yl]-2,3 -dihydro-1H-isoindol1-one 0 486.1 6 2-[(1S,2S)-1,2-bis(5-fluoropyride in-2-yl)-2hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4oxadiazol-2-yl]-2, 3-dihydro-1H-isoindol1-one R 4861

- 36 045216

7 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(lR,2R)-2-(6-φτopπpyridin-2-yl)-2hydroxy-l-(πopπridin-2-yl)ethyl]-2,3- d ihydro-1H-isoindol-1-one 468.2

Table 1-2

EXAMPLE NAME GORAS Structure MS 8 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1S,2S)-2-(6-fluoropyridin-2-yl)-2hydroxy-1-(pyridin-2-yl)ethyl]-2,3- d ihydro-1H-ISOINDOL-1-one 468.2 9 2-[(1R,2S)-1-cyclopropyl-2-(4-fluorophenyl)2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4oxadiazol-2-yl]-2,3- Dihydro-1H-isoindol1-one R 430.3 10 2-[(III,28)-1-cyclopropyl-2-(3-fluorophenyl)2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4oxadiazol-2-yl]-2,3-dihydro -1H-isoindol1-one 430.1 eleven 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]2-[(1E,28)-2-hydroxy-1,2-diphenylethyl]2,3-dihydro-1H-isoindol- 1-he R I TU/ \-:n 446.2 12 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1B,2B)-2-hydroxy-1,2-diphenylethyl] - 2,3-dihydro-1H-isoindol-1-one 448.2 13 6-[5-(difluoromethyl)-1,3,4 oxadiazol-2-yl] - 2-[(1S,2S)-2-hydroxy-1,2-diphenylethyl] - 2,3-dihydro-1H-isoindol-1-one Ηίγγζ,Ρ \_an 448.2 14 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1S,2B)-2-hydroxy-1,2-diphenylethyl]- 2,3-dihydro-1H-isoindol-1-one H'vU R | N \nON 448.2

Table 1-3

EXAMPLE NAME GORAS Structure MS 15 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(1B8,2B8)-2-hydroxy-2-(pyridin-2-yl)1-(3, 4,5-trifluorophenyl)ethyl]-2,3-dihydro1H-IZOIDOL-1-OI 503.1 16 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(1B8,28B)-2-(3-fluorophenyl)-1-(4fluorophenyl)-2-hydroxyethyl] -2,3-dihydro1H-IZOIDOL-1-OI F F'\-.he 484.2 17 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-{(1RS,28B)-2-hydroxy-2-phenyl-1-[6(trifluoromethyl)pyr idin- 3 -yl]ethyl } -2,3 - Dihydro-1H-isoindol-1-one 517.2

- 37 045216

18 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-{(lRS,2SR)-2-(4-φτopφenyl)-2-hydroxy1-[6-(trifluoromethyl) pyridin-3-yl]ethyl}2,3-dihydro-1H-isoindol-1-one F “Ή Hv 4 535.1 19 2-[(lRS,2SR)-2-cycloπpopyl-l-(4- fluorophenyl)-2-hydroxyethyl]-6-[5(d iforomethyl)-1,3,4-oxadiazol-2-yl]-2,3 dihydro-1H-IZOIDOL-1-one F Ν_ _κ 428.2 20 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(lRS,2SR)-l-(3-φτopφenyl)-2-hydroxy2-phenylethyl]-2,3 -dihydro-1H-isoindol-1one F N-K 466.1 21 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(lRS,2SR)-l-(3-φτopφenyl)-2-(4fluorophenyl)-2-hydroxyethyl] -2,3-d ihydro- 1 H-isoind ol-1-one F X F ⁰ X/ Nil-/ F ^Z 484.1

Table 1-4

EXAMPLE IUPAC NAME Structure MS 22 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(lRS,2SR)-2-(4-φτopφenyl)-2-hydroxy1-phenylethyl]-2,3 -dihydro-1H-isoindol-one F N-N 466.1 23 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(lRS,2SR)-2-(3-φτopφenyl)-2-hydroxy- 1-phenylethyl]-2,3-dihydro-1 H-isoin ol-1 - He F Ν-Ν °\/ V-OH F 466.1 24 6-[5-(d iforomethyl)-1,3,4-oxadiazol-2-yl] 2-{(1C8,2C8)-2-hydroxy-2-(pyridin-2-yl)1 - [3 - (trifluoromethyl)phenyl]ethyl}-2,3 dihydro-1H-isoindol-1-one F А ^h / \ 4 Qt ^F d' 517.0 25 2-[(lRS,2SR)-2-(4,4-diφopcyclocyclicyl)-2hydroxy-1-phenylethyl]-6-[5- (diforomethyl)-1,3,4-oxadiazol-2-yl]-2,3 dihydro-1H-isoindol-1-one F N-N 490.1 26 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-{(1C8,2C8)-2-hydroxy-2-(pyridin-2-yl)1 - [4- (trifluoromethyl)phenyl]ethyl}-2,3 dihydro-1H-isoindol-1-one 517.1 27 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(IRS,2SR)-1 -(2-fluorophenyl)-2-hydroxy2-phenylethyl] -2,3 -dihydro-1 H-isoin ol-1 - He F ⁰ X/ |Nhv/ ⁴ F 466.1 28 6-[5-(diforomethyl)-1,3,4'oxad iazol-2-yl] 2-[(lRS,2SR)-l-(2-φτopφenyl)-2-(4fluorophenyl)-2-hydroxyethyl ]-2,3-dihydro- 1 H-isoind ol-1-one ₽ n. _n °\7OHF ^? 484.1

- 38 045216

Table 1-5

EXAMPLE IUPAC NAME Structure MS 29 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(1C8.28K)-2-(2-fluorophenyl)-1-(4fluorophenyl)-2-hydroxyethyl] -2,3-dihydro1H-isoindol-1-one ΗνΛ-Ρ\·ΰΗ 484.1 thirty 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(lRS,2SR)-l-(4-f!uorophenyl)-2-rmjpoKCH2-(oxane-4 -yl)ethyl] -2,3 - dihydro-1Nisoindol-1-one O 474.2 31 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(lRS,2RS)-l-(2,4-diφτopφenyl)-2hydroxy-2-(pyrid in- 2-yl)ethyl]-2,3 dihydro-III-isoindol-1-one 485.1 32 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] - 2-[(W*,28*)-1-(2,4-difluorophenyl)-2-(4- fluorophenyl)-2-hydroxyethyl]-2,3-dihydro- lH-isoindol-1-one (enantiomer 1) ° О* ^{F rj} TTl al ^f V·on F ^Z 500.1 33 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(1B*,28*)-1-(2,4-difluorophenyl)-2-(4fluorophenyl)- 2-hydroxyethyl]-2,3-dihydro1H-isoindol-1-one (enantiomer 2) \_He G 500.1 34 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] - 2-[(W*,28*)-2-(4-fluorophenyl)-1-(6- fluoropyridin-3-yl)-2-hydroxyethyl]-2,3 dihydro-III-isoindol-1-one (enantiomer 1) )-1 OH 485.1 35 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] - 2-[(W*,28*)-2-(4-fluorophenyl)-1-(6- fluoropyridin-3-yl)-2-hydroxyethyl]-2,3 dihydro-III-isoindol-1-one (enantiomer 2) %%% R %' 485.1

Table 1-6

EXAMPLE IUPAC NAME Structure MS 36 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]2-[(1R*,2S*)-2-(4-fluorophenyl)-2-hydroxy-1 (pyridin-2- yl)ethyl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 1) F O I I )—an 467.1 37 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]2-[(1R*,2S*)-2-(4-fluorophenyl)-2-hydroxy-1 (pyridin-2- yl)ethyl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 2) 467.1 38 2-[(1R,2R)-1-cyclopropyl-2-hydroxy-2(pyridin-2-yl)ethyl]-6-[5-(difluoromethyl)- 1,3,4'oxadiazol-2-yl]-2,3-dihydro-III- isoindol-1-one 413.2

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39 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]2-{(1E8,2E8)-2-hydroxy-2-(pyridin-2-yl)1 - [2-(trifluoromethyl )phenyl]ethyl } -2,3 dihydro-1 H-isoindol-1 -one Q. 517.1 40 3-[(lRS,2SR)-1 -{6-[5-(difluoromethyl)-1,3,4oxadiazol-2-yl]-1-oxo-1,3-dihydro-2Nizoindol-2-yl} -2-hydroxy-2phenylethylbenzonitrile >4 vU b 471.2 41 4-[(1RS,2SR)-1 - {6-[5-(difluoromethyl)-1,3,4oxadiazol-2-yl]-1-oxo-1,3-dihydro-2Nizoindol-2-yl} -2-hydroxy-2phenylethylbenzonitrile Hour? 471.1 42 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]2-[(1 RS ,28E)-2-hydroxy-1-(1 -methyl-1Hpyrazol-4-yl)-2 -phenylethyl]-2,3-dihydro1H-isoindol-1-one ^si 452.1

Table 1-7

EXAMPLE IUPAC NAME Structure MS 43 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(1E8,28E)-2-(4-fluorophenyl)-2-hydroxy1 -(1 -methyl-1 N-pyrazol-4-yl)ethyl]-2,3dihydro-1H-isoindol-1-one 468.2 44 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(1E8,28E)-2-(6-ethoxypyridin-3-yl)-2hydroxy-1-phenylethyl] -2,3-dihydro-1Nisoindol-1-one Нррр В Г ^N,, '\ ^/ \— he N /“° n,s 493.1 45 6-[5-(d iforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(1E*,28*)-1-(4-fluorophenyl)-2-hydroxy2-phenylethyl]-2 ,3-dihydro-1H-isoindole-1one (enantiomer 1) 0\-.on 464.2 46 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(III*,28*)-1-(4-fluorophenyl)-2-hydroxy2-phenylethyl]-2 ,3-dihydro-1 H-isoindole-1 he (enantiomer 2) NRA 0 Il I ^N, \ 464.2 47 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(1E*,2E*)-2-hydroxy-1-phenyl-2(pyridin-2-yl) ethyl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 1) X? 449.2 48 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(1E*,2E*)-2-hydroxy-1-phenyl-2(pyridin-2-yl) ethyl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 2) 449.2 49 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(1E*,28*)-1-(4-fluorophenyl)-2-hydroxy2-(pyride in- 3-yl)ethyl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 2) HPud 467.1

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Table 1-8

EXAMPLE NAME GORAS Structure MS 50 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2R*)-1-(3,4-difluorophenyl)-2hydroxy-2-(pyridin-2-yl)ethyl]-2,3- Dihydro-1H-isoindol-1-one (enantiomer 1) 485.1 51 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2R*)-1-(3,4-difluorophenyl)-2hydroxy-2-(pyridin-2-yl)ethyl]-2,3- Dihydro-1H-isoindol-1-one (enantiomer 2) 485.1 52 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2S*)- 1-(4-fluorophenyl)-2-hydroxy-2(pyridin-3-yl)ethyl]-2,3-dihydro-1H- isoindol-1-one (enantiomer 1) ABOUT 467.1 53 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(lRS,2SR)-2-(3,4-difluorophenyl)-1-(6ethoxypyridin-3-yl)-2-hydroxyethyl]-2,3 dihydro-1H-isoindol-1-one SI, V 529.1 54 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2- {(1R*,2S*)-1 -(4-fluorophenyl)-2-hydroxy- 2-[6-(trifluoromethyl)pyr idin-3-yl]ethyl } - 2,3-dihydro-1H-isoindol-1-one (enantiomer - 533.1 1) 55 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2- {(1R*,2S*)-1 -(4-fluorophenyl)-2-hydroxy- 2-[6-(trifluoromethyl)pyr idin-3-yl]ethyl } - 2,3-dihydro-1H-isoindol-1-one (enantiomer 2) 533.2 56 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(lRS,2SR)-2-(3,4-difluorophenyl)-1-(6- fluoropyridin-3-yl)-2-hydroxyethyl]-2,3- d ihydro-1 H-isoindol-1-one Nyi d I 501.2

- 41 045216

Table 1-9

EXAMPLE NAME GORAS Structure MS 57 2-[(lR,2R)-1-cyclopropyl-2-(5- fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3d ihydro-1 H-isoindol-1-one \-0H 0 431.2 58 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1RS,2SR)-1 -(4-fluorophenyl)-2-(6fluoropyridin-3-yl)-2-hydroxyethyl]-2,3- d ihydro-1 H-isoindol-1-one F p 483.2 59 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2R*)-1 -(5-fluoropyride in-2-yl)-2hydroxy-2-(pyridin-2-yl)ethyl]-2,3dihydro-1H-isoindol-1-one ( enantiomer 1) F 468.2 60 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2R*)-1 -(5-fluoropyride in-2-yl)-2hydroxy-2-(pyridin-2-yl)ethyl]-2,3dihydro-1H-isoindol-1-one ( enantiomer 2) 468.2 61 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2S*)-2-(3-fluorophenyl)-2-hydroxy-1(pyridin-2-yl)ethyl]-2,3-dihydro-1H- isoindol-1-one (enantiomer 1) f^n-n 467.1 62 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]2-[(1R*,2S*)-2-(3-fluorophenyl)-2-hydroxy-1 (pyridin-2- yl)ethyl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 2) Χγ 467.1 63 2-[(1R,2S)-1-cyclopropyl-2-(6- fluoropyridin-3-yl)-2-hydroxyethyl]-6-[5(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3d ihydro-1 H-isoindol-1-one F N-N j-g 429.2

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Table 1-10

EXAMPLE IUPAC NAME Structure MS 64 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(1H,28)-2-(3-fluorophenyl)-2-hydroxy-1(oxan-4- yl)ethyl]-2,3-dihydro-1NISOINDOL-1-OH 472.2 65 2-[(1 RS ,2RS )-2-(5-chloropyrid in-2-yl)-1 - cyclopropyl-2-hydroxyethyl]-6-[5(d iforomethyl)-1,3,4-oxadiazol-2-yl] -2,3 - Dihydro-1H-isoindol-1-one pt P \-»he P 447.1 66 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(1H*,2H*)-1-(5-fluoropyridin-2-yl)-2-(6fluoropyridine -2-yl)-2-hydroxyethyl]-2,3dihydro-1H-isoindol-1-one (enantiomer 1) Ppp 486.1 67 6- [ 5 - (difluoromethyl)-1,3,4'oxad iazol-2-yl ] 2-[(lR*,2R*)-l-(5-φτopπpiridin-2-yl)-2-( 6fluoropyridin-2-yl)-2-hydroxyethyl]-2,3dihydro-1H-isoindol-1-one (enantiomer 2) F 486.1 68 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(1H*,28*)-2-(3-fluorophenyl)-2-hydroxy- 1 -(pyrimidin-2-yl)ethyl]-2,3 - dihydro-1Nisoindol-1-one (enantiomer 1) 468.1 69 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(1H*,28*)-2-(3-fluorophenyl)-2-hydroxy- 1 -(pyrimidin-2-yl)ethyl]-2,3 - dihydro-1Nisoindol-1-one (enantiomer 2) 468.2 70 2-[(1H*,28*)-2-(3-chlorophenyl)-2-hydroxy-1(oxan-4-yl)ethyl]-6-[5-(difluoromethyl)-1,3,4oxadiazol-2 -yl]-2,3-dihydro-1 H-isoindol1-one (enantiomer 1) ρ a 488.1

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Table 1-11

EXAMPLE NAME GORAS Structure MS 71 2-[(1R*,2S*)-2-(3-chlorophenyl)-2-hydroxy-1 (oxan-4-yl)ethyl]-6-[5-(difluoromethyl)-1,3,4oxadiazol-2 -yl]-2,3 - dihydro-1 H-isoin ol1-one (enantiomer 2) He Y 488.1 72 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]2-[(1R.2S)-2-(4-fluorophenyl)-2-hydroxy-1(oxan-4-yl )ethyl]-2,3-dihydro-1Nisoindol-1-one 472.2 73 2-[(1R*,2R*)-1-cyclopropyl-2-hydroxy-2(pyrimidin-2-yl)ethyl]-6-[5-(difluoromethyl)1,3,4-oxadiazol-2-yl] -2,3-dihydro-1Nisoindol-1-one (enantiomer 1) O 414.2 74 2-[(1R*,2R*)-1-cyclopropyl-2-hydroxy-2(pyrimidin-2-yl)ethyl]-6-[5-(difluoromethyl)1,3,4-oxadiazol-2-yl] -2,3-dihydro-1Nisoindol-1-one (enantiomer 2) O 414.2 75 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2R*)-1 -(6-fluoropyride in-2-yl)-2hydroxy-2-(pyridin-2-yl)ethyl]-2,3dihydro-1H-isoindol-1-one ( enantiomer 1) F ^h -N η 468.2 76 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2R*)-1 -(6-fluoropyride in-2-yl)-2hydroxy-2-(pyridin-2-yl)ethyl]-2,3dihydro-1H-isoindol-1-one ( enantiomer 2) F ⁴ -Ν _o /AF 468.2 77 2-{(1R*,2S*)-1-cyclopropyl-2-hydroxy-2[6-(trifluoromethyl)pyridin-3-yl]ethyl}-6-[5(difluoromethyl)-1,3,4-oxadiazole -2-yl]-2,3dihydro-1H-isoindol-1-one (enantiomer 1) 479.1

- 44 045216

Table 1-12

EXAMPLE NAME GORAS Structure MS 78 2-{(1R*,2S*)-1-cyclopropyl-2-hydroxy-2[6-(trifluoromethyl)pyridin-3-yl]ethyl} -6-[5(difluoromethyl)-1,3,4-oxadiazole -2-yl]-2,3dihydro-1H-isoindol-1-one (enantiomer 2) F AU 479.1 79 2-[(1R*,2R*)-1-cyclopropyl-2-(6fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5(difluoromethyl)-1,3,4-oxadiazol-2-yl] -2,3- Dihydro-1H-isoindol-1-one (enantiomer 1) F^-N F 431.2 80 2-[(1R*,2R*)-1-cyclopropyl-2-(6fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5- (difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3dihydro-1H-isoindol-1-one (enantiomer 2) AU 0 431.2 81 2-[(1 RS ,2RS)-1 -(4,4-difluorocyclohexyl)-2hydroxy-2-(pyridin-2-yl)ethyl]-6-[5(difluoromethyl)-1,3,4-oxadiazol- 2-yl]-2,3- d ihydro-1 H-isoindol-1-one F N-K A 491.1 82 2-[(1RS,2SR)-1 -(4,4-difluorocyclohexyl)-2(6-fluoropyridin-3-yl)-2-hydroxyethyl]-6[5-(methyl difluoro)-1,3,4- oxadiazol-2-yl] 2,3-dihydro-1H-isoindol-1-one - 507.2 83 2-[(1R*,2S*)-2-(4-chlorophenyl)-2-hydroxy-1 (oxan-4-yl)ethyl]-6-[5-(difluoromethyl)-1,3,4oxadiazol-2 -yl]-2,3 - dihydro-1 H-isoin ol1-one (enantiomer 1) Fn- ^N A-P P 488.1 84 2-[(1R*,2S*)-2-(4-chlorophenyl)-2-hydroxy-1 (oxan-4-yl)ethyl]-6-[5-(difluoromethyl)-1,3,4oxadiazol-2 -yl]-2,3 - dihydro-1 H-isoin ol1-one (enantiomer 2) F 488.2

- 45 045216

Table 1-13

EXAMPLE NAME GORAS Structure MS 85 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2S*)-2-(3,4-difluorophenyl)-2hydroxy-1-(pyrazin-2-yl)ethyl]-2,3- Dihydro-1H-isoindol-1-one (enantiomer 1) CH 486.1 86 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2S*)-2-(3,4-difluorophenyl)-2hydroxy-1-(pyrazin-2-yl)ethyl]-2,3- Dihydro-1H-isoindol-1-one (enantiomer 2) ^f N- ο OH 486.1 87 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2S*)-2-(3,4-difluorophenyl)-2hydroxy-1-(oxan-4-yl)ethyl]-2,3-dihydro1H-isoindol-1-one (enantiomer 1) 490.2 88 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2S*)-2-(3,4-difluorophenyl)-2hydroxy-1-(oxan-4-yl)ethyl]-2,3-dihydro1H-ISOINDOL-1-OI (enantiomer 2) 490.1 89 6-[5-(difluoromethyl)-1,3,4'oxadiazol-2-yl]- 2-[(1R*,2S*)-2-(3-fluorophenyl)-1-(6fluoropyridin-2-yl)-2-hydroxyethyl]-2,3- Dihydro-1H-isoindol-1-one (enantiomer 1) \-iQH 485.1 90 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2S*)-2-(3-fluorophenyl)-1-(6fluoropyridin-2-yl)-2-hydroxyethyl]-2,3- Dihydro-1H-isoindol-1-one (enantiomer 2) 485.0 91 2-[(1R*,2S*)-2-(3-chloroenyl)-2-hydroxy-1(pyrazin-2-yl)ethyl]-6-[5-(d fluoromethyl)1,3,4- Oxadiazol-2-yl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 1) HVZ p II Г ^h,, \ \-rCH Cl 484.1

- 46 045216

Table 1-14

EXAMPLE NAME GORAS Structure MS 92 2-[(1R*,2S*)-2-(3-chlorophenyl)-2-hydroxy-1 (pyrazin-2-yl)ethyl]-6-[5-(difluoromethyl)1,3,4-oxadiazol- 2-yl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 2) ngo · I o a 484.1 93 2-[(1C8.28K)-2-(4-chlorophenyl)-2-hydroxy1-(pyrimidin-2-yl)ethyl]-6-[5- (difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3d ihydro-1H-isoindol-1-one k;- = O 484.1 94 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2S*)-2-(3,4-difluorophenyl)-2hydroxy-1-(pyrimidin-2-yl)ethyl]-2,3- Dihydro-1H-isoindol-1-one (enantiomer 1) s About me? 486.1 95 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2S*)-2-(3,4-difluorophenyl)-2hydroxy-1-(pyrimidin-2-yl)ethyl]-2,3- Dihydro-1H-isoindol-1-one (enantiomer 2) ; ABOUT 486.1 96 2-[(1R*,2S*)-2-(4-chlorophenyl)-2-hydroxy-1 (pyrazin-2-yl)ethyl]-6-[5-(difluoromethyl)1,3,4-oxadiazol- 2-yl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 1) ^F lj X// a 484.1 97 2-[(1R*,2S*)-2-(4-chlorophenyl)-2-hydroxy-1(pyrazin-2-yl)ethyl]-6-[5-(d fluoromethyl)1,3,4-oxadiazole -2-yl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 2) 484.1 98 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2S*)-2-(4-fluorophenyl)-2-hydroxy-1(pyrazin-2-yl)ethyl]-2,3-dihydro-1H- isoindol-1-one (enantiomer 1) 468.2

- 47 045216

Table 1-15

EXAMPLE IUPAC NAME Structure MS 99 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl] 2-[(III*,28*)-2-(4-fluorophenyl)-2-hydroxy-1(pyrazin-2 -yl)ethyl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 2) 468.2 100 6-[5-(difluoromethyl)-1,3,4'oxad iazol-2-yl] - 2-[(1R*,2S*)-2-(3-fluorophenyl)-2-hydroxy-1(pyrazin-2-yl)ethyl]-2,3-dihydro-1H- isoindol-1-one (enantiomer 1) 468.2 101 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(III*,28*)-2-(3-fluorophenyl)-2-hydroxy-1(pyrazin- 2-yl)ethyl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 2) A/W P % 468.2 102 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(III*,28*)-2-hydroxy-2-phenyl-1(pyridin-2-yl) ethyl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 1) 449.2 103 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(1B*,28*)-2-hydroxy-2-phenyl-1(pyridin-2-yl) ethyl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 2) % 449.2 104 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-{(1R* ^*)-2-hydroxy-1 -(pyridin-2-yl)2-[5 -(trifluoromethyl)pyride in-2-yl]ethyl } 2,3-dihydro-1H-isoindol-1-one (enantiomer 1) HXU р γ 518.2 105 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-{(1R* ^*)-2-hydroxy-1 -(pyridin-2-yl)2-[5 -(trifluoromethyl)pyride in-2-yl]ethyl} 2,3-dihydro-III-isoindol-1-one (enantiomer 2) 518.2

- 48 045216

Table 1-16

EXAMPLE IUPAC NAME Structure MS 106 2-[(1C8.28K)-2-(3-chloro-5-fluorophenyl)-2hydroxy-1-(oxan-4-yl)ethyl]-6-[5- (difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3 dihydro-III-isoindol-1-one 506.1 107 2-[(1C8.28K)-2-(3-chloro-4-fluorophenyl)-2hydroxy-1-(oxan-4-yl)ethyl]-6-[5- (difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3 dihydro-III-isoindol-1-one AG 506.2 108 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2[(1R*,2S*)-2-(3,4-difluorophenyl)-2-hydroxy1 -(azine pyride 3-yl)ethyl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 1) [1 I ^4, \y. He 486.1 109 6-[5-(difluoromethyl)-1 _g 3,4-oxadiazol-2-yl]-2[(1R*,2S*)-2-(3,4-difluorophenyl)-2-hydroxy1 -(azine pyride 3-yl)ethyl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 2) 486.1 BY 2-[(III*,28*)-2-(4-chlorophenyl)-2-hydroxy-1(pyridazin-3-yl)ethyl]-6-[5-(d fluoromethyl)1,3,4-oxadiazole -2-yl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 1) 484.1 111 2-[(1K*,28*)-2-(4-chlorophenyl)-2-hydroxy-1(pyridazin-3-yl)ethyl]-6-[5-(difluoromethyl)1,3,4-oxadiazol- 2-yl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 2) A' 484.1 112 2-[(1R*,2R*)-2-(5-chloropyridin-2-yl)-2hydroxy-1-(pyridin-2-yl)ethyl]-6-[5(methyl difluoro)-1,3 ,4-oxadiazol-2-yl] -2,3 - Dihydro-III-isoindol-1-one (enantiomer 1) R 484.1

Table 1-17

EXAMPLE IUPAC NAME Structure MS 113 2-[(1R*,2R*)-2-(5-chloropyridin-2-yl)-2hydroxy-1-(pyridin-2-yl)ethyl] -6-[5(methyl difluoro)-1,3 ,4-oxadiazol-2-yl] -2,3 - Dihydro-III-isoindol-1-one (enantiomer 2) 484.1 114 2-[(1B*,2B*)-2-(6-chloropyridin-2-yl)-2hydroxy-1 -(pyridin-2-yl)ethyl] -6-[5(methyl difluoro)-1,3 ,4-oxadiazol-2-yl] -2,3 - Dihydro-III-isoindol-1-one (enantiomer 2) A 484.1 115 2-[(1B*,2B*)-2-(6-chloropyridin-2-yl)-2hydroxy-1 -(pyridin-2-yl)ethyl] -6-[5(methyl difluoro)-1,3 ,4-oxadiazol-2-yl] -2,3 - Dihydro-III-isoindol-1-one (enantiomer 1) AG a 484.0

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116 6- [ 5 - (difluoromethyl)-1,3,4'oxad iazol-2-yl] 2- {(IRS ,28E)-2-hydroxy-1 -(oxan-4-yl)-2[3 -(trifluoromethyl)phenyl]ethyl}-2,3dihydro-1H-IZOIDOL-1-one 522.1 117 2-[( 1R*,2R*)-1,2-bis(6-fluoropyridin-2-yl)2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4oxadiazol-2-yl]- 2,3-dihydro-1H-isoindol1-one (enantiomer 1) F 486.1 118 2-[( 1R*,2R*)-1,2-bis(6-fluoropyridin-2-yl)2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4oxadiazol-2-yl]- 2,3-dihydro-1H-isoindol1-one (enantiomer 2) \mON 486.1 119 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] - 2-{(1R*,2R*)-2-hydroxy-1 -(pyridin-2-yl)2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}- 2,3-dihydro-1H-isoindol-1-one (enantiomer 1) Z N F F 518.1

Table 1-18

EXAMPLE IUPAC NAME Structure MS 120 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] - 2-{(1R*,2E*)-2-hydroxy-1 -(pyridin-2-yl)2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}- 2,3-dihydro-1H-isoindol-1-one (enantiomer 2) i 1 1 ^N '\ \-on Ζ Ν K F 518.1 121 2-[(1E*,28*)-2-(3-chlorophenyl)-2-hydroxy-1(pyridazin-3-yl)ethyl]-6-[5-(difluoromethyl)1,3,4-oxadiazol- 2-yl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 1) WITH 484.1 122 2-[(1E*,28*)-2-(3-chlorophenyl)-2-hydroxy-1(pyridazin-3-yl)ethyl]-6-[5-(d fluoromethyl)1,3,4-oxadiazole -2-yl]-2,3-dihydro-1Nisoindol-1-one (enantiomer 2) yum-ya Voh α 484.1 123 2-[(1E*,2E*)-2-(4-chloropyridin-2-yl)-2hydroxy-1 -(pyridin-2-yl)ethyl]-6-[5(d iforomethyl)-1, 3,4-oxadiazol-2-yl] -2,3 - Dihydro-III-isoindol-1-one (enantiomer 1) F _ο /^χ У 1 i ^Ν Λ V.OH α—-Ζ ν 484.1 124 2-[(1E*,2E*)-2-(4-chloropyridin-2-yl)-2hydroxy-1 -(pyridin-2-yl)ethyl]-6-[5(d iforomethyl)-1, 3,4-oxadiazol-2-yl]-2,3 dihydro-III-isoindol-1-one (enantiomer 2) >4'^7 I ^F TG ^Ν, \ <^-^2 OH α—Ζ \ 484.1 125 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(1E*,2E*)-2-(5-fluoropyridin-2-yl)-1-(6fluoropyridine -2-yl)-2-hydroxyethyl]-2,3dihydro-1H-isoindol-1-one (enantiomer 1) M. HE R 486.1 126 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]2-[(1E*,2E*)-2-(5-fluoropyridin-2-yl)-1-(6fluoropyridin-2 -yl)-2-hydroxyethyl]-2,3dihydro-1H-isoindol-1-one (enantiomer 2) _Nyin Ya R 486.1

- 50 045216

Table 1-19

EXAMPLE NAME GORAS Structure MS 127 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2S*)-2-hydroxy-2-phenyl-1(pyrazin-2-yl)ethyl]-2,3-dihydro-1H- isoindol-1-one (enantiomer 1) ΆΕμ Р ^F Т ILn·/ ' V-ι he 450.1 128 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2S*)-2-hydroxy-2-phenyl-1(pyrazin-2-yl)ethyl]-2,3-dihydro-1H- isoindol-1-one (enantiomer 2) 450.1 129 2- [(1R* ,2R* )-2-(6-chloropyrid in-2-yl)-1 ring oppropyl-2-hydroxyethyl] -6- [5- (difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3dihydro-1H-isoindol-1-one (enantiomer 1) A 447.1 130 2- [(1R* ,2R* )-2-(6-chloropyrid in-2-yl)-1 ring oppropyl-2-hydroxyethyl] -6- [5- (difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3- Dihydro-1H-isoindol-1-one (enantiomer 2) F ν-ν o A 447.1 131 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2S*)-1 -(4-fluorophenyl)-2-(6fluoropyridin-3-yl)-2-hydroxyethyl]-2,3- Dihydro-1H-isoindol-1-one (enantiomer 1) Н VM р 1 1 ^{N ,j,} \ \-сн р 485.1 132 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1R*,2S*)-1 -(4-fluorophenyl)-2-(6fluoropyridin-3-yl)-2-hydroxyethyl]-2,3- Dihydro-1H-isoindol-1-one (enantiomer 2) \-1Н F ^Z 485.1 133 2-[(lRS,2SR)-2-(3-chlorophenyl)-2-hydroxy1-(pyrimidin-2-yl)ethyl]-6-[5- (difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3d ihydro-1H-isoindol-1-one \-iOM A 484.1

Table 1-20

EXAMPLE NAME GORAS Structure MS 134 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl] 2-[(1B8.28B)-2-(4-fluorophenyl)-2-hydroxy1-(pyrimidin-2-yl) ethyl] -2,3 - dihydro-1NISOINDOL-1-OH OH, X 468.2 135 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]2-[(1RS,28B)-2-hydroxy-1,2-di(pyridin-2yl)ethyl]-2, 3-dihydro-1H-isoindol-1-one H-uv p 450.1 136 6-[5-(difluoromethyl)-1,3,4'oxad iazol-2-yl] 2-[(1C8,2C8)-2-(3-fluorophenyl)-2-hydroxy1 -(pyrimidin-2-yl )ethyl]-2,3-dihydro-1Nisoindol-1-one 468.2 137 2-[( 1 R,2R)-1 -cyclopropyl-2-(4fluorophenyl)-2-hydroxyethyl]-6-[5(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3 Dihydro-1H-isoindol-1-one 430.2 138 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl] 2-[( 1 SR,2SR)-1 -(4-fluorophenyl)-2-hydroxy2-phenylethyl]-2,3 -dihydro-1H-isoindol-1one 446.1

- 51 045216

139 6-[5-(diforomethyl)-1,3,4-oxadiazol-2-yl] 2-[(1E8,2E8)-2-(2-fluorophenyl)-2-hydroxy1-phenylethyl] -2,3 -dihydro-1 H-isoindole-1 he F ^N 'N ⁰ x 7 Ζ ⁴ */ \. _(| he 466.1 140 2-[(1 RS ,2RS )-2-cyclopropyl-1 -(4- fluorophenyl)-2-hydroxyethyl]-6-[5- (diforomethyl)-1,3,4-oxadiazol-2-yl] -2,3 - Dihydro-1H-isoindol-1-one 430.2

Table 1-21

EXAMPLE IUPAC NAME Structure MS 141 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]2-[(1E8,2E8)-2-(4-fluorophenyl)-2-hydroxy- 1 -(pyridin-2-yl)ethyl]-2,3 - dihydro-1Nisoindol-1-one ΆΑ/Ζ \.„ohm 467.1 142 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]2-{(1RS,2RS)-1-(4-fluorophenyl)-2-hydroxy- 2-[6-(trifluoromethyl)pyridin-3-yl]ethyl } - 2,3-dihydro-1H-isoindol-1-one 533.1 143 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1RS,2RS)-2-hydroxy-2-phenyl-1(pyridin-2-yl)ethyl]-2,3-dihydro-1Nisoindol-1-one Нpu p A 449.2 144 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]2-[(1E8,28E)-1-(5-fluoropyridin-2-yl)-2hydroxy-2-(pyridin-2 -yl)ethyl]-2,3- d ihydro-1 H-isoindol-1-one >.I OH oh 468.2 145 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]2-[(1 SR,2SR)-2-(3-τopφenyl)-2-hydroxyl -(pyridin-2-yl) ethyl]-2,3-dihydro-1Nisoindol-1-one 467.1 146 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1 SR,2SR)-1 -(2,4-difluorophenyl)-2-(4fluorophenyl)-2-hydroxyethyl]-2,3-dihydro- АУм d ιϊ Γ ^F OH f' 500.1 1 H-isoindol-1-one 147 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]2-[(1C8,2C8)-2-(3-fluorophenyl)-1-(4fluorophenyl)-2-hydroxyethyl]-2 ,3-dihydro- 1 H-isoindol-1-one F ^FN -N a / ¾ I I ViOH F 484.1

- 52 045216

Table 1-22

EXAMPLE NAME GORAS Structure MS 148 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]- 2-[(1 R,2R)-2-(4-φτopφenyl)-2-hydroxy-1 (oxan-4-yl)ethyl]-2,3 - dihydro-1Nisoindol-1-one ^F 472.2 149 6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]2-[(1R,2R)-2-(3-fluorophenyl)-2-hydroxy-1(oxan-4-yl )ethyl]-2,3-dihydro-1Nisoindol-1-one CDU F 472.2 150 2-[(III,28)-1-cyclopropyl-2-(5- fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2,3d ihydro- 1H-IZOIDOL-1-one F ^N -N _o U JL ^N, “ 431.2

Experimental Example 1: HDAC6 Enzyme Inhibition Study.

HDAC6 enzyme, obtained by transduction of the full-length HDAC6 gene into Sf-9 insect cells and purified on a GST affinity column, was purchased from SignalChem. Using this enzyme, the inhibitory activity of the compound of the present invention against the HDAC6 enzyme was examined. Enzymes were used after preservation at -70°C. The inhibitory activity of the compound of the present invention against the HDAC6 enzyme was determined using the HDAC-Glo™ I/II Assay kit (Promega) according to the following experimental procedure. The test compound was diluted with assay buffer (24 mM Tris-HCl (pH 7.5), 1 mM MgCl ₂ , 0.35 mM KCl, 135 mM NaCl, 0.6 mM glutathione, 0.01% Tween-20), and added 2 µl into a 384-well plate. Then, 4 μL of HDAC6 enzyme solution diluted in assay buffer was added and the plate was incubated at room temperature for 60 min. After incubation of HDAC, a substrate-developer solution was prepared according to the Promega protocol, added to the assay kit and 2 μl was added to a 384-well plate and the enzyme reaction was started. After reacting at room temperature for 20 min, the luminescence intensity was determined using an Envision plate reader (PerkinElmer). The inhibitory activity of each example compound was calculated as a relative activity value, assuming that the luminescence intensity in wells without enzyme corresponds to 100% inhibition. The results are shown in table. 2-1 and 2-2.

Table 2-1

Example p no. Inhibition degree HDAC6 (%) (10 µM) Example No. HDAC6 inhibition rate (%) (10 µM) Example No. HDAC6 inhibition rate (%) (10 µM) 1 101 31 97 61 100 2 100 32 99 62 100 3 101 33 100 63 100 4 100 34 100 64 100 5 99 35 100 65 98 6 100 36 101 66 100 7 102 37 100 67 99 8 99 38 100 68 101 9 100 39 101 69 100

- 53 045216

10 100 40 100 70 101 eleven 99 41 100 71 101 12 100 42 100 72 100 13 99 43 100 73 100 14 100 44 100 74 96 15 99 45 100 75 99 16 99 46 100 76 100 17 100 47 99 77 100 18 99 48 100 78 99 19 99 49 99 79 99 20 100 50 99 80 100 21 100 51 99 81 100 22 99 52 100 82 100 23 100 53 100 83 101 24 99 54 100 84 100 25 100 55 98 85 100 26 99 56 100 86 100 27 101 57 100 87 100 28 99 58 100 88 99 29 99 59 100 89 100 thirty 99 60 99 90 100

Table 2-2

Example No. HDAC6 inhibition rate (%) (10 µM) Example No. Inhibition degree HDAC6 (%) (10 µM) 91 100 121 101 92 100 122 100 93 100 123 101 94 100 124 100 95 99 125 101 96 100 126 101 97 99 127 99 98 100 128 99 99 100 129 100 100 100 130 98 101 100 131 99 102 100 132 99 103 100 133 100 104 100 134 101 105 99 135 99 106 100 136 99 107 101 137 100 108 100 138 99 109 100 139 100 BY 100 140 98 111 99 141 99 112 99 142 100 113 100 143 100 114 99 144 100

- 54 045216

115 100 145 99 116 101 146 95 117 101 147 99 118 102 148 101 119 101 149 100 120 101 150 99

As can be seen from table. 2-1 and 2-2, the compound of the present invention has excellent HDAC6 inhibitory activity.

Experimental example 2. Increase in the content of acetylated tubulin in the brain.

The drug was suspended in a mixture with 0.5% methylcellulose to prepare an administration suspension having the concentration shown in table. 3. The suspension was orally administered to male C57BL/6J mice aged 8 to 10 weeks and after the time indicated in the table. 3, the brain was removed and the hippocampus was isolated. The hippocampus was homogenized in RIPA extract (FUJIFILM Wako Pure Chemical Corporation) to which a protease inhibitor (Thermo Fisher Scientific) and a phosphatase inhibitor (Thermo Fisher Scientific) were added and centrifuged at 15,000 g for 15 min to obtain a protein extract. The content of acetylated tubulin and total tubulin in the extract was determined by the following ELISA. Anti-tubulin antibodies (Sigma) were immobilized onto a 96-well plate (Microlite2+, Thermo Fisher Scientific) and the plate was 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 the reaction was carried out at 37°C for 2 hours. The plate was washed four times with PBS-T and the above protein extract was added to capture tubulin on antibodies. The plate was kept at 37°C for 2 h and washed four times with PBS-T. Anti-acetylated tubulin antibodies or anti-total tubulin antibodies (Cell Signaling Technology) were all diluted in add-on blocking buffer and reacted at 37°C for 1 hour. The plate was then washed four times with PBS-T and reacted using anti-mouse HPR (Cell Signaling Technology) at 37°C for 30 minutes. The plate was washed, HRP substrate was added, and the luminescence intensity was determined using a plate reader. The contents of acetylated tubulin and total tubulin were quantified by logistic dependence based on serial dilution using mouse hippocampal tissue extract, and the ratio of the amount of acetylated tubulin to the amount of total tubulin was calculated and determined as the degree of relative acetylation of tubulin. The study was conducted using the SAS 8 system. After using the Fisher's test for the vehicle group and the drug group, the significance of the differences between the two groups was analyzed using the Student's t test or Welsh test (indicated as *p< .05, ** p<0.01, n.s.: not significant). The graph shows the average values ± standard error. The results are shown in Fig. 1-3. For mice administered the compound of Example 1, 3 or 5, a significant increase in the degree of tubulin acetylation was found.

Table 3

Example No. concentration (mg/ml) Dose (mg/kg) Time (hours) after administration of test compound Age of C57BL/6J mice Number of mice C57BL/6Jnum ber 1 0.01,0.1, 1, 10 0.1, 1, 10, 100 4 9 6 3 0.01,0.1, 1, 10 0.1, 1, yu, 100 4 8 6 5 0.03, 0.1 0.3, 1 4 10 6

Experimental Example 3 Effect on improving cognition in a mouse model of neurodegenerative disease.

The drug was suspended in a mixture with 0.5% methylcellulose to prepare a suspension for administration. The suspension was repeatedly administered to 6-week-old male P301S mutant human tau (4R1N) Tg mice once daily for 3 months, and a novel object recognition test was performed as follows. The study included the experience of contact with an object on the first day and the experience of storing a familiar object and a new object in memory on the second day. The drug was administered to mice 1 hour before the experiment on both days. For experience in mouse recognition

- 55 045216 was placed in a test box (30x30x25 cm), in which two identical objects were placed and the frequency of contacts and the duration of contacts with objects for 5 minutes were measured under illumination of 50 lux. In the present invention, perception means the behavior of sniffing an object (Sniffing). The next day, one of the objects was replaced by a new object, and the frequency of contacts and duration of contacts with each object were measured for 5 minutes. Novelty Discrimination Index (NDI), as an index of cognitive function by the expression (frequency of contact with a new object)/(duration of contact with a new object + duration of contact with a familiar object)%. The study was performed using the SAS 8 system. After using Fisher's test for vehicle administration in wild-type animals and vehicle administration in Tg animals, the significance of the differences between the two groups was analyzed using Student's t test or Welsh test (indicated as **p< 0.01). In addition, Bartlett's test for homogeneity of variance was used for vehicle administration or drug administration in Tg animals, and the significance of differences was analyzed using a one-tailed Williams test (indicated as ## p < 0.005). Each group included 14 or 15 mice. The graph shows the average values ± standard error. The results are shown in Fig. 4 and 5.

Experimental Example 4: Rat Toxicity Study.

A two-week rat toxicity study was conducted using the following test system.

Test system.

Rats, Sprague-Dawley [Crl:CD(SD)].

Administration method/period.

Oral administration, which is the administration mode for clinical use, is selected as the route of administration, and the administration period is 2 weeks. The dosing frequency is once daily (7 days per week), which is typically used in multiple dose studies. For oral administration to rodents, the administration method is general feeding through a gastric tube. The dose is 5 ml/kg and is administered by gastric tube using a flexible gastric tube (08:00 to 15:00). Animals in the control group were similarly administered the diluent. The dose for each animal is calculated based on the most recent body weight.

Thinner and preparation method.

0.5% w/v The methylcellulose solution and the required amount of methylcellulose (METOLOSE SM-100) are weighed out and gradually added to the appropriate amount of warm water for injection while stirring to disperse the methylcellulose. It is cooled until the methylcellulose is dissolved and additional water for injection is added to it to obtain a 0.5% solution.

The blood test protocol is described below as an example of toxicity assessment. Materials.

At the time of scheduled sacrifice, all animals in the study group that have fasted overnight since the previous day (approximately 16 to 21 h) undergo laparotomy under isoflurane inhalation anesthesia and blood (approximately 1 ml) is drawn from the abdominal aorta into a blood sample vial containing EDTA-2K. The resulting blood is examined for the content of components and according to the methods given below.

Equipment used.

Automatic blood cell counter (ADVIA2120i, Siemens Healthcare Diagnostics). Components under study (measurement technique).

Red blood cell count (flow cytometry technique using a 2-beam laser); hematocrit (calculated from the number of red blood cells and MCV);

hemoglobin concentration (modified cyanomethemoglobin technique);

the average amount of hemoglobin in a red blood cell (calculated using MCH, the number of red blood cells and hemoglobin concentration);

average hemoglobin concentration in an erythrocyte (calculated by MSHC, number of red blood cells, MCV and hemoglobin concentration);

mean erythrocyte volume (MCV, flow cytometry technique using 2-beam laser);

red blood cell distribution volume width (RDW, flow cytometry technique using a 2-beam laser);

reticulocyte count (absolute count, laser flow cytometry with RNA staining);

platelet count (flow cytometry technique using a 2-beam laser);

leukocyte count (flow cytometry technique using a 2-beam laser);

classification of leukocytes (absolute number, flow cytometry with peroxidase staining + flow cytometry using a 2-beam laser);

morphological indicator of erythrocytes (MICRO: microcytic erythrocytes, MACRO: macrocytic erythrocytes, HYPO: hypochromic erythrocytes, HYPER: hyperchromic erythrocytes, ANISO:

- 56 045216 difference in red blood cell size, HCVAR: difference in hemoglobin concentration, RBCF: destroyed red blood cells).

Experimental example 5. Study of bacterial reversion.

Materials and methods.

Strains studied: Salmonella typhimurium TA100 or TA98.

Metabolic activation system.

The Ames test mixture S9 was prepared from the livers of 7-week-old male Sprague-Dawley rats treated with phenobarbital and 5,6-benzoflavone. Doses: 78.1, 156.3, 312.5, 625, 1250, 2500 or 5000 mcg/tablet.

Research methodology.

After growing the bacterial cells at 37°C for 8 hours, the optical density (at 660 nm) of the cell suspension is measured using a spectrophotometer to determine whether the bacterial cells are growing well. Cell numbers calculated from optical density were confirmed to be within an acceptable range (cell count: >1x109/ml). The cells are exposed to the test sample using a pre-incubation technique (37°C, 20 min) in the presence or absence of the S9 mixture. After mixing with the top agar, the cells are plated onto the plate. The plates are incubated at 37°C for 48 hours. Bacterial contamination of the top agar, solvent and test sample is determined.

Mutagenicity criteria.

A test sample is considered positive if the test sample results in a dose-dependent increase in the number of revertant colonies to a level greater than or equal to two times the average value for the negative control for any test strain in the presence or absence of the S9 mixture.

Experimental example 6. In vitro study of micronuclei.

Materials and methods.

Test system.

TK6 cells derived from human lymphoblastoid cells.

Growing conditions.

Cells are grown in a 6-well plastic plate at 37°C and 5% CO ₂ in RPMI1640 supplemented with 10 vol% heat-inactivated horse serum, 2 mmol/L sodium pyruvate, 100 U/ml penicillin and 100 μg/ml streptomycin.

Metabolic activation system.

S9 rat liver mixture was 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 mixture for 3 h, then growth for 21 h;

(2) continuous treatment for 21 h without S9 mixture.

Doses: from 450.0 to 12.6 mcg/ml.

At each concentration, two cultures were prepared.

Cytotoxicity.

Cell numbers were counted and relative population doubling (RPD) as an index of cytotoxicity was calculated using the following formula:

Logio2 ([number of cells at the end of cultivation]/

Population doubling [number of cells at the beginning of treatment*]) (PD) Log ₁₀ 2 *: 1 ^χ 10 ⁵ cells/ml

PD for study sample group

RPD (%) = ________________________________________________________________

PD for simultaneously studied negative control ^x 100 group

Microkernel research.

For each treatment condition, the highest concentrations for micronucleus analysis were selected based on test sample sedimentation and cytotoxicity, and the two consecutive lowest concentrations were tested. The number of micronucleated cells in 4000 mononuclear cells with cytoplasm is counted using a microscope.

Statistical analysis.

Fisher's exact test with upper bounded confidence levels of 5 and 1% was used to compare the prevalence of micronucleated cells in the test or positive control group with that in the negative control group for all treatment conditions. If Fisher's exact test resulted in statistical significance for a group of study samples, the Cochran-Armitage exact test for trend was used.

-

Claims (12)

Decision criteria. A test sample is considered positive if the prevalence of micronucleated cells in any group of test samples satisfies both criteria (1) and (2) below. 1. The compound described by formula (I) R ² where R ¹ means (1) a C _3-10 cycloalkyl group, optionally substituted with 1 to 3 halogen atoms, (2) a C 6 _-14 aryl group, optionally substituted with 1 to 3 substituents selected from (i ) a halogen atom, (ii) a cyano group and (iii) a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (3) a 5- or 6-membered monocyclic aromatic heterocyclic group containing as a ring-forming atom , in addition to the carbon atom, from 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and optionally substituted with from 1 to 3 substituents selected from (i) a halogen atom, (ii) a C _1-6 alkyl group , optionally substituted with 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 containing as ring-forming atom, other than carbon, from 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom; And R ² means - 58 045216 (1) a C _3-10 cycloalkyl group, optionally substituted with 1 to 3 halogen atoms, (2) a C6 _-14 aryl group, optionally substituted with 1 to 3 substituents selected from (i) a halogen atom and (ii) a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (3) a 5- or 6-membered monocyclic aromatic heterocyclic group containing as ring-forming atom, other than carbon, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and optionally substituted with 1 to 3 substituents selected from (i) a halogen atom, (ii) a C _1-6 alkyl group, optionally substituted with 1 to 3 halogen atoms, and (iii) a C _1-6 alkoxy group, or (4) a 3-8 membered monocyclic non-aromatic heterocyclic group containing as ring-forming atom, in addition to the carbon atom, from 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom; or a pharmaceutically acceptable salt thereof. 1) connection of example 1 30 g 1), 2), 3) Example and 4) are mixed and placed in a gelatin capsule. drug 2 (receiving a tablet)._________________ 1) connection of example 1 30 mg (1) Statistical analysis revealed a significant difference in the prevalence of micronucleated cells compared to the negative control group, and statistical analysis also revealed a dose-dependent increase in prevalence. 2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, which is described by formula (I') wherein each symbol is as defined in claim 1. 2) lactose 50 g 2) finely ground powdered cellulose 10 mg (2) The prevalence of micronucleated cells is greater than the historical reference range (mean + 2 standard errors). Otherwise, the test sample is considered negative. Example of drug 1 (obtaining a capsule). 3. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ means (1) a C _3-10 cycloalkyl group, optionally substituted with 1 to 3 halogen atoms, or (2) a 5- or 6-membered monocyclic aromatic heterocyclic group containing as a ring-forming atom other than a carbon atom, from 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and optionally substituted with from 1 to 3 substituents selected from (i) a halogen atom, (ii) a C _1-6 alkyl group, optionally substituted with from 1 to 3 halogen atoms, and (iii) C _1-6 alkoxy groups; And R ² means (1) a C _6-14 aryl group, optionally substituted with 1 to 3 substituents selected from (i) a halogen atom and (ii) a C _1-6 alkyl group, optionally substituted with 1 to 3 atoms halogens, or (2) a 5- or 6-membered monocyclic aromatic heterocyclic group containing, as ring-forming atom, other than carbon, from 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, optionally substituted by 1 to 3 substituents selected from (i) a halogen atom, (ii) a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (iii) a C _1-6 alkoxy group. 3) corn starch 15 g 3) lactose 19 mg 4. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ means (1) a C _3-10 cycloalkyl group, or (2) a 6-membered monocyclic aromatic heterocyclic group, optionally substituted with 1 to 3 halogen atoms; And R ² means (1) a C _6-14 aryl group, optionally substituted with 1 to 3 halogen atoms, or (2) a 6-membered monocyclic aromatic heterocyclic group, optionally substituted with 1 to 3 halogen atoms. 4) calcium salt carboxymethylcellulose 44 g 4) magnesium stearate 1 mg Total 60 mg 5. 6-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[( 1 R,2R)-2-hydroxy-1,2-di(pyridin-2-yl) ethyl]-2,3dihydro-III-isoindol-1-one or a pharmaceutically acceptable salt thereof. 5) magnesium stearate 1 g 1000 tablets in total 140 g The entire amount of 1), 2) and 3) and 4) (30 g) is mixed with water, dried in a vacuum and sifted. The sieved powder is mixed with 4) (14 g) and 5) (1 g) and the mixture is compressed in a tableting machine to obtain 1000 tablets containing 30 mg of the compound of Example 1 per tablet. Industrial Application The compound of the present invention has HDAC inhibitory activity and may be useful for the treatment of diseases of the central nervous system, including neurodegenerative diseases (Alzheimer's disease, progressive supranuclear palsy, etc.) and the like. The present application is based on Patent Application No. 2019-177815, filed on September 27, 2019 in Japan, and its entire contents are included in the present invention. CLAIM 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 pharmaceutically acceptable salt thereof. 7. 2-[(1R,2R)-1,2-Bis(5-fluoropyridin-2-yl)-2-hydroxyethyl]-6-[5-(difluoromethyl)-1,3,4-oxadiazol-2yl] -2,3-dihydro-III-isoindol-1-one or a pharmaceutically acceptable salt thereof. 8. A medicinal product containing a compound or a pharmaceutically acceptable salt thereof according to claim 1. 9. The drug according to claim 8, which is an inhibitor of histone deacetylase 6. 10. The medicinal product according to claim 8, which is an agent for the prevention or treatment of Alzheimer's disease or progressive supranuclear palsy. 11. Use of a compound or pharmaceutically acceptable salt according to claim 1 for the prevention or treatment of Alzheimer's disease or progressive supranuclear palsy. 12. A method of inhibiting histone deacetylase 6 in a mammal, which includes administering -